Handbook of Inter Derm PDF

Peter A.
Lio Toral Patel

Neill T. Peters Sarah Kasprowicz
Handbook of
Integrative
Dermatology
An Evidence-Based
Approach
123
Handbook of Integrative
Dermatology
Peter A. Lio Toral Patel
Neill T. Peters Sarah Kasprowicz
Handbook
of Integrative
Dermatology
An Evidence-Based Approach
Peter A. Lio, M.D. Toral Patel, M.D., M.S.
Assistant Professor of Clinical Instructor of Clinical
Dermatology & Pediatrics Dermatology
Northwestern University Northwestern University
Feinberg School of Medicine Feinberg School of Medicine
Chicago, IL, USA Chicago, IL, USA
Medical Dermatology D&A Dermatology
Associates of Chicago Chicago, IL, USA
Chicago, IL, USA
Sarah Kasprowicz, M.D.
Neill T. Peters, M.D. NorthShore University
Instructor of Clinical HealthSystem
Dermatology Clinical Assistant Professor
Northwestern University University of Chicago, Pritzker
Feinberg School of Medicine School of Medicine
Chicago, IL, USA Chicago, IL, USA
Medical Dermatology
Associates of Chicago
Chicago, IL, USA
ISBN 978-3-319-17815-8 ISBN 978-3-319-17816-5 (eBook)

DOI 10.1007/978-3-319-17816-5
Library of Congress Control Number: 2015938919
Springer Cham Heidelberg New York Dordrecht London

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To my wife, Lisa, who makes it all possible. And to my
mother, Catherine, who made me possible.
P.A.L.
To Neil, Alisha, Dilan, Mom, Dad, and Nilay: thank you for
your unwavering love and support.
T.P.
For Anju, my loving wife, best friend, and biggest supporter.

Thank you for always encouraging me take on new challenges.
N.T.P.
To MSR and my parents for their unconditional support.

S.K.
Preface
The fact that you are reading this means that you have at
least some interest in integrative, alternative, or complemen-
tary medicine. But why should you? Isnt it true thatpractically
by definitionthis approach to medicine is not evidence-based?
And, as rational and responsible healthcare practitioners,
isnt it our charge to focus on the evidence when treating
patients? Importantly, couldnt it even be dangerous to learn
about and discuss these treatments, since it could be per-
ceived as an endorsement of unaccepted therapies? We think
that the simple answer to all three questions is yes, but that
the real answer is far more complex. And, as difficult as it
may seem to reconcile these ideas, we feel that there are
several compelling reasons to read this book:
The first is that, like it or not, many of our patients are
interested in, using, or asking about alternative and comple-
mentary medicine. Indeed, the National Institutes of Healths
National Center for Complementary and Alternative
Medicine notes: many Americans, nearly 40%, use health
care approaches developed outside of mainstream Western,
or conventional medicine for specific conditions of overall
well-being (http://nccam.nih.gov/health/whatiscam). Part of
being informed and able to connect with ones patients
depends on understanding at least a little bit about this area,
since so many people are talking about it. If for no other rea-
son than to learn a little bit about some of these alternatives,
we feel that this book is necessary.
vii
viii Preface
The second is that any serious scholar of medicine knows

that the vast majority of our modern treatment armamen-
tarium stems from humbler beginnings. Plants used by
indigenous peoples constitute the bulk of medicines that
underpin all of modern therapy. Indeed, massive research
efforts continue in the present day to screen natural products
for bioactivity in the search for new drugs, while the promise
of rational drug designso exciting 20 years ago as a medi-
cal studentseems ever to remain just beyond the horizon.
Thus, we look to these simpler, more elemental treatments in
some ways as a preview about what could be next in conven-
tional medicine, knowing full well that once sufficient data is
amassed, such treatments instantly cease being alternative
and enter into the mainstream.
Finally, we sail these relatively uncharted waters because,
as healers, sometimes we must. As Celsus wrote: Satius est
enim anceps auxilium experiri quam nullum. (It is better to
try a doubtful remedy than none at all.) (Spivak 1991).
Despite the best evidence, there are situations when the
disease has not read the book, so to speak, and the patient is
not responding to the treatment. Other times, the side effects
of the treatments outweigh their therapeutic benefit, either
actually or in the mind of the patient.
In dermatology, perhaps more than in other areas of medi-
cine, we are faced with a large group of somewhat mysterious
inflammatory conditions, most of which have very little
chance for a cure. To offer hope, even if it is uncertain, is an
important part of being a healer and is what makes us funda-
mentally different than a technician. If we are to offer any
hope, however, we must learn about what is known and what
evidence exists. For the naysayers who feel that there is noth-
ing here at all, we think they will be pleasantly surprised (or
particularly annoyed!) to see that there is actually a body of
data for some of these treatments that, at the very least, war-
rants further exploration. At the same time, we hope to point
out some therapies and systems that we feel are not worthy
of more time or energy, in that they have sufficient evidence
against them to put them to rest. These too, we feel, can be
Preface ix
helpful for clinicians trying to guide patients through these

sometimes turbulent waters.
We sincerely hope that this book offers some guidance,
inspiration, and support when thinking about practical alter-
native and complementary treatments for patients. We will
continue to refine and add to this book as more evidence is
obtained and, as such, view itlike all of medicineas a per-
petual work in progress.
Chicago, IL Peter A. Lio

Toral Patel
Neill T. Peters
Sarah Kasprowicz
References
http://nccam.nih.gov/health/whatiscam. Accessed 25 Mar 2014.
Spivack BS, Celsus AC. Roman medicus. J Hist Med Allied Sci.
1991;46:14357.
Contents
1 Introduction to Integrative Dermatology................... 1

References ...................................................................... 4
2 General Skin Care ......................................................... 7
Introduction.................................................................... 7
Top Considerations ....................................................... 8
Green Tea ....................................................................... 8
Evidence for Green Tea ............................................ 9
Flavonoids ...................................................................... 10
Evidence for Flavonoids ........................................... 11
Vitamin C ....................................................................... 12
Evidence for Vitamin C ............................................ 12
Carotenoids .................................................................... 13
Evidence for Carotenoids ......................................... 13
Soy ................................................................................... 14
Evidence for Soy........................................................ 15
Licorice ........................................................................... 16
Evidence for Licorice ................................................ 16
Niacinamide.................................................................... 17
Evidence for Niacinamide ........................................ 17
Case 1 .............................................................................. 18
Case 2 .............................................................................. 19
References ...................................................................... 19
3 Sun Protection ............................................................... 23
Introduction.................................................................... 23
xi
xii Contents
Niacinamide.................................................................... 25
Evidence for Niacinomide ........................................ 26
Polyphenols .................................................................... 27
Evidence for Polyphenols ......................................... 27
Carotenoids .................................................................... 28
Evidence for carotene ............................................ 29
Polypodium Leucotomos .............................................. 30
Evidence for Polypodium Leucotomos .................. 31
Case 1 .............................................................................. 32
Case 2 .............................................................................. 33
References ...................................................................... 33
4 Skin Cancer .................................................................... 35
Introduction.................................................................... 35
Clinical Considerations ................................................. 36
Ingenol Mebutate .......................................................... 39
Evidence for Ingenol Mebutate ............................... 40
Solasodine Glycosides (BEC) ...................................... 40
Evidence for Solasodine Glycosides (BEC) .......... 41
Vitamin D ....................................................................... 42
Evidence for Vitamin D ............................................ 43
Coenzyme Q10 ............................................................... 43
Evidence for CoQ10.................................................. 44
Escharotics...................................................................... 45
Evidence Against Escharotics .................................. 46
Gossypin ......................................................................... 47
Case 1 .............................................................................. 47
Case 2 .............................................................................. 48
References ...................................................................... 48
5 Acne ................................................................................ 53
Introduction.................................................................... 53
Secondary Considerations ............................................ 56
Vitamin C ....................................................................... 57
Evidence for Topical Vitamin C............................... 57
Topical Nicotinamide .................................................... 58
Evidence for Topical Nicotinamide ......................... 59
Contents xiii
Dietary Modifications ................................................... 61

Evidence for Dietary Modifications........................ 61
Topical Green Tea.......................................................... 63
Evidence for Topical Green Tea .............................. 63
Topical Tea Tree Oil ...................................................... 64
Evidence for Topical Tea Tree Oil ........................... 65
Oral Probiotics ............................................................... 66
Evidence for Oral Probiotics ................................... 66
Oral Zinc ........................................................................ 67
Evidence for Oral Zinc ............................................. 67
Case 1 .............................................................................. 68
Case 2 .............................................................................. 69
References ...................................................................... 70
6 Rosacea ........................................................................... 73
Introduction.................................................................... 73
Nicotinamide .................................................................. 76
Evidence for Nicotinamide ...................................... 76
Azelaic Acid ................................................................... 77
Evidence for Azelaic Acid ........................................ 78
Chrysanthellum Indicum .............................................. 78
Evidence for Chrysanthellum Indicum ................... 79
Quassia Extract .............................................................. 80
Evidence for Quassia Extract .................................. 80
Case 1 .............................................................................. 80
Case 2 .............................................................................. 81
References ...................................................................... 81
7 Hair Loss ........................................................................ 83
Introduction.................................................................... 83
Androgenetic Alopecia ................................................. 84
Raspberry Ketone ......................................................... 85
xiv Contents
Evidence for Raspberry Ketone ............................ 86

Procyanidins ................................................................. 86
Evidence for Procyanidins...................................... 86
Alopecia Areata........................................................... 87
Garlic............................................................................. 87
Evidence for Garlic ................................................. 88
Onion Extract .............................................................. 88
Evidence for Onion Extract ................................... 88
Aromatherapy .............................................................. 89
Evidence for Aromatherapy .................................. 89
Hypnotherapy .............................................................. 90
Evidence for Hypnotherapy ................................... 90
Case 1 ............................................................................ 91
Case 2 ............................................................................ 91
References .................................................................... 92
8 Psoriasis ........................................................................ 95
Introduction.................................................................. 95
Clinical Considerations ............................................... 96
Top Considerations ..................................................... 97
Fish Oil .......................................................................... 97
Evidence for Fish Oil .............................................. 98
Indigo Naturalis ........................................................... 99
Evidence for Indigo Naturalis................................ 100
Turmeric (Curcumin) .................................................. 101
Evidence for Turmeric (Curcumin) ....................... 101
Aloe Vera ...................................................................... 103
Evidence for Aloe Vera .......................................... 103
Mahonia Aquifolium ................................................... 104
Evidence for Mahonia Aquifolium ....................... 104
Balneotherapy .............................................................. 105
Evidence for Balneotherapy .................................. 105
Mindfulness Based Stress Reduction ........................ 107
Evidence for Mindfulness Based
Stress Reduction ...................................................... 107
Case 1 ............................................................................ 107
Case 2 ............................................................................ 108
References .................................................................... 108
Contents xv
9 Atopic Dermatitis (Eczema) ...................................... 111

Introduction.................................................................. 111
Sunflower Seed Oil...................................................... 114
Evidence for Sunflower Seed Oil .......................... 115
Coconut Oil .................................................................. 117
Evidence for Coconut Oil ...................................... 117
Cardiospermum Plant Extract ................................... 119
Evidence for Cardiospermum Plant Extract........ 119
Oral Vitamin D Supplementation ............................. 120
Evidence for Oral Vitamin D
Supplementation ...................................................... 121
Topical Vitamin B12 Application .............................. 121
Evidence for Topical Vitamin B12 Application ... 122
Traditional Chinese Medicine (TCM) ...................... 122
Evidence for Traditional Chinese Medicine ......... 123
Acupuncture/Acupressure ......................................... 125
Evidence for Acupuncture/Acupressure .............. 126
Probiotics ...................................................................... 127
Evidence for Probiotics .......................................... 128
Diet Modification ........................................................ 129
Evidence for Diet Modification ............................. 129
Hypnosis and Biofeedback ......................................... 130
Evidence for Hypnosis and Biofeedback ............. 130
Case 1 ............................................................................ 131
Case 2 ............................................................................ 133
References .................................................................... 134
10 Urticaria and Angioedema ......................................... 137
Introduction.................................................................. 137
Stress Reduction .......................................................... 139
Evidence for Stress Reduction .............................. 140
Vitamin D Supplementation ...................................... 141
Evidence for Vitamin D Supplementation ........... 141
xvi Contents
Dietary Modification ................................................... 142

Evidence for Dietary Modification ....................... 143
Case 1 ............................................................................ 144
Case 2 ............................................................................ 145
References .................................................................... 145
11 Disorders of Pigmentation ......................................... 147
Introduction.................................................................. 147
Vitamin C ..................................................................... 149
Evidence for Vitamin C .......................................... 151
Soy ................................................................................. 152
Evidence for Soy...................................................... 152
Niacinamide.................................................................. 153
Evidence for Niacinamide ...................................... 153
Licorice ......................................................................... 155
Evidence for Licorice .............................................. 155
Ginkgo Biloba .............................................................. 156
Evidence for Ginkgo Biloba .................................. 157
l-Phenylalanine............................................................ 157
Evidence for l-Phenylalanine ................................ 158
Vitamins ........................................................................ 159
Evidence for Vitamins............................................. 159
Polypodium Leucotomos ............................................ 160
Evidence for Polypodium Leucotomos ................ 160
Case 1 ............................................................................ 161
Case 2 ............................................................................ 161
References .................................................................... 162
12 Warts and Molluscum ................................................. 165
Introduction.................................................................. 165
Top Considerations for Warts .................................... 167
Propolis ......................................................................... 167
Evidence for Propolis.............................................. 167
Zinc................................................................................ 168
Evidence for Zinc .................................................... 168
Garlic (Allium sativum) .............................................. 169
Evidence for Garlic (Allium sativum) .................. 170
Top Considerations for Molluscum ........................... 170
Contents xvii
Cantharidin................................................................... 171
Evidence for Cantharidin ....................................... 171
Lemon Myrtle Solution (Backhousia citriodora) .... 171
Evidence for Lemon Myrtle Solution
(Backhousia citriodora) .......................................... 172
Tea Tree Oil (Melaleuca alternifolia)
and Iodine Preparation ............................................... 172
Evidence for Tea Tree Oil (Melaleuca
alternifolia) and Iodine Preparation...................... 172
Case 1 ............................................................................ 173
Case 2 ............................................................................ 174
References .................................................................... 174
13 Fungal and Bacterial Infections ................................. 177
Introduction to Fungi .................................................. 177
Clinical Considerations for Fungi.............................. 178
Top Considerations for Fungal Infections ................ 179
Topical Tea Tree Oil .................................................... 179
Evidence for Topical Tea Tree Oil ......................... 180
Secondary Considerations .......................................... 181
Coriander Oil ............................................................... 181
Evidence for Coriander Oil.................................... 181
Oil of Bitter Orange .................................................... 182
Evidence for Oil of Bitter Orange ........................ 182
Solanum chrysotrichum .............................................. 183
Evidence for Solanum chrysotrichum ................... 183
Garlic............................................................................. 185
Evidence for Garlic ................................................. 185
Ageratina pichinchensis .............................................. 186
Evidence for Ageratina pichinchensis .................. 186
Introduction to Bacteria ............................................. 187
Top Considerations for Bacterial Infections ............ 188
Tea Tree Oil .................................................................. 188
Evidence for Tea Tree Oil ....................................... 189
Honey ............................................................................ 189
Evidence for Honey ................................................ 190
Case 1 ............................................................................ 191
Case 2 ............................................................................ 191
References .................................................................... 192
xviii Contents
14 Seborrheic Dermatitis ................................................. 195

Introduction.................................................................. 195
Tea Tree Oil .................................................................. 197
Evidence for Tea Tree Oil ....................................... 198
Honey ............................................................................ 199
Evidence for Honey ................................................ 199
Sulfur ............................................................................. 199
Evidence for Sulfur ................................................. 200
Salicylic Acid ................................................................ 200
Evidence for Salicylic Acid..................................... 201
Case 1 ............................................................................ 201
Case 2 ............................................................................ 202
References .................................................................... 202
15 Pruritus ......................................................................... 205
Introduction.................................................................. 205
Top Considerations for Pruritus ................................ 206
Hypnosis, Biofeedback, and Cognitive
Behavioral Therapy ..................................................... 207
Evidence for Hypnosis, Biofeedback,
and Cognitive Behavioral Therapy ....................... 207
Acupuncture/Acupressure ......................................... 208
Evidence for Acupuncture/Acupressure .............. 208
Sunflower Seed Oil...................................................... 210
Evidence for Sunflower Seed Oil .......................... 211
Aromatherapy .............................................................. 211
Evidence for Aromatherapy .................................. 212
Case 1 ............................................................................ 212
Case 2 ............................................................................ 213
References .................................................................... 214
16 Resources...................................................................... 215
Index...................................................................................... 217
Chapter 1
Introduction to Integrative
Dermatology
Modern medicine can take credit for tremendous

achievements and advances in the understanding of human
health and the prevention and treatment of disease.
Antibiotics, vaccination, hygiene improvements, and modern
pain control and anesthesia are just some examples of devel-
opments that have changed the world and, in some ways, have
eclipsed the accomplishments of the first several thousand
years of recorded medicine. But if modern medicine is so
great, why are people so interested in alternatives? In review-
ing studies and talking to many patients over the years, three
major reasons seem to surface: when diseases are not curable,
when our explanations are unsatisfying, and when our treat-
ments are thought to be unsafe, questionable, and/or only
symptomatic. An unspoken reason also seems to be that
the experience of seeing a modern doctor can often feel
rushed, overly-focused, and impersonal, where many alterna-
tive practitioners pride themselves on having a slower pace,
listening carefully to the patient, and generally being more
holistic in considering the patient and his or her health
issues.
A provocative study approached this from a slightly
oblique angle, but nicely demonstrates some of these princi-
ples in action. A very common form of alternative thinking
in patients with atopic dermatitis is that foods are causative
of, or at least significant contributors to their skin disease.
Springer International Publishing Switzerland 2015 1

P.A. Lio et al., Handbook of Integrative Dermatology,
DOI 10.1007/978-3-319-17816-5_1
2 1. Introduction to Integrative Dermatology
Indeed, in one study some 75% of patients had made

significant dietary modifications in an attempt to control the
disease (Johnston et al. 2004). While certainly not unreason-
able at face value given the high prevalence of actual food
allergies in patients with atopic dermatitis, it can be an area
of rumination and persistent worry, even after food allergens
are identified and avoided, that there is something in the diet
that is being missed. At times, severe dietary restrictions that
may be actually unsafe are instituted without much rationale
(Webber et al. 1989). Thompson and Hanifin found that fami-
lies who felt strongly that certain foods were driving atopic
dermatitis (in the absence of true allergy, of course), signifi-
cantly de-emphasized these concerns once the eczema was
under good control (Thompson and Hanifin 2005). That is to
say, when conventional medicine is working well, and doing
so safely, there seems to be less desire for alternatives, with
the converse equally true.
The concept of safety is also worth thinking about.
Although essentially all of the conventional medicines that
are approved by governing bodies such as the FDA have an
incredible amount of safety data, there are a number of con-
cerns about medication safety, undoubtedly encouraged by
intense media coverage of every dangerous drug that is
described, sometimes many years after it has been in wide
use. Within dermatology, we have several topical agents that
in recent years have come under increased scrutiny, including
topical corticosteroids and the topical calcineurin inhibitors
(Kojima et al. 2013). Concerns about preservatives (such as
parabens), antibiotic use, and chemicals in general, all con-
stitute real concerns from patients, some more reasonable
than others, but each one important to consider for patient
satisfaction and adherence to a regimen.
And were this movement limited to a tiny fringe group,
one might be inclined to simply ignore such sentiments.
However, in looking within the dermatology literature, most
studies suggest some 50% of patients have tried one or more
forms of alternative medicine; this movement will likely not
just go away (Jensen 1990; Simpson et al. 2003).
1. Introduction to Integrative Dermatology 3
So, what are they seeking? How do we define this area?

Complementary medicine can be defined as non-
mainstream modalities or approaches used in conjunction
with conventional medicine, while alternative medicine
typically refers to the use of non-mainstream approaches in
place of conventional medicine. Integrative medicine seeks to
incorporate both complementary and alternative approaches,
and implies pulling from multiple traditions rather than being
solely based on one form of healing. Thus, an Integrative
Dermatologist would be someone who is trained in conven-
tional medicine, but is able to apply concepts and treatments
from the naturopathic cannon and from Traditional Chinese
Medicine, for example, carefully selecting these therapies
based on studies and experience. It can be a very difficult line
to toe, however, as there is not much precedence for this in
medicine at large, let alone within the relatively small spe-
cialty of Dermatology.
Moreover, if we define conventional medicine as the type
of medicine being based on solid evidence, then we end up
with a functional definition of alternative and complemen-
tary medicine as essentially not being evidence-based. In an
ideal world, this is true because we have faith that our system
would whole-heartedly adopt a treatment that had sufficient
evidence, even if it seemed strange and mysterious, and had
an unknown mechanism. The truth is a little messier.
Generally, the therapies we will discuss in this book are those
that simply do not have sufficient evidence to make a defini-
tive statement, but hold promise clinically. For the most part,
we have avoided those treatments that have enough evidence
to say that they are ineffective, or perhaps even harmful, as
there are more comprehensive texts that review these, and we
wish to keep things concise and usable.
The problem is that this definition leaves us with a uni-
verse of possibilities, ranging from window cleaner for psoria-
sis, to magical incantations for acne, and everything in
between. Its overwhelming and impossible to study in any
systematic way. This leads to, for some, the far simpler idea
of totally rejecting the entire area to alleviate the cognitive
4 1. Introduction to Integrative Dermatology
dissonance. We shall not take that path. Instead, we will

examine the existing evidence, casting a wide net at first, but
then curating the assortment down to a handful of treatments
that: (1) have the best available evidence for safety and effi-
cacy; (2) are reasonable therapies to incorporate into a main-
stream medical setting; and (3) are likely to be obtainable
without tremendous difficulty. These criteria significantly
narrow our searchsometimes nearly too muchbut also
differentiate this work from other more encyclopedic texts
that discuss many things without much of an eye towards
practicality.
In the text that follows, we concentrate upon the most
common clinical areas in dermatology, presenting a clinical
scenario, and then discussing some of the options in the natu-
ral and alternative realms. We have tried to remain focused
on practical approaches with peer-reviewed data that are
suitable for use in a conventional Dermatology practice.
Rather than compile an exhaustive text, our aim has been to
create a user-friendly reference tool that could be easily
accessed in a clinical setting; a handbook style guide that
would hopefully be used every day. We hope youand your
patientsfind it helpful!
References
Jensen P. Use of alternative medicine by patients with atopic derma-
titis and psoriasis. Acta Derm Venereol. 1990;70(5):4214.
Johnston GA, Bilbao RM, Graham-Brown RA. The use of dietary

manipulation by parents of children with atopic dermatitis. Br J
Dermatol. 2004;150:11869.
Kojima R, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama

S, Ohya Y, Saito H, Matsumoto K. Factors associated with steroid
phobia in caregivers of children with atopic dermatitis. Pediatr
Dermatol. 2013;30(1):2935.
References 5
Simpson EL, Basco M, Hanifin J. A cross-sectional survey of comple-

mentary and alternative medicine use in patients with atopic
dermatitis. Am J Contact Dermat. 2003;14(3):1447.
Thompson MM, Hanifin JM. Effective therapy of childhood atopic

dermatitis allays food allergy concerns. J Am Acad Dermatol.
2005;53(2 Suppl 2):S2149.
Webber SA, Graham-Brown RA, Hutchinson PE, et al. Dietary

manipulation in childhood atopic dermatitis. Br J Dermatol.
1989;121:918.
Chapter 2
General Skin Care
Introduction
Patients often inquire about what natural products they
might introduce into their routine to promote healthy skin
and prevent sun damage. While photoprotection through the
use of broad-spectrum sunscreen remains a mainstay of anti-
aging and preventive regimens, there are numerous botanical
agents and dietary supplements that claim to be effective
against aging skin and UV-induced damage. Many of these
claims are not substantiated by well-designed studies.
However, a few agents have been studied in small trials which
show some efficacy and are worth considering.
Common complaints from patients inquiring about anti-
aging skincare include lentigines (sun spots), uneven pig-
mentation, fine lines and wrinkles (rhytides), textural changes,
and increased laxity. Chronic, unprotected sun exposure leads
to these changes, which are collectively known as dermatohe-
liosis, or photoaging, This process occurs when ultraviolet
radiation triggers a cascade of signal transduction that ulti-
mately results in increased expression of matrix metallopro-
teinases, enzymes that degrade types I and III collagen in the
dermis. Dermal vasculature is directly injured by UV radia-
tion and indirect DNA damage occurs via the generation of
reactive oxygen species (ROS). While UVA rays are thought

DOI 10.1007/978-3-319-17816-5_2
8 2. General Skin Care
be the primary culprit in photoaging due to their deeper

penetration into the dermis, UVB rays are also thought to
play a role in skin damage (Han et al. 2014; Fisher et al. 2002;
Sternlicht and Werb 2001).
Top Considerations
See Table 2.1.
Green Tea
Green tea is rich in plant polyphenols, compounds that
exhibit strong antioxidant, anti-inflammatory and immuno-
modulatory properties (Elmets et al. 2001; Katiyar et al.
2000). The primary antioxidants in green tea are epigallocat-
echin gallate (EGCG) and epicatechin gallate (ECG). The
Table 2.1. General skincare: Alternative treatment options.

Treatment How administered Notes
Topical Applied topically daily Unstable molecule, difficult
vitamin C or twice daily; oral to formulate; concentration,
consumption does not vehicle and pH must be
result in significant considered for optimal
cutaneous absorption cutaneous penetration
Topical Topically (twice daily) Safe, generally very tolerable
green tea
Oral flavonols Orally (e.g., 3.5 oz dark Safe, but amount consumed
chocolate daily) in studies may not be feasible
in a standard diet
Soy Orally or topically No standardized amount
for oral intake, concerns re:
phytoestrogen activity
Niacinamide Topically or orally Generally considered safe
Licorice Topically, often in Standardized concentrations
extract combination with other not established
skin lightening agents
Oral Orally (dietary Safe, unless excessive
carotenoids consumption) amounts are consumed
Green Tea 9
amount of oral green tea consumption for maximal health

benefit is typically 36 cups per day, although cutaneous con-
centrations of green tea polyphenols after oral consumption
have not been well quantified. While consumption of green
tea in moderation is considered to be very safe, concerns over
the safety of concentrated green tea extracts have arisen due
to case reports of hepatotoxicity (Sarma et al. 2008). Patients
should be counseled about these reports, and should be
advised to limit their consumption to reasonable amounts;
they should also be advised to exercise caution about taking
supplements containing green tea extracts, as these may be
impure and/or contain other potentially toxic ingredients.
Topical formulations of green tea have been studied for their
effects on photoprotection and photoaging (Li et al. 2009).
Evidence for Green Tea
1. Cutaneous photoprotection from ultraviolet injury by

green tea polyphenols. Elmets C, Singh D, Tubesing K, Matsui
M, Katiyar S, Mukhtar H. J Am Acad Dermatol. 2001
Mar;44(3):42532.
Varying concentrations of green tea polyphenols (GTPs) were
applied to the skin of healthy adult volunteers, followed by
exposure to simulated UV radiation; skin biopsies and chro-
mameter readings were performed at 24, 48 and 72 hours after
exposure. This study showed a dose-dependent reduction in
both UVA & UVB-induced erythema, a decrease in the num-
ber of sunburn cells after UV exposure; GTPs were also found
to protect Langerhans cells from UV-induced depletion.
EGCG & ECG were the two GTPs that were most effective in
cutaneous photoprotection.
2. Green tea polyphenol treatment to human skin prevents

formation of ultraviolet light B-induced pyrimidine dimers in
DNA. Katiyar S, Perez A, Mukhtar H. Clin Cancer Res. 2000
Oct;6:386469.
In this small study of six Caucasian subjects, varying doses of

green tea polyphenols were applied topically to buttock skin
prior to exposure to increasing doses of UVB. This study
showed a dose-dependent decrease in both UVB-induced ery-
thema and formation of cyclopyrimidine dimers.
3. Protective effects of green tea extracts on photoaging and

photoimmunosuppresion. Li Y, Wu Y, Wei H, Xu Y, Jia L,
Chen J, Yang X, Dong G, Gao, X, Chen H. Skin Res Technol.
2009 Aug;15(3):33845.
Twenty Chinese women were treated with a sunscreen contain-
ing varying amounts of green tea polyphenols prior to UV
exposure on back skin. Results of skin biopsies taken 72 hours
after the last exposure demonstrated dose-independent photo-
protective effects, including inhibition of matrix metallopro-
teinases, decrease in photoaging biomarkers, and inhibition of
Langerhans cell depletion. The authors note that some of these
effects have not been shown with sunscreen alone.
Flavonoids
Flavonoids are secondary plant metabolites, found in many
fruits and vegetables as well as in red wine, tea and cocoa
(Heinrich et al. 2006). These compounds have been shown to
demonstrate anti-oxidant and anti-inflammatory effects
in vitro and as such have been investigated for their potential
benefits in cutaneous aging and repair of ultraviolet damage.
There are no large randomized controlled trials focusing on
the cutaneous effects of oral flavonoid consumption, and
there are no definitive recommendations on the doses of fla-
vonoids needed to achieve clinically significant improvement
in the skin. In the two studies listed below, the amount of
flavanols (a particular class of flavonoids) consumed by the
subjects was 100 g (3.5 oz) daily; this is approximately the
weight of a standard chocolate bar. Since dark chocolate con-
tains more cocoa than milk chocolate, dark chocolate is richer
Flavonoids 11
in flavanols than milk chocolate; however, the final flavanol

concentration in any chocolate preparation is highly depen-
dent on the type and amount of processing (Ried et al. 2012;
Latham et al. 2014). Flavanol concentrations vary greatly
among different chocolate products, and the cocoa percent-
age often listed on the packaging is not a reliable indicator of
the concentration; two bars that contain 70% cocoa, for
example, may contain different flavanol concentrations (Ried
et al. 2012).
Evidence for Flavonoids
1. Long-term ingestion of high flavanol cocoa provides photo-

protection against UV-induced erythema and improves skin
condition in women. Heinrich U, Neukam K, Tronnier H, Sies
H, Stahl W. J Nutr. 2006 Jun;136(6):15659.
Twenty-four adult women were randomized to receive a high-
flavanol or low-flavanol cocoa powder dissolved in water once
daily for 12 weeks. This study found that women in the high-
flavanol group had decreased UV-induced erythema, increased
cutaneous blood flow, as well as improved skin texture and
skin hydration. The amount of flavanols in the high-flavanol
preparation was similar to the amount in 100 g of dark
chocolate.
2. Consumption of flavanol-rich cocoa acutely increases

microcirculation in human skin. Neukam K, Stahl W, Tronnier
H, Sies H, Heinrich U. Eur J Nutr. 2007 Feb;46(1):5356.
This was a follow-up study by the same group listed in
Heinrich et al. (2006). In a crossover study, ten adult women
consumed a high-flavanol or low-flavanol cocoa drink; der-
mal blood flow and hemoglobin oxygen saturation were mea-
sured at time points of 16 hours. This study showed a
significant increase in dermal blood flow 2 hours after inges-
tion of the high-flavanol drink.
Vitamin C
Vitamin C is the most abundant water-soluble antioxidant in
human skin; it cannot be synthesized by the body and must be
obtained through oral or topical administration. Oral vitamin
C consumption does not significantly increase cutaneous con-
centration, so topical formulations of vitamin C have been
extensively studied for their role in treating photodamage
and cutaneous aging. In one split face study, improvement in
dyspigmentation, rhytides and skin texture was noted on side
of the face treated with vitamin C (Xu et al. 2012). The active
form of vitamin C, l-ascorbic acid, is very difficult to formu-
late as it easily oxidizes and becomes unstable in solution.
Vitamin C esters have been created that may be more stable.
Nevertheless, vitamin-C containing products should be care-
fully selected before use to ensure that they contain a stabi-
lized vehicle with an effective concentration and optimal pH
(Farris 2005).
Evidence for Vitamin C

1. Split-face study of topical 23.8% l-ascorbic acid serum in
treating photo-aged skin. Xu T, Chen J, Li Y, Wu Y, Luo Y, Gao
X, Chen H. J Drugs Dermatol. 2012 Jan;11(1):5156.
This was a split-face study of twenty Chinese women; one-half
of the face was treated with L-ascorbic acid combined with a
penetration enhancer and iontophoresis once daily for
2 weeks, and the other half of the face was left untreated.
Results showed a significant decrease in dyspigmentation and
rhytides on the treated side, as well as improvement in skin
texture (measured as roughness).
2. Topically applied vitamin C enhances the mRNA level of

collagens I and III, their processing enzymes and tissue inhib-
itor of matrix metalloproteinase I in the human dermis.
Nusgens B, Humbert P, Rougier A, Colige A, Haftek M,
Carotenoids 13
Lambert C, Richard A, Creidi P, Lapiere C. J Invest Dermatol.

2001 Jun;116:85359.
Ten postmenopausal women were treated daily for 6 months
with a 5% vitamin C solution on the dorsal aspect of one fore-
arm and a placebo solution on the other. Follow up was at 3
and 6 months, with skin biopsies taken at 6 months. This study
found an increase in collagen I and III mRNA, as well as in
increase in tissue inhibitor of matrix metalloproteinase
I. Results suggest that topically applied vitamin C may up-
regulate collagen I and III expression and down-regulate an
enzyme involved in collagen degradation.
Carotenoids
Carotenoids are pigments found in plants that protect them
from photooxidative stress. Beta-carotene and lycopene are
among the most abundant carotenoids found in human tissue,
and have been studied for their potential benefits in cutaneous
photoprotection and aging. Beta-carotene imparts the orange
color to fruits and vegetables such as carrots, cantaloupes and
mangoes. While the majority of lycopene consumption in the
United States is from tomatoes, this compound is also found in
other fruits such as watermelon and papaya. Beta-carotene can
either be converted to vitamin A after being ingested, or can be
used by cells as an antioxidant to combat free-radical induced
damage. Lycopene cannot be converted to vitamin A. Excessive
consumption of carotenoid-rich foods can lead to orange/yellow
discoloration of the skin known as carotenemia; this condition is
harmless but can be mistaken for jaundice, and can be cosmeti-
cally unappealing to the patient. Patients should be counseled to
consume these foods in moderation (Sale and Stratman 2004).
Evidence for Carotenoids
1. Dietary tomato paste protects against ultraviolet light-

induced erythema in humans. Stahl W, Heinrich U, Wiseman S,
Eichler O, Sies H, Tronnier H. J Nutr. 2001 May;13(5):144951.
In this randomized placebo-controlled study, nine adults with

Fitzpatrick II skin type consumed a tomato paste rich in lyco-
pene (16 mg/day) daily for 10 weeks; the control group
received plain olive oil. Scapular skin was exposed to a solar
simulator to induce erythema at baseline, week 4 and week 10.
This study found that erythema formation was 40% lower in
the lycopene group at week 10; serum levels of lycopene had
also increased. The researchers suggest that while dietary sup-
plementation with lycopene rich foods may not provide the
same level of photoprotection as high SPF sunscreen, regular
intake may provide a base level of protection that is beneficial
for daily incidental sun exposure.
2. Tomato paste rich in lycopene protects against cutaneous

photodamage in humans in vivo: a randomized controlled
trial. Rizwan M, Rodriguez-Blanco I, Harbottle A, Birch-
Machin M, Watson R, Rhodes L. Br J Dermatol. 2011
Jan;164(1):15462.
This was a randomized controlled study of 17 women
(Fitzpatrick I-II), randomized to receive lycopene-rich tomato
paste in olive oil or olive oil alone, daily for 12 weeks. Skin
biopsies from UV-exposed and unexposed skin were analyzed
for matrix metalloproteinase 1 (MMP-1), procollagen and
fibrillin-1 expression, as well as for mitochondrial DNA
(mtDNA) damage (as a marker of cumulative UV exposure).
This study found that MMP-1 and mtDNA damage were
reduced in the tomato paste group; procollagen deposition was
increased in the tomato paste group. This study provides fur-
ther support to the 2001 study above that orally-ingested lyco-
pene provides protection against photodamage.
Soy
Soybeans, rich in protein and touted for their many potential
health benefits, are being increasingly studies for their use in
many diseases.
Soy 15
Soy contains the serine protease inhibitors soybean tryp-

sin inhibitor (STI) & Bowman-Birk protease inhibitor, both
of which prevent melanosome transfer to keratinocytes via
inhibition of PAR-2 receptors present on keratinocytes
(Paine et al. 2001). Soy extracts have been shown to inhibit
UVB-induced skin damage in vitro (Chen et al. 2008).
Soy isoflavones, including genistein, have antioxidant
activity, and have also been shown to stimulate the produc-
tion of hyaluronic acid and inhibit collagen degradation, all of
which hold promise for reversing the changes of aging
(Leyden and Wallo 2001).
Evidence for Soy
1. Oral intake of soy isoflavone aglycone improves the aged

skin of adult women. Izumi T, Saito M, Obata A, Arii M,
Yamaguchi H, Matsuyama A. J Nutr Sci Vitaminol (Tokyo).
2007;53(1):5762.
Twenty-six female volunteers were enrolled in this double-
blind, placebo-controlled trial, and were randomized to receive
a test food containing 40 mg of soy isoflavone aglycone, or
a placebo food. The food was consumed daily for 12 weeks.
Effects on lateral periocular rhytides and facial skin elasticity
were assessed at 4, 8 and 12 weeks. A statistically significant
decrease in fine wrinkles and improvement of malar skin elas-
ticity at week 12 were observed in the test food group com-
pared to placebo. No adverse events were noted in either
group.
2. Efficacy of a soy moisturizer in photoaging: a double-blind,

vehicle-controlled, 12-week study. Wallo W, Nebus J, Leyden
J. J Drugs Dermatol. 2007;6(9):91722.
Sixty-five women with photodamaged facial skin were ran-
domized to receive a soy moisturizer containing non-denatured
serine protease inhibitors or its vehicle; both the active mois-
turizer and vehicle contained SPF 30 sunscreen. Subjects
applied the product to the face twice daily for 12 weeks.

Subjects in both group demonstrated improvement in multiple
parameters of photodamage (including mottled pigmentation,
blotchiness and skin tone), but the active group was found to
be superior to vehicle (P < 0.05).
Licorice
Licorice root (glycyrrhiza glabra) has been shown to inhibit
tyrosinase (a rate limiting enzyme that controls the produc-
tion of melanin) and also possesses anti-oxidant and anti-
inflammatory properties (Adhikari et al. 2008). Licorice root
contains extracts known to affect melanin production: gla-
bridin has been found to be the constituent with the most
potent inhibitory effect on tyrosinase (Kim and Uyama
2005). Licorice extract is found in many over-the-counter skin
lightening preparations in varying concentrations, often com-
bined with other ingredients for a synergistic effect.
Evidence for Licorice

1. Comparison of efficacy of topical 2% liquiritin, topical 4%
liquiritin and topical 4% hydroquinone in the management of
melasma. Zubair S, Mujtaba G. J Pak Assoc Dermatol
2009;19:15863.
In this 8 week study, 90 patients with melasma were divided
into three treatment groups: 4% hydroquinone, 4% liquiritin
and 2% liquiritin. Interestingly, the researchers comment on
the number of married versus unmarried patients; the rele-
vance of this information is unclear. Final assessment was
done at 16 weeks. Efficacy was measured by intensity of
pigment, lesion size and photographic appearance. The authors
report improvement in 96.7% of patients in the 4% liquiritin
group, 86.6% in the 2% liquiritin group, and 73.3% in the 4%
hydroquinone group. No adverse effects were observed in
the liquiritin treated groups at either concentration; in the
Niacinamide 17
hydroquinone group, two patients developed contact dermati-

tis and one patient developed hyperpigmentation. The authors
suggest that liquiritin cream is a more effective de-pigmenting
agent than hydroquinone.
2. Topical liquiritn improves melasma. Amer M, Metwalli M.

Int J Dermatol. 2000;39(4):299301.
In this split-face study, 20 women with symmetric epidermal
melasma (as determined by Woods lamp examination) applied
liquiritin cream to one side of the face and vehicle cream to the
other side twice daily for 4 weeks. Sunscreen and/or sun avoid-
ance were also recommended. Intensity of pigment, lesion size
and overall improvement were assessed at 4 weeks; the authors
reported a good to excellent response in 90% of subjects
(18/20 women). The amount of liquiritn cream in this study
was 1 g/day; however, the precise formulation of the cream is
not provided.
Niacinamide
Niacinamide is a form of vitamin B3. It has been shown
in vitro to inhibit the transfer of melanocytes to keratinocytes
(Hakozaki et al. 2002), and therefore has been studied for its
effect of cutaneous hyperpigmentation. Niacinamide also
functions as an anti-oxidant (Otte et al. 2005).
Evidence for Niacinamide
1. A double-blind, randomized clinical trial of niacinamide

4% versus hydroquinone 4% in the treatment of melasma.
Navarrete-Solis J, Castaned-Cazares J, Torres-Alvarez B,
Oros-Ovalle C, Fuentes-Ahumada C, Gonzaled F, Martinez-
Ramierz J, Moncada B. Dermatol Res Pract. 2011;2011:379173.
This was a split-face study of 27 patients with melasma, who
applied 4% niacinamide cream to one side of the face and 4%
hydroquinone cream to the other side once daily for 4 weeks.

Colorimetry testing did not reveal significant differences
between the sides; however, good to excellent subjective
improvement was noted on both the niacinamide side (44% of
patients) and the hydroquinone side (55% of patients).
Histologic evaluation showed a reduction in mast cell infiltra-
tion on the niacinamide side. It is difficult to interpret this in a
clinical sense, but comparing against 4% hydroquinone is
helpful as this is very much the conventional standard
therapy.
2. The effect of niacinamide on reducing cutaneous pigmenta-

tion and suppression of melanosome transfer. Hakozaki T,
Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K,
Greatens A, Hillebrand G, Bissett D, Boissy R. Br J Dermatol.
2002;147(1):2031.
This was both an in vitro and clinical study of the effects of
niacinamide on melanogenesis and hyperpigmentation. In the
clinical portion, a split-face study of 18 patients with hyperpig-
mentation was performed with 5% niacinamide moisturizer
and vehicle. Additionally, 120 patients with a facial tan were
randomly assigned to receive 2% niacinamide with sunscreen,
suncreen alone, or vehicle. The authors report a significant
decrease in hyperpigmentation with niacinamide in both
groups after 4 weeks.
Case 1
A 39 year-old female comes to your office for a cosmetic
consultation. As she approaches her 40th birthday, she is
noticing more sun spots (lentigines), redness and overall dull-
ness of her complexion. She is worried that she looks tired
all the time and would like to establish an anti-aging skincare
regimen. She is confused by the plethora of over-the-counter
products and botanical ingredients and asks for your opinion
on effective products.
References 19
Discussion
This patient may benefit from a morning moisturizer contain-
ing soy extracts to aid with hyperpigmentation. Her evening
regimen could include a serum containing green tea polyphe-
nols, along with a niacinamide cream, to reduce erythema and
dyspigmentation. The patient should also be advised to incor-
porate foods rich in flavonoids (such as dark chocolate) and
carotenoids (such as tomatoes) into her diet.
Case 2
A 55 year-old female presents to you complaining of sagging
skin; as she has gotten older, she has noticed that her skin
seems to be more lax, and the texture has gotten rougher. While
she understands that neuromodulators and injectable fillers
may be needed for optimal correction, she is not ready to con-
sider these treatments yet, and would like to start by using topi-
cal products that improve skin elasticity and laxity. She has very
sensitive skin and cannot tolerate retinoids and alpha hydroxy
acids, so she is interested in more natural products.
Discussion
This patient would benefit from a soy-containing sunscreen in
the morning to improve skin tone, and twice daily application
of a vitamin C preparation to increase collagen production
and improve skin tone. She should also be advised to incorpo-
rate flavonoid and carotenoid-rich foods into her diet.
References
Adhikari A, Devkota H, Takano A, Masuda K, Nakane T, Basnet P,
Skalko-Basnet N. Screening of Nepalese crude drugs tradition-
ally used to treat hyperpigmentation: in vitro tyrosinase inhibi-
tion. Int J Cosmet Sci. 2008;30(5):35360.
Chen N, Scarpa R, Zhang L, Seiberg M, Lin C. Nondenatured soy

extracts reduce UVB-induced skin damage via multiple mecha-
nisms. Photochem Photobiol. 2008;84(6):15519.
Elmets C, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar

H. Cutaneous photoprotection from ultraviolet injury by green
tea polyphenols. J Am Acad Dermatol. 2001;44(3):42532.
Farris P. Topical vitamin C: a useful agent for treating photoaging

and other dermatologic conditions. Dermatol Surg. 2005;
31(7 Pt 2):8147.
Fisher G, Kang S, Varani J, et al. Mechanisms of photoaging and

chronological skin aging. Arch Dermatol. 2002;138(11):146270.
Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A,

Miyamoto K, Greatens A, Hillebrand G, Bissett D, Boissy R. The
effect of niacinamide on reducing cutaneous pigmentation and
suppression of melanosome transfer. Br J Dermatol. 2002;
147(1):2031.
Han A, Chien A, Kang S. Photoaging. Dermatol Clin. 2014;32:

2919.
Heinrich U, Neukam K, Tronnier H, Sies H, Stahl W. Long-term

ingestion of high flavanol cocoa provides photoprotection against
UV-induced erythema and improves skin condition in women. J
Nutr. 2006;136(6):15659.
Katiyar S, Perez A, Mukhtar H. Green tea polyphenol treatment to

human skin prevents formation of ultraviolet light B-induced
pyrimidine dimers in DNA. Clin Cancer Res. 2000;6:38649.
Kim Y, Uyama H. Tyrosinase inhibitors from natural and synthetic

sources: structure, inhibition mechanism and perspective for the
future. Cell Mol Life Sci. 2005;62(15):170723.
Latham LS, Hensen ZK, Minor DS. Chocolateguilty pleasure or

healthy supplement? J Clin Hypertens (Greenwich). 2014;
16(2):1016.
References 21
Leyden J, Wallo W. The mechanism of action and clinical benefits of

soy for the treatment of hyperpigmentation. Int J Dermatol.
2001;50(4):4707.
Li Y, Wu Y, Wei H, Xu Y, Jia L, Chen J, Yang X, Dong G, Gao X,

Chen H. Protective effects of green tea extracts on photoaging
and photoimmunosuppresion. Skin Res Technol. 2009;15(3):
33845.
Otte N, Borelli C, Korting C. Nicotinamide-biologic actions of an

emerging cosmetic ingredient. Int J Cosmet Sci. 2005;27:25561.
Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M. An

alternative approach to depigmentation by soybean extracts via
inhibition of the PAR-2 pathway. J Invest Dermatol. 2001;
116(4):58795.
Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Effect of cocoa
on blood pressure. Cochrane Database Syst Rev. 2012;8:CD008893.
Sale TA, Stratman E. Carotenemia associated with green bean inges-

tion. Pediatr Dermatol. 2004;21(6):6579.
Sternlicht M, Werb Z. How matrix metalloproteinases regulate cell

behavior. Annu Rev Cell Dev Biol. 2001;17:463516.
Xu T, Chen J, Li Y, Wu Y, Luo Y, Gao X, Chen H. Split-face study of

topical 23.8% L-ascorbic acid serum in treating photo-aged skin.
J Drugs Dermatol. 2012;11(1):516.
Chapter 3
Sun Protection
Introduction
Sun protection (photoprotection) is the process of defending
the skin from the harmful effects of Ultraviolet radiation
(UVR). UVR itself is a conundrum. Fun in the sun
describes the enjoyable experience of tanning and outdoor
activity. UVR is also an important natural source of Vitamin
D. Low levels of Vitamin D increase fracture risk and may
play a role in cardiovascular disease, auto-immunity and
malignancies (Kannan and Lim 2014). Thus, being in the sun
is desirable and appears to have health benefits. On the other
hand, UVR induces both skin cancer and photoaging. Some
of these cancers, such as melanoma, are life threatening.
Importantly, the incidence of melanoma is rising faster than
the incidence of any other cancer. Oral intake of vitamin
D-enriched foods or vitamin D supplements, therefore, is
recommended over seeking UVR to maintain proper serum
levels. Overall, the rising risk of skin cancer warrants imple-
mentation of comprehensive photoprotection strategies to
limit exposure to UVR.
UVR is comprised of UVB (290320 nm) and UVA (320
400 nm). UVB causes erythema and direct DNA damage
through the formation of pyrmidine dimers. It also can be a
source of oxidative stress. UVA penetrates more deeply into
the dermis and is the most powerful source of oxidative stress

DOI 10.1007/978-3-319-17816-5_3
24 3. Sun Protection
in human skin. UVA induced oxidative stress creates reactive

oxygen species (ROS) including hydrogen peroxide, oxygen
singlets and other superoxide radicals (Jansen et al. 2013).
These ROS cause both DNA damage, lipid peroxidation
leading to cell membrane damage, inflammation, and activa-
tion of matrix metalloproteinases. The latter alters collagen
and the extracellular matrix thereby contributing to wrin-
kling, loss of elasticity and the formation of actinic comedo-
nes. Poilkiloderma (collective changes due to sun damage
including: hyperpigmentation, hypopigmentation, epidermal
atrophy, and telangiectasia) and lentigenes, are also caused by
UVA and further constitute the photoaging effects of
UVR. Immediate pigment darkening and progressive pig-
ment darkening as well as delayed tanning with adaptive
epidermal hyperplasia and skin cancer formation are also
part of the cutaneous response to UVR exposure.
Primary prevention of UVR exposure is crucial to preven-
tion of both photoaging and skin cancer. Strategies for pho-
toprevention include sun avoidance, protective clothing and
the use of sunscreens. The latter is the most widely used
approach in developed countries and presently is the main
defense against the harmful effects of UVR. Counseling
patients on optimal sunscreen use includes guidance on how
much and how frequent to apply them and is critical to maxi-
mizing their benefit (Jansen et al. 2013). Inadequate applica-
tion limits the benefit of sunscreens. Sweating and swimming
may remove these agents from the skin, further compromis-
ing their efficacy. Thus, the most widely used form of photo-
protection has limitations.
Systemic photoprotection is potentially advantageous in
that it may provide a more uniform prolonged total body sur-
face protection independent of vehicle properties, density of
application or factors such as sweating or swimming. In fact,
systemic photoprotection via dietary supplements is a bur-
geoning area of study. Ingested in the diet, specific micronutri-
ents may provide endogenous photoprotection by accumulating
in the skin in sufficient concentrations to provide local benefits
(Jansen et al. 2013). Mechanisms of action include antioxidant,
Niacinamide 25
immunomodulatory and anti-inflammatory effects. The anti-

oxidant effects modulate stress dependent signaling and may
suppress cellular and tissue inflammatory responses
(Fernandez-Garcia 2014). While UV exposure leads to the
formation of oxygen free radicals that are mutagenic and trig-
ger activation of matrix metalloprotienases that degrade col-
lagen, contributing to photoaging, antioxidants scavenge these
free radicals and may inhibit the harmful effects of ultraviolet
light. Topically applied agents have long been recommended
adjectively, including agents such as Vitamin C, Vitamin E, cof-
feeberry extract, licorice, and green leaf tea extracts. Newer
efforts have looked at the potential benefits of specific orally
ingested antioxidants. Particular attention has been given to
polyphenols, carotenoids, Polypodium luecotomos and niacina-
mide (Fernandez-Garcia 2014).
Research is needed to quantify benefits, identify the most
efficacious agents, and to determine optimized dosing. At
present, there is enough evidence to suggest that some of
these agents are potential adjuncts in the prevention of pho-
toaging, sunburn and possibly skin cancer. The use of systemic
photoprevention in combination with sunscreen, protective
clothing and direct sun avoidance will likely constitute the
most comprehensive strategy for photoprotection.
Top Considerations
See Table 3.1.
Niacinamide
Niacinamide is the amide form of Vitamin B3. This water-
soluble vitamin, which is also referred to as nicotinomide, is
present in foods such as chicken, pork, beef and mushrooms.
Unlike niacin, niacinamide is not associated with flushing.
The disease model indicating the role of Vitamin B3 in pho-
toprotection is Pellagra. Extreme deficiency of Vitamin B3
Table 3.1. Top considerations for systemic sun protection.

Niacinamide 500 mg orally daily; In vivo and in vitro
also 45% as a topical studies support some
formulation benefit; safe and well-
tolerated
Polyphenols Dietary and supplements; In vivo and in vitro
specifically green tea, studies support benefit;
curcumin, and wine difficult to recommend
specific preparations or
dosages at this time
Carotenoids Dietary and supplements; Some promising
specifically -carotene in evidence; difficult to
supplementation at doses recommend specific
of 30120 mg daily or 40 g preparations or dosages
of tomato paste daily at this time
Polypodium Oral supplement, dosages Strong evidence, but
leucotomos ranged from approximately fairly modest effect; can
7.515 mg/kg before be expensive as a daily
receiving ultraviolet supplement, safe
radiation
(Pellagra) is associated with diarrhea, dementia and photo-

sensitive dermatitis. Supplementation with niacinamide
reverses these changes including the photosensitivity. Overall,
niacinamide is thought to enhance repair of UVR induced
DNA damage and prevent UVR induced immunosuppres-
sion (Damian 2010).
Evidence for Niacinomide
1. Niacinamide: A B vitamin that improves aging facial skin

appearance. Bisset D, Oblong JE, Berge CA. Dermatol Surg.
2005 Jul;7(2):8605.
In vivo studies in mice treated orally with niacinamide show
inhibition of photcarcinogenesis and reduced sensitivity to
UVR. Topically applied 5% niacinamide cream in humans
displayed reduced yellowing, wrinkling, and hyperpigmenta-
tion on aging facial skin vs. placebo in a 12-week double blind
placebo controlled trial.
Polyphenols 27
2. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damien D.

Oral nicotinomide reduces actinic keratosis in phase II dou-
ble blinded randomized controlled trials. J Invest Dermatol.
2012;132:1497500.
This randomized, placebo controlled trial conducted in
Australia assessed the role of oral nicotinomide 500 mg daily
for 4 months in the reduction of actinic keratoses (AKs).
Patients that ingested nicotinomide displayed a 29% reduc-
tion in AK counts vs. placebo. These results suggest a role for
nicotinomide in systemic photoprevention. Larger placebo
controlled trials are called for given these promising early
findings.
Polyphenols
Polyphenols are found in dry legumes, honey, red wine, green
tea, turmeric (curcurmin), milk thistle (silymarin), grape seed
proanthocyanidins and grape derived resveratrol, silibin, pome-
granate and chocolates (flavonoids). Polyphenols are powerful
antioxidants, anti-inflammatory agents and potentially anti-
carcinogenic. UV-induced skin inflammation, proliferation,
immunosuppression, DNA damage, and dysregulation of
important cellular signaling pathways all appear to be reduced
by consumption of polyphenols (Afaq and Katiyar 2011).
Evidence for Polyphenols
1. Effects of oral epigallocatechin gallate supplementation on

the minimal erythema dose and UV-induced skin damage.
Jeon HY, Kim JK, Kim WG, Lee SJ. Skin Pharmacol Physiol.
2009;22(3):13741.
This study confirmed that drinking green tea, which contains
the polyphenol epigallocatechin-3-gallate (EGCG), reduced
UVR-induced erythema in women. A murine study showed
that regular intake of EGCG strengthened the skins tolerance
to UVR by increasing the minimal dose to induce erythema
and thus preventing UV-induced skin damage. These results

suggest that EGCG is a viable candidate for systemic photo-
protection. Larger controlled trials are needed to validate these
findings.
2. Curcumin inhibits UV radiation-induced skin cancer in

SKH-1 mice. Phillips J, Moore-Medlin T, Sonavane K,
Ekshyyan O, McLarty J, Nathan C-AO. Otolaryngol Head
Neck Surg. 2013;148:797803.
This rodent study suggests that curcumin may prevent photo-
carcinogenesis. Curcumin, a polyphenol which is used as a
flavoring and coloring agent in curry pastes and other foods as
turmeric, blocks UVR-induced ROS formation and inhibits
matrix metalloproteinase activation in murine models. Mice
fed turmeric were also protected against UVR-induced ery-
thema and squamous cell carcinoma formation. Human stud-
ies are needed to validate these findings.
3. Polyphenols: skin photoprotection and inhibition of photo-

carcinogenesis. Afaq F, Katiyar SK. Mini Rev Med Chem.
2011 Dec;11(14):120015.
This study of the diets of 1,119 adults in Queensland, Australia
found an association between a reduced incidence of actinic
keratosis and moderate consumption of wine. In this study the
average wine consumption was one glass every 2 days. Further
studies are needed to examine the polyphenol content of select
wines and to correlate the amount consumed to outcomes in a
prospective, placebo controlled trial before any firm conclu-
sions can be made.
Carotenoids
Carotenoids include and carotenes, lutein and lycopenes.
Transported to the skin by lipoproteins, they accumulate
within the epidermis proportionate to dietary intake and with
variations based on body site. Higher levels are accumulated
Carotenoids 29
on the forehead, palms and soles with lower levels in the dorsal
hand and forearm regions. Carotenoids are amongst the most
powerful scavengers of oxygen singets (Stahl and Sies 2007).
Evidence for carotene
1. -Carotene and other carotenoids in protection from

sunlight. Stahl W, Sies H. Am J Clin Nutr. 2012 Nov;96(5):
1179S84S.
In rodents, -carotene reduces lipid peroxidation and quenches
singlet oxygen mediated photochemical reactions. However,
studies assessing the potential benefits of -carotenes in
humans are contradictory. In studies that display benefit, dos-
ing of carotenoids was longer than 8 weeks and at least 20 mg
PO QD were administered. In studies not showing benefit,
dosing spanned 38 weeks and lower amounts were provided.
These contradictory results suggest that higher doses given for
extended periods may be necessary for successful systemic
photoprotection to occur. Overall, carotenoids appear capable
of providing benefit in preventing UV damage, however, fur-
ther research is indicated to better quantify efficacy and opti-
mized dosing.
2. Photosensitivity disorders in children: part I. Chantorn R,

Lim HW, Shwayder TA. J Am Acad Dermatol. 2012
Dec;67(6):1093.
While there is lack of evidence confirming the efficacy of
-carotene in EPP, supplementation at doses of 30120 mg PO
QD continues to be recommended for the management of this
condition. This is, nonetheless, an example of adjunctive use of
systemic photoprotection in clinical practice.
3. Tomato paste rich in lycopene protects against cutaneous

photodamage in humans in vivo: a randomized controlled
trial. Rizwan M, Rodriguez-Blanco I, Harbottle A, Birch-
Machin MA, Watson REB, Rhodes LE. Br J Dermatol.
2011;164:15462.
Lycopene is found in tomatoes, guava, pink grapefruit, papaya

and apricots. In vitro studies indicate that lycopene is an effi-
cient quencher of singlet oxygen and a potential scavenger of
oxygen free radicals. Human trials reveal that ingestion of 40 g
of tomato paste (16 mg of lycopene) daily for 10 weeks led to
a 40% reduction in skin erythema following exposure to
UVR. Further trials are needed to elucidate optimal dosing and
benefits; however, this study suggests that lycopenes offer sys-
temic photoprotective effects.
Polypodium Leucotomos
Polypodium leucotomos (PLE) is a botanical product derived
from tropical ferns grown in Central and South America.
Used traditionally by Native Americans as an anti-
inflammatory agent, PLE looks very promising as an oral
agent capable of providing systemic photoprotection and
modulation of UV-induced immune responses. PLE may
achieve these effects via oral antioxidant and immunomodu-
latory effects. PLE prevents apoptosis and promotes DNA
repair via the p53 tumor suppressor gene and other pathways
(Bhatia 2015). Containing phenolic antioxidants such as caf-
feic and ferulic acids, PLE can diminish UV induced ery-
thema and inhibit UV induced immunosuppression. PLE also
has demonstrated efficacy in reducing angiogenesis, photo-
carcinogenesis, and solar elastosis.
PLE is a promising agent for systemic photoprotection
and may also offer chemoprevention of UV-induced cutane-
ous malignancies. Further research is needed to determine
optimized dosing, duration of effect, and the utility of using
PLE in combination with topically-applied sunscreens
(Bhatia 2015). Murine models suggest a potential for PLE as
a chemopreventative agent, however, to date, there are no
controlled trials in humans demonstrating this effect. This
may be an exciting area of future study.
Polypodium Leucotomos 31
Evidence for Polypodium Leucotomos
1. Orally administered Polypodium leucotomos extract

decreases psoralen UVA-induced phototoxicity, pigmenta-
tion, and damage of human skin. Middelkamp-Hup MA,
Pathak MA, Parrado C, Garcia-Caballero T, Rius-Diaz F,
Fitzpatrick T, Gonzalez S. J Am Acad Dermatol. 2004;50:419.
Ten healthy volunteers were exposed to psoralen plus UVA
(PUVA) alone, and then PUVA after taking PLE 7.5 mg/kg as
a single oral dose. PLE-treated skin had significantly less pho-
totoxicity and hyperpigmentation (P < 0.005). On histology,
PLE treated skin had fewer sunburn cells as well as preserva-
tion of langerhans cells (P 0.01) and demonstrated height-
ened activation of p53 tumor suppressor gene. The authors
conclude that PLE is photoprotective against PUVA and
potentially prevents immunosuppression. Further trials are
needed to determine optimized dosing and duration of therapy
to maximize benefit.
2. Oral administration of Polypodium leucotomos delays skin

tumor development and increases epidermal p53 expression
and the antioxidant status of UV-irradiated hairless mice.
Rodrguez-Yanes E, Cuevas J, Gonzalez S, Mallol J. Exp
Dermatol.2014;23(7):5268.
Hairless mice were exposed to UVA/UVB lamps for 42 weeks.
Half were fed 300 mg/day PLE, half served as control. At the
end of the study, the PLE-treated mice had significantly fewer
actinic keratoses and squamous cell cancers (P = 0.023).
Histology also showed differences in p53 activation in the
PLE treated mice. The authors propose PLE may, therefore,
be chemopreventative by heightening p53-induced apoptosis
and enhancing DNA repair. Human trials are needed to con-
firm that PLE can be chemopreventative and to determine the
optimal dose and duration of therapy required to safely
achieve this effect.
3. Oral administration of a hydrophilic extract of Polypodium

leucotomos for the prevention of polymorphic light eruption.
Tanew A, Radakovic S, Gonzalez S, Venturini M, Calzavara-
Pinton P. J Am Acad Dermatol. 2012 Jan;66(1):5862.
Thirty-five patients with PMLE were exposed to UVA or
UVB. 30/35 flared upon UVA provocation, 18/20 with UVB
exposure. The patients were then treated with PLE for 2 weeks
with dosing based on weight (<55 kg = 720 mg/day,
5670 kg = 960 mg/day, >70 kg = 1,200 mg/day). After PLE,
only 21/35 flared upon UVA exposure, and only 13/20 with
UVB exposure. Also, PLE-treated patients who did ultimately
flare required an increase in the mean number of UV expo-
sures in order to induce flaring. The authors conclude that
PLE may suppress UV induced flaring of PMLE. Larger
RCT studies validating these results are needed, but this data
suggests PLE may be a possible adjunctive therapy for patients
with idiopathic photodermatoses such as PMLE.
Case 1
A 26 year-old healthy female presents with a history of
poorly-controlled polymorphous light eruption (PMLE).
Despite careful sunscreen use, she reports repeated flares. She
declines hydroxychloroquine and inquires about alternative
therapy options. She inquires about the use of Polypodium
leucotomos (PLE). Is there a basis for this therapy option?
Discussion
PLE could be discussed as an adjunct to therapy, but it should
be emphasized that systemic photoprotection does not replace
the need for conventional photoprotection with sunscreen and
protective clothing. Literature demonstrating reduced flaring
in PMLE patients pretreated with PLE prior to UV exposure
could be reviewed and PLE 7.5 mg/kg PO BID starting
2 weeks before planned sun exposure could be considered for
this patient.
References 33
Case 2
A 37 year old woman with a history of basal cell carcinoma
(BCC) presents looking to discuss using dietary modification
to replace topical sunscreens as her means of photoprotec-
tion. How would you counsel this patient?
Discussion
Literature supporting the potential benefits of lycopenes,
niacinamide, and polyphenols such as turmeric could be
reviewed as potentially providing some level of systemic pho-
toprotection. While in vivo and in vitro data exists for these
agents, it is important to stress that the literature does not fully
delineate optimized dosing for any of these items nor does it
specifically quantify efficacy individually or on a comparative
basis. While some of these items may indeed provide a degree
of adjunctive photoprotection, she should be advised to con-
tinue to use protective clothing and sunscreens to minimize her
risk of future BCC.
References
Afaq F, Katiyar SK. Polyphenols: skin photoprotection and inhibi-
tion of photocarcinogenesis. Mini Rev Med Chem. 2011;11(14):
120015.
Bhatia N. Polypodium leucotomos: a potential new photoprotective

agent. Am J Clin Dermatol. 2015;16(2):739.
Damian D. Photoprotective effects of nicotinomide. Photochem

Photobiol Sci. 2010;9:57885.
Fernandez-Garcia E. Skin protection against UV light by dietary

antioxidants. Food Funct. 2014;5(9):19942003.
Jansen R, Wang SQ, Burnett M, Osterwalder U, Lim HW.

Photoprotection: part I. Photoprotection by naturally occurring,
physical, and systemic agents. J Am Acad Dermatol. 2013;

69(6):853.
Kannan S, Lim HW. Photoprotection and vitamin D: a review.

Photodermatol Photoimmunol Photomed. 2014;23:13745.
Stahl W, Sies H. Carotenoids and flavonoids contribute to nutritional

protection against skin damage from sunlight. Mol Biotechnol.
2007;37(1):2630.
Chapter 4
Skin Cancer
Introduction
It is estimated that one in five Americans will develop skin
cancer in their lifetime and that up to 50% of Americans who
live to age 65 will develop either basal cell carcinoma (BCC) or
squamous cell carcinoma (SCC) at least once (http://
progressreport.cancer.gov). Treatment of non-melanoma skin
cancers has increased by 77% between 1992 and 2006 (Rogers
2010; http://cancer.org/acs/group/content/@epidemiologysur-
veilance/document036845.pdf), leading to continual reassess-
ment of treatment. Morbidity has been minimized with
techniques such as Mohs Micrographic surgery, and excellent
cure rates have been reported (Clark et al. 2014; Mostterd et al.
2008). For malignant melanoma, by far the most dangerous of
these three skin cancers, the outcomes are far less rosy, with
good cure rates for thin tumors, but poor rates for thicker, inva-
sive lesions. Importantly, options for metastatic melanoma are
limited, with modest life prolongation at best. In fact, patients
with visceral metastases have medial survival rates of only 4
months (Fox et al. 2013). Nonetheless, newer immunotherapies
such as ipilimumab and PD1 inhibitors now offer hope to mela-
noma patients with advanced disease (Fox et al. 2013).
Some skin cancer patients find the cost and/or resultant
excision scar unsatisfactory, or fear surgery altogether.
Perhaps surprisingly, complementary and alternative (CAM)
therapy options are being increasingly sought out and

DOI 10.1007/978-3-319-17816-5_4
36 4. Skin Cancer
utilized by skin cancer patients. In one survey, the prevalence

of CAM use among adults reporting skin problems was
nearly 50% (Smith et al. 2010).
As patients seek alternative options to conventional therapy
for skin cancer, the use of natural products cannot be assumed
to mean safe. Health providers need to be aware of several
specific alternative therapies for skin cancer, some promising
and others plainly dangerous. Some of these natural products
have lead to major discoveries in skin cancer research (cyclopa-
mine) or have proven efficacy (ingenol mebutate). However,
randomized controlled trials (RCT) demonstrating efficacy and
safety of alternative therapies are necessary before they can be
considered viable options in the management of skin cancer.
It is important to stress that invasive basal and squamous
cell cancers, as well as all melanomas can metastasize and
cause significant morbidity and even mortality. Failing to use
proven techniques to properly diagnose (i.e., biopsy) and to
surgically resect or debulk these tumors greatly increases the
risk for poor outcomes, and may increase the medicolegal risk
in such cases. Because of the inherent dangers of skin cancer,
only adjuvants to conventional care should be considered
until sufficient evidence displaces current standards of care.
Clinical Considerations
See Figs. 4.1, 4.2, 4.3, and 4.4.
Fig. 4.1. Basal cell carcinoma.

Clinical Considerations 37
Fig. 4.2. Actinic keratosis.
Fig. 4.3. Squamous cell carcinoma.
Fig. 4.4. Malignant melanoma.

38 4. Skin Cancer
Top Considerations
See Table 4.1.
Not Recommended
The escharotics (i.e., bloodroot, sanguinarine, and related
compounds) should be avoided for known malignancies as
they are unpredictable and have not reliably been shown
to be a viable treatment without concomitant surgery.
Gossypin (an extract from cotton and hibiscus plants)
has some promising data in mice and in vitro for mela-
noma, but is simply too experimental for clinical use at
this time.
Table 4.1. Top considerations for skin cancer.

Ingenol Topically as 0.05% gel FDA-approved and effective
mebutate for the body (applied for AKs, easy to apply for
once daily for 2 days) short duration; local reactions
and 0.015% for the face common, but relatively mild
and scalp (once daily for
3 days)
Solasodine Topically as 0.005% Limited data for AK, SCC, and
glycosides cream (BID 760 days) BCC; no data for melanoma.
(BEC) Perhaps could be used in special
circumstances as an adjunct to
surgery or alternative trial for
low-risk lesions under close
supervision
Vitamin D Daily or weekly Some studies suggest protective
supplementation. effect and survival advantage for
Optimal dosing is melanoma; Safe and inexpensive
unclear
Coenzyme 200 mg PO BID May reduce risk of metastasis
Q10 and potentiate efficacy of
adjuvant therapies; data is very
limited
Ingenol Mebutate 39
Ingenol Mebutate
Actinic keratoses (AKs) are common scaling, epidermal
lesions occurring on sun exposed skin (Uhlenake 2013).
These lesions have the potential to transform into SCC, and
estimates of the annual rate of transformation range from
0.025 to 20% (Marks et al. 1988). Given the lack of clinical
features that allow clinicians to identify the lesions most
likely to progress, clinicians are obligated to treat AKs as a
preventative measure (Uhlenake 2013). These therapies
include cryotherapy, photodynamic therapy, topical chemo-
therapy, and topical field therapy with agents such as
imiquimod and ingenol mebutate (Uhlenake 2013). Ingenol
is a novel agent derived from Euphorbia peplus, a temperate
annual weed, known as radium weed, petty spurge, or milk-
weed (Rosen et al. 2012). The sap of E peplus is irritating and
has been used for centuries as a natural folk remedy for warts
and AK (Rosen et al. 2012). It was approved for the treat-
ment of AK in 2013 and is available in 0.05% gel for the body
(applied once daily for 2 days) and 0.015% for the face and
scalp (once daily for 3 days), Ingenol is thought to have sev-
eral mechanisms of action. These include disruption of
mitochondrial membranes resulting in cytotoxicity, activation
of proinflamatory cytokines, recruitment of neutrophils, and
generation of tumor specific antibodies (Rosen et al. 2012).
Complete clearance of facial lesions was 47% of individuals
at 57 days and mean reduction of lesions was 87% mean
reduction of lesions from baseline for face and scalp. Pooled
analysis of 4 trials (2 face and scalp, 2 body) concluded that
42.2% of face and scalp lesions cleared and 34.1% affected
body areas cleared. Adverse reactions include erythema,
scabbing and scaling and were mild to moderate in severity.
Unlike escharotics, randomized controlled trials have con-
firmed the efficacy of naturally occurring ingenol mebutate
for the topical field treatment of actinic keratoses. Ingenol is
presently being studied for therapy of BCC (Clark et al.
2014) and it has been recently reported to help pediatric mol-
luscum as an off label indication (Javed and Tyring 2014).
40 4. Skin Cancer
Evidence for Ingenol Mebutate
1. The European Medicines Agency approval of ingenol

mebutate (Picato) for the cutaneous treatment of non-
hyperkeratotic, non-hypertrophic actinic keratosis in adults:
Summary of the scientific assessment of the Committee for
Medicinal Products for Human Use (CHMP). Tzogani K,
Nagercoil N, Hemmings RJ, Samir B, Gardette J, Demolis P,
Salmonson T, Pignatti F. Eur J Dermatol. 2014 Jul-Aug;
24(4):45763.
A large scientific review that examined 25 clinical studies, 18 in
patients with AK. A complete response rate of 42.2% on the
face and scalp and 34.1% on the trunk and extremities was
reported, with local skin reactions being the most common side
effects. This medication is now FDA-approved in the United
States as being safe and effective for the treatment of AK.
Solasodine Glycosides (BEC)

Sometimes marketed under the name Curaderm, BEC is
used for AK and non-melanoma skin cancer. Containing
naturally occurring glycoalkaloids found in both eggplant
and Solanum sodomaeum (Devils Apple), the manufacturer
suggests that the compound is highly toxic to skin cancer cells
when applied twice daily for 760 days for AK and small skin
cancers ( http://www.antiaging-systems.com/23-bec5-
curaderm?Aff=WRC1). The manufacturer also indicates that
Curaderm causes no harm to healthy cells. The active ingredi-
ent is thought to be rhamnose sugar moieties (solasodine
glycosides). Healthy skin cells do not express receptors for
these sugar moieties while cancer cells do. Via these recep-
tors, it is thought that BEC binds, is internalized and then
induces apoptosis through lysosomal destruction (http://
www.antiaging-systems.com/23-bec5-curaderm?Aff=WRC1).
Anecdotal evidence showing apparent improvement is cited
Solasodine Glycosides (BEC) 41
on various web sites; however, biopsy confirmation of com-

plete clearance is not provided and controlled trials are not
available (Cham et al. 1991). There is a case report of success-
ful use of BEC5 in squamous cell cancer in situ of the genital
region with biopsy confirmation of tumor resolution. Until
larger controlled trials are performed, the efficacy and role of
this treatment cannot be determined, but there may be some
promise in the future for this agent (Leonard et al. 2011).
Evidence for Solasodine Glycosides (BEC)
1. Topical treatment of malignant and premalignant skin

lesions by very low concentrations of a standard mixture
(BEC) of solasodine glycosides. Cham BE, Daunter B, Evans
RA. Cancer Lett. 1991 Sep;59(3):18392.
A low concentration formulation of BEC (0.0005%) was used
in an open study of 56 AKs, 39 BCCs and 29 SCCs showed that
all regressed to some extent in the treatment arm compared to
a placebo that showed no effect on a smaller number of treated
lesions.
2. Solasodine glycoalkaloids: a novel topical therapy for basal

cell carcinoma. A double-blind, randomized, placebo-
controlled, parallel group, multicenter study. Punjabi S, Cook
LJ, Kersey P, Marks R, Cerio R. Int J Dermatol. 2008
Jan;47(1):7882.
A multi-center, double-blind, randomized, placebo-controlled
trial of a 0.005% mixture of solasodine glycosides for the treat-
ment of histologically-confirmed BCC. Ninety-four patients
with BCC were randomized to the treatment twice daily under
occlusion or placebo for 8 weeks, with endpoint being histo-
logically confirmed clearance of BCC at 8 weeks. Efficacy was
66% cure in the experimental group vs. 25% in the placebo
(p < 0.001). Seventy-eight percent of the experimental group
had no recurrence at 1 year.
42 4. Skin Cancer
Vitamin D
The relationship of Vitamin D with melanoma continues to
be evaluated and remains complex. Some studies link low
levels of Vitamin D to melanomas with thicker Breslow
depths, positing antiproliferative and prodifferentiation
effects of the hormone (Berwick and Erdei 2013), while oth-
ers fail to show such a link. A study by Newton-Bishop et al.
demonstrated a survival advantage among melanoma patients
with higher Vitamin D levels at the time of diagnosis
(Newton-Bishop et al. 2009). Nurenberg et al. reported that
serum 25(OH)D levels were lower in patients with Stage IV
melanomas at the time of diagnosis compared to the levels in
patents with Stage I melanoma (Nurnberg et al. 2009). Data
on the role of dietary supplements of Vitamin D and mela-
noma risk have shown varying results. Weinstock and col-
leagues found no association between use of Vitamin D
supplementation and melanoma risk (Weinstock et al. 1992).
On the other hand, Vinceti et al. found an inverse association
between dietary intake of Vitamin D and melanoma risk
(Berwick and Erdei 2013). The VitaL cohort examined 68,611
participants who reported dietary and supplemental Vitamin
D intake (Asgari et al. 2009). Their review revealed no asso-
ciation between Vitamin D intake and melanoma risk for the
455 incident melanomas. In conclusion, there is inadequate
evidence to verify that Vitamin D supplementation decreases
melanoma risk (Berwick and Erdei 2013) even though some
studies suggest a survival benefit with Vitamin D supplemen-
tation. Results of ongoing studies will establish if supplemen-
tation is justified, and what the proper dosing should be.
Advising supplementation may be reasonable pending the
establishment of a final consensus, especially in light of the
fact that strict sun avoidance is generally recommended for
skin cancer prevention, which directly contributes to vitamin D
insufficiency.
Coenzyme Q10 43
Evidence for Vitamin D
1. Serum 25-hydroxyvitamin D3 levels are associated with

Breslow thickness at presentation and survival from mela-
noma. Newton-Bishop JA, Beswick S, Randerson-Moor J,
Chang YM, Affleck P, Elliott F, Chan M, Leake S, Karpavicius
B, Haynes S, Kukalizch K, Whitaker L, Jackson S, Gerry E,
Nolan C, Bertram C, Marsden J, Elder DE, Barrett JH, Bishop
DT. J Clin Oncol. 2009 Nov 10;27(32):543944.
A prospective cohort study of 872 patients with melanoma
were found to have a significant positive correlation between
serum vitamin D levels and lower Breslow thickness at diagno-
sis (p = 0.002). They were also found to have lower relapse and
mortality rates (p = 0.01), suggesting that vitamin D serum
levels have positive associations for melanoma.
2. A cohort study of vitamin D intake and melanoma risk.

Asgari MM, Maruti SS, Kushi LH, White E. J Invest Dermatol.
2009 Jul;129(7):167580.
Sixty-eight thousand six hundred and eleven participants of
the Vitamins and Lifestyle cohort study reported dietary vita-
min D intake over past years and use of supplements. Four
hundred and fifty-five melanomas were identified and rela-
tionships using several statistical methods were sought between
vitamin D intake and melanoma. There was no melanoma risk
reduction found for the highest quartiles of vitamin D intake,
suggesting no association.
Coenzyme Q10
Coenzyme Q10 (CoQ10) is a critical part of the electron
transport chain in mitochondria and is thought to plan an
important role in cellular regulation and function, as well as
immune system function. Historically, studies have found low
levels of CoQ10 in patients with various cancers (Rusciani
et al. 2006). Accordingly, CoQ10 levels have been found to be
44 4. Skin Cancer
significantly lower in melanoma patients raising the notion

that it could potentially be used for treatment. In looking at
the two small studies, overall benefit is speculative and larger
trials will be needed to validate these findings. However,
these small studies suggest that there may be benefit to
supplementing melanoma patients with CoQ10.
Evidence for CoQ10
1. Low plasma coenzyme Q10 levels as an independent prog-

nostic factor for melanoma progression. Rusciani L, Proietti I,
Rusciani A, Paradisi A, Sbordoni G, Alfano C, Panunzi S, De
Gaetano A, Lippa S. J Am Acad Dermatol. 2006 Feb;54(2):
23441.
A prospective study of 117 consecutive melanoma patients
were tested for CoQ10 levels and were correlated with evi-
dence for metastatic disease. CoQ10 level was significantly
lower in melanoma patients versus healthy controls (p < 0.0001)
and lower in the group that developed metastases compared to
those who did not (p < 0.0001). While fairly small, the powerful
correlation warrants further study of CoQ10 as an indepen-
dent prognostic factor of melanoma progression.
2. Recombinant interferon alpha-2b and coenzyme Q10 as a

postsurgical adjuvant therapy for melanoma: a 3-year trial
with recombinant interferon-alpha and 5-year follow-up.
Rusciani L, Proietti I, Paradisi A, Rusciani A, Guerriero G,
Mammone A, De Gaetano A, Lippa S. Melanoma Res. 2007
Jun;17(3):17783.
Thirty-two patients with stage I and II melanoma were
assigned to receive a combination of interferon alpha and
CoQ10 (200 mg twice daily by mouth) were compared to 49
patients with similar stage disease who received only the inter-
feron alpha as controls. Over 8 years there was found to be
evidence of a statistically significant association between the
CoQ10 and decreased risk of metastasis (p = 0.006). CoQ10
also appeared to improve quality of life in the study compared
to controls, and appeared to be very safe and well-tolerated.
Escharotics 45
Escharotics
Escharotic agents are frequently mentioned by patients and
alternative practitioners and warrant further discussion
beyond simply being not recommended. Escharotics con-
tain primarily zinc chloride and bloodroot (an alkaloid called
sanguinarine derived from the root of the plant, Sanguinaria
canadensis). In a notable reversal, these agents were used
initially as a tissue fixative in the conventional Mohs micro-
graphic surgery (MMS). This technique, pioneered by Dr.
Frederick Mohs in the early 1930s, involved fixation of
cancerous tissue with a version of this compoundreferred to
as Mohs pasteprior to excision. The disadvantages of the
initial technique included caustic destruction of adjacent
healthy tissue, pain, and prolonged surgical time. Over the
past 50 years, MMS has converted to fresh frozen tissue
analysis to achieve expedited, precise margin control with tis-
sue sparing. Overall, the Mohs technique routinely achieves
excellent cure rates and good cosmetic outcomes without the
use of escharotics.
At the same time that the Mohs technique was introduced,
Harry Hoxsey, a self-proclaimed cancer specialist with an
eighth grade education, touted an herbal tonic and paste
designed to treat both internal and external cancers (Elston
2005). Hoxseys paste resembled the original Mohs paste, con-
taining both zinc chloride and bloodroot. Hoxsey recom-
mended applying the paste to skin cancers and noted that
within days to weeks, the area would necrose and fall out. This
treatment was never scientifically tested or proven efficacious.
In the 1950s, the U.S. Food and Drug Administration (FDA)
condemned Hoxseys formulas. However, the use of escharot-
ics continues to be promoted by alternative practitioners as a
primary self-directed therapy for skin cancer. Via the internet,
patients searching for alternative skin cancer therapies can
purchase escharotics such as Black Salve (Cansema). The
content of these products and the purity of their ingredients
are not regulated, and, as such cannot be recommended.
46 4. Skin Cancer
Despite warnings from the FDA and National Cancer

Institute that these products are not accepted treatments for
skin cancer, self-directed use of escharotics continues.
Published examples of recurrent skin cancer within escharotic-
induced scar, anatomic deformity from use (Eastman et al.
2011), and need for extensive surgery to eradicate the recur-
rent tumor have been reported (Jellinek and Maloney 2005;
McDaniel and Goldman 2002). Overall, escharotics are not
indicated for any biopsy-confirmed malignancy. Their indis-
criminate use on undiagnosed lesions can mask potentially
serious malignancies. Use on aggressive tumors such as
melanoma or advanced SCC may delay appropriate care and
increase the risk of metastasis and poor outcomes (Cienki
and Zaret 2010; Adler and Freidman 2014).
Evidence Against Escharotics
1. Closing a gap in clinical knowledge: Analysis of cases of

self-treatment of moles and skin cancer with escharotic and
nonescharotic agents in the Internet age. Adler B, Freidman
A. Poster Abstract. JAAD. 2014 May;70(5):Supplement 1;
Page AB133.
This analysis of 26 published cases shows that 88.5% of cases
treated with cancer salves (escharotics and non-escharotics)
resulted in poor cosmesis, 38.5% of cases resulted in severe
tissue damage, and 56.3% have biopsy confirmed residual
disease after self treatment. Amongst those self-treating for
BCC, 71.4% of patients who had an apparent response to
therapy had residual disease on biopsy. 31.3% of cases fea-
tured metastasis (3 BCC, 1 SCC, 1 melanoma). Only 5/13 BCC
patients were found to have no residual disease, indicating a
cure rate of only 38.5%. The authors conclude that this is unac-
ceptably low when compared to cure rates achieved in stan-
dard practice (>95%).
Case 1 47
Gossypin
Gossypin is extracted from cotton and hibiscus plants and has
been studied in vitro for melanoma. Gossypin reduced tumor
size and prolonged life in mice with melanoma tumors
(Bhaskaran 2013). Gossypin appears to inhibit melanoma cell
proliferation in human cel cultures as well. It is believed that
Gossypin inhibits kinase activities of BRAFV600E and
CDK4, in vitro, possibly through direct binding of gossypin
with these kinases. For cells harboring the BRAFV600E
mutation, gossypin inhibited cell proliferation through
abrogation of the MEK-ERK-cyclin D1 pathway (Bhaskaran
2013). Gossypin is a novel agent with dual inhibitory effects
for BRAFV600E kinase and CDK4 for treatment of mela-
noma. Although this may be a promising option in the future,
current research does not support a role for gossypin in
patient care at this time.
Case 1
A 58 year old male presents with a bleeding, erythematous
pearly papule on the nasal ala in the setting of severe sun
damage and multiple actinic keratoses on the face. Your skin
biopsy confirms a basal cell carcinoma, nodular type. You
advise the patient to proceed with Mohs micrographic exci-
sion of the lesion. Due to a fear of surgery and concerns
about scarring, the patient inquires regarding your opinion
on the use of the escharotic, black salve, to treat his BCC. How
would you advise the patient?
Discussion
It is important to stress to the patient that escharotics are
unsafe, unproven and seem to have poorer outcomes in terms
of scars, recurrence and even metastasis. While there may be a
role defined for them in the treatment of skin cancers in the
future, they simply cannot be recommended at this time and
48 4. Skin Cancer
more conventional approaches should be considered. Other

non-surgical options such as radiation therapy could be
discussed, and minimal surgery with complementary measures
such as ingenol mebutate or solasodine glycosides to possibly
help decrease future development of skin cancers in the area
could also be discussed.
Case 2
You diagnose a melanoma of the left leg (Breslow depth
1.01 mm) in a 43 year-old patient. She is scheduled for a wide
local excision of the primary tumor with a sentinel lymph
node dissection. Before proceeding with the advised surgery,
she inquires if there are any supplements that could be of
benefit in her care. How would you counsel this patient?
Discussion
Vitamin D supplementation could be recommended as there is
some evidence that it could be helpful in this context. Moreover,
given that strict sun protection is emphasized for melanoma
patients, Vitamin D supplementation of 5002,000 IU per day
is a safe and inexpensive adjunct that may be worthwhile.
While the data on Coenzyme Q10 is very limited, there may be
benefit in the setting of melanoma progression, so CoQ10
200 mg PO BID may be reasonable here.
References
Adler B, Freidman A. Closing a gap in clinical knowledge: analysis of
cases of self-treatment of moles and skin cancer with escharotic
and nonescharotic agents in the Internet age. Poster Abstract.
JAAD. 2014;70(5 (Suppl 1)):AB133.
American Cancer Society cancer facts & figures. 2013. http://cancer.org/

acs/group/content/@epidemiologysurveilance/document036845.
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Asgari MM, Maruti SS, Kushi LH, White E. A cohort study of vita-
min D intake and melanoma risk. J Inves Dermatol. 2009;129(7):
167580.
Berwick M, Erdei EO. Vitamin D and melanoma incidence and mor-

tality. Pigment Cell Melanoma Res. 2013;26(1):915.
Bhaskaran S. Gossypin as a novel selective dual inhibitor of V-RAF

murine sarcoma viral oncogene homolog B1 and cyclin-
dependent kinase 4 for melanoma. Mol Cancer Ther. 2013;12(4):
36172.
Cham BE, Daunter B, Evans RA. Topical treatment of malignant

and premalignant skin lesions by very low concentrations of a
standard mixture (BEC) of solasodine glycosides. Cancer Lett.
1991;59(3):18392.
Cienki JJ, Zaret L. An internet misadventure: bloodroot salve toxic-

ity. J Altern Complement Med. 2010;16(10):11257. doi:10.1089/
acm.2010.0140. Epub 2010 Oct 9.
Clark CM, Furniss M, Mackay-Wiggan JM. Basal cell cancer: an evi-

dence based treatment update. Am J Clin Dermatol. 2014;15:
197216.
Eastman KL, McFarland LV, Raugi GJ. Buyer beware: a black save
caution. JAAD. 2011;65:e1545.
Elston DM. Escharotic agents, Fred Mohs, and Harry Hoxsey: a

commentary. JAAD. 2005;53:5235.
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TM. Management options for metastatic melanoma in the era of
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ingenol mebutate. J Am Acad Dermatol. 2014;70(5):e105.
50 4. Skin Cancer
Jellinek N, Maloney ME. Escharotic and other botanical agents for

the treatment of skin cancer: a review. JAAD. 2005;53:48795.
Leonard GH, Landau JM, Moody MN, Vergilis-Kalner IJ. Treatment

of Bowens disease on the penis with low concentration of stan-
dard mixture of solasodine glycosides and liquid nitrogen.
Dermatol Surg. 2011;37:85861.
Marks R, Rennie G, Selwood RS. Malignant transformation of

solar keratoses to squamous cell carcinoma. Lancet. 1988;
1(8589):7967.
McDaniel S, Goldman GD. Consequences of using escharotic agents

as primary treatment for nonmelanoma skin cancer. Arch
Dermatol. 2002;138:15936.
Mostterd K, Krekels GA, Nieman FH, et al. Surgical excision v Mohs

micrographic surgery for primary and recurrent basal cell cancer
if the face; a prospective randomized controlled trial with 5-years
follow-up. Lancet Oncol. 2008;9(12):114956.
Newton-Bishop JA, et al. Serum 25-hydroxyvitaminD3 levels are

associated with breslow thickness at presentation and survival
form melanoma. J Clin Oncol. 2009;27(32):543944.
Nurnberg B, et al. Reduced serum 25-hydroxyvitamin D levels in

stage IV melanoma patients. Anticancer Res. 2009;29(9):
366974.
Rogers H. Your new study of non melanoma skin cancers. New York:
Skin Cancer Foundation, Skin Cancer.org; 2010.
Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of

Ingenol mebutate gel for the topical treatment of actinic kerato-
sis: rapid necrosis followed by specific immune response. JAAD.
2012;66(3):486693.
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Panunzi S, De Gaetano A, Lippa S. Low plasma coenzyme Q10
levels as an independent prognostic factor for melanoma pro-
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Chapter 5
Acne
Introduction
Common acne, or acne vulgaris, is one of the most common
skin conditions seen by practitioners; it can also be one of the
most frustrating conditions to treat. Acne is thought to affect
more than 80% of adolescents and will commonly persist into
adulthood (Bhate and Williams 2013). The clinical and histo-
logical features of acne are well described, with conventional
thinking that Propionibacterium acnes (P. acnes) bacteria
normally present on the skincolonizes the duct of the seba-
ceous gland, resulting in a non-inflammatory comedo or
inflammatory papule, pustule or nodule (Gollnick et al.
2003). However, in the last decade much has been written
about the pathophysiology of acne and many would argue
that an inflammatory state is present long before the clinical
formation of the acne lesion (Thiboutot et al. 2009). Evidence
now suggests a role for several inflammatory mediators such
as cytokines, defensins, peptidases, and sebum lipids (Tanghetti
2013), triggering the beginning of a paradigm shift in how
acne is viewed.
Despite decades of research and clinical trials, there
remains a surprisingly limited treatment armamentarium for
acne. Adding to the challenge is that acne can be classified
into numerous clinical categories: hormonal female acne,

DOI 10.1007/978-3-319-17816-5_5
54 5. Acne
adult acne, adolescent acne, and acne in pregnancy and

lactation, to name only a few. Treatment approaches vary
depending on both the clinical category of the acne and the
severity. In general, the following traditional topical prepara-
tions are prescribed: retinoids, antimicrobials, benzoyl perox-
ide and salicylic acid. Oral preparations such as antibiotics
(most commonly the tetracyclines), antiandrogens and
isotretinoin may also be utilized. While often effective, tradi-
tional therapies can have a number of adverse side effects.
Dryness and irritation are common for the topical prepara-
tions, while oral antibiotics and systemic isotretinoin have
lengthy pages of adverse reactions to consider. As there is
increasing media coverage and evidence supporting concerns
over antibiotic resistance and environmental toxins as well as
a general movement towards products and foods sourced in
a healthier manner, patients and health care providers are
looking for more natural treatment options.
As both the clinician and the patient look for options, it is
important to understand what may be available to comple-
ment traditional therapies or what may be available in lieu of
traditional therapies. Unfortunately, as in many other areas,
there exists only a small pool of evidence supporting avail-
able options. However, as we increase our understanding
about the pathophysiology of acne, it follows that there is
increased need to explore other options for treatment, and
some of those options may yet be in the alternative arena.
Here, we review some of the evidence for such alternative
therapies: topical vitamin C, topical nicotinamide, dietary
modifications, topical green tea, topical tea tree oil, oral pro-
biotics and oral zinc.
See Figs. 5.1 and 5.2.
Clinical Considerations 55
Fig. 5.1. Inflammatory acne.
Fig. 5.2. Comedonal acne.

56 5. Acne
Top Considerations
See Table 5.1.
Secondary Considerations
See Table 5.2.
Table 5.1. Top considerations.

Topical Applied topically daily Safe, can be expensive, can be
vitamin C or twice daily irritating, stability concerns,
products added benefit of anti-oxidant
for anti-aging effects and
hyperpigmentation
Topical Applied topically daily Safe, generally very tolerable
nicotinamide or twice daily
Dietary Reduction of dairy in the Highly variable depending
modifications diet, reduction of high on baseline diet, need to
glycemic foods in the consider overall impact on
diet and introduction of nutrition
a more Mediterranean
focused diet
Topical tea Applied topically once Can be irritating and
tree oil or twice daily, diluted allergenic, variability in the
delivery
Table 5.2. Secondary considerations.

Topical Applied topically Safe, generally very tolerable, hard to
green tea twice daily source, may have the added benefit of
anti-oxidant for anti-aging effects
Oral Orally, once or Generally safe if reasonable dose in
probiotics twice daily a healthy patient, numerous strains
and doses available, concern over
gastrointestinal tolerability, concerns
over some strains in immune-
compromised patients
Oral zinc Orally, daily Concerns about gastrointestinal
tolerability, caution about potential
copper deficiency with prolonged use
Vitamin C 57
Vitamin C
Vitamin C (ascorbic acid) is well known for the association of
its deficiency with scurvy. It was isolated in 1928 and is known
to be essential for the development and maintenance of con-
nective tissue. It supports the immune system, reduces the
severity of allergic reactions, and plays a role in fighting
infections (Chambial et al. 2013). Vitamin C is also a powerful
antioxidant and may be efficacious against P. acnes in the skin
(Klock et al. 2005). Several randomized, controlled trials have
found that topical application of a stable precursor of ascor-
bic acid is effective in reducing acne lesion counts, both alone,
or in combination with topical retinol (Ruamrak et al. 2009;
Woolery-Llyod et al. 2010). Vitamin C appears to be a very
safe and tolerable treatment but, depending on the concen-
tration and vehicle, irritation may occur. Ascorbic acid is also
notoriously unstable, so the proper formulation must be used.
Such a preparation, if in an appropriate vehicle, would likely
be considered pregnancy and lactation safe, as this water-
soluble vitamin is absorbed from many foods and could serve
as a helpful adjuvant option for acne treatment in this popu-
lation as well.
Evidence for Topical Vitamin C
1. Comparison of clinical efficacies of sodium ascorbyl phos-

phate, retinol and their combination in acne treatment.
Ruamrak C, Lourith N, Natakankitkul S. Int J Cosmet Sci.
2009 Feb;31(1):416.
Randomized and double-blind studies on the comparison of
the efficacies of topical formulations containing 5% sodium
ascorbyl phosphate (SAP) and 0.2% retinol, separately as well
as in combination application, were conducted. The most
effective treatment was the combination of 5% SAP and 0.2%
retinol. They concluded that sodium ascorbyl (a vitamin C
preparation) was helpful in treating acne either alone or in
combination.
58 5. Acne
2. Sodium L-ascorbyl-2-phosphate 5% lotion for the treat-

ment of acne vulgaris: a randomized, double-blind, controlled
trial. Woolery-Llyod H, Baumann L, Ikeno H. J Cosmet
Dermatol. 2010 Mar;9(1):227.
Fifty subjects were randomized in a double-blind controlled trial
to receive sodium-L-ascorbyl-2-phosphate (APS) 5% lotion or
vehicle for 12 weeks. Evaluation included an Investigators
Global Assessment Score, a Subjects Global Assessment Score,
lesion counts, cutaneous tolerability and adverse events. APS 5%
lotion demonstrated statistically significant improvement when
compared to vehicle in all of the parameters measured. The
adverse event frequency and cutaneous tolerability profile for
APS 5% lotion were similar to vehicle.
3. Sodium ascorbyl phosphate shows in vitro and in vivo

efficacy in the prevention and treatment of acne vulgaris.
Klock J, Ikeno H, Ohmori K, et al. Int J Cosmet Sci. 2005
Jun;27(3):1716.
This group showed that 1% sodium ascorbyl phosphate
(SAP), a stable precursor of vitamin C, has a strong antimicro-
bial effect in P. acnes in a time-kill study. Additionally, they
showed in a human in vivo study with 20 subjects a SAP for-
mulation significantly reduces the UVA-induced sebum oxida-
tion by up to 40%. And lastly, they performed an open in vivo
study with 60 subjects with a 5% SAP lotion over 12 weeks.
The efficacy ranked as excellent.
Topical Nicotinamide
Nicotinamide, also known as niacinamide, is a water-soluble
vitamin and is part of the vitamin B group. It is known that
nicotinamide is involved in numerous oxidation-reduction
reactions in mammalian biological systems. It also acts as an
antioxidant (Otte et al. 2005). Numerous studies have inves-
tigated the use of nicotinamide both topically and orally in
the role of acne vulgaris. Reasonable evidence exists for the
use of this agent in the treatment of acne, placing it on par
Topical Nicotinamide 59
with topical clindamycin, but without the undesirable effect

of possibly inducing bacterial resistance.
Evidence for Topical Nicotinamide
1. Topical 4% nicotinamide vs 1% clindamycin in moderate

inflammatory acne vulgaris. Khodeaeiani E, Fouladi R,
Amirnia M, et al. Int J Dermatol. 2013;52:9991004.
A randomized, double-blind clinical trial looked at moderate
inflammatory facial acne vulgaris and compared 1% clindamy-
cin gel to 4% nicotinamide gel. The study found the two topical
approaches to be equally efficacious in treating moderate acne.
2. Topical clindamycin 1% vs linoleic acid-rich phosphatidyl-

choline and nicotinamide 4% in the treatment of acne: a mul-
ticenter-randomized trial. Morganti P, Berardesca E, Guarneri
B, et al. Int J Cosmet Sci. 2011 Oct;33(5):46776.
A multi-center, double-blind, 12-week randomized vehicle and
parallel-active control study was conducted to evaluate the
efficacy, tolerability and safety of 4% nicotinamide-
phospholipidic emulsion vs. 1% topical clindamycin phos-
phate applied once daily. The nicotinamide-phospholipidic
treatment resulted in a slightly superior response.
3. Topical nicotinamide compared with clindamycin gel in the

treatment of inflammatory acne vulgaris. Shalita A, Smith J,
Parish L, et al. Int J Dermatol. 1995 Jun;34(6):4347.
In a double-blind investigation the safety and efficacy of topi-
cally applied 4% nicotinamide gel was compared to 1%
clindamycin gel for the treatment of moderate inflammatory
acne vulgaris. This trial demonstrated that 4% nicotinamide
gel is of comparable efficacy to 1% clindamycin gel in the
treatment of acne vulgaris.
4. The effect of 2% niacinamide on facial sebum production.

Draelos Z, Matsubara A, Smiles K. J Cosmet Laser Ther.
2006;96107.
60 5. Acne
Separate clinical trials were conducted in both Japan and the

USA to evaluate the effect of topical 2% niacinamide in differ-
ent ethnic groups. Sebum excretion rate (SER) was measured.
The results of the Japanese study demonstrated that the SER of
the two groups was not significantly different at baseline but
the 2% niacinamide treated group demonstrated significantly
lower SER after 2 and 4 weeks of application. The results dif-
fered in the Caucasian population. After 6 weeks of treatment,
the casual sebum levels (CSL) was significantly reduced but
the SER was not. They concluded that topical 2% niacinamide
may be effective in lowering the SER in Japanese individuals
and CSL in Caucasian individuals.
5. The Nicomide Improvement in Clincal Outcomes Study

(NICOS): results of an 8-week trial. Niren N, Torok H. Cutis.
2006 Jan;77(1 Suppl):1728.
An open-label, multicenter, prospective cohort study looked at
the clinical utility of oral pharmacologic doses of nicotinamide
and zinc in 198 patients with acne vulgaris and/or rosacea. The
study formulation consisted of nicotinamide 750 mg, zinc
25 mg, copper 1.5 mg and folic acid 500 g and is marketed as
Nic/Zn. Nic/Zn tablets appear to be an effective oral therapy
for the treatment of acne vulgaris and rosacea when used alone
or with other topical therapies and should be considered as a
useful alternative approach to oral antibiotics for the treatment
of acne vulgaris and rosacea.
6. Nicotinamide inhibits Propionibacterium acnes-induced

IL-8 production in keratinocytes through the NF-KB and
MAPK pathways. Grange P, Raingeaud J, Calvez V, et al.
Journal of Dermatol Sci. 2009;56:106112.
This study investigated the molecular mechanism underlying
the anti-inflammatory properties of nicotinamide in keratino-
cytes stimulated by P. acnes and concluded that nicotinamide
inhibits the IL-8 production through the NF-kB and MAPK
pathways in an in vitro keratinocytes/P. acnes model of
inflammation.
Dietary Modifications 61
Dietary Modifications
The relationship between diet and acne has been very contro-
versial. It is often one of the first questions a patient will ask:
Is it anything I am eating, or not eating? The answer to that
question has evolved with time. Historically, foods such as
chocolates, oils and sweets were implicated in exacerbating
acne. These associations have since been dispelled. But in the
last decade the question has re-emerged and new evidence
points to the possibility that dairy and carbohydrates may
indeed exacerbate acne (Bowe et al. 2010). In addition, peo-
ple are starting to consider what types of foods may have
therapeutic benefit for acne. Overall, evidence is surfacing to
more comprehensively answer this question for patients.
Evidence for Dietary Modifications
1. High glycemic load diet, milk and ice cream consumption

are related to acne vulgaris in Malaysian young adults: a case
control study. Ismail, N, Manaf Z, Azizan N. BMC Dermatol.
2012;12:13.
A case-control study was conducted with 44 acne vulgaris
patients and 44 controls. The comprehensive acne severity
scale was used (CASS). Cases had a significantly higher
dietary glycemic load compared to controls. The frequency of
milk and ice cream consumption was significantly higher in
cases compared to controls. Glycemic load diet and frequen-
cies of milk and ice cream intake were positively associated
with acne vulgaris.
2. Mediterranean diet and familial dysmetabolism as factors

influencing the development of acne. Skroza N, Tolino E,
Semyonov L, Proietti I. Scand J Pub Health 2012;40:466474.
A community case-based-case-control study was carried out in
Italy. Food consumption was evaluated with a validated food-
frequency questionnaire. The Mediterranean diet was assessed
62 5. Acne
by a 10-point Mediterranean diet scale that incorporated the

main characteristics of this diet. The Mediterranean diet score
>6 revealed a protective effect towards acne.
3. Clinical and histological effect of a low glycemic load diet in

treatment of acne vulgaris in Korean patients: a randomized,
controlled trial. Kwon H, Yoon J, Hong J, Jung J et al. Acta
Derm Venereol. 2012 May;92(3):2416.
A total of 32 patients with mild to moderate acne were ran-
domly assigned to either a low glycemic load diet or a control
group diet, and completed a 10-week, parallel dietary interven-
tion trial. A reduction in diet glycemic load of the diet for 10
weeks resulted in improvements of acne.
4. Family history, body mass index, selected dietary factors,

menstrual history, and risk of moderate to severe acne in
adolescents and young adults. Di Landro A, Cazzaniga S,
Parazzini F, Ingordo V, et al. J Am Acad Derm. 2012
Dec;67(6):112935.
A case-controlled study in dermatology outpatient clinics in
Italy was conducted. Moderate to severe acne was strongly
associated with a family history of acne in first-degree relatives.
The risk was reduced in people with lower body mass index
with a more pronounced effect in male compared to female
individuals. The risk increased with milk consumption in those
consuming more than 3 portions per week. The association
was more marked for skim than whole milk. Consumption of
fish was associated with a protective effect.
5. High school dietary dairy intake and teenage acne.

Adebamowo C, Spiegelman D, Danby F, et al. J Am Acad
Dermatol. 2005 Feb;52(2):20714.
Data from the Nurses Health Study II were studied to retro-
spectively evaluate whether intake of dairy foods during high
school was associated with physician-diagnosed severe teenage
acne. 47,355 women were evaluated. They found a positive
association with acne for intake of total milk and skim milk.
Topical Green Tea 63
6. Milk consumption and acne in teenage boys. Adebamowo

C, Spiegelman, D, Berkey C, Danby, et al. J Am Acad
Dermatol. 2008 May;58(5):78793.
A prospective cohort study studied 4,273 boys. They found a
positive association between intake of skim milk and acne.
7. The effect of a high-protein, low glycemic-load diet versus a

conventional, high glycemic-load diet on biochemical param-
eters associated with acne vulgaris: a randomized, investiga-
tor-masked, controlled trial. Smith R, Mann N, Braue A. J Am
Acad Dermatol. 2007 Aug;57(2):24756.
Forty-three male patients with acne completed a 12-week, par-
allel, dietary intervention study with investigator-masked der-
matology assessments. At 12 weeks total lesion counts had
decreased more in the experimental group compared with the
control group. They concluded that nutrition-related lifestyle
factors play a role in acne pathogenesis.
Topical Green Tea

Black, oolong and green tea are produced from the leaves of
C. sinensis which is native to eastern Asia but can be grown in
other areas of the world. Green tea is the dried leaf component
of C. sinensis. The dried, cured leaves of C. sinensis have been
used medicinally for more than 5,000 years (DerMarderosian
and Beutler 2012). Green tea is traditional consumed orally for
good health but topical forms of green tea are also available.
Here, we present evidence that green tea, when used topically
may function to inhibit both acne formation and sebum pro-
duction known to contribute to acne formation.
Evidence for Topical Green Tea
1. The efficacy of topical 2% green tea lotion in mild-to-

moderate acne vulgaris. Elsaie M, Abdelhamid M, Elsaaiee L,
Emam H. J Drugs Dermatol. 2009 April;8(4).
64 5. Acne
Twenty patients used green tea topically twice daily for 6

weeks. The authors used total lesion count (TLC) and severity
index (SI) to evaluate. The mean TLC decreased, with statisti-
cal significance 54% after 6 weeks of treatment. The SI
decreased, with statistical significance 39%. The studies showed
that topical 2% green tea lotion was an effective treatment for
acne vulgaris.
2. Outcomes of 3% green tea emulsion on skin sebum pro-

duction in male volunteers. Mahmood T, Akhtar N, Khan B,
Khan H, Saeed T. Bosn J Basic Med Sci. 2010 Aug;10(3):
2604.
Four percent ethanolic green tea extract was applied to the
cheeks of healthy male volunteers. Skin sebum production was
measured. Statistically significant reduction in sebum reduc-
tion was found after 8 weeks.
3. Epigallocatechin-3-Gallate Improves Acne in Humans by

Modulating Intracellular Molecular Targets and Inhibiting P.
acnes. Yoon J, Kwon H, Min S, Thiboutot D, Suh D. J Invest
Dermatol 2013;133:42940.
This group examined the effects of EGCG, the major polyphe-
nol in green tea, on human SEB-1 sebocytes and in patients
with acne. They found that EGCG reduced sebum by modulat-
ing the AMPK-SREBP-1 signaling pathway. They also found
that EGCG reduced inflammation by suppressing the NF-kB
and AP-1 pathways. And finally, they found that in an 8-week
randomized, split-face, clinical trial it was well tolerated and
improved acne.
Topical Tea Tree Oil

Tea tree oil is an essential oil from the leaves of the Australian
native tree, Melaleuca alternifolia. The indigenous people of
Australia have used tea tree oil from crushed leaves as a tra-
ditional remedy for coughs and colds as well as to treat
Topical Tea Tree Oil 65
wounds and skin infections (DerMarderosian and Beutler

2012). Tea tree oil is commonly used as a topical antimicro-
bial agent. There have been a number of papers describing
the antiseptic properties of tea tree oil, which has potential
antibacterial activity through disruption of bacterial mem-
branes (Carson et al. 2006). Tea tree oil can be very irritating
and a source of allergic contact dermatitis so it is important
to counsel patients about this potential.
Evidence for Topical Tea Tree Oil
1. The efficacy of 5% topical tea tree oil gel in mild to moder-

ate acne vulgaris: A randomized, double-blind placebo-
controlled study. Enshaiieh S, Jooya A, Siadat AH, Iraji
F. Indian J Dermatol Venereol Leprol. 2007;73(1):2225.
Sixty patients with mild to moderate acne vulgaris were ran-
domly divided equally into two groups and were treated with
tea tree oil gel or placebo. There was a significant difference
between tea tree oil and placebo in the improvement of the
total acne lesions counting (TLC) and the acne severity index
(ASI). The tea tree oil was 3.55 times more effective than pla-
cebo in the TLC and 5.75 times more effective than placebo in
the ASI suggesting topical 5% tea tree oil is an effective treat-
ment in mild to moderate acne vulgaris.
2. A comparative study of tea-tree oil versus benzoyl peroxide

in the treatment of acne. Bassett IH, Pannowitz DL, Barnetson
RS. Med J Aust. 1990;153(8):4558.
A single-blind, randomized clinical trial with 124 patients with
mild to moderate acne compared 5% tea-tree oil gel with 5%
benzoyl peroxide lotion. The results showed that both 5% tea-
tree oil and 5% benzoyl peroxide had a significant effect in
reducing both inflammatory and non-inflammatory acne
lesions. They note that the onset of action in the case of tea-tree
oil was slower but, fewer side effects were experienced by
patients treated with tea-tree oil.
66 5. Acne
Oral Probiotics
Probiotics are live microorganisms that are associated with
beneficial effects. The probiotics most commonly used in over-
the-counter supplementation are lactobacilli and bifidobacte-
rium. With the exception of atopic dermatitis, there are not
many studies focused on the use of probiotics in dermatology.
One of the potential benefits that probiotics may offer is the
reduction of inflammation in acne by decreasing the release of
inflammatory cytokines and recruitment of CD8 cells, and by
activating regulatory T cells (Muizzuddin et al. 2012).
Probiotics may also decrease sebum content in the skin lead-
ing to decreased formation of acne lesions (Kim et al. 2010).
Additionally, probiotics have been shown to mitigate some of
the adverse effects of oral antibiotics, and may be useful as a
complementary treatment when administering oral antibiotics
for acne (Goldenberg et al. 2013). As our understanding of the
pathophysiology of acne evolves, there may be a role for the
use of probiotics, both oral and topically to treat acne.
Evidence for Oral Probiotics

1. Prospective, Randomized, open-label trial comparing the
safety, efficacy and tolerability of an acne treatment regimen
with and without a probiotic supplement and minocycline in
subjects with mild to moderate acne. Jung G, Tse J, Guiha I,
Rao J. J Cutan Med Surg. 2013 (March/April);17(2).
Forty-five 1835 year old females were randomly assigned to
three treatment arms. The first group received probiotic sup-
plementation, the second group received only minocycline and
the third group received both probiotic and minocycline. All
patients demonstrated a significant improvement in total lesion
count. The third group (probiotic and minocycline) had a sig-
nificant decrease in total lesion count versus the other two
groups. They concluded that probiotics may be considered a
therapeutic option or adjunct treatment in two ways: providing
Oral Zinc 67
an anti-inflammatory effect and also reducing the potential

adverse events associated with chronic antibiotic use.
Oral Zinc
Zinc is a metallic element that serves as an essential cofactor
in many biochemical reactions in the body. Zinc is also
thought to be bacteriostatic against P. acnes and to inhibit the
production of inflammatory cytokines. It has been shown that
the use of zinc is beneficial in the treatment of acne. In addi-
tion, there is discussion that newer preparations of zinc are
better dissolved by the stomach and more completely
absorbed, making it possible to administer lower doses of
zinc, with better gastrointestinal tolerability. Furthermore,
zinc is being looked at as beneficial in the treatment of resis-
tant strains of P. acnes to antibiotics (Sardana et al. 2014).
Evidence for Oral Zinc
1. Effect of zinc gluconate on propionibacterium acnes resis-

tance to erythromycin in patients with inflammatory acne:
in vitro and in vivo study. Dren B, Foulc P, Reynaud A, et al.
Eur J Dermatol. 2005 MayJun;15(3):1525.
Thirty patients with inflammatory acne were treated with zinc
gluconate with a daily dose of 30 mg for 2 months. This study
showed a reduction in the number of inflammatory lesions
after a 2-month treatment.
2. Low doses of zinc gluconate for inflammatory acne. Dreno

B, Amblard P, Agache P, Sirot S, Litoux P. Acta Derm Venereol.
1989;69(6):5413.
Patients with inflammatory acne were included in a double-
blind trial looking at low dose zinc gluconate (200 mg/day,
corresponding to 30 mg zinc metal). A significant reduction in
lesions was seen in the zinc group vs. the placebo group.
68 5. Acne
3. Multi-center comparative double-blind controlled clinical

trial of the safety and efficacy of zinc gluconate versus mino-
cycline hydrochloride in the treatment of inflammatory acne
vulgaris. Dreno B, Moyse D, Alirezai M, et al.
Zinc was compared to minocycline in a multi-center random-
ized double-blind trial. Three hundred and thirty-two patients
received either 30 mg elemental zinc or 100 mg minocycline
over 3 months. They concluded that both minocycline and zinc
gluconate were effective in the treatment of inflammatory acne,
but minocycline had a superior effect.
4. An observational study of methionine-bound zinc with

antioxidants for mild to moderate acne vulgaris. Sardana K,
Garg V. Dermatol Ther. 2010;23:4118.
APC is a novel methionine-based zinc complex with anti-
oxidants that has been used in acne as a nutritional supple-
ment. In this exploratory trial, 48 patients were treated with
oral APC thrice a day for 3 months followed by a 4-week
treatment-free period. At the end of the treatment (week 12)
there was a statistically significant improvement in the global
acne count. Seventy-nine percent of the patients had 80100%
improvement, although there was no control group.
Case 1
A 15 year old male with a history of well controlled moderate
acne who has been on antibiotics for 6 months, once daily
benzoyl peroxide and once daily retinoid comes in with his
mother who is interested in stopping the oral antibiotic and
not pursuing additional oral therapies. What are some com-
plementary therapeutic options in this case?
Discussion
This is a tough and all too common clinical scenario. Diet is
often an easy and high-yield area to examine. Is there an exces-
sive dairy intake? Is there an abundance of sugar or
Case 2 69
carbohydrate-rich foods? Is the diet balanced? Counseling the

patient on evidence that points to the importance of specific
dietary changes can be very helpful here and may help with the
inflammatory component once the antibiotic is stopped. In
addition, adding oral zinc and/or niacinamide here could also
be considered in lieu of the antibiotic, or perhaps in addition to
a low-dose antibiotic. Thus, his plan might be to continue with
the benzoyl peroxide in the morning and the retinoid at night,
but now to take 500 mg of niacinamide twice daily, as well as
trying to avoid or limit dairy and high-glycemic index foods. It
is always important to counsel on other sources of calcium
intake if dairy reduction or elimination is suggested. At the fol-
low up visit the addition of oral zinc could also be considered.
Case 2
A 34 year old female with mild hormonal acne, well con-
trolled on a daily retinoid comes in wanting to start preg-
nancy planning and stop her retinoid. What are some
complementary therapeutic options in this case?
Discussion
This is another tough clinical scenario as there are so few topical
and oral products allowed in pregnancy planning and pregnancy
and this is a very common concern for patients. It is helpful to
look at all the topical products she is using to see if the program
can be re-worked to include products with vitamin C or niacina-
mide. Vitamin C serums can be used at night and sunscreens can
be found that include niacinamide for use during the day.
Increasing the intake of foods rich in probiotics such as probiotic
juices and yogurt is also a reasonable suggestion and examining
the diet for high levels of sugar or carbohydrate-rich foods and
encouraging more of a Mediterranean-focused diet may also be
useful. Starting the patient on prescription topical azelaic acid in
the pregnancy planning stage is an option as it is only of the only
FDA approved topical in pregnancy and considered more natu-
ral than many topical prescription acne products.
70 5. Acne
References
Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol.
2013;168(3):47485.
Bowe W, Joshi S, Shalita A. Diet and Acne. JAAD. 2010;63:12441.
Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (Tea

Tree) oil: a review of antibacterial and other medicinal properties.
Clin Microbiol Rev. 2006;19(1):5062.
Chambial S, Dwivedi S, Shukla KK, John PJ, Sharma P. Vitamin C in

disease prevention and cure: an overview. Indian J Clin Biochem.
2013;28(4):31428.
DerMarderosian A, Beutler JA. The review of natural products

paperback. 7th ed. St. Louis: Lippincott Williams & Wilkins; 2012.
Language: English. ISBN-10: 1574393464.
Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO,

Thorlund K, Guyatt GH, Johnston BC. Probiotics for the preven-
tion of Clostridium difficile-associated diarrhea in adults and
children. Cochrane Database Syst Rev. 2013;(5):CD006095.
Gollnick H, Cunliffe W, Nerson D. Management of acne: a report

from a Global Alliance to Improve Outcomes in Acne. JAAD.
2003;49(1 Suppl):S137.
Kim J, Ko Y, Park YK, Kim NI, Ha WK, Cho Y. Dietary effect of

lactoferrin-enriched fermented milk on skin surface lipid and
clinical improvement of acne vulgaris. Nutrition. 2010;26:9029.
Klock J, Ikeno H, Ohmori K, et al. Sodium ascorbyl phosphate shows

in vitro and in vivo efficacy in the prevention and treatment of
acne vulgaris. Int J Cosmet Sci. 2005;27(3):1716.
Muizzuddin N, Maher W, Sullivan M, Shnittger S, Mammone

T. Physiological effect of probiotics on skin. J Cosmet Sci.
2012;63:38595.
References 71

Ruamrak C, Lourith N, Natakankitkul S. Comparison of clinical effi-

cacies of sodium ascorbyl phosphate, retinol and their combina-
tion in acne treatment. Int J Cosmet Sci. 2009;31(1):416.
Sardana K, Chugh S, Garg VK. The role of zinc in acne and preven-
tion of resistance: have we missed the base effect? Int
J Dermatol. 2014;53(1):1257.
Tanghetti EA. The role of inflammation in the pathology of acne.

J Clin Aesthet Dermatol. 2013;6(9):2735.
Thiboutot D, Gollnick MD, Bettoli V, et al. New insights into the

management of acne: an update from the Global Alliance to
improve Outcomes in Acne Group. JAAD. 2009;60:S150.
Woolery-Llyod H, Baumann L, Ikeno H. Sodium L-ascorbyl-2-

phosphate 5% lotion for the treatment of acne vulgaris: a ran-
domized, double-blind, controlled trial. J Cosmet Dermatol.
2010;9(1):227.
Chapter 6
Rosacea
Introduction
It is estimated that rosacea affects 16 million people in the
US. Rosacea is a chronic inflammatory skin disorder charac-
terized by increased cutaneous sensitivity and inflammation
that is most commonly limited to the central part of the face.
Rosacea typically affects adults in the third decade and it is
predominantly seen in women. Clinical features may include:
erythema, papules and pustules, facial flushing, telangiecta-
sias and/or an associated ocular disease. Typically, rosacea is
classified into four sub-types: Erythematotelangiectatic, pap-
ulopustular, phymatous and ocular (Emer et al. 2011). Disease
exacerbation has been associated with a variety of triggers,
including but not limited to: caffeine, exercise, UV radiation,
stress, microbial colonization of the face, spicy food, alcohol,
and heat.
In the last decade it has become clear that little is known
about the pathophysiology of rosacea. Recent studies suggest
that rosacea initially occurs in individuals when inappropri-
ate innate immune responses to environmental stimuli lead
to inflammation and vascular abnormalities (Steinhoff et al.
2013). As the innate immune system plays a key role in the
immunologic skin barrier, agents that promote a competent
barrier are likely to be beneficial adjuncts in the treatment of
this disease.

DOI 10.1007/978-3-319-17816-5_6
74 6. Rosacea
One of the most difficult aspects of rosacea to treat is the

associated erythema. Few conventional therapies adequately
target the background erythema or flushing, while papules
and pustules also leave residual redness behind, once treated
(Layton and Thiboutot 2013). Given the dearth of conven-
tional treatment options for the erythema of rosacea,
botanically-derived ingredients can be looked at to fill this
void. As with other areas, there is a paucity of data for
integrative treatments for rosacea, with few randomized
controlled trials. Below we detail several and then focus on
secondary considerations that hold potential for benefit by
improving the barrier and targeting inflammation.
Fig. 6.1. Multiple erythematous papules and pustules on the mid-

face and chin in papulopustular rosacea.
Secondary Considerations 75
Fig. 6.2. Erythema with some edematous papules on the mid-face in

erythematotelangiectatic rosacea.
Top Considerations
See Table 6.1.
See Table 6.2.

Topical Applied topically Safe, generally well-
nicotinamide tolerated
Azelaic acid Applied once or twice daily Safe, generally well-
tolerated

Chrysanthemum Applied topically Difficult to acquire
indicum
Quassia extract Applied topically Very limited in vivo work
76 6. Rosacea
Top Considerations
Nicotinamide
Nicotinamide is also known as niacinamide and nicotinic acid.
It is a water-soluble vitamin found in meat, fish and wheat.
It does not have the same pharmacologic effects of niacin, and
therefore it does not cause a flushing reaction. Nicotinamide
acts as an anti-oxidant and has anti-inflammatory properties,
skin-lightening properties, and can decrease the production of
sebum (Niren 2006). Topical application of nicotinamide has a
stabilizing effect on epidermal barrier function and reduces
transepidermal water loss (Draelos et al. 2005). In addition,
nicotinamide increases protein synthesis and potentiates the
differentiation of keratinocytes making it a natural alternative
to improve the skin integrity (Niren 2006).
Evidence for Nicotinamide
1. Niacinamide-containing facial moisturizer improves skin

barrier and benefits subjects with rosacea. Draelos Z, Ertel K,
Berge C. Cutis. 2005 Aug;76(2):13541.
A randomized investigator-blind, controlled observational study
(N = 50) designed to assess whether a niacinamide-containing
facial moisturizer would improve the stratum corneum barrier
and thus provide a clinical benefit to subjects with rosacea.
Instruments provided objective measures of stratum corneum
barrier function and hydration on the face. Results of the tests
conducted on the forearms showed that the niacinamide-con-
taining facial moisturizer improved stratum corneum barrier
function and hydration. Similar trends in these parameters were
seen on facial skin. Results suggest that patients with rosacea
can benefit from a moisturizer that improves the skin barrier.
2. Topical application of 1-methylnicotinamide in the treat-

ment of rosacea: a pilot study. Wozniacka A, Wieczorkowska
M, Gebick J, et al. Clin Exp Dermatol. 2005 Nov;30(6):6325.
Azelaic Acid 77
1-Methylnicotinamide (MNA (+)) is a metabolite of nicotin-

amide. A total of 34 patients with rosacea were treated with a
gel containing 0.25% MNA (+) twice daily for 4 weeks and
improvement was seen in 26/34 cases. The improvement was
good in 9/34 and moderate in 17/34, but no clinical effect was
noted in seven subjects. In only one case was skin irritation
given as the reason for treatment withdrawal. These results
indicate that MNA(+) might be a useful agent for treating.
3. The nicomide improvement in clincal outcomes study

(NICOS): results of an 8-week trial. Niren N, Torok H. Cutis.
2006 Jan;77(1 Suppl):1728.
An open-label, multicenter, prospective cohort study looked at
the clinical utility of oral pharmacologic doses of nicotinamide
and zinc in 198 patients with acne vulgaris and/or rosacea.
The study formulation consisted of nicotinamide 750 mg, zinc
25 mg, copper 1.5 mg and folic acid 500 g and is marketed as
Nic/Zn. Nic/Zn tablets appear to be an effective oral therapy
for the treatment of acne vulgaris and rosacea when used alone
or with other topical therapies and should be considered as a
useful alternative approach to oral antibiotics for the treatment
of acne vulgaris and rosacea.
Azelaic Acid
Azelaic acid is a saturated dicarboxylic acid produced natu-
rally by the yeast, Malassezia furfur that lives on the skin of
animals and humans. It is also found in plants such as wheat,
rye and barley (Draelos et al. 2013). Azelaic acid has signifi-
cant anti-inflammatory, anti-oxidative effects and is bacteri-
cidal against a range of gram-negative and gram-positive
micro-organisms as well including antibiotic-resistant bacte-
rial strains (Sieber and Hegel 2014). Although it is considered
conventional therapy for rosacea, we highlight it here because
it has been proven to be well tolerated in numerous clinical
trials and is considered a very safe topical.
78 6. Rosacea
Evidence for Azelaic Acid
1. Azelaic acid in the treatment of papulopustular rosacea: a

systematic review or randomized controlled trials. Liu R,
Smith M, Basta S, et al. Arch Dermatol. 2006;142(8):
10471052.
This systematic review looked at randomized controlled trials
involving topical azelaic acid (cream or gel) for the treatment
of rosacea compared with placebo or other topical treatments.
Five studies were included (873 patients). The conclusion was
that azelaic acid in 20% cream or 15% gel formulation
appears to be effective in the treatment of papulopustular rosa-
cea. Furthermore, they cite that compared to metronidazole,
azelaic acid appears to be an equally effective, if not superior,
treatment option.
2. Azelaic acid foam 15% in the treatment of papulopustular

rosacea: a randomized, double-blind, vehicle-controlled study.
Draelos Z, Elewski B, Staedtler G, Havlickova B. Cutis.
2013;92:306317.
Randomized, double-blind, vehicle-controlled, multicenter,
parallel-group study conducted over 12 weeks with a 4-week
follow-up period evaluated the efficacy and safety of a new
formulation of azelaic acid foam, a 15% concentration com-
pared to vehicle alone in patients with rosacea. Results indi-
cated that this formulation was effective compared to placebo
and well-tolerated.
Chrysanthellum Indicum
Wild chrysanthemum (Chrysanthemum indicum) is tradi-
tionally used in Chinese folk medicine as an anti-inflammatory
agent. It has been shown to possess anti-inflammatory and
anticancer activities (Kim et al. 2013). It is also used in the
Chrysanthellum Indicum 79
southwest plateau region of China to prevent ultraviolet-

induced skin damage. Wild chrysanthemum extract can pro-
tect the skin from UVB-induced acute skin damage and
photoaging by reducing the intracellular reactive oxygen
species (ROS) level and inhibiting p38 MAPK phosphoryla-
tion (Sun and Jiang 2014). Chrysanthellum indicum contains
a unique combination of phenylpropenoic acids, flavonoids
and saponosids, and has a well-documented effect on vascular
wall permeability and increases the mechanical resistance of
capillaries (Rigopoulos et al. 2005). These favorable proper-
ties suggest potential for treating the erythema of rosacea.
Evidence for Chrysanthellum Indicum
1. Randomized placebo-controlled trial of a flavonoid-rich

plant extract cream in the treatment of rosacea. Rigopoulos
D, Kalogeromitros D, Gregoriou S, et al. J Eur Acad Dermatol
Venereol. 2005;19(5):6548.
This study looked at 246 patients diagnosed clinically as hav-
ing moderate rosacea. Patients were randomly allocated to 1%
C. indicum extract cream (n = 125) or placebo (n = 121).
Patients were advised to apply the products on their face twice
daily for a 12-week period. The patients were examined at the
end of each 4-week period. Severity of erythema and overall
severity of rosacea, were recorded at each visit on days 0, 28, 56
and 84. Treatment with C. indicum extract-based cream
resulted in significant improvement (P < 0.05) in severity of
erythema and overall rosacea severity compared to baseline
and placebo. Investigator and patient overall efficacy assess-
ment scores were also improved (P = 0.046 and P = 0.001,
respectively) compared with placebo scores. Adverse reactions
were mild and did not differ between the C. indicum extract-
based cream and the placebo groups. Chrysanthellum indicum
extract-based cream appears to be an effective and well-
tolerated topical agent for the treatment of moderate rosacea.
80 6. Rosacea
Quassia Extract
Quassia extract comes from the Quassia amara tree, a small
tree that originates from South America. It is thought to have
anti-inflammatory properties as well as anti-parasitic activi-
ties (Toma et al. 2003). Quassia amara contains high levels of
active phytochemicals and has been shown to be effective
against facial seborrheic dermatitis as compared to topical
ketoconazole 2% (Diehl and Ferrari 2013).
Evidence for Quassia Extract
1. Evaluation of the efficacy and tolerance of a topical gel

with 4% quassia extract in the treatment of rosacea. Ferrari
A, Diehl C. J Clin Pharmacol. 2012;52:8388.
This study aimed to evaluate the efficacy and safety of a topical
gel with 4% Quassia amara extract in the treatment of various
grades of rosacea. A group of 30 patients with various grades
of rosacea (IIV) were investigated in a single-center, open-
label study. They were treated with topical gel with Quassia
amara extract for 6 weeks. Response was evaluated by the
flushing, erythema, telangiectasia, papules and pustules scores.
At the end of therapy, overall improvement, safety and tolera-
bility were assessed. Twenty-seven of the 30 patients completed
the study. The authors state that the treatment was effective
and the results that were achieved were in line with those pub-
lished with topical metronidazole and azelaic acid.
Case 1
A 55-year-old female presents with a 15-year history of ery-
thematotelangiectatic rosacea. She has decided not to pursue
laser therapy and is not interested short-acting vasoconstric-
tors as she is concerned about the possibility of rebound. She
continues to cover the redness with green makeup, but asks
if there is anything natural and safe out there that she could
add to her facial regimen that could possibly help?
References 81
Discussion
This is a very common clinical situation and a challenge as
there are very few topical treatments that affect erythematotel-
angiectatic rosacea beyond topical brimonidine and lasers.
Topical niacinamide may be of some help here and is certainly
safe. It is present in some sunscreens and moisturizers, making
it very easy to integrate into a regimen.
Case 2
A 67 year old man presents with 1 year onset of papulopus-
tular lesions, in the malar cheek area. He has had multiple
medication allergies in the past and is on numerous medica-
tions currently so is not interested in an oral therapy. He also
notes a history of C. difficile colitis and is wary of topical
clindamycin that multiple doctors have suggested he use for
the rosacea.
Discussion
Topical azelaic acid once to twice daily is a safe medication
and most people tolerate it with out complication. It is impor-
tant to counsel patients that there may be an initial stinging
sensation that will likely dissipate. In addition, most patients do
well with once daily application but some appear to have
improved response to twice daily application. It is also helpful
to counsel patient to apply the cream to well dried (air dried
for 30 min) skin.
References
Diehl C, Ferrari M. Efficacy of topical quassia amara gel in facial
seborrheic dermatitis: a randomized, double-blind, comparative
study. J Drugs Dermatol. 2013;12(3):3125.
Draelos Z, Ertel K, Berge C. Niacinamide-containing facial moistur-

izer improves skin barrier and benefits subjects with rosacea.
Cutis. 2005;76(2):13541.
82 6. Rosacea
Draelos Z, Elewski B, Staedtler G, Havlickova B. Azelaic acid foam

15% in the treatment of papulopustular rosacea: a randomized,
double-blind, vehicle-controlled study. Cutis. 2013;92:30617.
Emer J, Waldorf H, Berson D. Botanicals and anti-inflammatories:

natural ingredients for rosacea. Semin Cutan Med Surg.
2011;30:14855.
Kim C, Kim M, Kim S. Chrysanthemum indicum L. extract induces

apoptosis through suppression of constitutive STAT3 activation
in human prostate cancer DU145 cells. Phtother Res. 2013;27(1):
308.
Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad

Dermatol. 2013;69:S5765.
Niren NM. Pharmacologic doses of nicotinamide in the treatment of

inflammatory skin conditions: a review. Cutis. 2006;77:116.
Rigopoulos D, Kalogeromitros D, Gregoriou S, et al. Randomized

placebo-controlled trial of a flavonoid-rich plant extract cream in
the treatment of rosacea. J Eur Acad Dermatol Venereol.
2005;19(5):6548.
Sieber M, Hegel J. Azelaic acid: properties and mode of action. Skin

Pharmacol Physiol. 2014;27 suppl 1:917.
Steinhoff M, Schauber J, Leyden J. New insights into rosacea patho-

physiology: a review of recent findings. J Am Acad Dermatol.
2013;69:S1526.
Sun S, Jiang P, Su W, et al. Wild chrysanthemum extract prevents

UVB radiation-induced acute cell death and photoaging.
Cytotechnology. 2014
Toma W, Gracioso J, Hiruma-Lima CA, et al. Evaluation of the anal-

gesic and antiedematogenic activities of Quassia amara bark
extract. J Ethnopharmacol. 2003;85:1923.
Chapter 7
Hair Loss
Introduction
Hair loss is a commonly encountered complaint in dermatology,
and it is a condition that can cause significant psychosocial
distress and decreased quality of life in affected patients
(Reid et al. 2012). Androgenetic alopecia and alopecia areata,
both nonscarring forms of hair loss, are perhaps the most
common types of alopecia encountered in practice. While a
number of complementary and alternative therapies have
been anecdotally reported to be effective in their treatment,
there remains a lack of robust evidence supporting any of
these modalities to be as effective as standard pharmacologic
therapies. Nevertheless, it is beneficial to be aware of the
small case reports in the literature, as patients often inquire
about natural remedies for their hair loss, and many times
the results of standard pharmacotherapy are suboptimal.
Additionally, as hair loss has few significant medical implica-
tionsthough clearly has tremendous psychological impact,
of coursethe risk-benefit calculation may be very different
than that of a more threatening condition.
See Fig. 7.1.

DOI 10.1007/978-3-319-17816-5_7
84 7. Hair Loss
Fig. 7.1. Characteristic patches of hair loss in alopecia areata.
Top Considerations
See Tables 7.1 and 7.2.
Androgenetic Alopecia
Androgenetic alopecia (AGA) is a hereditary, nonscarring
form of hair loss mediated by the effects of dihydrotestoster-
one (DHT) on the hair follicle. Progressive miniaturization
of the hair follicle leads to hair loss in both male and female
pattern hair loss. Male pattern AGA classically manifests as
thinning over the vertex and fronto-temporal scalp; female
pattern AGA can manifest as thinning over the crown with
Raspberry Ketone 85
Table 7.1. Top clinical considerations for androgenic alopecia.

Raspberry Topically once daily May be difficult to find commercial
ketone preparation, minimal data
Procyanidins Topically once daily May be difficult to find commercial
preparation, minimal data
Table 7.2. Top clinical considerations for alopecia areata.

Garlic Five percent gel: May be difficult to find
topically twice daily commercial preparation, has
potential to be irritating and
malodorous
Onion Fresh juice: Has potential to be irritating and
topically twice daily malodorous
Aromatherapy Mixture of essential Very gentle and fairly easy to
oils: topically once obtain and use as an adjunct
daily
Hypnotherapy No defined protocol Can be expensive and requires
time commitment; unclear
protocol adds variability
preservation of the frontal hairline, widening of the central

part, or thinning with bitemporal recession (Blume-Peytavi
et al. 2011).
Raspberry Ketone
Raspberry ketone (RK) is an aromatic compound found in
red raspberries; it is similar in structure to capsaicin. The
mechanism of action for raspberry ketone in promoting hair
growth is thought to be due the increase of dermal insulin-
like growth factor-1 via the stimulation of sensory neurons
(Ulbricht et al. 2013). Applied topically, it may have some
effect on both AGA and alopecia areata (AA), perhaps via
induction of insulin-like growth factor-1.
86 7. Hair Loss
Evidence for Raspberry Ketone
1. Effect of topical application of raspberry ketone on dermal

production of insulin-like growth factor-1 in mice and on hair
growth and skin elasticity in humans. Harada N, Okalima K,
Narimatsu N, Kurihara H, Nakagata N. Growth Horm IGF
Res. 2008 Aug;18(4):33544.
In this small study, a topical formulation containing 0.01 % RK
was applied once daily to the scalp of ten human volunteers for 5
months: 6 with androgenetic alopecia, 4 with alopecia areata. The
authors state that hair growth was seen in five of the ten volun-
teers after 5 months of use. Remarkably, they do not offer further
breakdown of the data, but the figure does show both AGA and
AA apparently improving with the topical RK application.
Procyanidins
Procyanidins are a class of flavonoids found in red wine,
chocolate, barley, grape seed and apples, among other sources.
They are increasingly being studied for their health benefits
due to their potent antioxidative properties (Hammerstone
et al. 2000; Chun et al. 2007). Procyanidin B-2, found in high
concentrations in apples, has been specifically studied as a
therapeutic agent for androgenetic alopecia.
Evidence for Procyanidins
1. The first clinical trial of topical application of procyanidin

B-2 to investigate its potential as a hair growing agent.
Takahashi T, Kamimura A, Yokoo Y, Honda S, Watanbe
Y. Phytother Res. 2001;15(4):3316.
In this placebo controlled, double-blind study, 19 men with
male pattern baldness were treated with a tonic containing
procyanidin B-2 (extracted from apples), which was applied to
the scalp twice daily for 4 months. Results showed a statistically
Garlic 87
significant improvement in hair diameter and number of total

hairs in the treatment group compared to placebo. No adverse
events were observed in either group.
2. Investigation of the topical application of procyanidin

oligomers from apples to identify their potential use as a hair-
growing agent. Takahashi T, Kamimura A, Kagoura M, Toyoda
M, Morohashi M. J Cosmet Dermatol. 2005 Dec;4(4):2459.
A double-blind placebo-controlled trial of 43 male subjects
treated with daily application of 0.7 % apple procyanidin
oligomers showed significant hair growth in the treatment
group compared to placebo. No adverse effects were observed
in the treatment group.
Alopecia Areata
Alopecia areata is an autoimmune, nonscarring form of hair
loss mediated by lymphocytic infiltration of the hair follicle.
It is most commonly seen on the scalp but can also affect the
eyebrows, eyelashes and body hair. Multiple patterns of alo-
pecia areata exist, with the totalis (entire scalp) and universa-
lis (all hair on scalp and body) forms being the most severe
(Wasserman et al. 2007). The natural progression of alopecia
areata is unpredictable and highly variable; spontaneous
regrowth may occur in up to 50 % of patients after 1 year.
The extent and pattern of alopecia areata are the most
important prognostic factors (Alkhalifah et al. 2010).
Garlic
Garlic (Allium sativum) has been used worldwide for medici-
nal purposes due to its antimicrobial, anti-inflammatory and
immunomodulatory properties. While the mechanism of action
of garlic in many conditions has not been fully elucidated yet,
it has been hypothesized that it may be a useful treatment for
autoimmune forms of hair loss such as alopecia areata as an
88 7. Hair Loss
immunomodulatory agent (Mikaili et al. 2013). The primary

active compound in garlic is a sulfur compound known as alliin,
which is converted to allicin after the clove is harvested.
Evidence for Garlic
1. Combination of topical garlic gel and betamethasone valer-

ate cream in the treatment of localized alopecia areata: a dou-
ble-blind randomized controlled study. Hajheydari Z,
Jamshidi M, Akbari J, Mohammadpour R. Indian J Dermatol
Venereol Leprol. 2007 Jan-Feb;73(1):2932.
The safety and efficacy of garlic gel in combination with beta-
methasone 0.1 % cream for alopecia areata were studied in a
randomized, double-blind, placebo controlled trial of 40 patients
(age 5 and up). Both groups applied betamethasone twice daily
for 3 months; the treatment group also applied 5 % garlic gel
twice daily during the study period. The study found an statisti-
cally significant increase in the number of terminal and total hairs
in the garlic/betamethasone group compared to the placebo/
betamethasone group at the end of the third month; a decrease in
size of the patches of alopecia areata was also seen. No adverse
effects were seen in either group. The authors suggest that garlic
gel may be an effective adjunct therapy for alopecia areata.
Onion Extract
Like garlic, onions (Allium cepa) contain alliin as well as
flavonoids including quercitin. It is thought that onion extract
may promote hair growth due to its induction of a contact
dermatitis and subsequent immune response (Sharquie and
Al-Obaidi 2002).
Evidence for Onion Extract

1. Onion juice (Allium cepa L.), a new topical treatment for
alopecia areata. Sharquie J, Al-Obaidi H. J Dermatol. 2002
Jun;29(6):3436.
Aromatherapy 89
In a small study of 38 male and female patients with alopecia

areata, subjects were randomized to apply onion juice or tap
water to affected areas twice daily for 2 months. Hair re-growth
was seen in 20 (86.9 %) of the onion juice-treated patients at 6
weeks; hair re-growth was significantly higher among males
than females. Only 2 (13 %) of patients in the control group
exhibited hair re-growth at 8 weeks.
Aromatherapy
Aromatherapy refers to the medicinal use of essential oils and
essences derived from plants, flowers and wood resins; these
substances are typically massaged into the skin. Aromatherapy
has been studied for the treatment of hair loss, although the
mechanism of action for this treatment is unknown.
Evidence for Aromatherapy
1. Randomized trial of aromatherapy. Successful treatment

for alopecia areata. Hay I, Jamieson M, Ormerod A. Arch
Dermatol. 1998 Nov;134:134952.
Eighty-four patients with alopecia areata were randomized to
receive either essential oils (thyme, rosemary, lavender and
cedarwood) in a carrier oil mixture (jojoba and grapeseed) or
placebo (a carrier oil only). Each group massaged the oil mix-
ture into the scalp once daily for 7 months. Improvement was
determined by photographic comparisons as well as measure-
ment of the affected areas. Forty-four percent of patients in the
active group were noted to have improvement, compared to
15 % in the control group. No significant adverse events were
noted in either group. The specific formula for the essential oil
mixture was as follows (taken verbatim from the article):
Thyme vulgaris (2 drops, 88 mg), Lavandula agustifolia (3
drops, 108 mg), Rosmarinus officinalis (3 drops, 114 mg), and
Cedrus atlantica (2 drops, 94 mg). These oils were mixed in a
carrier oil, which was a combination of jojoba, 3 mL, and
grapeseed, 20 mL, oils.
90 7. Hair Loss
Hypnotherapy
Hypnosis as been defined as the agreement between a per-
son designated as the hypnotist and a person designated as
the client or patient to participate in a psychotherapeutic
technique based on the hypnotist providing suggestions for
changes in sensation, perception, cognition, affect, mood, or
behavior. (Montgomery et al. 2013). It has been utilized as
an alternative therapy in alopecia areata, although its mech-
anism of action for this disease has not been defined
(Willemsen et al. 2006).
Evidence for Hypnotherapy
1. Hypnosis in refractory alopecia areata significantly

improves depression, anxiety, and life quality but not hair
regrowth.Willemsen R, Haentiens P, Roseeuw D,Vanderlinden
J. J Am Acad Dermatol. 2010 Mar;62(3):5178.
Hypnosis was utilized as monotherapy or as an adjunctive
therapy for a 5-year period in 21 patients with extensive
alopecia areata; nine of these patients had alopecia totalis or
alopecia universalis. Twelve patients experienced 75100 %
hair growth after hypnotherapy. Five patients experienced a
significant relapse. Anxiety and depression scores decreased in
all patients. However, a followup prospective cohort study by
the same group comparing hypnotherapy alone to conven-
tional treatments failed to show statistically significant improve-
ment in hair regrowth in the hypnotherapy group.
2. Hypnotherapy for alopecia areata. Harrison P, Stepanek

P. Br J Dermatol. 1991 May;124(5):50910.
In this small study, 12 patients with extensive alopecia areata
were treated with hypnotherapy; 5 patients completed the
study protocol. Hair growth was noted in only 1 patient,
however.
Case 2 91
Case 1
A 45 year-old female presents to your office complaining of
gradual thinning of her scalp hair. She has had to start parting
her hair in different ways to cover up balding areas on the
front of her scalp. She denies any itching, redness or irritation
of the scalp, and is not losing hair elsewhere on her face or
body. Her father and siblings also have thinning hair. The
patient has read about the potential side effects of topical
minoxidil and prefers not to use it. She is wondering if there
are alternative therapies for her form of hair loss.
Discussion
In addition to reviewing the relative safety of topical minoxidil
and perhaps discussing oral 5-alpha-reductase inhibitors such as
finasteride and anti-androgens such as spironolactone, a regimen
of raspberry ketone applied topically once daily and procyanidin
applied topically once daily may be beneficial for this patient. A
treatment period of at least 12 weeks should be recommended.
Case 2
A 24 year-old male comes to see you because he has noticed
bald patches on his scalp over the past few months. He is a law
student and has been under an increased amount of stress in
the past year. There is a family history of hypothyroidism but
the patient has no history of thyroid disease. The patient saw
another physician recently for his hair loss, who prescribed
topical steroids and topical minoxidil, but these treatments
were ineffective. The patient has read that steroid injections
can be helpful for some forms of hair loss, but he is very afraid
of needles and is hoping for less invasive treatment options.
Discussion
This patient may benefit from the essential oil mixture cited
above, applied to the affected areas in the morning. If he is able
to tolerate the smell of onion juice or garlic paste, he could also
try application of one of these substances to the affected areas
92 7. Hair Loss
at night. A treatment of at least 12 weeks should be recom-

mended in this case before re-evaluation. In this case, in par-
ticular, stress may also be contributing to his disease, and
hypnosis may be helpful both directly for the alopecia areata
and indirectly by helping to control the stress from his studies.
References
Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia
areata update: part I. Clinical picture, histopathology, and patho-
genesis. J Am Acad Dermatol. 2010;62(2):17788.
Blume-Peytavi U, Blumeyer A, Tosti A, Finner V, Marmol M,

Trakatelli P, Reygagne A. S1 guideline for diagnostic evaluation
in androgenetic alopecia in men, women and adolescents. Br J
Dermatol. 2011;164(1):515.
Chun O, Chung S, Song W. Estimated dietary flavonoid intake and

major food sources of U.S. adults. J Nutr. 2007;137(5):124452.
Hammerstone J, Lazarus S, Schmitz H. Procyanidin content and vari-

ation in some commonly consumed foods. J Nutr. 2000;130(8):
20865925.
Mikaili P, Maadirad S, Moloudizargarj M, Aghajanshakeri S,

Sarahroodi S. Therapeutic uses and pharmacological properties
of garlic, shallot and their biologically active compounds. Iran J
Basic Med Sci. 2013;16(10):103148.
Montgomery G, Schnur J, Kravits K. Hypnosis for cancer care: over

200 years young. CA Cancer J Clin. 2013;63(1):3144.
Reid EE, Haley AC, Borovicka JH, Rademaker A, West DP,

Colavincenzo M, Wickless H. Clinical severity does not reliably pre-
dict quality of life in women with alopecia areata, telogen effluvium,
or androgenic alopecia. J Am Acad Dermatol. 2012;66(3):e97102.
Sharquie J, Al-Obaidi H. Onion juice (Allium cepa L.), a new topical

treatment for alopecia areata. J Dermatol. 2002;29(6):3436.
References 93
Ulbricht C, Catapang M, Conquer J, Costa D, Culwell S, DAuria D,

Isaac R, Le C, Marini E, Miller A, Mintzer M, Nguyen M, Salesses
K. Raspberry Ketone: an evidence-based systematic review by the
natural standard research collaboration. Alternat Complement
Ther. 2013;19(2):98100.
Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A.

Alopecia areata. Int J Dermatol. 2007;46(2):12131.
Willemsen R, Vanderlinden J, Deconinck A, Roseeuw D. Hypno-

therapeutic management of alopecia areata. J Am Acad Dermatol.
2006;55(2):2337.
Chapter 8
Psoriasis
Introduction
Psoriasis is a common dermatologic condition, affecting
approximately 23% of the population worldwide. The pres-
ence of large plaques on exposed areas of the body can cause
significant embarrassment and social anxiety for those with
psoriasis. There have been a number of exciting develop-
ments in the understanding of the pathogenesis of psoriasis,
and with those have come several new classes of medications
(Richard and Honigsmann 2014). Fortunately, there are mul-
tiple conventional options now that can manage psoriasis
very effectively, and many of these are appealing to patients
who prefer a more natural approach. From topical vitamin D
analogues (calcipotriene and calcipotriol), phototherapy uti-
lizing narrow band UVB light, and even a recently FDA-
approved blue light home treatment for psoriasis
(Kleinpenning et al. 2012), there are many potential choices
in the conventional armamentarium. Some of the most pow-
erful treatments, however, bring with them significant risks
such as hepatotoxicity for methotrexate, the possibility of
serious infections, malignancies, and autoimmune syndromes
from the biologic agents, and depression and suicidality from
a newer oral phosphodiasterase-4 inhibitor.
These risks, perhaps, as well as the chronic nature of the
disease remain frustrating for these individuals, and many
turn to complementary and alternative medicine (CAM) as an

DOI 10.1007/978-3-319-17816-5_8
96 8. Psoriasis
addition or even replacement for conventional therapies. In a

recent survey of 57 patients with psoriasis, almost 50% of
them had used a CAM method of treatment in the preceding
year (Damevska et al. 2014). CAM treatments included topi-
cals, systemic therapies, and dietary modifications. While there
is limited data on many of these therapies, it is important for
dermatologists to be aware that CAM use among psoriasis
patients is fairly common, and to be able to explain the risks
and benefits of the more commonly used therapies with a
relative degree of comfort. Patients should be encouraged to
report all medications they are using, both prescription and
alternative, so any possible interactions with concomitant
medications or other potential risks can be addressed.
Fig. 8.1. Cutaneous lesions of psoriasis typically manifest as ery-

thematous plaques with silver scale on the trunk and extremities,
often over areas subject to chronic friction such as the elbows and
knees. The scalp and face may also be involved, as well as the axillae
and groin (inverse psoriasis).
Fish Oil 97
Fig. 8.2. Psoriasis often affects the scalp, with erythematous scaly
plaques that may be pruritic.
Top Considerations
See Table 8.1.
Fish Oil
Oil from cold water fish such as salmon, cod, sardines and
herring are rich in the omega-3 essential fatty acids eicosa-
pentaenoic acid (EPA) and docosahexaenoic acid (DHA).
These fatty acids have been shown to possess anti-
inflammatory properties and have been studied for their use
in psoriasis (Nicolaou 2013). Other good sources of omega-3
fatty acids include walnuts, flax seed, and olive oil. There is no
standardized dosing for the use of omega-3 fatty acids in pso-
riasis; patients may be advised to increase intake via dietary
consumption or via oral supplements.
98 8. Psoriasis
Table 8.1. Top considerations for psoriasis.

Fish oil Capsules (up to 10 per Safe; fishy taste and GI upset
day in one study) may limit use in some patients,
dosage unclear (but was
approximately 10,000 mg of
EPA per day in one study)
Indigo Topically as cream Well-tolerated; may stain skin and
naturalis fabric, may be difficult to source
Curcumin Orally (34.5 g per Safe and inexpensive; GI upset
day in studies) or as in some patients
a topical gel (1%)
Aloe vera Topically as a gel Safe; possibility of cutaneous
irritation or contact dermatitis
Baking soda As a bath soak, 350 Inexpensive and well-tolerated
500 g (about 2 cups)
per full tub every
other day
Mahonia Topically as a cream May be difficult to find
aquifolium commercially; may cause
irritation and stain clothing
Balenotherapy Salts mixed in bath Safe and inexpensive; time
at home 37 times consuming and modest effect
per week
Mindfulness With therapist or via Very safe; may be difficult to find
relaxation recorded sessions practitioner, may be expensive
Evidence for Fish Oil
1. Double-blind, placebo-controlled study to evaluate the effi-

cacy of fish oil and low-dose UVB in the treatment of psoria-
sis. Gupta AK, Ellis CN, Tellner DC, Anderson TF, Voorhees
JJ. Br J Dermatol. 1989 Jun;120(6):8017.
Eighteen patients with psoriasis were randomized to receive
either fish oil or olive oil capsules in this 15 week study. Subjects
were treated with oil alone in week 03; UVB phototherapy was
added in weeks 311, followed by an additional 4 weeks of oil
alone. Statistically significant decreases in total body surface area
involvement, erythema, thickness and scale were seen in the fish
oil group compared to the olive oil group, suggesting the utility
of fish oil supplements as an adjunctive treatment for psoriasis.
Indigo Naturalis 99
2. Effect of dietary supplementation with very-long-chain n-3

fatty acids in patients with psoriasis. Syland E, Funk J, Rajka G,
Sandberg M, Thune P, Rustad L, Helland S, Middelfart K, Odu
S, Falk ES, et al. N Engl J Med. 1993 Jun 24;328(25):18126.
This was a 4 month double-blind trial, in which 145 patients
with moderate to severe psoriasis were randomize to receive
fish oil (omega-3 fatty acids) or an equivalent amount of corn
oil (primarily omega-6 fatty acids). All patients were advised to
reduce dietary intake of saturated fat. Serum lipid levels were
measured and fatty acid patterns were analyzed in both groups.
PASI scores did not change significantly in either group, and
there was no significant difference in clinical signs in either
groups. Notably, while serum omega-3 fatty acids were
increased in the fish oil group, this increase did not correlate
with significant clinical improvement.
3. A double-blind, randomized, placebo-controlled trial of fish

oil in psoriasis. Bittiner SB, Tucker WF, Cartwright I, Bleehen
SS. Lancet. 1998 Feb 20;1(8582):37880.
Twenty-eight patients with psoriasis were randomized to
receive fish oil or olive oil capsules daily for 8 weeks. A signifi-
cant decrease in pruritus, erythema and scale was noted in the
fish oil group at the end of therapy, compared to no significant
change in the olive oil (placebo group).
Indigo Naturalis
Indigo naturalis is an herb that is commonly used in tradi-
tional Chinese medicine for the treatment of psoriasis and
other dermatologic conditions (Koo and Arain 1998). It has
been shown to regulate keratinocyte differentiation and
proliferation, aid in repair of the epidermal barrier and to
have anti-inflammatory properties, all of which are benefi-
cial in the treatment of psoriasis (Lin et al. 2009a, 2013).
Indirubin, found in indigo naturalis, is thought to be the
primary constituent that is helpful in treating psoriasis
(Lin et al. 2009b).
100 8. Psoriasis
Evidence for Indigo Naturalis
1. Efficacy and safety of indigo naturalis extract in oil

(Lindioil) in treating nail psoriasis: a randomized, observer-
blind, vehicle-controlled trial. Lin Y, See L, Huang Y, Chang Y,
Tsou T, Lin T, Lin N. Phytomedicine. 2014;21(7):101520.
Thirty-one patients with nail psoriasis applied indigo naturalis
extract in oil to an affected nail on one hand, and placebo
(olive oil) to a similarly affected nail on the other hand for 12
weeks, followed by application of indigo naturalis to both
hands for 12 weeks. The Nail Psoriasis Severity Index (NAPSI)
was the primary outcome measured. Patients in the group with
treated with indigo naturalis for the entire study period had a
greater reduction in NAPSI scores than the control group. No
adverse events were reported. The authors note that true blind-
ing in this study was difficult to the naturally blue stain
imparted by indigo naturalis, which was not seen in the pla-
cebo group.
2. The efficacy and safety of topically applied indigo naturalis

ointment in patients with plaque-type psoriasis. Lin Y, Wong
W, Chang Y, Chang C, Tsay P, Chang S, Pang J. Dermatology.
2007;214(2):15561.
Fourteen patients with plaque psoriasis were instructed to
apply indigo naturalis ointment or vehicle to affected areas
daily for 8 weeks. Lesions were evaluated clinically and histo-
logically, as punch biopsies of treated areas were taken at the
end of the treatment periods. The authors report clinical
improvement in the lesions treated with indigo naturalis, as
well as histological improvement: expression of Ki-67 and
CD3 (proliferative and inflammatory markers, respectively)
were decreased, while filaggrin expression (a marker of kerati-
nocyte differentiation) in the epidermis was increased.
3. Clinical assessment of patients with recalcitrant psoriasis in

a randomized, observer-blind, vehicle-controlled trial using
indigo naturalis. Lin Y, Chang C, Chang Y, Wong W, Chang S,
Pang J. Arch Dermatol. 2008;144(11):145764.
Turmeric (Curcumin) 101
Forty-two patients with plaque psoriasis were randomized to

receive indigo naturalis ointment or vehicle ointment, and
instructed to apply the ointment to two symmetric, bilateral
lesions for 12 weeks. Statisticially significant reductions in ery-
thema, scaling and induration were observed in the indigo
naturalis group.
Turmeric (Curcumin)
Turmeric (Curcuma longa) contains curcumin (diferuloylmeth-
ane), and has a long tradition of use orally and topically to treat
wounds, ulcers, dermatitis and pruritus. Curcumin has anti-
inflammatory, antioxidant, anticarcinogenic and antimicrobial
properties (Gupta et al. 2013). Curcumin has been shown to
block tumor necrosis factor (TNF), an inflammatory mediator
that is important in the pathogenesis of psoriasis (Aggarwal
et al. 2013). While a very appealing agent, inexpensive and
familiar as it is frequently used in cooking, its clinical literature
is in relative disarray. Of note, diets high in turmeric only cor-
respond to 60100 mg of curcumin, dosages much lower than
those used in the studies (Kurd et al. 2008). There are several
clinical trials, but with variability on the dosage and formula-
tion, and often used along with other agents, somewhat obscur-
ing the effect of curcumin. More work needs to be done, but
early reports are encouraging. It appears very safe, however: the
most common side effect is gastrointestinal upset; curcumin is
contraindicated in patients with gallbladder disease.
Evidence for Turmeric (Curcumin)
1. Clinical and biological activity of curcumin in patients with

psoriasis vulgaris. Antiga E, Bonciolini V, Donciani D, Verdelli
A, Righeschi C, Volpi W, Bilia AR, Caproni M. Presentation
at 23rd European Academy of Dermatology and Venereology
Congress, Oct 812 2014.
A 12-week, randomized, placebo-controlled clinical trial of 60
patients with moderate psoriasis who, along with continuing
102 8. Psoriasis
their topical steroids, took either 3 g per day of a special oral

formulation of curcumin with liposomes vs. placebo. Of the 49
who completed the study, there was a significantly greater
improvement in the psoriasis (measured by the PASI score) in
the curcumin group. Additionally, serum levels of the inflam-
matory cytokine interleukin-22 were reduced by half in the
curcumin group while remaining unchanged in the controls.
2. Oral curcumin in the treatment of moderate to severe pso-

riasis vulgaris: a prospective clinical trial. Kurd SK, Smith N,
VanVoorhees A, Troxel AB, Badmaev V, Seykora JT, Gelfand
JM. J Am Acad Dermatol. 2008 Apr;58(4):62531.
An open-label trial with oral administration of 4.5 g daily
(divided TID) of a specific preparation of curcumin for 12 weeks.
Twelve subjects were enrolled, 8 completed the study; the PASI
scores were similar between those who completed the trial and
those who did not, but 25% of those who completed the trial
had at least 50% improvement, and it was noted that there 2
patients with greater than 80% improvement. This may suggest
that a sub-group of psoriasis patients will respond nicely to
curcumin, while others may not respond at all. The curcumin
was well-tolerated with no adverse events reported.
3. Drug-induced suppression of phosphorylase kinase activity

correlates with resolution of psoriasis as assessed by clinical,
histological and immunohistochemical parameters. Heng MC,
Song MK, Harker J, Heng MK. Br J Dermatol. 2000
Nov;143(5):93749.
A study of 60 patients that looked at levels of phosphorylase
kinase (PhK), a signal in cell migration and proliferation cor-
related with psoriatic activity, and compared various treatment
groups. One group had topical curcumin 1% gel applied. They
found inhibition of the PhK and clinical and histological
improvement in the psoriasis of the treated group, but the num-
bers were very small and it is difficult to parse from the rest of
this fairly complex study.
Aloe Vera 103
Aloe Vera
Aloe vera is a plant in the Liliaciae family. The gel of this
plant has been used for thousands of years to treat topical
conditions from sunburns to psoriasis. Aloe vera gel, obtained
from the inner portion of the leaves, has been shown to have
anti-inflammatory, anti-microbial and wound healing proper-
ties (Klein and Penneys 1998).
Evidence for Aloe Vera
1. A prospective, randomized clinical trial comparing topi-

cal aloe vera with 0.1% triamcinolone acetonide in mild to
moderate plaque psoriasis. Choonahakarn C, Busaracome P,
Sripanidkulchai B, Sarakarn P. J Eur Acad Dermatol Venereol.
2010;24(2):16872.
In this 8 week study, 8 psoriasis patients were randomized to
receive aloe vera cream or triamcinolone 0.1% cream to be
applied to affected areas twice daily. A statistically greater
improvement in the Psoriasis Area and Severity (PASI) score
was seen in the aloe vera group, but there was no difference
between the two groups in the Dermatology Life Quality
Index (DLQI) score.
2. Management of psoriasis with aloe vera extract in a hydro-

philic cream: a placebo-controlled, double-blind study. Syed T,
Ahmad S, Holt A, Ahmad S, Ahmad S, Afzal M. Trop Med Int
Health. 1996;1(4):5059.
In this 16 week study, 60 patients with plaque psoriasis applied
0.5% aloe vera cream or placebo to affected areas three times
daily for 5 consecutive days per week. The authors report a
greater improvement in the aloe vera treated patients com-
pared to placebo, with a decrease in the Psoriasis Area and
Severity Index (PASI) score from 9.3 to 2.2 in the aloe vera
group.
104 8. Psoriasis
Mahonia Aquifolium
Mahonia aquifolium (Oregon grape) is an evergreen shrub that
is native to North America, and is the state flower of Oregon.
It has been used for the treatment of inflammatory skin dis-
eases including psoriasis; while its exact mechanism of action
has yet to be elucidated, its chemical constituents are thought to
have anti-inflammatory effects on the skin (Galle et al. 1994).
Evidence for Mahonia Aquifolium
1. Treatment of mild to moderate psoriasis with Relieva, a

mahonia aquifolium extract- a double-blind, placebo controlled
study. Bernstein S, Donskyn H, Gulliver W, Hamilton D, Nobel S,
Norman R. Am J Ther. 2006;13(2):1216.
This was a 12 week study of 200 patients with psoriasis, who
were randomized to receive a proprietary extract of mahonia
aquifolium or placebo, which they applied twice daily to
affected areas. Statistically significant improvements in the
Psoriasis Area and Severity Index (PASI) and quality of life
scores were observed in the mahonia-treated group compared
to placebo. Less than 1% of mahonia-treated patients reported
rash, irritation and staining of clothing during treatment.
2. A report on three recent clinical trials using mahonia aqui-

folium 10% topical cream and a review of the worldwide
clinical experience with mahonia aquifolium for the treat-
ment of plaque psoriasis. Gulliver W, Donsky H. Am J Ther.
2005;12(5):398406.
Three studies of mahonia aquifolium were reviewed for their
safety and efficacy. Study 1 was a safety study. Study 2 was a
randomized controlled trial of mahonia aquifolium compared
to a cream containing calcipotriol and fluticasone. Study 3 was
a randomized controlled trial of mahonia aquifolium com-
pared to a gel containing calcipotriol and tazarotene. The
authors report that mahonia aquifolium was as effective as the
Balneotherapy 105
prescription topical medications that were studied, although no

statistical results were given in this study.
Balneotherapy
Balneotherapy refers to the practice of using baths (both hot
and cold) for the treatment of illnesses. In dermatology, this
practice is most commonly used for the treatment of psoriasis
and atopic dermatitis. High concentrations of salt, other
minerals and muds may be used in the baths. While the
mechanisms of action of balneotherapy have not been fully
elucidated, these baths are generally very low-risk treatments
that patients often find to be very soothing to the skin and
mentally comforting (Matz et al. 2003).
Evidence for Balneotherapy
1. Dead sea bath salt for the treatment of psoriasis vulgaris: a

double-blind controlled study. Halevy S, Giryes H, Friger M,
Sukenik S. J Eur Acad Dermatol Venereol. 1997;9:23742.
In this study of Dead Sea salt as monotherapy for psoriasis, 30
patients were randomized to bathe in Dead Sea salt or com-
mon salt daily for 3 weeks. Twenty-five patients completed the
study. PASI scores were significantly decreased in both groups
(34.8% decrease in Dead Sea Salt group, 27.5% common salt
group); the mean reduction was higher in the Dead Sea salt
group, but the difference was not statistically significant.
2. A pragmatic randomized controlled trial on the effective-

ness of highly concentrated saline spa water baths followed
by UVB compared to UVB only in moderate to severe pso-
riasis. Brockow T, Schiener R, Franke A, Resch K, Peter R. J
Altern Complement Med. 2008;13(7):72532.
One hundred and sixty adults with psoriasis were randomized
to receive high concentration salt water baths followed by
106 8. Psoriasis
UVB phototherapy or UVB phototherapy alone. Treatments

were performed 3 times per week for 6 weeks, or until remis-
sion was achieved (defined as PASI < 5), with the primary
outcome measure being reduction of PASI by at least 50%
(PASI 50). Eighty-six percent of salt water + UVB patients
achieved PASI 50 compared to 54% in the UVB group; this
finding was statistically significant.
3. A pragmatic randomized controlled trial on the effective-

ness of low concentrated saline spa water baths followed by
ultraviolet B (UVB) compared to UVB only in moderate to
severe psoriasis. Brockow T, Schiener R, Franke A, Resch K,
Peter R. J Eur Acad Dermatol Venereol. 2008;21(8):
102737.
The same group cited in the preceding study conducted this
trial of 143 adults with psoriasis, this time studying the effects
of low concentration salt water baths in psoriasis. Participants
were randomized to receive low concentration salt water baths
followed by UVB phototherapy or UVB phototherapy alone.
Treatments were performed 3 times per week for a maximum
of 6 weeks, or until remission (defined as PASI <5) was
achieved. The primary outcome measure was reduction of
PASI by at least 50% (PASI 50). Seventy-three percent of salt
water treated + UVB patients achieved this outcome, compared
to 50% of patients treated with UVB phototherapy alone; this
finding was statistically significant.
4. Old fashioned sodium bicarbonate baths for the treatment

of psoriasis in the era of futuristic biologics: an old ally to be
rescued. Verdolini R, Bugatti L, Filosa G, Mannello B, Lawlor
F, Cerio R. J Dermatolog Treat. 2005;16(1):2630.
Thirty-one patients with mild to moderate psoriasis were ran-
domized to receive daily baths with sodium bicarbonate (bak-
ing soda) or placebo for 3 weeks. Statistically significant
improvements in irritation and itching were observed in the
sodium bicarbonate group compared to placebo.
Case 1 107
Mindfulness Based Stress Reduction

Mindfulness based stress reduction incorporates elements of
meditation, yoga and breathing in an effort to generate
greater mind-body awareness, and to create a deeper under-
standing on ones subconscious thoughts on his or her physical
well-being. It has been shown that patients with psoriasis have
higher rates of anxiety, depression, and suicidal ideation
(Kurd et al. 2010); it is therefore of paramount importance
that the psychosocial impacts of this disease are discussed and
addressed with patients, and cognitive behavioral therapy may
play an important role in a patients treatment plan. It is also
possible that reducing stress has direct effects on the skin and
immune system as well.
Evidence for Mindfulness Based Stress Reduction
1. Influence of a mindfulness meditation-based stress reduc-

tion intervention on rates of skin clearing in patients with
moderate to severe psoriasis undergoing phototherapy
(UVB) and photochemotherapy (PUVA). Kabat-Zinn, J,
Wheeler E, Light T, Skillings A, Scharf MJ, Cropley TJ,
Hosmer D, Bernhard JD. Psychosom Med 1998;60(5):62532.
This was a small study of 37 patients with psoriasis. All patients
were scheduled to undergo UVB or PUVA, and were random-
ized to receive either mindfulness based stress reduction
(MBSR) with audiotape-guided meditation during photother-
apy treatments, or phototherapy alone. This study found that
subjects in the MBSR group achieved improvement in their
psoriatic skin lesions faster than subjects in the control group.
Case 1
A 35 year-old male with a many year history of plaque psoria-
sis comes to you to discuss treatment options. He has less than
5% body surface area involvement, with the largest plaques
108 8. Psoriasis
on his elbows and knees. The plaques are itchy and make the
patient very self-conscious; he has developed social anxiety
due to his condition. He has tried a number of topical steroids
over the years and prefers to avoid their use if possible. He has
no history of psoriatic arthritis and no joint pain currently.
Discussion
Since the patients body surface area in this case is small, he
may benefit from the use of bath soaks three times per week
coupled with the application of aloe vera gel to affected areas
twice daily. Cognitive behavioral therapy in the form of mind-
fulness based stress reduction should be encouraged, to help
decrease the psychosocial aspects of this patients condition.
Case 2
A 55 year old female with nail psoriasis is referred to you by
her primary care physician. She is tired of having to wear nail
polish to cover the pits and yellowing of her nails and is inter-
ested in a treatment with a low risk of side effects.
Discussion
The patient should be counseled that while nail psoriasis can
be very difficult to treat, indigo naturalis has shown some ben-
efit in the treatment of nail psoriasis. She could apply the
extract once daily for at least 12 weeks, and should be warned
about the risk of staining of the skin and clothing.
References
Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable
blocker of TNF and other pro-inflammatory biomarkers. Br J
Pharmacol. 2013;169(8):167292. doi:10.1111/bph.12131.
References 109
Damevska K, Neloska L, Nikolovska S, Gocev G, Duma S.

Complementary and alternative medicine use among patients
with psoriasis. Dermatol Ther. 2014;27(5):2813.
Galle K, Muller-Jakic B, Proebstle A, Jurcic K, Bladt S, Wagner

H. Analytical and pharmacological studies on mahonia aquifo-
lium. Phytomedicine. 1994;1(1):5962.
Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin:

lessons learned from clinical trials. AAPS J. 2013;15(1):195218.
doi:10.1208/s12248-012-9432-8.
Klein A, Penneys N. Aloe vera. J Am Acad Dermatol. 1998;18(4 Pt

1):71420.
Kleinpenning M, Otero M, van Erp P, Gerristen M, van de Kerkhof

P. Efficacy of blue light vs red light in the treatment of psoriasis: a
double-blind, randomized comparative study. J Eur Acad
Dermatol Venereol. 2012;26(2):21925.
Koo J, Arain S. Traditional Chinese medicine for the treatment of

dermatologic disorders. Arch Dermatol. 1998;134:138893.
Kurd SK, Smith N, VanVoorhees A, Troxel AB, Badmaev V, Seykora

JT, Gelfand JM. Oral curcumin in the treatment of moderate to
severe psoriasis vulgaris: a prospective clinical trial. J Am Acad
Dermatol. 2008;58(4):62531.
Kurd S, Troxel A, Crits-Christoph P, Gelfand J. The risk of depres-

sion, anxiety, and suicidality in patients with psoriasis: a
population-based cohort study. Arch Dermatol. 2010;46(8):
8915.
Lin Y, Leu Y, Huang T, Wu Y, Chung P, Su Pang J, Hwang T. Anti-

inflammatory effects of the extract of indigo naturalis in human
neutrophils. J Ethnopharmacol. 2009a;125(1):518.
Lin Y, Leu Y, Yang S, Chen H, Wang C, Pang J. Anti-psoriatic effects

of indigo naturalis on the proliferation and differentiation of
keratinocytes with indirubin as the active component. J Dermatol
Sci. 2009b;54(3):16874.
110 8. Psoriasis
Lin Y, Chen H, Yang Y, Fang Y, Su Pang J, Hwang T. Indigo naturalis

upregulates claudin-1 expression in human keratinocytes and
psoriatic lesions. J Ethnopharmacol. 2013;145(2):61420.
Matz H, Orion E, Wolf R. Balneotherapy in dermatology. Dermatol

Ther. 2003;16(2):13240.
Nicolaou A. Eicosanoids in skin inflammation. Prostaglandins

Leukot Essent Fatty Acids. 2013;88(1):1318.
Richard E, Honigsmann H. Phototherapy, psoriasis, and the age of bio-

logics. Photodermatol Photoimmunol Photomed. 2014;30(1):37.
Chapter 9
Atopic Dermatitis (Eczema)
Introduction
Atopic dermatitis (AD) is often used interchangeably with
the term eczema, but perhaps is more accurately thought of
as a specific type (or, more likely, a collection of similar sub-
types) of eczema that often includes other allergic diseases
such as food allergies or asthma (Bos et al. 2010). Regardless
of its name, it represents a chronic, relapsing, itchy skin dis-
ease that often begins in the first years of life, but affects
patients of all ages. Its etiopathogenesis is complex and still
not fully elucidated, but is likely related to a combination of
skin barrier dysfunction, allergic/immunologic aberrations,
microflora abnormalities and pruritus (Kabashima 2013;
Kong et al. 2012).
AD affects up to 20% of children in developed countries,
and recent estimates are as high as 10% of adults having
some form of eczema as well (Silverberg and Hanifin 2013).
For such a common condition, however, a great number of
questions remain. As with other areas of alternative and
complementary therapies, scattered small and medium-sized
studies with fundamental differences in methodology defy
meaningful pooling of the evidence.
The conventional approach to management is multifaceted
and includes addressing the four main areas of dysfunction
with moisturization, anti-inflammatory agents, anti-microbials,
and anti-pruritic therapy. Allergen identification and

DOI 10.1007/978-3-319-17816-5_9
112 9. Atopic Dermatitis (Eczema)
avoidance is also helpful when possible (Lio et al. 2014). While

most of these areas are uncontroversial, the main area of con-
tention seems to lie within the realm of anti-inflammatories:
topical corticosteroids are highly effective, but have a signifi-
cant number of concerning side effects that make them unwel-
come for certain patients. Importantly, this perception may
lead to poor adherence to the plan: one recent report found
that parents and adult atopic patients surveyed reported fear-
ing topical corticosteroids, and more than one third admitted
nonadherence to treatment (Aubert-Wastiaux et al. 2011).
Moreover, there is a perception that their effectas well as
that of the topical calcineurin inhibitorsis merely symptom-
atic, and fails to address the root of the problem. This makes
for a very rich area in alternative medicine, with many possi-
ble approaches, limited only by the relative lack of quality
studies. However, in sifting through a large number of papers,
several promising therapies surface and appear to be at the
very least worthy of further consideration, meeting the strin-
gent criteria of apparent safety, possible efficacy, and feasibil-
ity for a conventional practitioner.
There seem to be multiple subtypes of eczema, most of which
are poorly characterized. Of particular importance (Figs. 9.1
and 9.2):
Exudative and oozing lesions, wet pattern tends to
respond particularly well to antimicrobial therapies (such as
dilute bleach baths or compresses with aluminum acetate).
Eczema prominent on the head and neck area of young
adults seems to be intimately related to seborrheic dermatitis
and may share Malassezia yeast overgrowth and/or sensitiv-
ity as a contributing factor. Pulsing with oral anti-yeast agents
such as itraconazole can sometimes result in dramatic
improvement without immunosuppression.
Fig. 9.1. Oozing and crusting of facial eczema in an infant.
Fig. 9.2. Papulo-vesicles of dyshidrotic eczema of the hands. Dyshidrotic

eczema predominantly affects the hands and feet and is characterized
by tiny blisters and micro papules. Irritants and allergens can play a
strong role here, so protective and avoidance strategies are critical.
Top Considerations
Sunflower Seed Oil

Natural oils have been used as part of massage therapy and
as topical treatments on the skin for generations (Danby
et al. 2013). Sunflower (Helianthus annus) seed oil is rich in
linoleic acid, and has been used topically in the treatment of
essential fatty-acid deficiency, rapidly reversing the disease
(Lodn and Andersson 1996). These essential fatty acids can
also help maintain the skin barrier and decrease transepider-
mal water loss, both important features in thinking about the
barrier problem in atopic dermatitis (Eichenfield et al. 2009).
Several studies have also suggested that there are anti-
inflammatory properties of sunflower seed oil, perhaps via

Topical sunflower Applied twice Safe, inexpensive, generally
seed oil daily, directly or in not allergenic, helps with very
moisturizer dry skin
Topical coconut oil Applied twice Safe, inexpensive, generally
daily, directly or in not allergenic, has
moisturizer antimicrobial effects
Cardiospermum Applied twice daily Safe, inexpensive, rarely a
plant extract topically contactant
Oral vitamin D Orally, once per Safe, inexpensive, probably
supplementation day, about 1,000 helps best with those who
IUs for children, worsen in winter or are
up to 4,000 IUs for deficient in vitamin D
adults
Topical vitamin Applied twice daily Appears safe, difficult
B12 application in a cream form to obtain (must be
compounded), may stain
clothing pink color
Sunflower Seed Oil 115

Traditional Herbal decoction Not one simple regimen for all;
Chinese or pill form highly variable, some toxicities
medicine reported with certain herbs; can
become expensive over time
Acupuncture/ Treatments Not one simple regimen for
acupressure administered in all; some variability and can
office or at home become expensive over time
Diet Various Despite significant interest,
modification restrictions data does not generally support
depending on dietary change outside of
suspicion of allergy known allergen avoidance
or intolerance
Probiotic Orally to patient Uncertainty surrounding strain
supplementation and/or patients or strains, dosage, frequency
mother during of dosing, and timing for
gestation prevention vs. treatment of AD;
relatively safe and may have
other benefits beyond AD
Hypnosis and Treatments Not one simple regimen for
biofeedback administered in all; some variability and can
office or at home become expensive over time
the PPAR pathway, marking another seminal part of the

pathogenesis of AD (Eichenfield et al. 2009). There is some
thought that preparations that contain higher amounts of
linoleic acid versus oleic acid may be more beneficial in this
role and there is some clinical data to bear this out (Eichenfield
et al. 2009). Very safe and fairly inexpensive, sunflower oil
seems a reasonable consideration for any patient with AD, so
long as there is not a known sunflower seed allergy.
Evidence for Sunflower Seed Oil
1. New emollient with topical corticosteroid-sparing effect in

treatment of childhood atopic dermatitis: SCORAD and qual-
ity of life improvement. Msika P, De Belilovsky C, Piccardi N
et al. Pediatr Dermatol. 2008 NovDec;25(6):60612.
86 children with moderate AD were randomized to five groups

for 21 days: corticosteroids (from twice daily to one applica-
tion every other day) combined or not with the studied sun-
flower-oil-containing cream (twice daily). The studied cream
had a significant impact on lichenification and excoriation,
decreased corticosteroid use, and improved quality of life com-
pared to the control group.
2. Effect of olive and sunflower seed oil on the adult skin bar-
rier: implications for neonatal skin care. Danby SG, AlEnezi
T, Sultan A, Lavender T, Chittock J, Brown K, Cork MJ. Pediatr
Dermatol. 2013 JanFeb;30(1):4250. doi: 10.1111/j.1525-
1470.2012.01865.x.
19 adults were randomized to receive olive oil to one arm vs.
sunflower seed oil to the other for 4 weeks. The study found
that topical olive oil caused a worsening of the barrier function
and erythema in volunteers with and without a history of
AD. Sunflower seed oil, on the other hand, did not cause ery-
thema and preserved skin barrier function while actually
improving hydration.
3. Effect of skin barrier therapy on neonatal mortality rates in

preterm infants in Bangladesh: a randomized, controlled, clin-
ical trial. Darmstadt GL, Saha SK, Ahmed AS et al. Pediatrics.
2008;121:5229.
A randomized controlled trial of 497 preterm infants at high
risk for infection and mortality. They were randomized to
receive massages with sunflower seed oil, a petroleum-based
ointment, or no treatment. They found that the sunflower oil
treatment group had a significant reduction (26%) in mortal-
ity compared to untreated controls, suggesting that sunflower
seed oil has barrier-enhancing properties which make it
effective.
Coconut Oil 117
Coconut Oil
Coconut oil (Cocos nucifera), particularly virgin coconut oil
(VCO),1 has been shown to be comparable with mineral oil
as an emollient (Agero and Verallo-Rowell 2004). In addi-
tion, it has also been shown to address another important
aspect of atopic dermatitis: staphylococcal colonization. In a
randomized controlled trial it was found to clear an impres-
sive 95% of staphyoloccal colonization in patients with AD
(Verallo-Rowell et al. 2008). And, similar to the findings of
sunflower seed oil, VCO has been shown to improve barrier
function in low birthweight babies (Nangia et al. 2008). When
put to a more clinical test, it actually outperformed mineral
oil in treating pediatric AD over 8 weeks in a randomized
trial (Evangelista et al. 2014), thus making it an important
alternative consideration.
Evidence for Coconut Oil
1. The effect of topical virgin coconut oil on SCORAD index,

transepidermal water loss, and skin capacitance in mild to
moderate pediatric atopic dermatitis: a randomized, double-
blind, clinical trial. Evangelista MT, Abad-Casintahan F,
Lopez-Villafuerte L. Int J Dermatol. 2014 Jan;53(1):1008.
doi: 10.1111/ijd.12339.
An RCT study of 117 mild to moderate pediatric AD patients
comparing topical virgin coconut oil vs. mineral oil at 2, 4, and
8 weeks. The coconut oil group had significantly more
improvement than the mineral oil group (68% vs. 38%
1
N.B.: The term Virgin Coconut Oil is defined as coconut oil being
obtained from fresh, mature coconut kernels through mechanical or
natural means which do not lead to alteration of the oil [APCC
Standards]. This is in contrast to methods which use undesirable solvents
such as hexane to extract the oil.
decrease in mean SCORAD) as well as in transepidermal

water loss (TEWL) improvement and skin capacitance.
2. A randomized double-blind controlled trial comparing

extra virgin coconut oil with mineral oil as a moisturizer for
mild to moderate xerosis. Agero AL, Verallo-Rowell
VM. Dermatitis. 2004 Sep;15(3):10916.
A double-blind RCT trial comparing virgin coconut oil with
mineral oil in 34 patients with xerosis. The study found that
both oils were comparable in TEWL and skin pH changes,
suggesting that coconut oil is as effective as mineral oil as a
moisturizer.
3. Novel antibacterial and emollient effects of coconut and

virgin olive oils in adult atopic dermatitis. Verallo-Rowell
VM, Dillague KM, Syah-Tjundawan BS. Dermatitis. 2008
NovDec;19(6):30815.
A double-blind RCT of virgin coconut oil compared to virgin
olive oil on the skin of patients with AD. This trial involved 26
subjects and found that 95% of the coconut oil group cleared
staphylococcus colonization vs. only 50% in the olive oil
group, suggesting that coconut oil has clinically relevant anti-
bacterial effects.
4. Topical coconut oil application reduces transepidermal loss

in preterm very low birth weight neonates: a randomized
clinical trial. Nangia S, Paul V, Chawla D et al. Pediatrics.
2008;121:S139.
An RCT of 74 very low birth weight infants in India that com-
pared topical coconut oil applied twice daily for 7 days vs. no
oil. They found that the oil group had significantly lower
TEWL at all time points, by as much as 46% over the control.
This study is included here as further evidence of the barrier-
enhancing properties of coconut oil as well as evidence of its
safety profile; applied to very low birthweight neonates, it
appears to be very safe.
Cardiospermum Plant Extract 119
Cardiospermum Plant Extract

Cardiospermum halicacabum grows throughout India and
has long been used for medicinal purposes (Tyler et al. 2012).
A number of active agents have been identified among its
many compounds, including anti-inflammatory factors (Koch
et al. 1996). There are some clinical data suggesting modest
improvement in redness and decreasing the need for cortico-
steroids in clinical studies (Jong et al. 2013). As it is inexpen-
sive and available in over-the-counter preparations, this may
be useful as both a complementary medicine or even as an
alternative to corticosteroids in some situations.
Evidence for Cardiospermum Plant Extract
1. Cardiospermum-Salbe und Salbengrundlage im

Halbeseitenvergleich-eine kontrollierte Studie. Merklinger S,
Messemer C, Niederle S. Z Phytotherapie. 1995;16:2636.
Randomized controlled double-blind study of Cardiospermum
cream vs. control found that the Cardiospermum preparation
was superior to the vehicle in controlling the symptoms of AD.
2. Plant-based ointments versus usual care in the manage-

ment of chronic skin diseases: a comparative analysis on out-
come and safety. Jong MC, Ermuth U, Augustin M.
Complement Ther Med. 2013 Oct;21(5):4539. doi: 10.1016/j.
ctim.2013.07.002. Epub 2013 Aug 17
112 patients with chronic skin diseases were divided (non-
randomly) into a group treated with plant-based ointments
compared to usual care (corticosteroids). Looking at the AD
subgroup, the data are somewhat difficult to interpret, but the
authors conclude that the cardiospermum cream may improve
skin severity, patient satisfaction, and quality of life, and do
so safely.
3. Lokaltherapie der atopischen Dermatitis mit Cardiospermum

halicacabum. Rudolph R, Benthien H, Jappe U, Kunz B. Haut.
1994;1:636.
A study of 512 patients with dermatitis treated with cardiosper-
mum extract cream. A control group was treated with the base
cream alone. The cardiospermum cream significantly decreased
erythema and reduced use of antihistamines and corticoste-
roids compared to control.
Oral Vitamin D Supplementation

Vitamin D (commonly referred to in its D3 form as cholecal-
ciferol) is a fat-soluble hormone with many effects beyond
the intestinal absorption of calcium and phosphate. It can
also affect immune function and increasing the levels of cat-
helicidin, which are important anti-bacterial proteins on the
skin (Hck 2014). It also appears to improve the skin barrier
function, thus making it very enticing as a possible therapy in
AD. There is some controversy about supplementation in
conventional medicine, so we felt it was reasonable to discuss
it here. A recent paper analyzed 58 articles on the role of
vitamin D in AD and made several important conclusions: (1)
There is an inverse relationship between vitamin D levels and
AD severity; (2) Repletion with vitamin D promotes the epi-
dermal barrier; and (3) Clinical trials suggest a therapeutic
benefit from vitamin D supplementation, though the trials
are small and limited (Mutgi and Koo 2013). In thinking
about these somewhat variable results, it seems likely that
there is a subgroup of patients who responds to vitamin D
supplementation, and others who do not. Several authors
have noted that winter eczema seems to be more respon-
sive and this would make logical sense given the likely lower
vitamin D levels during that time of year.
Given the relative safety of vitamin D supplementation
and its low cost, it seems reasonable to suggest a trial in at
least those patients who report worsening in the winter
months until larger studies can further validate this claim.
Topical Vitamin B12 Application 121
Evidence for Oral Vitamin D Supplementation
1. Randomized controlled trial of vitamin D supplementation

for winter-related atopic dermatitis in Boston: a pilot study.
Sidbury R, Sullivan AF, Thadhani RI, Camargo CA. Br J
Dermatol. 2008;159:2457.
A small but impressive study of 11 children with AD that wors-
ened in the winter, randomized to vitamin D supplementation
or placebo. The study found significant improvement (80%
improved) in the experimental group over the control group
(17% improved).
2. Randomized trial of vitamin D supplementation for winter-

related atopic dermatitis in children. Camargo CA Jr, Ganmaa
D, Sidbury R, Erdenedelger Kh, Radnaakhand N, Khandsuren
B. J Allergy Clin Immunol. 2014 Oct;134(4):8315.
A double-blinded, placebo-controlled RCT of 107 children
with AD that worsened in the winter. At 1-month follow up
there was a significant improvement in the eczema severity
measured by EASI score and IGA score in the group treated
with vitamin D compared to placebo control. There were no
adverse effects reported.
Topical Vitamin B12 Application

Vitamin B12 (cobalamin) is a water-soluble vitamin that plays
a role in numerous metabolic processes, as well as in brain and
nervous system function. It also is a powerful scavenger of
nitric oxide (NO), which has been linked to triggering pruri-
tus; thus, the rationale is that B12 could help decrease pruritus
in AD. Additionally, in vitro studies have demonstrated that
B12 suppresses the cytokine production of T lymphocytes, as
well as multiple inflammatory cytokines, also promising for
AD therapy (Stcker et al. 2004). The concept of a safe, topi-
cally applied vitamin for AD is incredibly compelling and
could even be added to moisturizers as an adjunctive therapy,
much in the same way that niacinamide is now frequently

found in moisturizers targeted towards acne and rosacea. One
shortcoming is that a B12 cream is pink-to-red and can stain
clothing (although it is easily washed out).
Evidence for Topical Vitamin B12 Application
1. Topical vitamin B12a new therapeutic approach in atopic

dermatitis-evaluation of efficacy and tolerability in a random-
ized placebo-controlled multicentre clinical trial. Stcker M,
Pieck C, Stoerb C et al. Br J Dermatol. 2004 May;150(5):
97783.
An RCT of topical vitamin B12 vs. placebo for 8 weeks in 49
patients with AD found that the B12 group had significantly
better improvement in AD compared to placebo control.
2. Vitamin B12: the forgotten micronutrient for critical care.

Manzanares W, Hardy G. Curr Opin Clin Nutr Metab Care.
2010 Nov;13(6):6628.
A review of B12 as antioxidant and anti-inflammatory therapy,
with full discussion of possible mechanisms.
3. Evaluation of topical vitamin B(12) for the treatment of

childhood eczema. Januchowski R. J Altern Complement
Med. 2009 Apr;15(4):3879.
A double-blinded RCT of topical B12 in children with AD,
which found significant improvement in the active group over
the placebo at 2 and 4 weeks.
Traditional Chinese Medicine (TCM)

A complex, ancient, and nuanced system of health and dis-
ease, TCM has an underlying philosophy similar to a humoral
approach in that the goal is to find and restore imbalances
between forces in the body that become congested or defi-
Traditional Chinese Medicine (TCM) 123
cient (Bhuchar et al. 2012). From a Western standpoint, it is

difficult to deny that combinations of multiple herbs could
indeed have true pharmacologic effects; indeed, many of our
medicines are plant-derived.
Unfortunately, TCM is often reduced to a single herbal
therapy or cream in Western studies. This reductionist con-
straint limits a proper evaluation of the system as a whole,
and places it in an untenable situation of being judged
without full understanding. Compounding matters, most
conventional diseases do not have direct analogs in TCM;
indeed, someone with eczema could have a number of
TCM diagnoses, all of which include eczema as part of the
spectrum, but not necessarily as the underlying cause.
Because of this, the herbal therapies can be very different
even among patients with the same skin disease, invalidat-
ing the usual RCT approach. An analogy might be if some-
one were trying to determine if antibiotics were effective
for treating infections. It would be folly to only use penicil-
lin for pseudomonas bacteremia, and would certainly result
in the erroneous conclusion that antibiotics are ineffective
for infections, simply due to an incomplete understanding
and execution.
Perhaps surprisingly, despite these limitations, some prom-
ising evidence exists that TCM may be of help in AD. However,
of the treatments we have discussed so far, it is the most inac-
cessible to conventional clinicians as finding the right herbal
combination and sourcing them is not generally possible for
the uninitiated, and referral to a TCM practitioner may not
always be possible.
Evidence for Traditional Chinese Medicine
1. Chinese herbal medicine for atopic eczema. Zhang W,

Leonard T, Bath-Hextall F, Chambers CA, Lee C, Humphreys
R et al. Cochrane Database Syst Rev. 2005:CD002291. A
Cochrane systematic review.
Many studies were insufficient to include, but a combination of

multiple TCM herbal medications called Zemaphyte was
shown in vitro to decrease CD23 levels, which acts as a low-
affinity IgE receptor and is often elevated in AD subjects.
However, the clinical effectiveness of this preparation was
found to be mixed and limited, with some studies showing
marked improvement and others showing no difference com-
pared to placebo. An updated Cochrane review has eliminated
this as Zemaphyte has been off the market for years now, and
other studies have not been nearly as robust.
2. Efficacy of traditional Chinese herbal therapy in adult atopic

dermatitis. Sheehan MP, Rustin MH, Atherton DJ, Buckley C,
Harris DW, Brostoff J et al. Lancet. 1992;340:137.
Double blind RCT of 40 adults were treated with TCM herbal
preparation vs. placebo for 8 weeks; the experimental group
showed significantly decreased objective disease severity and
subjective improvement in sleep and pruritus sensation.
3. Follow-up of adult patients with atopic eczema treated with

Chinese herbal therapy for 1 year. Sheehan MP, Stevens H,
Ostlere LS, Atherton DJ, Brostoff J, Rustin MH. Clin Exp
Dermatol. 1995 Mar;20(2):13640.
1 year follow up of above study found that 12/17 patients on the
herbal treatment had greater than 90% reduction and the
remaining five had greater than 60% reduction in clinical
scores compared with baseline values. Clinical scores of
patients in the untreated group were significantly different from
those of the treated group at the end of the year. Importantly, no
patients felt that they were cured at the one year mark or were
able to fully wean off the herbal preparation.
4. Efficacy and tolerability of a Chinese herbal medicine

concoction for treatment of atopic dermatitis: a randomized,
double-blind, placebo-controlled study. Hon KL, Leung TF,
Ng PC, Lam MC, Kam WY, Wong KY et al. Br J Dermatol.
2007;157:35763.
Acupuncture/Acupressure 125
RCT of 85 children with AD of TCM herbal vs. placebo. At the

end of 12 weeks, experimental subjects demonstrated improve-
ment compared to controls. Experimental subjects also had
decreased use of corticosteroid and antihistamine use, even at
4 weeks after stopping TCM herbal therapy.
5. Efficacy and safety of traditional Chinese medicine for

treatment of atopic dermatitis (AD). Wisniewski J, Nowak-
Wegrzyn A, Steenburgh-Thanik E, Sampson H, Li X. J Allergy
Clin Immunol. 2009;3(2):S37.
14 children with refractory AD were treated with the following
regimen: drinking a TCM herbal tea twice daily, herbal bath
soaks for 20 min daily, application of an herbal cream three
times daily, plus acupuncture thrice weekly for 3 months.
SCORAD reduction ranged from 60 to 90% in 13 of 14 sub-
jects treated. Quality of life scores also improved by 50% in all
subjects, and a reduction in usage of topical corticosteroids
and antihistamines was also noted.
Acupuncture/Acupressure
While generally considered part of Traditional Chinese
Medicine, acupuncture and acupressure deserve independent
discussion as they have unique evidence in AD. It is based on
the idea that energy meridians in the body can become unbal-
anced and that by stimulating certain points (acupoints) with
needles, pressure, magnets, or even lasers, the flow can be
restored and rebalanced (Kampik 1976). From a conven-
tional standpoint, there are studies that show clear changes in
specific brain areas with acupuncture, and evidence that
there is endorphin production with acupuncture, suggesting a
neurocutaneous connection (Lu and Lu 2013). While formal
acupuncture would require a specially-trained practitioner,
more limited versions (including the single point study dis-
cussed below) could be performed by nearly anyone, includ-
ing patients themselves.
Evidence for Acupuncture/Acupressure
1. Influence of acupuncture on type I hypersensitivity itch and

the wheal and flare response in adults with atopic eczemaa
blinded, randomized, placebo-controlled, crossover trial. Pfab
F, Huss-Marp J, Gatti A, Fuqin J, Athanasiadis GI, Irnich D
et al. Allergy. 2010;65:90310.
Single session of acupuncture (Quchi and Xuehai points)
effectively decreased artificially induced wheal-and-flare
responses in patients with AD. Itch sensation was also signifi-
cantly decreased in experimental groups compared to control
and placebo groups. While somewhat contrived from a clinical
perspective, this is a powerful demonstration of direct modula-
tion of pruritus and inflammatory response by acupuncture
alone.
2. Effect of acupuncture on allergen-induced basophil activa-

tion in patients with atopic eczema:a pilot trial. Pfab F,
Athanasiadis GI, Huss-Marp J, Fuqin J, Heuser B, Cifuentes L
et al. J Altern Complement Med. 2011;17:30914.
Pilot study demonstrated decreased in vitro allergen-induced
CD63 basophil activation in AD patients, again suggesting a
direct anti-inflammatory effect of acupuncture.
3. Effectiveness of acupressure on pruritus and lichenification

associated with atopic dermatitis: a pilot trial. Lee KC, Keyes
A, Hensley JR, Gordon JR, Kwasny MJ, West DP et al.
Acupunct Med J Br Med Acupunct Soc. 2012;30:811.
Investigator blinded, randomized controlled pilot trial in
adults with AD examined the effect of self-applied acupres-
sure at Quchi three times weekly for 4 weeks. In the acupres-
sure group there was a statistically significant decrease in
itch and in lichenification compared to the control group
(Fig. 9.3).
Probiotics 127
Fig. 9.3. Image of large intestine 11 acupuncture point.
Probiotics
Bacterial imbalance is clearly an important part of AD, and
beyond simply killing the bad bacteria, the concept of add-
ing back healthy bacteria has appeal. Probiotics are defined
as living microorganisms that are similar to those found on
the body in a healthy state and may be beneficial (NCCAM
website). Probiotics have proven benefit in diarrhea and irri-
table bowel syndrome (Ritchie and Romanuk 2012), and
there are some tantalizing studies which suggest an effect
may exist for AD, both in terms of prevention and possibly in
the treatment of existing disease (Kim et al. 2014). From a
clinical perspective, probiotics appear to be safe and may
have a modest effect, but many questions remain: dosage,
frequency of administration, timing, and strain type or types
all represent heterogeneity that makes coming to a final con-
clusion very difficult.
Evidence for Probiotics
1. Probiotics in primary prevention of atopic disease: a ran-

domised placebo-controlled trial. Kalliomki M, Salminen S,
Arvilommi H, Kero P, Koskinen P, Isolauri E. Lancet.
2001;357:10769.
A randomized, placebo-controlled trial of 132 children that
showed Lactobacillus rhamnosus GG apparently decreasing
the risk of developing AD when administered to at-risk infants
over the first 7 years of life.
2. Effects of probiotics on atopic dermatitis: a randomised

controlled trial. Weston S, Halbert A, Richmond P, Prescott
SL. Arch Dis Child. 2005;90:8927.
Randomized, double-blind placebo controlled trial of 56 chil-
dren with moderate to severe AD were given Lactobacillus
fermentum VRI-033 PCC twice daily for 8 weeks. The group
found that eczema severity was significantly decreased in the
probiotic group compared to the placebo group, and this
appeared to persist even 8 weeks beyond the intervention.
3. Maternal probiotic supplementation during pregnancy and

breast-feeding reduces the risk of eczema in the infant.
Rautava S, Kainonen E, Salminen S, Isolauri E. J Allergy Clin
Immunol. 2012;130:135560.
Randomized, double-blind placebo-controlled trial of 241
mother-infant pairs, where the mothers had allergic disease
(and thus babies were at higher risk of developing AD and/
or allergies), and were given Lactobacillus rhamnosus and
Bifidobacterium longum BL999, or L paracasei ST11 and B
longum BL999 or placebo during pregnancy and breast-
feeding. The study found that the risk of the infants develop-
ing AD during the first 2 years of life was significant reduced
in both of the probiotic intervention groups compared to
control.
Diet Modification 129
Diet Modification
Perhaps the single most-asked question of new AD patients
and their families is: could it be something in the diet? This
notion, very appealing in its simplicity, has been heavily pro-
moted by healthcare practitioners and lay people as being a
fundamental root cause of AD (Gelmetti 2000). The truth,
however, appears to be more complex. Importantly, nearly a
third of patients with moderate or severe AD have true food
allergies; that is to say, they will develop urticaria and possi-
bly anaphylaxis within minutes of eating a food to which they
are allergic (Eigenmann et al. 1998). Undoubtedly, this type
of reaction could act as a trigger for an eczema flare, but it is
important to stress that this is not generally what people are
referring to when this topic is broached. Beyond causing an
eczematous reaction (which is difficult to test since it would
be expected to take many hours or even days to develop after
ingesting the offending food), the concept of food intoler-
ance which is sometimes described as a non-immunologic
reaction to certain foods, has further obfuscated this area
(Boettcher and Crowe 2013). While there is undoubtedly a
group for which avoiding certain foods leads to significant
improvement in eczema, this is overwhelmingly not the case
for most, and food avoidance without suggestive history or
testing has generally been found to be unhelpful.
Evidence for Diet Modification
1. Dietary exclusions for improving established atopic eczema

in adults and children: systematic review. Bath-Hextall F,
Delamere FM, Williams HC. Allergy. 2009;64:25864.
This is such a complex area and there are so many studies, I
have highlighted this systematic review from 2009 to summa-
rize much of the literature. The main conclusions from this
large review were: (1) In known egg allergy, there may be ben-
efit to avoiding egg; (2) In patients with unproven allergies, diet
exclusion did not show benefit. Importantly, this lack of
empiric effect suggests that even non-immunologic effects, if

they exist, are not robust enough to be measured easily.
2. Serum IgG antibodies to gliadin and other dietary antigens in

adults with atopic eczema. Finn R, Harvey MM, Johnson PM,
Verbov JL, Barnes RM. Clin Exp Dermatol. 1985;10:2228.
A small study found that 30% of adults with AD had detect-
able antibodies to gliadin compared to only 6.5% in the gen-
eral population, supporting the finding that such specific IgG
antibodies are increasingly found in patients with allergies
and/or eczema, but that the clinical implications are not clear.
3. Allergy prevalence in adult celiac disease. Ciacci C,

Cavallaro R, Iovino P, Sabbatini F, Palumbo A, Amoruso D
et al. J Allergy Clin Immunol. 2004;113:1199203.
1,000 patients with celiac disease were studied and it was found
that AD was about 3 times more common in them compared to
the general population. Importantly, however, a gluten-free diet
for up to 1 year did not measurably affect the AD severity.
Hypnosis and Biofeedback

Stress is known to be a significant trigger for AD, and the itch-
scratch cycle may become a deeply ingrained behavioral
response that is elicited more during times of anxiety
(Shenefelt 2003). It follows, then, that techniques to reduce
stress could be helpful in the management of AD. Safe and
somewhat holistic, hypnosis and biofeedback techniques do
seem to be helpful in both adults and children, and appear to
have a durable response. Cost, time, and availability of such
treatments can present barriers for utilizing these modalities.
Evidence for Hypnosis and Biofeedback
1. Hypnotherapy as a treatment for atopic dermatitis in adults

and children. Stewart AC, Thomas SE. Br J Dermatol.
1995;132:77883.
Case 1 131
Non-blinded, non-controlled study of 18 adults and 20 chil-

dren with severe AD were treated with hypnotherapy and
showed subjective and objective benefit. Adults maintained
benefit up to 2 years afterwards, while children maintained
benefit up to 18 months afterwards.
2. A comparison of hypnotherapy and biofeedback in the

treatment of childhood atopic eczema. Sokel B, Christie D,
Kent A, Lansdown R, Atherton D, Glover M et al. Contemp
Hypn. 1993;10(3):14554.
An RCT which examined hypnotherapy and biofeedback on
children with AD. Those in the hypnotherapy and biofeedback
groups showed a statistically significant reduction in the sever-
ity of surface damage and lichenification compared to the
control group.
3. Stress-induced changes in skin barrier function in healthy

women. Altemus M et al. J Invest Dermatol. 2001
Aug;117(2):30917.
A study that measured psychologic interview stress, sleep
deprivation and exercise stress on skin barrier function in non-
atopic healthy women. They found that both sleep deprivation
and interview stress caused a delay in skin barrier function
recovery, as well as an increase in circulating inflammatory
markers such as TNF-alpha, while exercise stress did not cause
a delay in barrier recovery. This study is included because of its
rigorous demonstration that stress can induce skin barrier dis-
ruption, a central concept for understanding how stress-
relieving techniques may be helpful.
Case 1
A 9-month-old girl presents with a long history of severe
atopic dermatitis. Since about 2 months of age, she has had
disrupted sleep, constant scratching, and open, oozing, and
bleeding skin. She has had multiple courses of oral antibiotics
and has used a number of topical corticosteroids, sometimes
for months at a time. Despite this, she has had very little sus-
tained improvement. Her mother is very upset and explains
that she wants to get to the root of the problem rather than
just treat the symptoms. Moreover, she has read a great deal
on the internet about the dangers of topical steroids and
wants to avoid them completely, preferring to take a more
natural route.
Discussion
AD can cause a tremendous amount of misery for both the
patient and the family; the sleep disturbance alone can make for
unhappy, curt, and sometimes angry interactions. Unfortunately,
this case is not an uncommon scenario. Generally, from a con-
ventional standpoint, optimization of the four key areas would
likely result in significant improvement: aggressive moisturiza-
tion, optimized corticosteroid use with a more potent agent and
used with wet wrap therapy for up to 4-7 days until improved,
then resting the skin, and adding dilute bleach baths daily for
antimicrobial effects. Given the concerns about corticosteroids,
we must look to other agents for anti-pruritic and anti-inflam-
matory effects here, and we can use more natural agents to
cover several of these areas at once.
Topical sunflower seed oil offers anti-inflammatory, anti-
itch, and moisturizing properties and is safe and inexpensive;
perhaps integrating this with an infant massage once or twice
daily would also help relax the family and improve adherence.
A more occlusive moisturizer should be applied over the oil,
and this could be done after a dilute bleach bath, so that the
skin is clean and hydrated, then the oil is applied, and finally
an occlusive emollient seals everything in. Oral vitamin D
supplementation is also safe and inexpensive and could be
added, along with probiotics (which remain somewhat con-
troversial and walk the line between alternative and conven-
tional medicine). Finally, topical B12 cream or topical
cardiospermum plant extract cream could be used in lieu of a
corticosteroid for several weeks; close follow up might show
some significant improvement and perhaps more willingness
to try an appropriate corticosteroid for brief bursts in severe
areas. Looking forward, although such plans do not truly
Case 2 133
address the root of the eczema, by breaking the scratch-itch

cycle, restoring the skin, and allowing the patient to sleep
properly and fully heal, the severity of disease often decreases
significantly after such a period of rest, and can usher in a
remission-like phase.
Case 2
A 29-year-old man with a history of sensitive skin presents
with widespread erythema, scaling, and multiple excoriations
over most of the body, including the head and neck area.
There is significant scaling on the scalp. The patient notes that
he has multiple food allergies, seasonal allergies, and that it
seems that nearly everything triggers a flare in the past several
years. He reports that the itch is maddening and that he can-
not stop rubbing his face some nights. He has used many topi-
cal corticosteroids, topical calcineurin inhibitors, and finds
that only oral prednisone gives him relief, albeit short-lived.
Discussion
This variant of AD is very difficult to treat and the head and
neck involvement suggests that there may be a component of
malassezia yeast, although this is not fully elucidated or agreed
upon. From a conventional medicine standpoint, a trial of a
systemic anti-yeast agent such as itraconazole could be very
helpful if malassezia is indeed playing a role. Failing that, this
patient is a candidate for systemic immunosuppression with an
agent such as cyclosporine, in addition to maximizing moistur-
ization and topical anti-inflammatory therapy.
From an integrative standpoint, topical coconut oil may be
helpful as it has antimicrobial effects and is soothing and mois-
turizing. Traditional Chinese Medicine may also be of help here;
herbal remedies seem to have an effect on these more allergic
variants and those with asthma, so might be worth exploring.
Finally, given that itch is such an important component, using
the large intestine 11 point for home acupressure or suggesting
formal acupuncture treatments may have significant benefits in
controlling the disease.
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Chapter 10
Urticaria and Angioedema
Introduction
Urticaria, or hives, is a common condition with a lifetime
prevalence of approximately 25% (Williams and Sharma
2015). Transient dermal red pruritic papules and plaques
form due to the release of various mediators from mast cells.
These mediators include both histamine and prostaglandins
and cause increased vascular permeability leading to edema
and lesion progression. Urticaria may be difficult to treat and
can significantly impair quality of life. Angioedema is an
acute swelling of the dermis and subcutaneous tissue or the
mucosa and submucosal tissue. This rapid swelling can cause
emergent airway obstruction and may warrant urgent care.
Classification of urticaria is based on the duration of the epi-
sode. Urticaria of less than 6 weeks duration is considered
acute while episodes persisting more than 6 weeks are classi-
fied as chronic.
The pathogenesis of urticaria is poorly understood.
Potential triggers are identified in only 1020% of cases.
Triggers for urticaria are either allergic or non-allergic.
Allergic triggers include medications and food substances.
Non- allergic triggers include stress, infections (viral, bacterial,

DOI 10.1007/978-3-319-17816-5_10
138 10. Urticaria and Angioedema
fungal, or parasitic) physical factors (pressure, water, sunlight,

vibration, heat or cold), drugs (NSAIDS, opiates and many
others), thyroid disease, and autoimmune disorders, making it
difficult to pinpoint a cause.
Conventional treatments include antihistamines such as
fexofenadine, cetirizine, diphenhydramine, and hydroxyzine,
as well as more potent immunosuppressive agents such as
prednisone and cyclosporine. In dapsone, colchicine and
omalizumab, we find immunomodulatory agents that can be
helpful in some cases (Greenberger 2014). Overall, there is
no single agent or combination of agents that is curative.
Treatment can be challenging and associated with side
effects. Patients often pursue alternative treatments to pre-
vent flares, reduce symptom severity, or prevent relapse once
control is achieved. However, evidence validating the effi-
cacy of these approaches is limited. For example, dietary
modification, through supplementation or exclusion, is a
popular treatment modality. Health care professionals
should be aware of literature pertaining to nutrition and self-
directed therapy that patients may turn to in an effort to
control their urticaria.
Some alternative therapies that have been reported to
provide adjunctive relief of urticaria include stress reduction
via hypnosis or massage, Vitamin D supplementation, oral
flavonoids, and dietary modification. Each of these modali-
ties is discussed here.
See Fig. 10.1.
Stress Reduction 139
Fig. 10.1. Urticarial papules in a geographic arrangement.
Top Considerations
See Table 10.1.
Stress Reduction
Many authors suggest that psychological stress can exacer-
bate urticaria; however, the exact mechanism by which this
occurs is not well-understood (Spickett 2014 and Dave et al.

Vitamin D 4,000 IU daily by May improve urticaria
mouth for 12 weeks independent of baseline serum
vitamin D levels; generally safe
and well-tolerated
Stress- Hypnosis or May improve symptoms and
reduction meditation quality of life
Dietary Avoidance of May benefit some patients;
modification allergens and Difficult to confirm sensitivity
pseudoallergens to pseudoallergens and high-
quality evidence lacking
2011). The autonomic nervous system appears to suppress

the production of IL-12 via catecholamines and corticoids
which seems to play a role in regulatory function, thus
fueling the potential for inflammation (Dave et al. 2011).
While randomized controlled trials (RTC) are lacking, ben-
efit has been observed and reported utilizing stress reduc-
tion techniques to improve urticaria, without the risks of
medications. Stress reduction may also have other positive
effects on the patient, making it a reasonable adjunctive
approach for almost anyone.
Evidence for Stress Reduction
1. Hypnosis in dermatology. Shenefelt PD. Arch Dermatol.

2000 Mar;136(3):3939.
Comprehensive review article on hypnosis in dermatology that
discusses several older studies and case-series using hypnosis
for urticaria, including a study where 8 of 12 patients under
hypnosis demonstrated an inhibition of immediate-type hyper-
sensitivity (urticaria). The author concludes that hypnosis is
useful as a complementary or alternative therapy for chronic
urticaria.
2. Immediate-type hypersensitivity reactions and hypnosis:

problems in methodology. Laidlaw TM, Richardson DH,
Booth RJ, Large RG. J Psychosom Res. 1994;38:56980.
Vitamin D Supplementation 141
A study of five subjects with asthma were given hypnotic sug-

gestion to control their reaction to histamine administered by
skin prick to the forearm. These were compared to sessions
with a control using Verbally Active Distraction. Hypnosis
significantly reduced the flare size, although not the wheal size,
interestingly.
3. Effects of relaxation therapy and hypnotizability in chronic

urticaria. Shertzer CL, Lookingbill DP. Arch Dermatol.
1987;123:9136.
In a study of 15 patients with chronic urticaria of 7.8 years
average duration, treatment with hypnosis was found to be
beneficial. Six patients were clear at 14 months, eight improved,
and 80% of patients reported requiring less medication to
control their hives. The authors conclude that in select cases,
hypnosis may be useful as either a complementary or even
primary alternative therapy for chronic urticaria.
Vitamin D Supplementation
Vitamin D (cholecalciferol) is a fat-soluble hormone that
plays a number of roles in regulation of the immune system,
and thus may be relevant to allergic disease pathogenesis and
treatment (Benson et al. 2012). Importantly, patients with
chronic urticaria tend to have lower serum Vitamin D levels
compared to controls (Murzaku et al. 2014), but improve-
ment in urticaria has been reported in patients treated with
Vitamin D supplements with both low or normal baseline
levels of vitamin D. The optimized dosing and the mechanism
of action have yet to be determined, but this relatively safe
supplement is clearly worthy of consideration.
Evidence for Vitamin D Supplementation
1. Idiopathic itch, rash, and urticaria/angioedema merit serum

vitamin D evaluation: a descriptive case series. Goetz DW. W
V Med J. 2011 JanFeb;107(1):1420.
This retrospective series of 63 patients (age 380 years) with

urticaria/angioedema reported that 90% of patients had low
vitamin D levels (<32 ng/dl) and that urticaria resolved in 70%
of participants who took 50,000 IU of vitamin D per week for
23 months followed by daily supplementation. Notably, the
rate of response was better for those with lower baseline vita-
min D levels, and symptom recurrence was noted if the insuf-
ficiency recurred in the following months.
2. Resolution of chronic urticaria coincident with vitamin D

supplementation. Sindher SB, Jariwala S, Gilbert J, Rosenstreich
D. Ann Allergy Asthma Immunol. 2012;109:35936.
A case report of a 58-year-old man with generalized hives for
4 months in the setting of vitamin D deficiency. He was started
on 400 IU of vitamin D supplementation without much
improvement; when increased to 2,000 IU daily he had rapid
improvement of the urticaria and was found to have normal
vitamin D levels.
3. Beneficial role for supplemental vitamin D3 treatment in

chronic urticaria: a randomized study. Rorie A, Goldner WS,
Lyden E, Poole JA. Ann Allergy Asthma Immunol. 2014
Apr;112(4):37682.
A double blind prospective study of 42 chronic urticaria patients
treated with conventional therapy (cetirizine, ranitidine, and
montelukast) were randomized to receive high dose (4,000 IU
per day) or low dose (600 IU per day) vitamin D3 supplementa-
tion. The high dose group displayed beneficial trends towards
improvement in hives, improved sleep quality, and itch reduc-
tion. This benefit occurred independent of baseline Vitamin D
serum levels and no adverse events were reported.
Dietary Modification
The relationship between diet and urticaria is complex and
controversial. Foods have been reported to both exacerbate
urticaria and ameloriate it, illustrating the conflicting infor-
Dietary Modification 143
mation on this topic. Some patients with chronic urticaria

attribute flares to food intolerance, yet the actual number of
patients with documented food-sensitive urticaria is very low.
Despite a paucity of evidence for elimination diets and anti-
inflammatory diets in the management of urticaria, patients
often alter their diets on their own, sometimes perhaps out of
desperation The role of alcohol, gluten, and pseudoallergens
in producing urticaria have been recently reviewed (Murzaku
et al. 2014). Pseudoallergens, including artificial preservatives,
dyes, and aromatic compounds in processed and natural
foods, are hypothesized to induce intolerance and hypersen-
sitivity reactions. Distinct from the conventional notion of
allergies, they lack specific IgE antibodies. The existence of
pseudoallergens is not universally accepted and thus consid-
ered controversial. Nonetheless, pseudoallergens are postu-
lated to induce or aggravate chronic urticaria in a subset of
patients. Evidence in favor of pseudoallergen-free diets ben-
efiting urticaria patients, is, however, limited.
Gluten-free diets likely are only of benefit to urticaria
patients with documented celiac disease. Gluten avoidance in
the absence of celiac disease is likely of little value in the
management of chronic urticaria patients.
Evidence for Dietary Modification
1. Psuedoallergen-free diet in the treatment of chronic urti-

caria. A prospective study. Zuberbier T, Chaintraine-Hess S,
Hartmann K, Czarnetzki BM. Acta Derm Venereol.
1995;75:4847.
This prospective study of 64 chronic urticaria patients screened
for common causes and then evaluated for potential benefits of
a stringent pseudoallergen-free diet. 73% of patients improved
within 2 weeks. However, only 19% of responders reacted to
pseudoallergens on provocation tests. Follow up at 6 months
showed complete remission in 46% of patients. The authors
propose that stringent additive-free diets may benefit some
patients with chronic idiopathic urticaria.
2. Prevalence of sensitivity to food and drug additives in

patients with chronic idiopathic urticaria. Rajan JP, Simon
RA, Bosso JV. J Allergy Clin Immunol Pract. 2014
MarApr;2(2):16871.
100 patients with chronic urticaria were tested to see if food
additives produced reactivity. Fewer than 1% were confirmed
to have positive reactions using a single blind challenge
followed by double blind placebo controlled challenges for
confirmation. The authors conclude that sensitivity to food
additives is rare and that pseudoallergen avoidance is not
recommended.
3. Urticaria and adult celiac disease. Scala E, Giani M, Pirrotta

L, Guerra EC, De Pit O, Puddu P. Allergy. 1999 Sep;54(9):
10089.
A 24-year old patient with worsening chronic urticaria was
tested and found to have celiac disease. She was reported to
have complete resolution of urticarial lesions and reduction of
anti-gliadin antibodies after adherence to a gluten free diet for
1 month, and remained clear at 1 year.
Case 1
A 34 year-old healthy woman with an 8-month history of
urticaria but no other active medical problems is referred to
you by her allergist for a skin biopsy to exclude urticarial
vasculitis. Her lesions last up to 24 hours and fail to clear with
cetirizine 10 mg PO QAM and fexofenadine 180 mg PO
QHS. Prednisone has temporarily cleared the lesions, but the
hives relapse after discontinuing oral corticosteroid therapy.
The skin biopsy is negative for urticarial vasculitis and the
patient expresses her frustration. She indicates that she is
prepared to follow a gluten-free diet and asks if you believe
this will be of benefit.
References 145
Discussion
You review with the patient that there is little evidence that
gluten-free diets help chronic idiopathic urticaria in the
absence of celiac disease. You should discourage her from this
approach, but could suggest further workup if she has not been
adequately evaluated. You could also discuss the possible role
of a pseudoallergen-free diet, as some evidence exists that it
may be helpful in some cases, and discuss stress-reduction
approaches such as hypnosis, which may be of benefit.
Case 2
A 26-year-old male with a 2-year history of urticaria presents
with chronic idiopathic urticaria. While daily cetirizine has
given him fairly good control, he prefers an alternative approach
and wishes to try vitamin D supplementation. You check his
serum Vitamin D level and it is within the normal range. Is
there a role for Vitamin D supplementation in this setting?
Discussion
In this case, you could cite a recent RTC that found that high
dose Vitamin D supplementation (4,000 IU/day) improved
chronic urticaria independent of baseline vitamin D status. You
can support the use of this dose for up to 12 weeks and note
that this can be done in conjunction with cetirizine.
References
Benson AA, Toh JA, Vernon N, Jariwala SP. The role of vitamin D in
the immunopathogenesis of allergic skin diseases. Allergy.
2012;67(3):296301.
Dave ND, Xiang L, Rehm KE, Marshall Jr GD. Stress and allergic
diseases. Immunol Allergy Clin North Am. 2011;31(1):5568.
Greenberger PA. Chronic urticaria: new management options. World

Allergy Organ J. 2014;7(1):31.
Murzaku EC, Bronsnick T, Rao BK. Diet in dermatology: Part

II. Melanoma, chronic urticaria, and psoriasis. J Am Acad
Dermatol. 2014;71(6):1053.e1e16.
Spickett G. Urticaria and angioedema. J R Coll Physicians Edinb.

2014;44(1):504.
Williams KW, Sharma HP. Anaphylaxis and urticaria. Immunol

Allergy Clin North Am. 2015;35(1):199219.
Chapter 11
Disorders of Pigmentation
Introduction
A substantial area of general dermatology comprises
pigmentary complaintseither too much pigmentation or
too little. From lentigines (sun spots), melasma, and post-
inflammatory hyperpigmentation, to pityriasis alba and vitil-
igo, there is a spectrum of disorders that results in dark or
light areas on the skin. Some of these are addressed in other
sections more directly; here we will focus exclusively on the
aspect of color. While generally not possessing serious under-
lying medical implications, dyspigmentation can have devas-
tating psychological effects and a significant impact on the
quality of life of patients (Lieu and Pandya 2012).
From a scientific standpoint, alterations in melanocyte
density, melanin concentration, or both can result in anoma-
lies of skin pigmentation (Nicolaidou and Katsambas 2014).
Some diseases of hyperpigmentation such as melasma may
have an epidermal component (which often responds to topi-
cal therapies), a dermal component (which is very difficult to
treat), or may be mixed (Sanchez et al. 1981).
Melasma is the representative disease in the category of
hyperpigmentation, and its pathogenesis appears to be multi-
factorial: genetics, hormones and sun exposure all appear to
play a role (Grimes 1995). Patients with melasma, sometimes
called the mask of pregnancy, often give a history of
current or previous oral contraceptive use, and the signs of

DOI 10.1007/978-3-319-17816-5_11
148 11. Disorders of Pigmentation
melasma may continue many years after such hormonal

changes have ceased.
Beyond stressing the importance of strict sun protection
and avoidance, conventional treatment regimens for melasma
generally involve the use of hydroquinonea bleaching
agent that appears to disrupt pigment synthesiswhich may
cause irritant contact dermatitis and, rarely, permanent
hyperpigmentation due to the development of exogenous
ochronosis (primarily seen when hydroquinone is used in
higher than recommended concentrations and/or prolonged
periods of time). Hydroquinone is generally considered to be
safe, and there has been no evidence linking topical hydroqui-
none to malignancy; however, public concerns about its safety
arose when the FDA classified hydroquinone as having some
evidence of carcinogenicity in animal studies, and recom-
mended further study of this medication (Nordlund et al.
2006). Continuous use of hydroquinone is not recommended
for longer than 34 months.
The most effective treatments for melasma and for hyper-
pigmentation in general appear to be combinations of hydro-
quinone along with other agents, particularly retinoids and
corticosteroids, both of which have pertinent risks as well
(Rivas and Pandya 2013). Alternative therapies, therefore,
play a crucial role in the treatment of melasma, either as true
alternatives to hydroquinone or as treatment options during
a hydroquinone holiday. While some of the studies men-
tioned in this chapter involved only melasma patients, their
results may be extrapolated to include patients with other
forms of hyperpigmentation such as solar lentigines and post-
inflammatory hyperpigmentation, as many skin lightening
agents may be effective in more than one form of
hyperpigmentation.
Vitiligo represents the other end of the spectrum, with
total loss of melanocytes from an area. Affecting some 14%
of the world population, with more than 50% appearing
before age 20 (Szczurko and Boon 2008), it is thought to be
an autoimmune disease whereby the actual pigment-
producing cells are destroyed (Speeckaert et al. 2015).
Vitamin C 149
However, there are other hypotheses proposed such as a

cytotoxic mechanism due to increased oxidative stress, and
debate continues about the actual pathophysiology, raising
the question that there may exist various subtypes with dis-
tinct pathogeneses. Vitiligo is also notoriously difficult to
treat (Speeckaert et al. 2015). Conventional therapy focuses
on topical anti-inflammatory preparations (corticosteroids
and calcineurin inhibitors) which have a number of risks,
particularly when used long-term, and light-based treatments,
particularly narrow-band ultraviolet B phototherapy and the
very similar excimer laser (Nicolaidou and Katsambas 2014).
In severe cases of widespread disease that is refractory, a
powerful permanent bleaching option called monobenzyl
ether or hydroquinone (essentially a more potent cousin of
hydroquinone discussed above) can be used to remove the
remaining pigmentation to achieve uniform color. When
these are ineffective or not possible due to time, risk, or cost,
alternatives become an important part of the discussion for
patients who do not want to use cosmetic cover-up or just
live with it.
Top Considerations
See Tables 11.1, 11.2, and 11.3.
Evidence for treating Hyperpigmentation:
Vitamin C
Vitamin C is the most abundant water-soluble antioxidant in
human skin; it cannot be synthesized by the body and must be
obtained through oral or topical consumption. Oral vitamin
C consumption does not significantly increase cutaneous
concentration, so topical formulations of vitamin C have
been extensively studied for their role in treating photodam-
age and cutaneous aging, but reports of improvement in
Table 11.1. Top considerations for hyperpigmentation.

Topical Applied topically daily Measurably effective, very
vitamin C or twice daily; oral safe; must carefully select
consumption does not preparation to ensure activity
result in significant
cutaneous absorption
Soy Topically once to Modest effect, unclear which
twice daily, a variety of formulation is best, generally
formulations exist appears safe
Niacinamide Tocally or orally, often Modest effect, Generally
in combination with considered safe
other products
Licorice Topically, often in Appears effective;
extract combination with other Standardized concentrations
skin lightening agents not established, may be
difficult to find commercially
Table 11.2. Top considerations for vitiligo.

Ginkgo biloba Orally at 60 mg Modest effect at slowing
twice daily or 40 mg progression of vitiligo,
three times daily suggestion of repigmentation
of standardized in some; caution in patients
preparation on anticoagulants as can
increase bleeding risk
Polypodium Orally 750 mg daily Some effect in improving
leucotomos repigmentation when used
with NB-UVB and PUVA;
safe but can be expensive in
the longer term
l-Phenylalanine Orally 50100 mg/kg/ Uncertain effect and may
day (suggested); also require UVA phototherapy;
topically 10% safe, inexpensive
Table 11.3. Secondary considerations for vitiligo.

Vitamins B12 (1,000 mcg BID) Likely small effect if any, or
and folate (5 mg BID) or may be limited to effect only in
E (900 IU daily) certain subtypes; safe
Vitamin C 151
dyspigmentation make it a valuable consideration. Its depig-

menting properties may work via chelation of copper ions
using in the enzymes for pigment synthesis (Rivas and
Pandya 2013). The active form of vitamin C, l-ascorbic acid,
is very difficult to formulate as it easily oxidizes and becomes
unstable in solution, thus vitamin C esters have been created
that may be more stable. Nevertheless, vitamin-C containing
products should be carefully selected before use to ensure
that they contain a stabilized vehicle with an effective con-
centration and optimal pH (Farris 2005).
Evidence for Vitamin C
1. A double-blind randomized trial of 5% ascorbic acid vs. 4%

hydroquinone in melasma. Espinal-Perez LE, Moncada B,
Castanedo-Cazares JP. Int J Dermatol. 2004 Aug;43(8):6047.
A double-blind, randomized trial of 16 women with melasma
who received either 5% ascorbic acid cream on one side of the
face and 4% hydroquinone on the other for 16 weeks in addi-
tion to using sunscreen regularly. Hydroquinone was signifi-
cantly better than the ascorbic acid (93% good to excellent
results vs. 62.5% for ascorbic acid), but side effects (irritation)
were far more common in the hydroquinone group (11/16 vs.
1/16). The lack of significant side effects, yet still some measur-
able efficacy makes ascorbic acid a reasonable consideration
as adjunct or alone.
2. A randomized, double-blind, placebo-controlled trial of vita-

min C iontophoresis in melasma. Huh CH, Seo KI, Park JY,
Lim JG, Eun HC, Park KC. Dermatology. 2003;206(4):31620.
A randomized, double-blind placebo-controlled trial of
29 women with melasma, where a vitamin C solution was
administered with iontophoresis to enhance penetration to one
side of the face vs. distilled water on the other for 12 weeks.
At the conclusion of the experiment, there was a significant
difference as measured by colorimetry of the treated side

(P = 0.002), suggesting that vitamin C is effective for treating
melasma when used with iontophoresis. Unfortunately, this is
not a readily-available setup, and may be difficult to reproduce
in a home setting.
Soy
Soybeans, rich in protein and touted for their many potential
health benefits, are being increasingly studies for their use in
many diseases. Soy contains the serine protease inhibitors
soybean trypsin inhibitor (STI) & Bowman-Birk protease
inhibitor, both of which prevent melanosome transfer to
keratinocytes via inhibition of PAR-2 receptors present on
keratinocytes (Paine et al. 2001). Soy extracts have also been
shown to inhibit UVB-induced skin damage in vitro, making
them good candidates for consideration in treating increased
pigmentation (Chen et al. 2008). However, the actual clinical
evidence is somewhat sparse, underscoring the need for fur-
ther study.
Evidence for Soy
1. Efficacy of a soy moisturizer in photoaging: a double-blind,

vehicle-controlled, 12-week study. Wallo W, Nebus J, Leyden
J. J Drugs Dermatol. 2007;6(9):91722.
65 women with photodamaged facial skin were randomized to
receive a soy moisturizer containing nondenatured serine pro-
tease inhibitors or its vehicle; both the active moisturizer and
vehicle contained SPF 30. Subjects applied the product to the
face twice daily for 12 weeks. Subjects in both group demon-
strated improvement in multiple parameters of photodamage
(including mottled pigmentation), but the active group was
found to be superior to vehicle (P < .05).
Niacinamide 153
2. Effects of soy on hyperpigmentation in Caucasian and

Hispanic populations. Gonzalez R, Cauwenbergh G. Poster
presented at: 59th Annual Meeting of the American Academy
of Dermatology. March 27, 2001; Washington, DC.
A study of 16 women of Hispanic heritage with mottled facial
pigmentation, that used a stabilized total soy extract applied
daily to the areas of dyspigmentation for 12 weeks, with
untreated areas of dyspigmentation as controls. Improvements
were observed in 14 of the 16 subjects, with a mean reduction
in hyperpigmentation of 12%. This was a small study, and has
not appeared in the peer-reviewed literature, so it is difficult to
extrapolate these findings widely, but this is suggestive of at
least a modest effect of topical soy.
Niacinamide
Niacinamide (also known as nicotinamide) is a form of vita-
min B3. It has been shown in vitro to inhibit the transfer of
melanocytes to keratinocytes (Hakozaki et al. 2002), and has
been studied for its effect of cutaneous hyperpigmentation.
Niacinamide also functions as an anti-oxidant, which may be
useful in prevention of further pigmentation (Otte et al.
2005). It is used in several other contexts safely (e.g., acne and
auto-immune bullous diseases), is inexpensive, and readily
available in a number of formulations making it an attractive
adjunctive therapy for pigmentation.
Evidence for Niacinamide
1. A double-blind, randomized clinical trial of niacinamide

4% versus hydroquinone 4% in the treatment of melasma.
Navarrete-Solis J, Castaned-Cazares J, Torres-Alvarez B,
Oros-Ovalle C, Fuentes-Ahumada C, Gonzaled F, Martinez-
Ramierz J, Moncada B. Dermatol Res Pract. 2011;2011:379173.
A split-face study of 27 patients with melasma, who applied
4% niacinamide cream to one side of the face and 4%
hydroquinone cream to the other side once daily for 4 weeks.

Colorimetry testing did not reveal significant differences
between the treated sides; however, good to excellent subjec-
tive improvement was noted on both the niacinamide side
(44% of patients) and the hydroquinone side (55% of
patients). Histologic evaluation showed a reduction in mast
cell infiltration on the niacinamide side.
2. The effect of niacinamide on reducing cutaneous pigmenta-

tion and suppression of melanosome transfer. Hakozaki T,
Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K,
Greatens A, Hillebrand G, Bissett D, Boissy R. Br J Dermatol.
2002;147(1):2031.
This was both an in vitro and clinical study of the effects of
niacinamide on melanogenesis and hyperpigmentation. In the
clinical portion, a split-face study of 18 patients with hyperpig-
mentation was performed with 5% niacinamide moisturizer
and vehicle. Additionally, 120 patients with a facial tan were
randomly assigned to receive 2% niacinamide with sunscreen,
suncreen alone, or vehicle. The authors report a significant
decrease in hyperpigmentation with niacinamide in both
groups after 4 weeks.
3. The effects of a daily facial lotion containing vitamins B3

and E and provitamin B5 on the facial skin of Indian women:
a randomized, double-blind trial. Jerajani HR, Mizoguchi H,
Li J, Whittenbarger DJ, Marmor MJ. Indian J Dermatol
Venereol Leprol. 2010 JanFeb;76(1):206.
A 10-week randomized control study of 246 Indian women
with facial hyperpigmentation using a topical lotion with a
combination of 4% niaciniamide, 0.5% panthenol and 0.5%
tocopheryl acetate and sunscreen vs. a control moisturizer. The
results demonstrated that the experimental group had signifi-
cant improvement in pigmentation at 10 weeks. However, this
is a difficult study to interpret given the multiple agents and the
inclusion of a sunscreen in the treatment group.
Licorice 155
Licorice
Licorice root (glycyrrhiza glabra) has been shown to inhibit
tyrosinase (a rate-limiting enzyme that controls the produc-
tion of melanin) and also possesses anti-oxidant and anti-
inflammatory properties (Adhikari et al. 2008). Licorice
root contains several components known to affect melanin
production: glabridin has been found to the constituent with
the most potent inhibitory effect on tyrosinase (Kim and
Uyama 2005). Licorice extract is found in many over-the-
counter skin lightening preparations in varying concentra-
tions, often combined with other ingredients potentially for
a synergistic effect.
Evidence for Licorice
1. Comparison of efficacy of topical 2% liquiritin, topical 4%

liquiritin and topical 4% hydroquinone in the management of
melasma. Zubair S, Mujtaba G. J Pak Assoc Dermatol.
2009;19:15863.
In this 8 week study, ninety patients with melasma were divided
into three treatment groups: 4% hydroquinone, 4% liquiritin
and 2% liquiritin. Interestingly, the researchers comment on
the number of married versus unmarried patients; the rele-
vance of this information is unclear. Final assessment was
done at 16 weeks; efficacy was measured by intensity of pig-
ment, lesion size and photographic appearance. The authors
report improvement in 96.7% of patients in the 4% liquiritin
group, 86.6% in the 2% liquiritin group, and 73.3% in the 4%
hydroquinone group. No adverse effects were observed in the
liquiritin treated groups at either concentration; in the hydro-
quinone group, two patients developed contact dermatitis and
one patient developed hyperpigmentation. The authors suggest
that liquiritin cream is a more effective depigmenting agent
than hydroquinone.
2. Topical liquiritn improves melasma. Amer M, Metwalli

M. Int J Dermatol. 2000;39(4):299301.
In this split-face study, 20 women with symmetric epidermal
melasma (as determined by Woods lamp examination) applied
liquiritin cream to one side of the face and vehicle cream to the
other side twice daily for 4 weeks. Sunscreen and/or sun avoid-
ance were also recommended. Intensity of pigment, lesion size
and overall improvement were assessed at 4 weeks; the authors
reported a good to excellent response in 90% of subjects
(18/20 women). The amount of liquiritn cream in this study
was 1 g/day; however, the precise formulation of the cream is
not provided.
Evidence for treating Depigmentation due to Vitiligo:
Ginkgo Biloba
Ginkgo biloba is a unique species of tree found in China,
widely cultivated and used in traditional medicines. Although
a specific mechanism of action is not known for ginkgo, it
appears to have anti-inflammatory, immunomodulatory, and
antioxidant properties all of which could potentially help in
vitiligo which may have an oxidative stress component
(Szczurko and Boon 2008). Interestingly, psychological stress
may play a role in vitiligo, and there is evidence that ginkgo can
have anxiolytic effects that may also be useful (Woelk et al.
2007). Indeed, this category of effect may in part by responsi-
ble for cognitive improvements in humans with dementia
(Szczurko and Boon 2008). In terms of safety, there is a litera-
ture that suggests it can increase risk of bleeding in some sce-
narios, particularly for patients on anticoagulants, but this does
not appear to be a major risk for otherwise healthy patients
(Mili et al. 2014). Its relative safety, low cost, and ease of
administration make it a very appealing option for vitiligo, but
it probably does not have pigment-stimulating effects directly
and is most likely limited to vitiligo because of this.
l-Phenylalanine 157
Evidence for Ginkgo Biloba
1. Ginkgo biloba for the treatment of vitilgo vulgaris: an open

label pilot clinical trial. Szczurko O, Shear N, Taddio A, Boon
H. BMC Complement Altern Med. 2011 Mar 15;11:21.
An open label pilot of 12 patients treated with 60 mg of gingko
biloba twice daily for 12 weeks, and followed using the Vitiligo
Area Scoring Index (VASI). There was significant improve-
ment (p = 0.021) in the VASI score and vitiligo spread, and no
significant changes in platelet count, PTT, or INR. This sug-
gests some efficacy for gingko and reassures about bleeding
risk in a population that is otherwise healthy.
2. Effectiveness of oral Ginkgo biloba in treating limited,

slowly spreading vitiligo. Parsad D, Pandhi R, Juneja A. Clin
Exp Dermatol. 2003 May;28(3):2857.
A double-blind, placebo-controlled study of 52 patients with
vitiligo, randomized to ginkgo biloba 40 mg three times daily
or placebo control. At 6 months, there was significant decrease
in disease progression in the treatment group vs. control
(p = 0.006) and a trend towards repigmentation in the treat-
ment group as well. Only mild nausea was reported by
2 patients, suggesting that this may be a useful option, espe-
cially in slowly-progressing disease.
l-Phenylalanine
Phenylalanine is an essential amino acid involved in melanin
synthesis. It is widely available and is part of dietary proteins
and supplements. In vitiligo treatment, supplemental l-
phenylalanine is thought to provide a substrate for melanin
synthesis, and is generally used along with ultraviolet photo-
therapy to encourage repigmentation (Tamesis and Morelli
2010). While it appears very safe, the age of the studies and lack
of recent evidence is not reassuring. Larger well-designed trials
would greatly help to answer the question of its efficacy and

determine if there is a place for l-phenylalanine in modern
treatment.
Evidence for L-Phenylalanine
1. Phenylalanine plus ultraviolet light: preliminary report of a

promising treatment for childhood vitiligo. Schulpis CH,
Antoniou C, Michas T, Strarigos J. Pediatr Dermatol. 1989
Dec;6(4):3325.
A pilot study of 13 children who took oral L-phenylalanine
followed by ultraviolet light (UVA) treatment. 3/13 experi-
enced repigmentation of all affected areas, while 6/13 showed
5090% improvement. 4/13 failed to respond. No side effects
were reported.
2. Vitiligo therapy with oral and topical phenylalanine with

UVA exposure. Antoniou C, Schulpis H, Michas T, Katsambas
A, Frajis N, Tsagaraki S, Stratigos J. Int J Dermatol. 1989
Oct;28(8):5457.
21 patients with vitiligo were divided into groups, both taking
L-phenylalanine orally in a dose of 100 mg/kg/day and receiv-
ing UVA phototherapy, but one group additionally receiving a
topical cream with 10% L-phenylalanine. The group that
received the cream was reported to have superior results, and
no side effects were noted.
3. l-phenylalanine and UVA irradiation in the treatment of

vitiligo. Siddiqui AH, Stolk LM, Bhaggoe R, Hu R, Schutgens
RB, Westerhof W. Dermatology. 1994;188(3):2158.
An open trial of 149 patients with vitiligo and a small double-
blinded trial of 32 patients looked at oral administration of
L-phenylalanine followed by UVA phototherapy found supe-
rior improvement in the L-phenylalanine groups. They suggest
that optimal dosing may be lower than 50 mg/kg/day of
L-phenylalanine, and UVA exposure should be administered
between 3045 min after ingestion.
Vitamins 159
Vitamins
In the search for safe, effective alternatives to treat vitiligo, cer-
tain vitamins have been suggested as potentially being thera-
peutic. Specifically, vitamin B12 deficiency has been correlated
with vitiligo, possibly as part of multi-system autoimmunity
(Shankar et al. 2012). Patients often ask about vitamins for vit-
iligo, cementing their presence here. Unfortunately, there is
extremely limited data available, but the sparse evidence seems
to suggest that folate, B12, or vitamin E supplementation will
probably not make a significant difference for most.
Evidence for Vitamins
1. Treatment of vitiligo vulgaris with narrow band UVB

(311 nm) for one year and the effect of addition of folic acid
and vitamin B12. Tjioe M, Gerritsen MJ, Juhlin L, van de
Kerkhof PC. Acta Dermato-Venereologica. 2002;82(5):
36972.
Randomized study of 27 patients with stable vitiligo received
either UVB phototherapy alone, or UVB + vitamin B12 (1,000
mcg BID) and folate (5 mg BID) for 1 year. 92% of patients
had complete or nearly-complete repigmentation, and there
was no difference between the groups. This study, while inter-
esting, is very limited in that it does not examine the role of
B12/folate in the absence of phototherapy, which could be very
useful in cases where phototherapy is not an option.
2. The effects of vitamin E on the skin lipid peroxidation and

the clinical improvement in vitiligo patients treated with
PUVA. Akyol M, Celik VK, Ozcelik S, Polat M, Marufihah M,
Atalay A. Eur J Dermatol. 2002;12(1):2426.
30 patients were divided into psoralen plus UVA therapy
(PUVA) or PUVA plus vitamin E (900 IU daily by mouth) for
6 months. At the conclusion of the study, there was no signifi-
cant difference between the groups clinically, but there was a
notable difference in levels of lipoperoxides suggesting that
vitamin E may prevent oxidative stress, something that has

been hypothesized to play a role in vitiligo. Like the above
study, it is very difficult to make a firm conclusion without
more information given the small size of the study and the lack
co-administration of PUVA, so further work is necessary.
Polypodium Leucotomos
Polypodium leucotomos (PL) is an extract from an indigenous
fern from Central and South America, used in traditional medi-
cine for inflammatory diseases of the skin (Palomino 2015).
When taken orally, there is a sizable body of evidence that PL
decreases sensitivity to ultraviolet radiation, blocking sunburn,
decreasing DNA damage and slowing tumor development, in
part due to its antioxidant properties (Middelkamp-Hup et al.
2004). Given the oxidative stress hypothesis for vitiligo, these
properties make PL a potential therapeutic candidate.
Evidence for Polypodium Leucotomos

1. Systemic immunomodulatory effects of Polypodium leu-
cotomos as an adjuvant to PUVA therapy in generalized vit-
iligo: A pilot study. Reyes E, Jan P, de las Heras E, Carrin F,
Alvarez-Mon M, de Eusebio E, Alvare M, Cuevas J, Gonzlez
S, Villarrubia VG. J Dermatol Sci. 2006 Mar;41(3):2136.
A small, randomized placebo-controlled trial of 19 patients
with generalized vitiligo, received PUVA with or without PL
(720 mg orally daily with an additional dose of 720 mg given
1 hour before UVA irradiation) for 12 weeks. At the end of the
study, there was a significant improvement in those with 50%
skin repigmentation or more in the PL group compared to
placebo, suggesting that PL can play a role as an adjunctive
therapy in vitiligo.
2. Treatment of vitiligo vulgaris with narrow-band UVB and

oral Polypodium leucotomos extract: a randomized double-
Case 2 161
blind placebo-controlled study. Middelkamp-Hup MA, Bos

JD, Rius-Diaz F, Gonzalez S, Westerhof W. J Eur Acad
Dermatol Venereol. 2007 Aug;21(7):94250.
A randomized, placebo-controlled trial of 50 patients with
vitiligo who received Narrow Band UVB (NB-UVB) photo-
therapy twice weekly with or without PL (250 mg orally thrice
daily) for 26 weeks. The study found that repigmentation was
significantly higher in the PL group for those patients who
were more adherent to the NB-UVB schedule (p < 0.002), and
nearly reached significance when all were considered (p = 0.06).
Interestingly, these findings only applied to the head and neck
area and not to other areas of the body where there was no
significant difference. These data support a role for PL in
vitiligo as an adjuvant therapy with NB-UVB.
Case 1
A 42 year-old woman presents for melasma and some solar
lentigines on the face. She has tried hydroquinone in the past
and had some improvement, but is now concerned about the
side effects of this medication and is not interested in chemi-
cal peels or intense pulsed light therapy. What are some inte-
grative options for her?
Discussion
In addition to stressing strict, daily photoprotection with a
broad-spectrum sunscreen (perhaps containing soy as well), she
may benefit from a trial of a topical vitamin C preparation twice
daily, and perhaps a topical licorice formulation if available.
Case 2
A 17 year-old boy presents with a 3-year-history of general-
ized vitiligo that continues to worsen. He tried topical corti-
costeroids for many months and developed striae on the arms
which he and his family are very upset about. They are inter-
ested in safe, alternative options for his vitiligo.
Discussion
Phototherapy, preferably NB-UVB, two to three times weekly
would be an excellent start for him. It is relatively safe and prob-
ably has the best evidence of the conventional treatments. If the
family were open to this, Polypodium leucotomos taken daily
and 1 hour before phototherapy may enhance repigmentation
and may decrease some of the risks of UV irradiation to the skin.
If phototherapy were not possible (or perhaps in addition to
the above), Ginkgo biloba could be recommended twice daily
with the caveat about potentially increasing bleeding risk in
some settings.
References
Adhikari A, Devkota H, Takano A, Masuda K, Nakane T, Basnet P,
Skalko-Basnet N. Screening of Nepalese crude drugs tradition-
ally used to treat hyperpigmentation: in vitro tyrosinase inhibi-
tion. Int J Cosmet Sci. 2008;30(5):35360.
Chen N, Scarpa R, Zhang L, Seiberg M, Lin C. Nondenatured soy

extracts reduce UVB-induced skin damage via multiple mecha-
nisms. Photochem Photobiol. 2008;84(6):15519.
Farris PK. Topical vitamin C: a useful agent for treating photoaging

and other dermatologic conditions. Dermatol Surg. 2005;31(7 Pt
2):8147. discussion 818.
Grimes P. Melasma: etiologic and therapeutic considerations. Arch

Dermatol. 1995;131(12):14537.
Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A,

Miyamoto K, Greatens A, Hillebrand G, Bissett D, Boissy R. The
effect of niacinamide on reducing cutaneous pigmentation and
suppression of melanosome transfer. Br J Dermatol. 2002;147(1):
2031.
References 163
Kim Y, Uyama H. Tyrosinase inhibitors from natural and synthetic

sources: structure, inhibition mechanism and perspective for the
future. Cell Mol Life Sci. 2005;62(15):170723.
Lieu TJ, Pandya AG. Melasma quality of life measures. Dermatol

Clin. 2012;30(2):26980. 2.
Middelkamp-Hup MA, Pathak MA, Parrado C, Goukassian D, Rius-

Daz F, Mihm MC, Fitzpatrick TB, Gonzlez S. Oral Polypodium
leucotomos extract decreases ultraviolet-induced damage of
human skin. J Am Acad Dermatol. 2004;51(6):9108.
Mili N, Milosevi N, Golocorbin Kon S, Bozi T, Abenavoli L,

Borrelli F. Warfarin interactions with medicinal herbs. Nat Prod
Commun. 2014;9(8):12116.
Nicolaidou E, Katsambas AD. Pigmentation disorders: hyperpig-

mentation and hypopigmentation. Clin Dermatol. 2014;32(1):
6672.
Nordlund J, Grimes P, Ortonne P. The safety of hydroquinone. J Eur

Acad Dermatol Venereol. 2006;20(7):7817.

Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M. An

alternative approach to depigmentation by soybean extracts via
inhibition of the PAR-2 pathway. J Invest Dermatol.
2001;116(4):58795.
Palomino OM. Current knowledge in Polypodium leucotomos effect

on skin protection. Arch Dermatol Res. 2015;307(3):199209.
Rivas S, Pandya AG. Treatment of melasma with topical agents, peels

and lasers: an evidence-based review. Am J Clin Dermatol.
2013;14(5):35976.
Sanchez N, Pathak M, Sato S, Fitzpatrick T, Sanchez J, Mihm

M. Melasma: a clinical, light microscopic, ultrastructural, and immu-
nofluorescence study. J Am Acad Dermatol. 1981;4(6):698710.
Shankar DS, Shashikala K, Madala R. Clinical patterns of vitiligo

and its associated co morbidities: A prospective controlled cross-
sectional study in South India. Indian Dermatol Online
J. 2012;3(2):1148.
Speeckaert R, Speeckaert MM, van Geel N. Why treatments do(nt)

work in vitiligo: An autoinflammatory perspective. Autoimmun
Rev. 2015;14(4):33240.
Szczurko O, Boon HS. A systematic review of natural health

product treatment for vitiligo. BMC Dermatol. 2008;8:2.
doi:10.1186/1471-5945-8-2.
Tamesis ME, Morelli JG. Vitiligo treatment in childhood: a state of

the art review. Pediatr Dermatol. 2010;27(5):43745.
Woelk H, Arnoldt K, Kieser M, Hoerr R. Ginkgo biloba special

extract EGb 761 in generalized anxiety disorder and adjustment
disorder with anxious mood: A randomized, double-blind,
placebo-controlled trial. J Psychiatr Res. 2007;41:47280.
Chapter 12
Warts and Molluscum
Introduction
Despite the fact that they are benign and generally self-
limited, warts and molluscum are responsible for an inordi-
nately high percentage of dermatology consultations: warts
alone constitute some 21% of all dermatology referrals
(Boull and Groth 2011), while molluscum has an estimated
prevalence in children of up to 11.5% (Olsen et al. 2014).
Warts are caused by the human papillomavirus (HPV) and
can infect epithelial and mucosal tissue throughout the body.
Certain strains have predilections for particular body areas,
such as HPV-2, HPV-27, and HPV-57 for warts on the hands
and feet (Tomson et al. 2011). Although warts often appear as
solitary, defined lesions, the virus may be present at distant
sites and may persist for many years. Conventional therapy is
focused on stimulating the innate immune response to the
virus via tissue destruction and irritation (Micali et al. 2004).
This comes to bear on the fact that over half of patients
report moderate-to-severe discomfort from their warts
(Ciconte et al. 2003), an aspect of warts that is often over-
looked, and is almost certainly exacerbated by destructive
and irritating therapies. Thus, it is possible that for this reason,
or perhaps because of the fact that even the best conventional
therapies rarely demonstrate efficacy above 60% that many
are drawn to alternative treatments.

DOI 10.1007/978-3-319-17816-5_12
166 12. Warts and Molluscum
The molluscum contagiosum virus (MCV) is the poxvirus

responsible for the small, dome-shaped, umbilicated papules of
molluscum. Similar to warts, these generally benign lesions can
spread via water, such as baths and pools, and from close con-
tact. Molluscum is more common in children with atopic derma-
titis, suggesting a role for skin barrier function in their prevention
(Braue et al. 2005). Patients often present with multiple lesions,
and there may be an associated dermatitis that can complicate
matters clinically and add to the discomfort. Conventional
therapy is nearly identical to that of warts, with an emphasis on
destruction and irritation, including cryotherapy, curettage,
and topical salicylic acid. As with warts, some conventional
therapies may make things worse (Katz 2014), thus opening up
the possibility for nonconventional treatments.
Fig. 12.1. Verrucous papules on the thumb.

Propolis 167
Fig. 12.2. Numerous dome-shaped umbilicated papules on the trunk

of a child characteristic of molluscum.
Top Considerations for Warts

See Table 12.1.
Propolis
Propolis is a botanical, resinous mixture that serves as a seal-
ant in bee hives, and has been used since antiquity as a medi-
cine (Kuropatnicki et al. 2013). In more modern times, it has
shown promise as an immunomodulator, suggesting a mecha-
nism of action in this setting (Sforcin 2007).
Evidence for Propolis
1. Propolis as an alternative treatment for cutaneous warts.

Zedan H, Hofny ER, Ismail SA. Int J Dermatol. 2009
Nov;48(11):12469.
Table 12.1. Top considerations for wart treatment.

Propolis Orally at 500 mg Safe, inexpensive, may have
daily immunomodulatory effects; risk of
allergy in bee-sensitive population
Zinc Orally at 10 mg/ Relatively safe, fairly compelling
kg/d up to 600 mg/d evidence; significant rate of nausea
of zinc sulfate; and gastrointestinal distress for oral
topically as 20% administration
ointment or 10%
solution twice daily
Garlic Freshly cut piece Safe, inexpensive, likely works by
rubbed to lesions irritant mechanism but may have
at night anti-viral effects as well; can be very
irritating and damaging if piece
of garlic affixed to skin, extract
preparation not readily available
135 patients were examined in a single-blind, randomized

controlled trial on warts. The propolis was dosed at 500 mg per
day for 3 months and cure was found in 73% of patients with
common warts compared to only 8% in the placebo group.
Zinc
Zinc may play a role in immunity against viruses, and levels have
been found to be deficient in some patients with refractory warts
(Lazarczyk et al. 2008). There are data for both oral zinc with its
significant risk of nausea, as well as topical preparations that do
not share this unpleasant side effect in the treatment of warts.
Evidence for Zinc
1. Oral zinc sulfate treatment for viral warts: an open-label

study. Mun JH, Kim SH, Jung DS, Ko HC, Kim BS, Kwon KS,
Kim MB. J Dermatol. 2011 Jun;38(6):5415.
In an open-label study of 31 patients with multiple warts, oral
zinc sulfate (10 mg/kg/d up to a maximum of 600 mg/day) was
administered for 2 months. Of those who completed the study,
Garlic (Allium sativum) 169
50% showed complete resolution, but a notable 16% reported

nausea and 3% developed gastric pain.
2. Evaluation of oral zinc sulfate effect on recalcitrant multi-

ple viral warts: a randomized placebo-controlled clinical trial.
Yaghoobi R, Sadighha A, Baktash D. J Am Acad Dermatol.
2009 Apr;60(4):7068.
A randomized, placebo controlled, double blinded trial of oral
zinc sulfate (same dosing as above) for patients with multiple
recalcitrant warts. After 2 months, 25/32 patients (78%) of the
zinc group cleared compared to only 3/23 (13%) of controls,
and this was significant.
3. Topical zinc sulphate solution for treatment of viral warts.

Sharquie KE, Khorsheed AA, Al-Nuaimy AA. Saudi Med J.
2007;28(9):141821.
A double-blinded placebo controlled trial of 10% topical zinc
solution applied twice daily cleared 85% of plane warts com-
pared to placebo; however, only 11% of common warts (ver-
ruca vulgaris) were cleared with the preparation.
4. Topical zinc oxide vs. salicylic acid-lactic acid combination

in the treatment of warts. Khattar JA, Musharrafieh UM,
Tamim H, Hamadeh GN. Int J Dermatol. 2007;46(4):42730.
44 patients were randomized to receive topical zinc oxide 20%
ointment or a combination of salicylic acid + lactic acid twice daily
to warts. By 3 months, 50% of the zinc group was cured compared
to 42% of the acid group; both treatments were well-tolerated.
Garlic (Allium sativum)

Garlic is a known skin irritant that has been a source of con-
tact dermatitis in food workers. It also has proven has antivi-
ral effects (Harris et al. 2001). Both of these features make it
an interesting treatment option for warts. Despite very little
evidence, the existing studies make a compelling case for
consideration of this readily available treatment.
Evidence for Garlic (Allium sativum)
1. Garlic cloves for verruca vulgaris. Silverberg NB. Pediatr

Dermatol. 2002;19(2):183.
A small case series of five children with warts on the hands
found that rubbing freshly cut raw garlic on the warts nightly
followed by covering with a bandage resulted in a clearance of
100% within 3 months. There was no control group here, the
study was unblinded, and the sample was very small, however.
2. Healing effect of garlic extract on warts and corns. Dehghani

F, Merat A, Penjehshahin MR, Handjani F. Int J Dermatol.
2005 Jul;44(7):6125.
A garlic extract (extracted with chloroform and methanol) was
applied twice daily to 23 patients with multiple, refractory
warts. After 12 weeks of treatment, the garlic group had total
clearance versus no clearance in the control group. It is not
clear if the study was blinded or randomized.
Top Considerations for Molluscum

See Table 12.2.
Table 12.2. Top considerations for molluscum treatment.

Cantharidin Applied topically Fairly effective, high rate of
in-office; washed patient satisfaction; can cause
off in several hours discomfort and blistering
Lemon myrtle Daily application Appears effective from single
solution of 10% solution study, well-tolerated; may be
(Backhousia of the essential oil difficult to source
citriodora) to the lesions
Tea tree Topically applied Appears safe and well-
(Melaleuca to lesions daily tolerated, significant
alternifolia) improvement in single study;
and iodine may be difficult to source this
preparation specific preparation
Lemon Myrtle Solution (Backhousia citriodora) 171
Cantharidin
An extract of the blister beetle (family Meloidae), canthari-
din has a long history in medicine, but specifically has been
used to treat molluscum since the 1950s. It is classified as a
vesicant (blister-producing agent), and its mechanism of
action is thought to be by causing acantholysis via degenera-
tion of desmosomal plaques (Bertaux et al. 1988) in the skin.
Despite its fairly wide usage, it has never been FDA-approved
in the US, yet remains a very viable, natural alternative.
Evidence for Cantharidin
1. Childhood molluscum contagiosum: experience with can-

tharidin therapy in 300 patients. Silverberg NB, Sidbury R,
Mancini AJ. J Am Acad Dermatol. 2000;43:5037.
A large study of 300 pediatric patients treated with cantharidin
for molluscum that found 90% clearance and an additional 8%
improved with an average of just over 2 treatments. Side effects
were minimal and included pain, blistering, and erythema.
2. Cantharidin: a comprehensive review of the clinical litera-

ture. Torbeck R, Pan M, DeMoll E, Levitt J. Dermatol Online
J. 2014 Jun 15;20(6).
A recent extensive review on clinical studies on cantharidin
that analyzed 37 articles and found that it is safe and effective
for molluscum, with generally mild adverse effects.
Lemon Myrtle Solution (Backhousia citriodora)

This Australian essential oil is used in perfumes, food flavor-
ings, and teas, and brings with it significant antimicrobial
properties (Hayes and Markovic 2002). Its mechanism in
molluscum is less certain, but one small study suggests an
effect when applied topically to the lesions.
Evidence for Lemon Myrtle Solution

(Backhousia citriodora)
1. Essential oil of Australian lemon myrtle (Backhousia citrio-
dora) in the treatment of molluscum contagiosum in children.
Burke BE, Baillie JE, Olson RD. Biomed Pharmacother. 2004
May;58(4):2457.
31 children were treated with once daily application of a 10%
solution of the lemon myrtle or vehicle (olive oil). At day 21,
90% reduction in molluscum was noted in 9/16 (56%) of the
patients in the experimental group compared to 0/16 in the
control group. No adverse effects were noted.
Tea Tree Oil (Melaleuca alternifolia)

and Iodine Preparation
Tea tree oil is a versatile agent, with antibacterial and antifun-
gal properties, including activity against methicillin-resistant
Staphylococcus aureus (Carson et al. 2006); it may also have
an irritant effect which could make it worth considering for
molluscum. Interestingly, the authors of this sole study
(Markum and Baillie) do not present a very compelling ratio-
nale for the inclusion of iodine, stating only that it has been
used topically for decades worldwide as a safe and effective
topical antiseptic, and that it is used by activated white
blood cells as part of the killing mechanism directed against
bacteria and viruses. The authors speculate that because
there was not much clinical inflammation or irritation, the
effect may be anti-viral, but this is unsubstantiated.
Evidence for Tea Tree Oil (Melaleuca alternifolia)

and Iodine Preparation
1. Combination of essential oil of Melaleuca alternifolia and
iodine in the treatment of molluscum contagiosum in
Case 1 173
children. Markum E, Baillie J. J Drugs Dermatol. 2012

Mar;11(3):34954.
53 children with molluscum were treated twice daily with tea
tree oil (TTO) organically bound to iodine (a proprietary,
patented product) compared to TTO alone or iodine alone.
The study found that at 1 month, 90% reduction of molluscum
was seen in 16/19 (56%) of the children in the combination
group, compared with either individual component: 1/16 (6%)
in the iodine and 3/18 (17%) in the TTO group. No adverse
events were noted.
Case 1
A 14 year-old-boy with warts on the hands and elbow for 3
years presents for evaluation. He had tried various prepara-
tions of salicylic acid night for nearly 1 year, had tried and
failed home cryotherapy and then in-office cryotherapy for
over 6 months, oral cimetidine, topical imiquimod, topical
5-fluorouricil cream, and even had some lesions surgically
removed, to no avail. One of the warts treated with cryo-
therapy developed a large, painful blister and became a ring
wart: a larger, ring-shaped wart at the edge of the blister.
The patient and his family are upset and want a non-
destructive therapy today.
Discussion
While other conventional methods are still possiblethere
are many options for treating wartsoffering something
more gentle, at least initially, may be useful in this situation.
Oral propolis (as long as he does not have a known bee
allergy) along with topical zinc oxide could be an effective
yet mild initial approach. Should that fail after several
months, considering a trail of topical garlic to the lesions
could also be worthwhile.
Case 2
A 9-year-old girl with a history of moderate atopic dermatitis
presents with dozens of molluscum on the arms, legs, and
drunk. She has developed a severe eczema flare in the treated
areas after using imiquimod cream for several days for the
molluscum. They recount how they were told that the mol-
luscum were totally harmless and did not have to be treated,
but now are frustrated that nearly a year has gone by and the
lesions are still present. They would like a gentle but effective
approach.
Discussion
Offering destructive therapy such as cryotherapy or curettage
would be very reasonable here, but if the skin is inflamed and
the child is afraid of these approaches, they can be very diffi-
cult. A trial of cantharidin is generally very well-tolerated, even
in the setting of inflamed skin. At home application of lemon
myrtle could be a gentle adjunctive therapy in such a case.
References
Bertaux B, Prost C, Heslan M, et al. Cantharide acantholysis: endog-
enous protease activation leading to desmosome plaque dissolu-
tion. Br J Dermatol. 1988;118:15765.
Boull C, Groth D. Update: treatment of cutaneous viral warts in chil-

dren. Pediatr Dermatol. 2011;28:21729.
Braue A, Ross G, Varigos G, et al. Epidemiology and impact of child-

hood molluscum contagiosum: a case series and critical review of
the literature. Pediatr Dermatol. 2005;22:28794.

Tree) oil: a review of antimicrobial and other medicinal proper-
ties. Clin Microbiol Rev. 2006;1:5062.
References 175
Ciconte A, Campbell J, Tabrizi S, Garland S, Marks R. Warts are not

merely blemishes on the skin: a study on the morbidity associated
with having viral cutaneous warts. Australas J Dermatol.
2003;44(3):16973.
Harris JC, Cottrell SL, Plummer S, Lloyd D. Antimicrobial proper-

ties of Allium sativum (garlic). Appl Microbiol Biotechnol.
2001;57(3):2826.
Hayes AJ, Markovic B. Toxicity of Australian essential oil Backhousia

citriodora (Lemon myrtle). Part 1. Antimicrobial activity and
in vitro cytotoxicity. Food Chem Toxicol. 2002;40(4):53543.
Katz KA. Imiquimod is not an effective drug for molluscum conta-

giosum. Lancet Infect Dis. 2014;14(5):3723.
Kuropatnicki AK, Szliszka E, Krol W. Historical aspects of propolis

research in modern times. Evid Based Complement Alternat
Med. 2013;2013:964149.
Lazarczyk M, Pons C, Mendoza J-A, Cassonnet P, Jacob Y, Favre

M. Regulation of cellular zinc balance as a potential mechanism
of EVER-mediated protection against pathogenesis by cutane-
ous oncogenic human papillomaviruses. J Exp Med.
2008;205(1):3542.
Micali G, DallOglio F, Nasca MR, Tedeschi A. Management of cuta-

neous warts: an evidence-based approach. Am J Clin Dermatol.
2004;5(5):3117.
Olsen JR, Gallacher J, Piguet V, Francis NA. Epidemiology of mol-

luscum contagiosum in children: a systematic review. Fam Pract.
2014;31(2):1306.
Sforcin J. Propolis and the immune system: a review. J

Ethnopharmacol. 2007;113(1):114.
Tomson N, Sterling J, Ahmed I, Hague J, Berth-Jones J. Human pap-

illomavirus typing of warts and response to cryotherapy. J Eur
Acad Dermatol Venderol. 2011;25(9):110811.
Chapter 13
Fungal and Bacterial
Infections
Introduction to Fungi
Cutaneous fungal infections can be classified into infec-
tions that are limited to the stratum corneum, hair and nails
and, infections that are seen deeper in the skin, involving
the dermis and the subcutaneous tissues. Superficial myco-
ses include: tinea versicolor, tinea nigra, pityrosporum fol-
liculitis, tinea corporis, tinea cruris, tinea barbae, tinea
capitis, tinea pedis, and tinea unguium. Numerous genera
are responsible for superficial mycoses including, but not
limited to: Malassezia, Trichophyton, Microsporum and
Epidermophyton. Diagnosis and treatment of these infec-
tions can pose a challenge. Topical antifungals may be inef-
fective if the organism exhibits resistance to the antifungal
agent. Additionally, the topical antifungals themselves can
cause allergic and irritant skin reactions. Oral agents are
sometimes used when topical agents are not helpful and
these agents are associated with a high incidence of sys-
temic side effects. Many patients seek alternative
approaches to traditional therapy to avoid these potential
side effects. Worldwide, many plants are used to treat vari-
ous bacterial and fungal infections. While some have been
looked at in vitro, a minuscule percentage of these plants
have been subjected to controlled clinical trials (Martin
and Ernst 2004). Here we present primary and secondary
considerations for treatment of fungal infections with plant

DOI 10.1007/978-3-319-17816-5_13
178 13. Fungal and Bacterial Infections
derivatives, though it must be emphasized that much of the

evidence in this section is fairly thin.
Clinical Considerations for Fungi

Fig. 13.1. Tinea Corporis (ringworm).
Fig. 13.2. Tinea pedis + onychomycosis.

Topical Tea Tree Oil 179
Top Considerations for Fungal Infections

Topical Tea Tree Oil

Australia have used tea tree oil from crushed leaves as a tra-
ditional remedy for coughs and colds as well as to treat
wounds and skin infections. Tea tree oil is commonly used as
a topical antimicrobial agent. There have been a number of
papers describing the antiseptic properties of tea tree oil,
which has potential antibacterial activity through disruption
of bacterial membranes (Carson et al. 2006). It is important
to counsel patients that tea tree oil can be very irritating and
Table 13.1. Top considerations for fungal infections.

Tea tree oil Topically to the affected areas High rate of contact
and irritant dermatitis
Table 13.2. Secondary considerations for fungal infections.

Coriander oil A 6% concentration in Good tolerability;
a wax-like base, topically Difficult to replicate
vehicle used in study
Oil of bitter Concentrations from Mild irritation noted
orange 20% to 100%, topically
Solanum Various regimens of May be difficult to source
chrysotrichum Solanum chrysotrichum
application, topically
Garlic (ajoene) Ajoene extract applied Difficult to extract ajoene
topically from garlic, difficult to
source
Ageratina Extract applied topically May be difficult to source
pichinchensis
a source of allergic contact dermatitis (Knight and Hausen

1994). Tea tree oil has been shown to have activity against
dermatophytes in vitro (Hammer et al. 2002).
Evidence for Topical Tea Tree Oil
1. Treatment of interdigital tinea pedis with 25% and 50% tea

tree oil solution: a randomized, placebo controlled, blinded
study. Satchell AC, Saurajen A, Bell C, Barnestson RS. Austalas
J Dermatol. 2002 Aug;43(3):1758.
This randomized, controlled, double-blinded study looked at
the efficacy and safety of 25% and 50% tea tree oil in the treat-
ment of interdigital tinea pedis. One hundred and fifty-eight
patients with tinea pedis clinically and microscopically diag-
nostic of a dermatophyte infection were randomized to receive
either a placebo, 25% or 50% tea tree oil solution. Patients
applied the solution twice daily to affected areas for 4 weeks
and were reviewed after 2 and 4 weeks of treatment. Clinical
response was seen in 68% of the half-strength tea tree oil group
and 72% of the quarter-strength tea tree oil group compared to
39% in the placebo group. Culture of skin scrapings also
showed a mycological cure rate of 64% in the half-strength tea
tree oil group compared to 31% in the placebo group. Of note,
3.8% of the patients did develop a moderate to severe contact
dermatitis from the tea tree oil.
2. Comparison of two topical preparations for the treatment

of onychomycosis: Melaleuca alternifolia (tea tree) oil and
clotrimazole. Buck DS, Nidorf DM, Addino JG. J Fam Pract.
1994 Jun;38(6):6015.
A double-blind, multicenter, randomized controlled trial was
conducted. One hundred and seventeen patients were looked
at with distal subungual onychomycosis, proven by culture.
Patients received twice-daily application of either 1% clotrim-
azole (CL) solution or 100% tea tree (TT) oil for 6 months.
Debridement and clinical assessment were performed at 0,
1, 3 and 6 months. Cultures were obtained at 0 and 6 months.
After 6 months of therapy, the two treatment groups were
Coriander Oil 181
comparable based on culture cure (CL = 11%, TT = 18%) and

clinical assessment documenting partial or full resolution
(CL = 61%, TT = 60%). They concluded that the use of topical
tea tree oil preparation in conjunction with debridement of the
nail was a useful clinical strategy.
Coriander Oil
Coriander (Coriander sativum) is an annual herb in the family
Apiaceae. Although coriander is the seed of the cilantro
(Chinese parsley) plant, their flavors and properties are very
different and they cannot be substituted for each other.
Coriander has both culinary and medicinal applications. It is
common in South Asian, Southeast Asian, Middle Eastern and
Latin American cuisine, to name only a few. In addition to culi-
nary uses, coriander has been touted as having many medicinal
and pharmacological applications including: anti-microbial,
anti-oxidant and anti-inflammatory properties (Sahib et al.
2013). Essential coriander oil has shown antibacterial activity
towards many bacterial strains including Streptococcus pyo-
genes, and methicillin-resistant Staphylococcus aureus (MRSA)
in vitro (Casett et al. 2012). In addition, in vitro studies also
indicate that coriander essential oil shows promise in eradicat-
ing Candida (Freires et al. 2014).
Evidence for Coriander Oil
1. Topical treatment of tinea pedis using 6% coriander oil in

unguentum leniens: a randomized, controlled, comparative
pilot study. Beikert FC, Anastasiadou Z, Fritzen B, Frank U,
Augustin M. Dermatology. 2013; 226(1):4751.
This study evaluated the efficacy and tolerability of 6% coriander
oil in ungeuentum leniens (a wax base) in the treatment of
interdigital tinea pedis. This was a half-side comparative pilot
study on subjects with symmetric, bilateral interdigial tinea
pedis. Active drug and placebo control were applied twice

daily on the affected areas, and follow up visits were performed
on days 14 and 28. Forty participants were included in the
study. A highly significant improvement in the clinical signs
(p < 0.0001) was observed during the entire observation period;
the number of fungal cultures also tended to decrease
(p = 0.0654). It was concluded that coriander oil in this wax
base was effective and well tolerated in the treatment of inter-
digital tinea pedis.
Oil of Bitter Orange

The bitter orange (Citrus aurantium) is native to Southeast
Asia. During the 10th and 11th centuries traders introduced
the plant to the Mediterranean and the Spanish and the
Portuguese brought the plant to the Americas in the fifteenth
century. Globally it is widely cultivated. The bitter orange is
an evergreen tree that can grow up to 10 m with long spines
and very fragrant flowers. The entire plant is used for vari-
ous purposes from culinary to medicinal to body care. From
the flowers comes Neroli oil which is a popular oil used
in fragrances. From the leaves and twigs comes Petitgrain
essential oil, also used in aromatherapy and perfumery
(DerMarderosian and Beutler 2012). The extracts from the
plant have been looked at for their potential anti-inflamma-
tory, antibacterial, anti-cholesterol and antifungal properties.
Neroli oil, extracted from blossoms of the bitter orange tree
has been shown, in vitro, to have antibacterial activity against
Pseudomonas aeruginosa as well as strong antifungal activity
when compared to Nystatin (Ammar et al. 2012).
Evidence for Oil of Bitter Orange
1. Oil of bitter orange: a new topical antifungal agent.

Ramadan W, Mourad B, Ibrahim S, Sonobol F. Int J Dermatol.
1996 Jun; 35(6):4489.
Solanum chrysotrichum 183
Sixty patients were classified into three groups of 20 patients

each. All groups had comparable numbers of patients with
tinea corporis, tinea cruris and tinea pedis. Group 1 was treated
with a 25% emulsion of oil of bitter orange (OBO) three times
daily. Group 2 was treated with 20% OBO in alcohol three
times daily. And, Group 3 was treated with pure OBO, once
daily. Clinical and mycological examinations were performed
before therapy and every week until a complete cure had
occurred. In Group 1, 80% of patients were cured in 12 weeks
and 20% in 23 weeks. In Group 2, 50% were cured in 12
weeks, 30% in 23 weeks, and 20% in 34 weeks. In Group 3,
25% of patients did not continue the trial. The authors note
mild irritation was seen with the oil but oil of bitter orange
showed promise in exerting fungistatic and fungicidal activity.
Solanum chrysotrichum
Solanum is a diverse genus of flowering plants. Included in the
Solanum group are the tomato and the potato. The genus con-
tains both species used for food crops and ornamentals.
Solanum chrysotrichum is one species that is used in folk medi-
cine. A recent randomized controlled trial showed that saponin
SC-2 from Solanum chrysotrichum showed its effectiveness on
women with vulvovaginal candidiasis. It was shown to have a
similar clinical effectiveness to that of ketoconazole, but
obtained a smaller percentage of mycological effectiveness
and 100% tolerability (Herrera-Arellano et al. 2013). An addi-
tional study found the Saponin SC to be effective against can-
dida non-albicans species, or fluconazole and ketoconazole
resistant strains of yeast (Herrera-Arellano et al. 2007).
Evidence for Solanum chrysotrichum
1. Clinical and mycological evaluation of therapeutic effec-

tiveness of Solanum chrysotrichum standardized extract on
patients with Pityriasis capitis (dandruff). A double blind and
randomized clinical trial controlled with ketoconazole.
Herrera-Arellano A, Jimenez-Ferrer E, Vega-Pimentel AM

et al. Planta Med. 2004 Jun;70(6):4388.
This randomized, double blind and controlled clinical study
compared the therapeutic effectiveness and tolerability of a
shampoo containing a standardized extract of S. chrysotri-
chum (applied every third day for 4 weeks), against 2% keto-
conazole in the topical treatment of Pityriasis capitis. There
were 51 subjects in the experimental group and 52 in the con-
trol group. In 45.6% of the cases M. furfur was identified as the
pathogenic agent, in 44.66% M. globosa was isolated, and
9.71% of the patients had a multiple strains. At the end of the
treatment period, the S. chrysotrichum compound achieved a
clinical effectiveness (total absence of signs and symptoms) of
92.16%; the mycological effectiveness (absence of Malassezia
spp. in the direct examination and culture) was 68.63%; and
the mycological effectiveness (absence of Malassezia spp. in
the direct examination and culture) was 68.63%; the tolerabil-
ity (absence of side effects prompting subjects to abandon
treatment) was 100%. The comparison of these results with
that obtained from the group treated with 2% ketoconazole
showed no significant differences. In conclusion, this study
showed effectiveness and tolerability of Solanum chrysotri-
chum extract on local treatment of pityriasis capitis associated
with yeast of genus Malassezia.
2. Effectiveness and tolerability of a standardized phytodrug

derived from Solanum chrysotrichum on Tinea pedis: a con-
trolled and randomized clinical trial. Herrera-Arellano A,
Rodriquez-Soberanes A, de los Angeles Maritinez-Rivera M
et al. Planta Med. 2003 May;69(5):3905.
This randomized, controlled, double-blind study looked at 101
patients diagnosed with tinea pedis and compared the thera-
peutic effect and the tolerability of a standardized phytodrug
from S. chrysotrichum (experimental group) with 2% ketocon-
azole (control group) applied externally for 4 weeks. After the
treatment, the results showed a clinical effectiveness (> or
=75% improvement of signs and symptoms) of 96.08% for the
Garlic 185
group treated with the S. chrysotrichum extract and 91.67% for

the ketoconazole group (chi 2, p > 0.38); the mycologic effec-
tiveness (direct examination and negative culture) was 78.43%
and 77.78%, respectively (chi2, p > 0.94), and both treatments
were tolerable.
Garlic
Garlic (Allium sativum) is perennial blub most known for its
culinary uses. Folk uses of garlic have ranged from the treat-
ment of leprosy and tuberculosis to simple bacterial infections
(Bayan et al. 2014). Garlic is comprised of sulfur-containing
compounds, vinyldithiins, and ajoenes. The bulb also contains
an odorless, colorless, sulfur-containing amino acid called
alliin. When the bulb is ground, alliin is converted to
2-propenesulfenic acid which dimerizes to form allicin and
allicin is what gives the pungent odor of garlic. One study
looked at the effect of garlic and pure allicin on the growth of
hyphae in T. rubrum using electron microscopy and found that
allicin is more efficient in inhibition of the growth of hyphal
cells compared to garlic extract but that both were successful
in the treatment of dermatophytosis (Aala et al. 2014).
Evidence for Garlic
1. Efficacy of ajoene in the treatment of tinea pedis: a double-

blind and comparative study with terbinafine. Ledezma E,
Marcano K et al. J Am Acad Dermatol. 2000 Nov;43(5 Pt
1):82932.
This study looked at seventy participants with clinical and
mycologic diagnosis of tinea pedis. Forty-seven were available
for final evaluation. They compared the safety and effective-
ness of twice-daily topical application during 1 week of 0.6%
ajoene, 1% ajoene and 1% terbinafine. The patients were ran-
domly distributed into each of the three groups. Clinical follow
up shows a rapid decline in signs and symptoms in all groups.
Efficacy of the treatments, measured as mycological cure, 60

days after the end of therapy was 72%, for 0.6% ajoene, 100%
for 1% ajoene and 94% for 1% terbinafine.
2. Efficacy of ajoene, an organosulphur derived from garlic, in

the short-term therapy of tinea pedis. Ledezma E, DeSousa L,
Jorquera A et al. Mycoses. 1996 SepOct;39(910):3935.
This study used ajoene as a 0.4% cream that resulted in com-
plete clinical and mycological cure in 27 of 34 patients (79%)
after 7 days of treatment. The remaining seven patients (21%)
achieved complete cure after seven additional days of treat-
ment. All patients were evaluated for recurrence of mycotic
infections 90 days after the end of treatment, yielding negative
cultures for fungus.
Ageratina pichinchensis
Ageratina pichinchensis is a perennial in the family Asteraceae.
In Mexican traditional medicine, the extract obtained from
this plant is utilized to treat skin injuries, such as wounds and
infections cause by fungi (Romero-Cerecero et al. 2013).
Clinical trials have supported the use of Ageratina pichinche-
nis for the use of onychomycosis and tinea pedis.
Evidence for Ageratina pichinchensis
1. Double-blind clinical trial for evaluating the effectiveness

and tolerability of Ageratina pichinchensis extract on patients
with mild to moderate onychomycosis. A comparative study
with ciclopirox. Romero-Cerecero O, Zamlipa A, Jimenez-
Ferrer JE et al. Planta Med. 2008 Oct;74(12):14305.
This study evaluated the therapeutic effectiveness and tolera-
bility of topical administration of A. pichinchensis extract on
the nails of patients with the clinical and mycological diagnosis
of onychomycosis. A phytopharmaceutical formulation was
developed in a lacquer solution containing the extract of
Introduction to Bacteria 187
A. pichinchensis. A similar lacquer solution containing 8%

ciclopirox was used as a control. Treatments were assigned
randomly and administered topically for 6 months. Ninety-six
patients concluded the study (49 in the experimental group and
47 in the control); 71.1% of patients from the experimental and
80.9% from the ciclopirox group showed therapeutic effective-
ness, whereas 59.1% and 63.8% from the experimental and
ciclopirox group, respectively, achieved mycological effective-
ness. Therapeutic success was observed in 55.1 and 63.8%,
respectively. No patient exhibited marked side effects.
2. Therapeutic effectiveness of Ageratina pichinchenis on the

treatment of chronic interdigital tinea pedis: a randomized,
double-blind clinical trial. Romero-Cerecero O, Zamilpa A,
Jimenez-Ferrer E, Tortoriello J. J Altern Complement Med.
2012 Jun;18(6):60711.
This randomized, double-blind clinical trial looked at one hun-
dred and sixty patients. They were divided into three groups and
treated topically for 4 weeks with the following: Group 1: the
lower concentration of A. pichinchensis extract; Group 2: the
higher concentration; and Group 3: 2% ketoconazole. The pri-
mary outcome variables were: clinical effectiveness, mycological
effectiveness, therapeutic cure, tolerability, and treatment com-
pliance. At the end of treatment, therapeutic cure was achieved
by 34.1%, 41.8%, and 39.53% of Groups 1, 2 and 3, respectively.
No statistical difference between the groups was observed.
Introduction to Bacteria
It is thought that roughly 20% of outpatient dermatology
visits are for bacterial skin infections. Skin infections are
caused by both gram-positive (e.g., staphylococci and strepto-
cocci) and gram-negative (e.g., pseudomonas aeruginosa)
organisms. A rapidly increasing number of resistant organisms
are making these infections increasingly difficult to treat.
Costly drugs, decreased access to therapies and a global
increase in multi-drug resistance of pathogens has precipitated
an interest in alternative compounds for the treatment of

bacterial infections. While numerous compounds show prom-
ise in treating bacterial infections in vitro, few controlled
clinical trials on plant extracts have been published that are
methodologically sound. One study looked at nine essential
oils and inhibitory activity against Streptococcus mutans. The
study showed that cinnamon oil, lemongrass oil, and cedar-
wood oil all exhibited antibacterial activity against the bacte-
ria (Chaudhari et al. 2012). Another study looked at the
anti-infective properties of epigallocatecin-3-gallate (EGCG),
a component of green tea and found that EGCG binds to
lipid membranes and affects the folic acid metabolism of bac-
teria and fungi by inhibiting the cytoplasmic enzyme dihydro-
folate reductase (Steinmann et al. 2013). While it is not
realistic to extrapolate in vitro work to clinical applications
directly, it does suggest a need for more thorough investiga-
tion into some of these compounds to see if there is a role for
these extracts in treating bacterial infections of the skin. Here
we present two compounds worth considering in practice.
Top Considerations for Bacterial Infections

See Table 13.3.
Tea Tree Oil

Australia have used tea tree oil from crushed leaves as a
Table 13.3. Top considerations for bacterial infections.

Tea tree oil Topically Effective antimicrobial; High rate
of contact dermatitis
Honey Topically Safe and gentle; Can be costly and
difficult to apply
Honey 189
traditional remedy for coughs and colds as well as to treat

wounds and skin infections. Tea tree oil is commonly used as
a topical antimicrobial agent. There have been a number of
papers describing the antiseptic properties of tea tree oil,
which has potential antibacterial activity through disruption
of bacterial membranes (Carson et al. 2006). Tea tree oil can
be very irritating and a source of allergic contact dermatitis
so it is important to counsel patients that this is a possibility.
Evidence for Tea Tree Oil
1. A randomized, controlled trial of tea tree topical prepara-

tions versus a standard topical regimen for the clearance of
MRSA colonization. Dryden MS, Dailly S, Crouch M. J Hosp
Infect. 2004 Apr;56(4):2836.
Two topical MRSA eradication regimens were compared in
hospital patients: a standard treatment with mupirocin 2%
nasal ointment, chlorhexidine 4% soap, silver sulfadiazine
1% cream versus a tea tree oil regimen, which included tea
tree 10% cream, tea tree 5% body wash, both given for 5 days.
One hundred and ten received tea tree oil regimen and 46
(41%) were cleared. There was no significant difference
between treatment regimens. Mupiricin was significantly more
effective at clearing nasal carriage (78%) than tea tree cream
(47%; P = 0.0001) but the tea tree treatment was more effective
than chlorhexidine or silver sulfadiazine at clearing superfi-
cial skin sites and skin lesions. It was concluded that the tea
tree preparations were effective, safe and well tolerate and
could be considered in regimes for eradication of MRSA
carriage.
Honey
Honey is a bee product made using the nectar from flowers.
It is a supersaturated solution composed of mainly fructose
and glucose, as well as proteins and amino acids, vitamins,
enzymes and minerals. Antimicrobial properties in dermatol-

ogy applications are thought to be due to the enzymatic
release of hydrogen peroxide. The hyperosmolarity of honey
impedes bacterial growth, while factors in honey called inhib-
ines, which include hydrogen peroxide, flavonoids and pheno-
lic acids, elicit antibacterial effects directly (Wahdan 1998).
Honey has been looked at as a dressing for wounds and
burns. One study showed greater efficacy of honey over silver
sulphadiazine for treating superficial and partial-thickness
burns (Malik et al. 2010). In addition honey has been looked
at as a treatment for pityriasis, tinea, seborrhea, and psoriasis
(Burlando and Cornara 2013). One study looked at the effect
of manuka honey (honey produced in New Zealand by bees
that pollinate the native manuka bush and result in com-
pounds rich in methylglyoxal) in Streptocococcus pyogenes
biofilms. They found that the manuka honey permeated
established biofilms of S. pyogenes, resulting in significant
cell death and dissociation of cells from the biofilm (Maddocks
et al. 2012). Another study looked at the activity of honey
against communityassociated methicillin resistant
Staphylococcus aureus (CA-MRSA) and found that honey
(two different types) had an antimicrobial activity against the
CA-MRSA organisms tested (Maeda et al. 2008).
Evidence for Honey
1. Use of Medihoney as a non-surgical therapy for chronic

pressure ulcers in patients with spinal cord injury. Biglar B, vd
Linden PH, Simon A et al. Spinal Ord. 2012 Feb;50(2):1659.
The prospective observational study looked at 20 spinal cord-
injured (SCI) patients with chronic pressure ulcers treated with
Medihoney (a commercial manuka honey product). 25% of
patients had grade IV ulcers and 75% had grade III ulcers
according to the National Pressure Ulcer Advisory Panel.
After 1 week of treatment with Medihoney all swabs were void
of bacterial growth. And 90% of patients showed complete
wound healing after a period of 4 weeks. No negative effects
associated with Medihoney were noted.
Case 2 191
Case 1
A 29 year old man comes in with recurrent (culture positive)
Staphylococcus aureus skin infections. He works as a nurse in
the ICU and none of his cultures have ever shown resistant
strains. On physical exam he has a few erythematous follicu-
lar papules and a crusted area overlying a fissure on his lower
leg. He has taken numerous courses of antibiotics to treat
these infections including cephalosporins and tetracyclines.
He has a history of childhood eczema and notes that is skin is
always dry. He comes in very frustrated and worried about
antibiotic resistance especially in light of his professional
exposures. He is asking what other things can be done both
to prevent and treat these infections.
Discussion
This is a very common scenario, both in that in involves a
healthcare worker and an atopic dermatitis patient. In addition
to counseling this type of patient on the use of dilute bleach
baths, a very important consideration in this case, one could
also recommend washing with a tea tree oil cleanser. As the
irritant and contact dermatitis rate with tea tree oil is not insig-
nificant, using a suitable concentration is imperative. One
could recommend either a commercially available tea tree oil
wash, or consider adding 1012 drops of the essential oil to a
full bath tub. This regimen can be done every day for treatment
and once a week for prophylaxis or de-colonization.
Case 2
A 45 year old woman comes in with a long-standing history
of tinea versicolor. She notes it is worse in the summer with
the increase in humidity and she has done everything to
treat it including a dose of oral ketoconazole and recently an
application of baking soda that she read about on the
Internet. She is frustrated by the appearance and is looking
for additional options she could try. On physical exam she has
red brown round scaling on the chest and upper back that are
KOH positive for tinea versicolor.
Discussion
Tinea versicolor, albeit a benign and often asymptomatic erup-
tion for patients, tends to illicit frustration and may be challeng-
ing to treat. Topically, sulfur washes, ketoconazole, or selenium
sulfide are all commonly recommended and can be effective.
When a patient is looking for something in addition or in lieu
of these prescription options they could consider washing the
area with a tea tree oil product, either a commercially available
wash with tea tree oil in it or by adding 1012 drops of the
essential oil of tea tree to a full bath tub and using as a soak. In
addition, topical oil of bitter orange has been shown to be effec-
tive against fungal species and can be tried in the same dilution.
Note: neither product should be ingested orally.
References
Aala F, Yusuf UK, Nulit R, Rezaie S. Inhibitory effect of allicin and
garlic extracts on the growth of cultured hyphae. Iran J Basic
Med Sci. 2014;17(3):1504.
Ammar AH, Bouajila J, Lebriihi A, et al. Chemical composition and

in vitro antimicrobial and antioxidant activities of Citrus aurantium l.
flowers essential oil (Neroli oil). Pak J Biol Sci. 2012;15(21):103440.
Bayan L, Koulivand PH, Gorhi A. Garlic: a review of potential thera-

peutic effects. Avicenna J Phytomed. 2014;4(1):114.
Burlando B, Cornara L. Honey in dermatology and skin care: a

review. J Cosmet Dermatol. 2013;12:30613.

Tree) oil: a review of antibacterial and other medicinal properties.
Clin Microbiol Rev. 2006;19(1):5062.
References 193
Casett F, Bartelke S, Beihler K, et al. Antimicrobial activity against

bacteria with dermatological relevance and skin tolerance of the
essential oil from Coriandrum sativum L. fruits. Phytother Res.
2012;26(3):4204.
Chaudhari LK, Jawale BA, Sharma S, et al. Antimicrobial activity of

commercially available essential oils against Streptococcus
mutans. J Contemp Dent Pract. 2012;13(1):714.
DerMarderosian A, Beutler JA. The review of natural products

paperbackNovember 15, 2012. Lippincott Williams & Wilkins;
Seventh edition. ISBN-10: 1574393464.
Freires IA, Murata RM, Furlett VF, et al. Coriandrum sativum L.

(Coriander) essential oil: antifungal activity and mode of action
on Candida spp. And molecular targets affected in human whole-
genome expression. PLoS One. 2014;9:e99086.
Hammer KA, Carson FC, Riley TV. In vitro activity of Melaleuca

alternifolia (tea tree) oil against dermatophytes and other fila-
mentous fungi. J Antimicrob Chemother. 2002;50(2):1959.
Herrera-Arellano A, Martinez-Rivera L, Hernandez-Cruz M, et al.

Mycological and electron microscopic study of Solanum chrysot-
richum saponin SC-2 antifungal activity on Candida species of
medical significance. Planta Med. 2007;73(15):156873.
Herrera-Arellano A, Lopez-Villegas EO, Rodriquez-Tovar AV, et al.

Use of antifungal saponin SC-2 of Solanum chrysotrichum for the
treatment of vulvovaginal candidiasis: in vitro studies and clinical
experiences. Afr J Tradit Complement Alern Med. 2013;10(3):
4107.
Knight TE, Hausen BM. Melaleuca oil (tea tree oil) dermatitis. J Am
Acad Dermatol. 1994;30:4237.
Maddocks SE, Lopex MS, Rowlands RS, Cooper RA. Manuka honey
inhibits the development of Streptococcus pyogenes biofilms and
causes reduced expression of two fibronectin binding proteins.
Microbiology. 2012;158(pt3):78190.
Maeda Y, Loughrey A, Earle JA, et al. Antibacterial activity of honey

against community-associated methicillin-resistant Staphylococcus
aureus (CA-MRSA). Complement Ther Clin Pract. 2008;14(2):
7782.
Malik KI, Malik MA, Aslam A. Honey compared with silver sulphad-
iazine in the treatment of superficial partial-thickness burns. Int
Wound J. 2010;7(5):4137.
Martin K, Ernst E. Herbal medicines for treatment of fungal infec-

tions: a systematic review of controlled clinical trials. Mycoses.
2004;47:8792.
Romero-Cerecero O, Zamilpa A, Gonzalex-Corazar M, et al.

Pharmacological and chemical study to identify wound-healing
active compounds in Ageratina pichinchensis. Planta Med.
2013;79(08):6227.
Sahib NG, Anwar F, Gilani AH, et al. Coriander (Coriandrum sati-

vum L.): a potential source of high-value components for
functional foods and nutraceuticalsa review. Phytother Res.
2013;27(10):143956.
Steinmann J, Buer J, et al. Anti-infective properties of

epigallocatechin-3-gallate (EGCG), a component of green tea.
Br J Pharmacol. 2013;168(5):105973.
Wahdan HA. Causes of the antimicrobial activity of honey. Infection.

1998;36:2631.
Chapter 14
Seborrheic Dermatitis
Introduction
Seborrheic dermatitis (SD) is characterized by a scaly, inflam-
matory reaction pattern in typically oily areas of the face,
scalp, and occasionally chest. Although not completely under-
stood, the pathophysiology is intimately linked with the com-
mon skin commensal yeast Malassezia. An overgrowth of this
yeast, and/or an overzealous immune response to it appears
to lie at the heart of this chronic intermittent eruption
(Pedrosa et al. 2014).
Fittingly, there are two major categories of conventional
treatments available to address SD: those which calm the
aberrant immune response, including topical corticosteroids;
and those which putatively decrease the Malassezia on the
skin, including a number of anti-yeast agents. Several of the
alternative therapies discussed below appear to have fea-
tures of both of these categories, and are often used along-
side conventional agents with good effect (Dessinioti and
Katsambas 2013). Of note, SD is intimately related to scalp
psoriasis and can be difficult to distinguish; one paper below
is from the scalp psoriasis literature, but seems broadly
applicable to the matter at hand.

DOI 10.1007/978-3-319-17816-5_14
196 14. Seborrheic Dermatitis
Seborrheic dermatitis is a perfect example of a condition

in which seemingly benign home remedies can worsen the
condition rather than improve it. Many individuals with seb-
orrheic dermatitis assume they have dry scalp, and, in an
effort to ameliorate the dryness, will apply olive oil or other
oils to the affected areas. The saturated fats found in these
oils provide a rich growth medium for Malassezia, and pro-
liferation of this yeast can cause worsening of seborrheic
dermatitis. In addition, olive oil (as compared to other natu-
ral oils such as sunflower oil) has actually been shown to
damage the skin barrier instead of repairing it (Danby et al.
2013). Thus, patients should be advised not to apply plant
oils such as olive oil to the areas (Siegried and Glenn 2012).
It has been suggested that an inorganic oil such as mineral
oil may be a better alternative if patients insist on the appli-
cation of oil for this condition.
Fig. 14.1. Seborrheic dermatitis may affect the lower face, present-
ing as erythematous patches with a greasy appearing scale.
Tea Tree Oil 197
Fig. 14.2. Seborrheic dermatitis is common on the lower forehead

and eyebrows, and patients often assume this condition is dry skin.
Top Considerations
See Table 14.1.
Tea Tree Oil

Tea tree oil is derived from Melaleuca alternifolia, a plant
native to Australia. It has been shown to have antimicrobial,
antifungal, antiviral and anti-inflammatory properties, and
therefore has been tried in the treatment of many cutaneous
infectious and inflammatory conditions (Carson et al. 2006).
Tea tree oil can be found in numerous over-the-counter
skincare products in varying concentrations and formula-
tions, and as such, contact dermatitis to tea tree oil is an
increasing problem (Rutherford et al. 2007). Patients should
be counseled about this risk, and advised to report any
symptoms suggestive of contact dermatitis, such as erythema
and pruritus, after initiating the use of tea tree oil-containing
preparations.

Tea tree Topically (shampoo) Appears to be effective;
Patients should be warned of
risk of contact dermatitis
Honey Topically (diluted) Very gentle and inexpensive;
May be difficult to apply due
to consistency
Sulfur Topically (either Well-tolerated and multiple
preparations as monotherapy preparations available; Avoid
or in combination or use with caution in patients
with sodium with sulfa allergy. Some
sulfacetamide) patients may not be able to
tolerate due to smell
Salicylic acid Topically (shampoo) Inexpensive and well-
preparations tolerated; Avoid or use with
caution in patients with
salicylate allergy, can be
irritating
Evidence for Tea Tree Oil

1. Treatment of dandruff with 5% tea tree oil shampoo.
Satchell AC, Saurajen A, Bell C, Barnetson RS. J Am Acad
Dermatol. 2002 Dec;47(6):8525.
126 patients (ages 14 and older) were randomized to receive
5% tea tree oil shampoo or placebo, and were instructed to
wash with the shampoo daily for 4 weeks. The tea tree oil
group showed a greater improvement in severity scores than
the placebo group (41% vs. 11%), as well as a greater
improvement in patient self-assessment scores in the areas of
itchiness and greasiness. A difference in patient self-assess-
ment scores for scaliness was not statistically significant
between both groups. No adverse events were observed in
this study.
Sulfur 199
Honey
Honey has been used as a therapeutic skin treatment since
ancient times, and is still a mainstay of therapy in Eastern
medicine such as Ayurveda and Traditional Chinese medicine.
It has been shown to possess anti-inflammatory and antimi-
crobial properties (Burlando and Cornara 2013). Due to its
viscous nature, it is often diluted prior to use.
Evidence for Honey
1. Therapeutic and prophylactic effects of crude honey on

chronic seborrheic dermatitis and dandruff. Al-Waili NS. Eur
J Med Res. 2001;6(7):3068.
In this small study of thirty patients with seborrheic dermatitis
of the scalp, diluted honey (90% honey in warm water) was
applied to the affected areas of the scalp every other day for 4
weeks. The honey was rubbed into the scalp, left on for three
hours, and then rinsed off. The 4 week treatment period was
followed by a 6 month prophylactic period; half of the
patients were instructed to continue applying honey to the
scalp once a week, and the other half were control patients.
The author found that all patients improved in this study, with
resolution of scaling, reduction in itching and improvement in
hair loss. Patients who continued maintenance treatments with
once weekly honey application did not relapse, while the
majority of patients in the control group relapsed within a few
months of treatment.
Sulfur
Sulfur is a yellow, non-metallic element with antifungal, anti-
bacterial and keratolytic properties. It is often used in combi-
nation with other agents, such as salicylic acid or sodium
sulfacetamide (a sulfonamide with antibacterial properties),
for the treatment of cutaneous disorders including seborrheic

dermatitis (Gupta and Nicol 2004).
Evidence for Sulfur
1. The multifunctionality of 10% sodium sulfacetamide, 5%

sulfur emollient foam in the treatment of inflammatory facial
dermatoses. Draelos ZD. J Drugs Dermatol. 2010;9(3)2346.
In this open label study, 24 patients with various skin condi-
tions (acne, rosacea and seborrheic dermatitis) were treated
with a sodium sulfacetamide and sulfur-containing foam; 8
patients had seborrheic dermatitis. Statistically significant
reductions in erythema, desquamation and symptoms such as
burning and itching were observed at 4 and 8 weeks in the
patients with seborrheic dermatitis.
2. Effects of sulfur and salicylic acid in a shampoo base in the

treatment of dandruff: a double-blind study using corneocyte
counts and clinical grading. Leyden J, McGinley K, Mills O,
Kyriakopoulos A, Kligman A. Cutis. 1987;39(6)55761.
Forty-eight patients with moderate to severe scaling were ran-
domized to receive one of the four following shampoos (the
vehicle was the same for all): 2% sulfur with 2% salicylic acid;
2% sulfur alone; 2% salicylic acid alone; or shampoo vehicle
alone. Response was measured in terms of degree of scaling and
corneocyte count (as a measure of desquamation). The authors
report significantly greater reductions in both scaling and cor-
neocyte counts in the group who received the combination
shampoo containing sulfur and salicylic acid, compared to those
groups who received either active ingredient alone or vehicle.
Salicylic Acid
Salicylic acid, derived from bark of the willow tree, is best
known as the precursor to aspirin (acetylsalicylic acid), but is
also frequently used as a topical treatment for cutaneous
Case 1 201
conditions due to its keratolytic and antimicrobial effects.

While toxicity from topical salicylate use is rare, patients
should be advised to avoid application to large body surface
areas over prolonged periods of time (Madan and Levitt
2014). Patients with known allergy to salicylates should avoid
use of these topical preparations.
Evidence for Salicylic Acid
1. Salicylic acid 6% in an ammonium lactate emollient foam

vehicle in the treatment of mild-to-moderate scalp psoriasis.
Kircik L. J Drugs Dermatol. 2011;10(3):2703.
This was a small open-label study of 10 patients with scalp pso-
riasis. Statistically significant reductions in all parameters of
psoriasis severity were noted after 4 weeks of monotherapy with
a salicylic acid/ammonium lactate foam. Given the significant
overlap between scalp psoriasis and seborrheic dermatitis, this
may also be an effective treatment for seborrheic dermatitis.
Case 1
A 25 year old male presents with a few year history of dan-
druff of the scalp. He reports itching, flaking and irritation,
and sometimes also has redness and flaking of his eyebrows
and ears. He has tried a number of over-the-counter sham-
poos with minimal improvement, and has tried applying olive
oil to treat his dry scalp. The patient is concerned about
potential side effects of prescription shampoos and topical
steroids and is interested in natural treatment methods.
Discussion
This patient could be counseled to discontinue the use of olive
oil as a topical treatment for his scalp, as it may be worsening
his condition. He may benefit from the use of a tea tree oil
shampoo several times weekly, alternating with a salicylic acid
formulation to decrease scaling.
Case 2
A 35 year old female presents with itching and flaking of the
scalp, which has persisted despite the use of prescription anti-
fungal shampoos. She is interested in alternative therapies for
her condition.
Discussion
This patient may benefit from a solution of dilute honey
applied to the scalp every other day for 1 month, along with the
use of a topical sulfur/sodium sulfacetamide preparation a few
times per week.
References
Burlando B, Cornara L. Honey in dermatology and skin care: a
review. J Cosmet Dermatol. 2013;12(4):30613.
Carson C, Hammer K, Riley T. Melaleuca alternifolia (tea tree oil): a

review of antimicrobial and other medicinal properties. Clin
Microbiol Rev. 2006;19(1):5062.
Danby S, AlEnezi T, Sultan A, Lavender T, Chittock J, Brown K,

Cork M. Effect of olive and sunflower seed oil on the adult skin
barrier: implications for neonatal skin care. Pediatr Dermatol.
2013;30(1):4250.
Dessinioti C, Katsambas A. Seborrheic dermatitis: etiology, risk

factors, and treatments: facts and controversies. Clin Dermatol.
2013;31(4):34351.
Gupta A, Nicol K. The use of sulfur in dermatology. J Drugs

Dermatol. 2004;3(4):42731.
Madan R, Levitt J. A review of toxicity from topical salicylic acid

preparations. J Am Acad Dermatol. 2014;70(4):78892.
Pedrosa A, Lisboa C, Goncalves R. Malassezia infections: a medical

conundrum. J Am Acad Dermatol. 2014;71(1):1706.
References 203
Rutherford T, Nixon R, Tam M, Tate B. Allergy to tea tree oil: retro-

spective review of 41 cases with positive patch tests over 4.5 years.
Australas J Dermatol. 2007;48(2):837.
Siegried E, Glenn E. Use of olive oil for the treatment of seborrheic

dermatitis in children. Arch Pediatr Adolesc Med. 2012;166(10):967.
Chapter 15
Pruritus
Introduction
Pruritus (synonymous with itch) can be defined as an
unpleasant sensation that provokes the desire to scratch
(Pfab et al. 2013). It is a common feature of many inflam-
matory skin diseases such as atopic dermatitis, irritant and
allergic dermatitis, scabies, and lichen planus, but may also
be seen in a large number of systemic conditions, including
cholestasis, thyroid disorders, and kidney failure. Thus, it is
important to determine the cause of the itch before
attempting solely symptomatic treatment. Itch is classified
as either acute (<6 weeks in duration) or chronic (>6 weeks
in duration), and there is a significant psychosocial impact
to pruritus that should not be overlooked (Callahan and
Lio 2012). Beyond this, defining whether the itch is local-
ized or generalized is also important for both diagnosis and
therapy.
The pathophysiology of itch is nearly as diverse as its causes:
there are both central and peripheral mechanisms involved,
and a number of different pathways have been identified

DOI 10.1007/978-3-319-17816-5_15
206 15. Pruritus
(Pfab et al. 2013). Conventional approaches to therapy

beyond treating the underlying disease when knownare
somewhat lacking in clinical efficacy. These include topical
agents such as corticosteroids, menthol, anesthetics, and capsa-
icin, as well as systemic agents such as antihistamines, antide-
pressants, and opioid antagonists (Yosipovitch and Bernhard
2013). It may be the somewhat limited efficacy of many of
these treatments and/or their risk for significant side effects
that drives interest in alternative agents.
Top Considerations for Pruritus

See Table 15.1.
Table 15.1. Top considerations for pruritus.

Hypnosis, Treatments No single approach;
biofeedback, and administered in variable response and
cognitive behavioral office or at home can become expensive
therapy over time
Acupuncture/ Treatments No single approach;
acupressure administered in variable response and
office or at home, can become expensive
specific point LI11 over time
has several studies
supporting effect
Topical sunflower Applied twice daily, Safe, inexpensive,
seed oil directly or generally not allergenic
in moisturizer
Aromatherapy Oils applied topically Safe, relaxing; risk for
while massaging the contact dermatitis given
hand three times per botanical nature of oils
week
Hypnosis, Biofeedback, and Cognitive Behavioral Therapy 207
Hypnosis, Biofeedback, and Cognitive

Behavioral Therapy
Stress is known to be a significant trigger for atopic dermati-
tis, and the itch-scratch cycle may become a deeply ingrained
behavioral response that is elicited more during times of
anxiety, regardless of the cause (Shenefelt 2003). It follows,
then, that techniques to reduce stress could be helpful in the
management of itch. Safe and somewhat holistic, hypnosis
and cognitive behavioral techniques do seem to be helpful in
both adults and children, and appear to have a durable
response. Cost, time, and availability of such treatments can
present barriers for utilizing these modalities.
Evidence for Hypnosis, Biofeedback,

and Cognitive Behavioral Therapy
1. Hypnotherapy as a treatment for atopic dermatitis in adults
and children. Stewart AC, Thomas SE. Br J Dermatol.
1995;132:77883.
Non-blinded, non-controlled study of 18 adults and 20 chil-
dren with severe atopic dermatitis were treated with hypno-
therapy and showed subjective and objective benefit in itching
and scratching, as well as decreased sleep disturbance and
improvements in mood. Adults maintained benefit up to 2 years
afterwards, while children maintained benefit up to 18 months
afterwards in 10 of 12 cases.
2. Effectiveness of the nursing programme Coping with itch:

a randomized controlled study in adults with chronic pruritic
skin disease. van Os-Medendorp H, Ros WJ, Eland-de Kok
PC et al. Br J Dermatol. 2007;156:123544.
Pilot study of 32 patients with severe chronic itch, that exam-
ined a multi-pronged outpatient program that included cogni-
tive behavioral therapy to reduce itch and help patients cope.
At 3 and 9 months, there was significant reduction of itch and
208 15. Pruritus
scratching behaviors, and significant reduction in the psycho-

social morbidity. Surprisingly, however, there was no signifi-
cant change found in the quality of life.
3. A comparison of hypnotherapy and biofeedback in the

treatment of childhood atopic eczema. Sokel B, Christie D,
Kent A, Lansdown R, Atherton D, Glover M et al. Contemp
Hypn. 1993;10(3):14554.
A randomized controlled trial that examined hypnotherapy
and biofeedback on children with itchy atopic dermatitis.
Those in the hypnotherapy and biofeedback groups showed a
statistically significant reduction in the severity of surface dam-
age and lichenification (an indicator of scratching behavior)
compared to the control group.
Acupuncture/Acupressure
Acupuncture is based on the idea that energy meridians in
the body can become unbalanced and that by stimulating
certain points (acupoints) with needles, pressure, magnets,
or even lasers, the flow can be restored and rebalanced
(Kampik 1976). From a conventional standpoint, there are
studies that show clear changes in specific brain areas with
acupuncture, and evidence that there is endorphin produc-
tion with acupuncture, suggesting a neurocutaneous connec-
tion (Lu and Lu 2013). While formal acupuncture would
require a specially-trained practitioner, more limited ver-
sions (including the single point study discussed below)
could be performed by nearly anyone, including patients
themselves.
Evidence for Acupuncture/Acupressure
1. Acupuncture in haemodialysis patients at the Quchi (LI11)

acupoint for refractory uraemic pruritus. Che-Yi C, Wen CY,
Min-Tsung K, Chiu-Ching H. Nephrol Dial Transplant.
2005;20(9):19125.
Acupuncture/Acupressure 209
Fig. 15.1. Image of large intestine 11 acupuncture point.
40 patients with refractory uremic pruritus were randomized to

acupuncture thrice weekly for 1 month to unilateral Quchi
(Fig. 15.1) or a sham point. Pruritus was found to be signifi-
cantly lower in the true acupuncture group compared to sham
acupuncture at 1 and 3 months.
2. Influence of acupuncture on type I hypersensitivity itch and

the wheal and flare response in adults with atopic eczemaa
blinded, randomized, placebo-controlled, crossover trial. Pfab
F, Huss-Marp J, Gatti A, Fuqin J, Athanasiadis GI, Irnich D
et al. Allergy. 2010;65:90310.
Single session of acupuncture (Quchi and Xuehai points)
decreased itch sensation in artificially induced wheal-and-flare
responses compared to control and placebo groups. While
somewhat contrived from a clinical perspective, this is a
210 15. Pruritus
powerful demonstration of direct modulation of pruritus and

inflammatory response by acupuncture alone.
3. Effectiveness of acupressure on pruritus and lichenification

associated with atopic dermatitis: a pilot trial. Lee KC, Keyes
A, Hensley JR, Gordon JR, Kwasny MJ, West DP et al.
Acupunct Med. 2012;30:811.
Investigator blinded, randomized controlled pilot trial in
adults with atopic dermatitis examined the effect of self-
applied acupressure at Quchi three times weekly for 4 weeks.
In the acupressure group there was a statistically significant
decrease in itch and in lichenification compared to the control
group.
Sunflower Seed Oil

Sunflower seed oil is discussed in detail in Chap. 9 (Atopic
Dermatitis), but warrants mention here as well, since there is
evidence especially relevant to pruritus. The itch-scratch cycle
with its associated barrier damage and secondary inflamma-
tion can occur even in the absence of primary skin disease.
Sunflower (Helianthus annus) seed oil is rich in linoleic acid,
and has been used topically in the treatment of essential
fatty-acid deficiency, rapidly reversing the disease (Lodn
and Andersson 1996). These essential fatty acids can also help
maintain the skin barrier and decrease transepidermal water
loss, both important features in thinking about the barrier
problem in atopic dermatitis and, presumably, in other situa-
tions where the barrier has been damaged (Eichenfield et al.
2009). Several studies have also suggested that there are anti-
inflammatory properties of sunflower seed oil, perhaps via
the PPAR pathway, which may also be helpful given that the
mechanical act of scratching can contribute to inflammation
in the skin (Eichenfield et al. 2009). Safe and inexpensive,
sunflower oil could play a role in managing itch, regardless of
the etiology.
Aromatherapy 211
Evidence for Sunflower Seed Oil
1. New emollient with topical corticosteroid-sparing effect in

treatment of childhood atopic dermatitis: SCORAD and qual-
ity of life improvement. Msika P, De Belilovsky C, Piccardi N
et al. Pediatr Dermatol. 2008 NovDec;25(6):60612.
86 children with moderate atopic dermatitis were randomized
to five groups for 21 days: corticosteroids (from twice daily to
one application every other day) combined or not with the
studied sunflower-oil-containing cream (twice daily). The
studied cream had a significant impact on lichenification and
excoriation, decreased corticosteroid use, and improved qual-
ity of life compared to the control group.
2. Effect of olive and sunflower seed oil on the adult skin bar-
rier: implications for neonatal skin care. Danby SG, AlEnezi
T, Sultan A, Lavender T, Chittock J, Brown K, Cork MJ. Pediatr
Dermatol. 2013 JanFeb;30(1):4250. doi:10.1111/j.1525-
1470.2012.01865.x.
19 adults were randomized to receive olive oil to one arm vs.
sunflower seed oil to the other for 4 weeks. The study found
that topical olive oil caused a worsening of the barrier function
and erythema in volunteers with and without a history of
atopic dermatitis. Sunflower seed oil, on the other hand, did
not cause erythema and preserved skin barrier function while
actually improving hydration. Dysfunctional barrier almost
certainly occurs after scratching or rubbing of the skin and
likely contributes to the itch-scratch cycle, regardless of the
underlying etiology.
Aromatherapy
Aromatherapy refers to the use of essential oils extracted
from botanical sources to treat diseases (Cooke and Ernst
2000). It is commonly administered by massaging into the
skin, although can be vaporized and inhaled, taken orally, or
212 15. Pruritus
even used in the bath. Aromatherapy often implies a mixture

of oils, rather than a single oil. Because of the wide range of
botanicals, their variable concentrations, and the multiple
routes of administration, it is difficult to postulate a single
mechanism of action. Clinically, however, several studies sug-
gest that aromatherapy can cause a reduction in anxiety and
improves mental status (Imura et al. 2006), which could play
a role in the perception of itch (Shenefelt 2003).
Evidence for Aromatherapy
1. Effect of aromatherapy on pruritus relief in hemodialysis

patients. Shahgholian N, Dehghan M, Mortazavi M, Gholami
F, Valiani M. Iran J Nurs Midwifery Res. 2010;15(4):2404.
In this small unblinded and noncontrolled study of 20 hemo-
dialysis patients with pruritus, hand massage was given for
7 min three times weekly with a mixture of the following essen-
tial oils: lavender, mint, and tea tree at 5% concentration. After
2 weeks, the pruritus scores were significantly decreased
(though modestly so), suggesting that the intervention had an
effect. Given the severe impact of pruritus in this population
and the fact that it is generally very refractory to treatment, this
safe, inexpensive approach merits further study. Were it to be
simply an indirect effect related to relaxation, this could still be
potentially harnessed clinically to give some actual relief.
Case 1
A 25-year-old woman presents with a 10 year history of itchy
skin. She feels it worsens during times of stress and she
admits to scratching and picking at her skin regularly. She has
had extensive evaluation by two internists in the past 2 years
which did not identify an underlying cause, and she has failed
a number of conventional topical and oral therapies. On
exam, she has multiple excoriated papules and nodules, espe-
cially on the arms and legs. She is asking for something safe
that will give her relief.
Case 2 213
Discussion
From the description, she may have prurigo nodularis, a
poorly-understood condition without a true primary skin issue
beyond itch. The hint that her itching worsens during times of
stress supports at least a behavioral component.
Beyond ensuring that her skin is well-moisturized and that
her barrier is as functional as possible, sunflower seed oil (ide-
ally followed by a more occlusive moisturizer) also has the
potential of being anti-inflammatory and thus may help with
the pruritus here. Asking her to massage it into the skin may
help in a fashion similar to that of the Aromatherapy study.
Discussing hypnosis, biofeedback, acupressure, or cognitive
behavioral therapy seems very appropriate in this case given
the long history and the exacerbation with stress.
Case 2
A 79-year-old man with a history of sensitive skin presents
with total body pruritus for 1 year without any rash. He com-
plains of inability to sleep at night due to the itch, and that he
is going crazy because of it. He tried several antihistamines
without relief, but is wary of starting antidepressants due to
side effects. Topical therapies have had almost no effect.
Discussion
Elderly patients present even more of a challenge, as there is
greater possibility of harm from conventional medications. In
this case, more powerful medications may not be the answer,
and so alternatives are more attractive. After a suitable evalua-
tion for the pruritus has been performed to exclude systemic
diseases, acupuncture is gentle and may provide significant
relief, especially if he is able to seek treatments with an experi-
enced practitioner. Aromatherapy with massage might also be
reasonable here as it could be done in the home, especially if
going to the acupuncturist is unfeasible.
214 15. Pruritus
References
Callahan SW, Lio PA. Current therapies and approaches to the treat-
ment of chronic itch. Int J Clin Rev. 2012. doi:10.5275/
ijcr.2012.02.01.
Cooke B, Ernst E. Aromatherapy: a systematic review. Br J Gen

Pract. 2000;50(455):4936.
Eichenfield LF, McCollum A, Msika P. The benefits of sunflower

oleodistillate (SOD) in pediatric dermatology. Pediatr Dermatol.
2009;26(6):66975.
Imura M, Misao H, Ushijima H. The psychological effects of

aromatherapy-massage in healthy postpartum mothers.
J Midwifery Womens Health. 2006;51(2):e217.
Kampik G. Acupuncture. Theory and practice. Fortschr Med.

1976;94(10):55962.
Lodn M, Andersson AC. Effect of topically applied lipids on

surfactant-irritated skin. Br J Dermatol. 1996;134(2):21520.
Lu DP, Lu GP. An historical review and perspective on the impact of

acupuncture on U.S. medicine and society. Med Acupunct.
2013;25(5):3116.
Pfab F, Schalock PC, Napadow V, Athanasiadis GI, Yosipovitch G,

Ring J. Complementary integrative approach for treating pruri-
tus. Dermatol Ther. 2013;26(2):14956.
Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hyp-

nosis in dermatology: is it all in your mind? Dermatol Ther.
2003;16:11422.
Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N

Engl J Med. 2013;368(17):162534. doi:10.1056/NEJMcp1208814.
Chapter 16
Resources
As complementary and alternative medicine (CAM) gains

traction amongst practitioners of traditional medicine, so have
the concern and press on regulation of alternative products
and modalities. Many of the products used in CAM fall out-
side the scope of government regulatory agencies so safety
requirements are not nearly as stringent as they are for con-
ventional medications. Nonetheless, the safety of any alterna-
tive products should be called into question just as one would
scrutinize a conventional products safety. Oftentimes, because
something is considered a vitamin, supplement, or alter-
native it is presumed to be harmless. This is potentially a
dangerous presumption and one that should be discussed with
patients seeking alternative therapies.
A reliable reference source for alternative products and
modalities is the National Center for Complementary and
Integrative Health (NCCIH) (formerly known as the National
Center for Complementary and Alternative Medicine) web-
site (nccih.nih.gov). The NCCIH is the Federal Governments
lead agency for scientific research on the diverse medical and
health care systems, practices and products that do not fall
under the umbrella of conventional medicine. On this web-
site the practitioner and patient can find reliable health infor-
mation, references and research on products and modalities
as well as relevant alerts and advisories. To date, the NCCIH
has funded the establishment of over a dozen research

DOI 10.1007/978-3-319-17816-5_16
216 16. Resources
centers to explore the safety and efficacy of CAM therapies

for a wide range of health conditions.
We feel the future of CAM and specifically, CAM within
dermatology, is bright. Two of the major dermatology text-
books now have dedicated chapters on alternative therapies
in dermatology in their latest editions. In addition, a major
integrative medicine textbook includes an entire section on
dermatology.
We recognize that much more research is necessary to
understand the full efficacy or limits of the products and
modalities we have detailed herein. In addition, countless
products and interventions were uncovered in our research
with potential for inclusion, but were intentionally left out of
this manual; in time, we expect some of those to amass
enough evidence to be included, while others we have dis-
cussed may be found to be lacking and will thus be removed.
We hope we have provided the reader with evidence-
based ideas for treating the dermatologic patient and planted
a seed, so to speak, of curiosity about what else may be avail-
able to us in the dermatologic treatment armamentarium. It
was that curiosity that led us to write this manual and it is that
curiosity that motivates our patients to continue to ask the
questions.
Index
A AKs. See Actinic keratoses (AKs)

Acne Aloe vera
comedonal, 54, 55 Dermatology Life Quality
dietary modifications, 6163, 69 Index (DLQI) score, 103
dryness and irritation, 54 psoriasis, 103, 108
features, 53 Psoriasis Area and Severity
green tea, 6364 (PASI) score, 103
hormonal, 69 sunburns, 103
inflammatory, 54, 55 Alopecia areata (AA)
nicotinamide, 5860 aromatherapy, 89
probiotics, 66 garlic, 8788
tea tree oil, 5960 hypnotherapy, 90
treatment, 5354, 56 onion extract, 8889
vitamin C, 5758 treatment, 85
zinc, 6768 Androgenetic alopecia (AGA)
Actinic keratoses (AKs), 39, 41 dihydrotestosterone (DHT), 84
Acupressure. See Acupuncture hypnotherapy, 90
Acupuncture procyanidins, 8687
atopic dermatitis, 125127, 210 raspberry ketone, 8586
endorphin production, 208 treatment, 85
large intestine 11 point, 126127 Angioedema
Quchi and Xuehai points, 209 dietary modification, 138
uremic pruritus, 209 low vitamin D levels, 142
AD. See Atopic dermatitis (AD) stress-reduction, 139
AGA. See Androgenetic alopecia swelling of dermis, 137
(AGA) vitamin D, 142
Aging Antihistamines
carotenoids, 13 conventional treatments, 138
photoprotection, 9 and corticosteroids, 120
skincare regimen, 18 systemic agents, 206
vitamin C, 12 Anti-pruritic therapy, 111

DOI 10.1007/978-3-319-17816-5
218 Index
Argeratina pichinchensis Balneotherapy

on nails, 186 Dead Sea salt, 105
skin injuries, 186 sodium bicarbonate (baking
Aromatherapy soda), 106
essential oils, 211, 212 treatment of psoriasis, 105
hemodialysis patients, pruritus, Basal cell carcinoma (BCC), 33,
211, 212 36, 40, 46, 47
Petitgrain essential oil, 182 BCC. See Basal cell carcinoma
treatment of hair loss, 89 (BCC)
Ascorbic acid. See Vitamin C Biofeedback
Atopic dermatitis (AD) AD, 208
acupuncture/acupressure, and hypnosis, 130131
125127 lichenification, 208
allergen identification, 111112 surface damage, 208
calcineurin inhibitors, 112
cardiospermum plant extract,
119120 C
coconut oil (Cocos nucifera), CAM. See Complementary and
117118 alternative medicine (CAM)
conventional approach, 111 CA-MRSA. See Community
diet modification, 129130 associated methicillin
food allergies or asthma, 111 resistant Staphylococcus
hypnosis and biofeedback, aureus (CA-MRSA)
130133 Cancer
oral vitamin D actinic keratosis, 36, 37
supplementation, 120121 BCC, 36
probiotics, 127128 BEC, 4041
sunflower seed oil, 114116, 132 CoQ10, 44
topical corticosteroids, escharotics, 4546
112, 116 gossypin, 47
Traditional Chinese Medicine ingenol mebutate, 3940
(TCM), 122125, 133 ipilimumab and PD1
treatment, 114115 inhibitors, 35
vitamin B12 application, melanoma, 36, 37, 48
121122 non-melanoma skin cancers, 35
wet wrap therapy, 132 SCC, 36, 37
Azelaic acid, 7778 treatment, 38
vitamin D, 4243, 48
Cantharidin, 171, 174
B Cardiospermum plant extract
Bacterial infections Cardiospermum halicacabum,
EGCG, 188 119
gram-positive and-negative, corticosteroids, 119
187188 cream vs. control, 119
honey, 190 Carotenemia, 13
Streptococcus mutans, 188 Carotenoids
tea tree oil, 188189 beta-carotene, 13
Index 219
lycopene, 13 BCC, 33
sun protection, 2830 urticaria, 138, 142144
Chrysanthellum indicum, 7879 Docosahexaenoic acid (DHA), 97
Cobalamin. See Vitamin B12
Coenzyme Q10 (CoQ10)
cancers, 43 E
melanoma, 44 Eczema. See also Atopic
Cognitive behavioral therapy dermatitis (AD)
psychosocial aspects, 108 dyshidrotic, 113
skin and immune system, 107 exudative and oozing lesions,
Communityassociated 112
methicillin resistant facial eczema, 112, 113
Staphylococcus aureus itraconazole, 112
(CA-MRSA), 185 seborrheic dermatitis, 112
Complementary and alternative Eicosapentaenoic acid (EPA), 97
medicine (CAM), 9596 Epicatechin gallate (ECG), 9
conventional products safety, Epigallocatechin-3-gallate
215 (EGCG), 9, 2728, 188
dozen research centers, 215216 Erythema, 133
NCCIH, 215 Escharotics
Complementary medicine, 3, 119 BCC, 4546
Conventional medicine, 2, 3, 120, FDA and National Cancer
132, 133, 215 Institute, 45
Coriander (Coriander sativum) oil MMS, 45
antibacterial activity, 181
interdigital tinea pedis, 181
Curcumin. See Turmeric (curcumin) F
Fish oil
omega-3 fatty acids, 97
D PASI scores, 99
Dandruff psoriasis, 9799
honey, 199 Flavonols, 1011
sulfur, 199200 Food and Drug Administration
tea tree oil, 197198 (FDA), 45
Depigmentation Food intolerance, 129
ginkgo biloba, 156157 Fungal infections
l-phenylalanine, 157158 ageratina pichinchensis, 186187
polypodium leucotomos, coriander oil, 181182
160161 garlic, 185186
vitamins, 159160 oil of bitter orange, 182183
Dermatoheliosis, 7 solan chrysotrichum, 183185
Dermatology Life Quality Index superficial mycoses, 177
(DLQI) score, 103 tea tree oil, 179, 181
Dietary modifications tinea corporis (ringworm), 178
acne, 6163 tinea pedis + onychomycosis, 178
angioedema, 138 topical antifungals, 177
atopic dermatitis (AD), 129130 treatment, 179
220 Index
G Medihoney, 190
Garlic (Allium sativum) Staphylococcus aureus skin
antiviral effects, 169 infections, 191
fungal infections, 185186 therapeutic and prophylactic
hair loss, 8788 effects, 199
tinea pedis, 185186 tinea versicolor, 192
warts, 169170 Traditional Chinese medicine,
Gingko biloba 199
anxiolytic effects, 156 Hoxsey, H., 45
repigmentation, 157 Human papillomavirus (HPV).
vitiligo, 156157, 160 See Warts
Vitiligo Area Scoring Index Hyperpigmentation
(VASI), 157 hydroquinone, 148
Gossypin, 47 lentigines, 148
Green tea licorice, 155156
acne, 6364 melasma, 147148
EGCG and ECG, 8 niacinamide, 1718, 153154
GTPs, 9 soy, 152153
UVA & UVB induced sunscreen vs. control
erythema, 910 moisturizer, 154
Green tea polyphenols (GTPs), 9 treatment, 150
vitamin C, 149, 151152
Hypnosis
H alopecia areata, 90
Hair loss atopic dermatitis, 130131
alopecia areata, 87 definition, 90
androgenetic alopecia (AGA), itch-scratch cycle, 130
8385 stress, 130
aromatherapy, 89 stress-relieving techniques,
garlic (Allium sativum), 8788 131
hypnotherapy, 9092 Verbally Active Distraction,
onion extract, 8889 141
procyanidins, 8687 Hypnotherapy. See also Hypnosis
raspberry ketone (RK), 8586 AD, 130, 207
Hanifin, J.M., 2 hair regrowth, 90
Heinrich, U., 11
Hives. See Urticaria
Honey I
antimicrobial properties, 190 Indigo naturalis
Ayurveda, 199 Chinese medicine, 99
burns, 190 Nail Psoriasis Severity Index
CA-MRSA, 190 (NAPSI), 100101
inhibines, 190 plaque psoriasis, 99
itching and hair loss, reduction, Ingenol mebutate
201 AKs, 39, 40
manuka honey, 190 ingenol, 3940
Index 221
Itch Melaleuca alternifolia. See Tea

atopic dermatitis, 126, tree oil (TTO)
131, 207 Melanoma
chronic, 207 CoQ10, 4344
dandruff, 201 gossypin, 47
in hair loss, 199 malignant, 35
prurigo nodularis, 213 sun protection, 48
solely symptomatic treatment, vitamin D, 42
205 Melasma
Itch-scratch cycle, 133, 207, 208 the mask of pregnancy,
Itraconazole, 112, 133 147148
niacinamide, 153
pigmentation, 147148
L polypodium leucotomos, 160
Lemon myrtle solution vitamin C, 151
(Backousia citriodora) Mindfulness based stress
atopic dermatitis, 174 reduction (MBSR)
molluscum, 171173 cognitive behavioral therapy, 108
Lentigines meditation and yoga, 107
hyperpigmentation, 148 nail psoriasis, 108
polypodium leucotomos, 160 psoriasis, 107
sun spots, 147 Modern medicine, 1
Licorice Mohs, F., 45
anti-oxidant and anti- Mohs micrographic surgery
inflammatory properties, 155 (MMS), 45
epidermal melasma, 156 Moisturizer
glabridin, 155 coconut oil, 118, 133
liquiritin, 155156 niacinamide, 122
root, 1617 soy, 152
tyrosinase, 155 sunflower seed oil, 132, 213
Lycopene, 13, 30 Molluscum contagiosum virus
(MCV)
atopic dermatitis, 166
M cantharidin, 174
Mahonia aquifolium (Oregon lemon myrtle solution, 171172
grape) poxvirus, 166167
psoriasis, 104 treatment, 166, 174
Psoriasis Area and Severity TTO, 172173
Index (PASI), 105 umbilicated papules, 167
Malassezia
anti-yeast agents, 195
itraconazole, 133 N
seborrheic dermatitis, 196 Nail infections
MBSR. See Mindfulness based ageratina pichinchensis, 186187
stress reduction (MBSR) tea tree oil, 180
MCV. See Molluscum Nail Psoriasis Severity Index
contagiosum virus (MCV) (NAPSI), 100101
222 Index
Narrow Band UVB (NB-UVB) melanin concentration, 147

phototherapy, 161, 162 melasma, 147148
National Center for vitiligo, 148149
Complementary and PLE. See Polypodium leucotomos
Integrative Health (PLE)
(NCCIH), 215 PMLE. See Polymorphous light
NB-UVB. See Narrow Band UVB eruption (PMLE)
(NB-UVB) phototherapy Polymorphous light eruption
NCCIH. See National Center for (PMLE), 32
Complementary and Polyphenols
Integrative Health benefits, 27, 33
(NCCIH) EGCG, 2728
Newton-Bishop, J.A., 42 green tea, 810, 19
Niacinamide Polypodium leucotomos (PL)
acne, 5859 lentigines, 161
anti-oxidant, 153 melasma, 161
hyperpigmentation, 17, 153 NB-UVB phototherapy, 161, 162
melanogenesis, 153 PUVA, 160
melasma, 17, 153 vitiligo, 160162
rosacea, 7577 Polypodium leucotomos (PLE)
sagging skin, 18 BCC, 33
sun protection, 2627 murine models, 30
vitamin B3, 25, 26, 153 phenolic antioxidants, 30
Nicotinamide. See Niacinamide PMLE, 32
Nurnberg, B., 42 PUVA, 31
UVA and UVB, 32
Probiotics
O acne, 66
Oil of bitter orange (OBO) bacterial imbalance, 127
neroli oil, 182 lactobacillus rhamnosus GG, 128
tinea corporis, 182 prevention and treatment, 127
Onion extract (Allium cepa), 88 Procyanidins, 8687
Propolis
immunomodulator, 167
P warts, 173
l-Phenylalanine Pruritus
melanin synthesis, 157 acupuncture/acupressure,
ultraviolet light (UVA) 208210
treatment, 158 acute/chronic, 205
vitiligo treatment, 157 in AD, 111, 121, 125, 126
Photoaging. See Dermatoheliosis aromatherapy, 211213
Photoprotection. See Sun biofeedback, 208
protection cognitive behavioral therapy,
Pigmentation 207
hydroquinone, 148 curcumin, 101
hyperpigmentation, 147 definition, 205
Index 223
fish oil, 99 erythematotelangiectatic

hemodialysis patients, 213 rosacea, 80
hypnosis, 207208 erythematous papules and
inflammatory skin diseases, 205 pustules, 74
prurigo nodularis, 213 nicotinamide, 7677
sensitive skin, 213 papulopustular lesions, 81
solely symptomatic treatment, quassia amara, 8081
205 treatment, 75
sunflower seed oil, 210211
topical and systemic agents, 206
Psoralen plus UVA therapy S
(PUVA), 159 Safety, 2, 4
Psoriasis Salicylic Acid
aloe vera, 103 ammonium lactate emollient
baking soda, 106 foam, 201
balneotherapy, 105106 antimicrobial, 201
CAM, 95 keratolytic, 201
curcumin, 101102 scalp psoriasis, 201
cutaneous lesions, 96 SAP. See Sodium ascorbyl
erythematous scaly plaques, 97 phosphate (SAP)
fish oil, 9799 Scratch
indigo naturalis, 99101 anxiety, 130
mahonia aquifolium, 104105 dysfunctional barrier, 211
mindfulness based stress psychosocial morbidity, 208
reduction, 107108 secondary inflammation, 210
pathogenesis, 95 Seborrheic dermatitis (SD)
risk factor, 9596 aberrant immune response,
treatments, 95, 96 195
Psoriasis Area and Severity Index antifungal shampoos, 202
(PASI), 102104 dandruff, 201
dry skin, 196, 197
eczema, 112
Q erythematous patches, 196
Quassia amara, 8081 honey, 199
malassezia, 195, 196
oil application, 196, 197
R olive oil, 196, 201
Raspberry ketone (RK), 8586 salicylic acid, 200201
Reactive oxygen species (ROS), 24 scalp psoriasis, 195
ROS. See Reactive oxygen species sulfur, 199200
(ROS) tea tree oil, 197198
Rosacea topical corticosteroids, 195
azelaic acid, 7778 Skin barrier
chrysanthellum indicum, 7879 coconut oil (Cocos nucifera),
classification, 73 117118
erythema/flushing, 74, 75 sunflower seed oil, 114116
224 Index
Skin care shampoos, 200

carotenoids, 1314 sodium sulfacetamide, 199
dermatoheliosis/photoaging, 7 Sunflower seed oil
flavonoids, 1011 corticosteroids, 211
green tea, 810 cream, 116
licorice, 1617 fatty acids, 114, 210
niacinamide, 1719 infection and mortality, 116
photoprotection, 7 linoleic acid vs. oleic acid,
soy, 1416 114115
treatment, 8 vs. olive oil, 116, 211
UV-B rays, 8 PPAR pathway, 114115, 210
vitamin C, 1213 sunflower seed allergy, 115
Sodium ascorbyl phosphate Sun protection
(SAP), 57 antioxidant effects, 25
Solan chrysotrichum carotenoids, 2830
ketoconazole, 183184 niacinamide, 2527
saponin SC-2, 183 pigment darkening, 24
tinea pedis, 184 PLE, 3033
Solasodine glycosides (BEC) polyphenols, 2728
AK and non-melanoma skin ROS, 24
cancer, 40 systemic photoprotection, 2425
squamous cell cancer, 41 UVR, 23
Soy
Bowman-Birk protease
inhibitor, 15 T
dyspigmentation, 153 Tea tree oil (TTO)
health benefits, 1415 acne, 6465
PAR-2 receptors, 15 debridement and clinical
STI, 15 assessment, 180
sunscreen, 161 dermatophyte infection, 180
UVB-induced skin damage, 152 distal subungual
Soybean trypsin inhibitor (STI), onychomycosis, 180
15, 152 erythema, 197
Squamous cell carcinoma (SCC), and iodine preparation,
3637, 39, 41, 46 172173
STI. See Soybean trypsin inhibitor Melaleuca alternifolia,
(STI) 179, 188, 197
Stress-reduction molluscum, 172
hypnosis, 145 MRSA eradication regimens,
psychological stress, 139 189
urticaria, 139 mupiricin, 189
Sulfur pruritus, 197
corneocyte count and scaling, shampoo/placebo, 198
200 topical antimicrobial agent,
cutaneous disorders, 200 179, 189
emollient foam, 200 treatment, 189
salicylic acid, 200 Thompson, M.M., 2
Index 225
Topical calcineurin inhibitors, V

2, 112, 133, 149 Virgin coconut oil (VCO)
Topical corticosteroids, 112, 115 vs. mineral oil, 117118
anti-inflammatory, 132 RCT trial, 118
antimicrobial effects, 132 staphylococcal colonization,
anti-pruritic, 132 117
Traditional Chinese Medicine Vitamin B3, 17, 2526
(TCM) Vitamin B12
AD, 133 moisturizers, 121122
herbal medications nitric oxide, 121
(Zemaphyte), 124 RCT, 121
herbal vs. placebo, 125 Vitamin C
pharmacologic effects, 123 acne, 57
RCT approach, 123 l-ascorbic acid, 12
SCORAD reduction, 125 carotenoids, 13
single herbal therapy or cream, depigmenting properties, 151
123 melasma, 151
TTO. See Tea tree oil (TTO) photodamage and cutaneous
Turmeric (curcumin) aging, 149
PASI score, 102 postmenopausal women, 13
phosphorylase kinase (PhK), 102 SAP, 57
psoriasis, 101 water-soluble antioxidant, 149
tumor necrosis factor (TNF), 101 Vitamin D
in AD, 120
anti-bacterial proteins, 120
U cholecalciferol, 120, 141
Ultraviolet radiation (UVR), 23 conventional therapy, 142
Urticaria EASI score and IGA score, 121
chronic idiopathic, 143145 melanoma, 4243
classification, 137 supplementation, 42
conventional treatments, 138 urticaria/angioedema, 142
dietary modification, 138, 142145 winter eczema, 120
elimination and anti- Vitiligo. See Depigmentation
inflammatory diets, 143 cytotoxic mechanism, 149
gluten-free diets, 143145 gingko biloba, 156, 162
hypnosis, 140141 loss of melanocytes, 148149
or hives, 137 monobenzyl ether or
pathogenesis, 137 hydroquinone, 149
pseudoallergen-free diet, 143 l-phenylalanine, 157158
RTC, 145 pigmentation, 148149
stress-reduction, 140 polypodium leucotomos,
treatment, 140 160162
urticarial papules, 140 psychological stress, 156
vitamin D, 142 treatment, 150
UVB phototherapy, 159 vitamin B12 deficiency, 159
UVR. See Ultraviolet radiation Vitiligo Area Scoring Index
(UVR) (VASI), 157
226 Index
W Z
Warts Zemaphyte. See Traditional
garlic, 170 Chinese Medicine (TCM)
human papillomavirus, 165 Zinc
oral propolis, 173 acne, 68
treatment, 165, 168 oral zinc sulfate, 168, 169
verrucous papules, 166 warts, 168169
zinc, 168169
Weinstock, M.A., 42
Winter eczema, 120
Woods lamp examination, 156

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Peter A.

Lio Toral Patel

ISBN 978-3-319-17815-8 ISBN 978-3-319-17816-5 (eBook)

Library of Congress Control Number: 2015938919

Springer Cham Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer

For Anju, my loving wife, best friend, and biggest supporter.

To MSR and my parents for their unconditional support.

The second is that any serious scholar of medicine knows

helpful for clinicians trying to guide patients through these

Chicago, IL Peter A. Lio

1 Introduction to Integrative Dermatology................... 1

Dietary Modifications ................................................... 61

Evidence for Raspberry Ketone ............................ 86

9 Atopic Dermatitis (Eczema) ...................................... 111

Dietary Modification ................................................... 142

14 Seborrheic Dermatitis ................................................. 195

Modern medicine can take credit for tremendous

Springer International Publishing Switzerland 2015 1

Indeed, in one study some 75% of patients had made

So, what are they seeking? How do we define this area?

dissonance. We shall not take that path. Instead, we will

Johnston GA, Bilbao RM, Graham-Brown RA. The use of dietary

Kojima R, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama

Simpson EL, Basco M, Hanifin J. A cross-sectional survey of comple-

Thompson MM, Hanifin JM. Effective therapy of childhood atopic

Webber SA, Graham-Brown RA, Hutchinson PE, et al. Dietary

Springer International Publishing Switzerland 2015 7

be the primary culprit in photoaging due to their deeper

Table 2.1. General skincare: Alternative treatment options.

amount of oral green tea consumption for maximal health

Evidence for Green Tea

1. Cutaneous photoprotection from ultraviolet injury by

2. Green tea polyphenol treatment to human skin prevents

In this small study of six Caucasian subjects, varying doses of

3. Protective effects of green tea extracts on photoaging and

in flavanols than milk chocolate; however, the final flavanol

Evidence for Flavonoids

1. Long-term ingestion of high flavanol cocoa provides photo-

2. Consumption of flavanol-rich cocoa acutely increases

Evidence for Vitamin C

2. Topically applied vitamin C enhances the mRNA level of

Lambert C, Richard A, Creidi P, Lapiere C. J Invest Dermatol.

Evidence for Carotenoids

1. Dietary tomato paste protects against ultraviolet light-

In this randomized placebo-controlled study, nine adults with

2. Tomato paste rich in lycopene protects against cutaneous

Soy contains the serine protease inhibitors soybean tryp-

Evidence for Soy

1. Oral intake of soy isoflavone aglycone improves the aged

2. Efficacy of a soy moisturizer in photoaging: a double-blind,

applied the product to the face twice daily for 12 weeks.

Evidence for Licorice

hydroquinone group, two patients developed contact dermati-

2. Topical liquiritn improves melasma. Amer M, Metwalli M.

Evidence for Niacinamide

1. A double-blind, randomized clinical trial of niacinamide

hydroquinone cream to the other side once daily for 4 weeks.

2. The effect of niacinamide on reducing cutaneous pigmenta-

Chen N, Scarpa R, Zhang L, Seiberg M, Lin C. Nondenatured soy

Elmets C, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar

Farris P. Topical vitamin C: a useful agent for treating photoaging