Review

Keloids: a review of therapeutic management

Samuel F. Ekstein1, BS, Saranya P. Wyles2, MD, PhD, Steven L. Moran3,4, MD and
Alexander Meves2, MD, FAAD

1
Mayo Clinic Alix School of Medicine, Mayo
Clinic, Rochester, MN, USA, 2Department
of Dermatology, Mayo Clinic, Rochester,
MN, USA, 3Division of Plastic Surgery,
Mayo Clinic, Rochester, MN, USA, and
4
Department of Orthopedic Surgery, Mayo
Clinic, Rochester, MN, USA
Correspondence
Alexander Meves, MD
Mayo Clinic, 200 First Street S.W.
Rochester, MN 55905
USA
E-mail: meves.alexander@mayo.edu
Conflict of interest: None.
Funding source: This work was supported
by the National Cancer Institute; grant
CA215105.
doi: 10.1111/ijd.15159
Abstract
Keloid scar formation arises from a disorganized fibroproliferative collagen response that
extends beyond the original wound margins because of excessive production of
extracellular matrix (ECM). Despite treatment options for keloid scars including medical
and surgical therapies, such as intralesional steroid injection and surgical excision, the
recurrence rate remains high. Herein we consolidate recently published narrative reviews,
systematic reviews, and meta-analyses to provide an overview of updated treatment
recommendations for keloidal scar formation. PubMed search engine was used to access
the MEDLINE database to investigate updates regarding keloid incidence and treatment.
More than 100 articles were reviewed. Keloid management remains a multimodal
approach. There continues to be no gold standard of treatment that provides a consistently
low recurrence rate; however, the increasing number of available treatments and
synergistic combinations of these treatments (i.e., laser-based devices in combination with
intralesional steroids, or 5-fluorouracil (5-FU) in combination with steroid therapy) is
showing favorable results. Future studies could target the efficacy of novel treatment
modalities (i.e., autologous fat grafting or stem cell-based therapies) for keloid
management. This review article provides updated treatment guidelines for keloids and
discusses insight into management to assist patient-focused, evidence-based clinical
decision making.

later,9 causing cosmetic deformation, functional impairment,

Introduction
Keloid, meaning “crab’s claw,” was derived from Greek to
describe its characteristic clinical presentation.1-3 Historically,
the earliest known keloid scarring was reported around 1700
CE Egypt in the Smith Papyrus.4 The term was first introduced
5
into modern medical literature in 1814. Later that century, a
medical textbook published, “In regards to treatment, we are
almost helpless. It is pretty certain to reappear after excision,
even though the incisions be carried far into the healthy skin”.6
Today, despite various treatment options, keloid scarring contin-
ues to escape the normal process of wound healing and
remains recalcitrant.7,8
From a clinical perspective, keloids appear as elevated, firm,
bosselated papules and ill-defined plaques accompanied by
variation in color, including erythematous, violaceous, or brown
pigmentation.9 In contrast to normal and hypertrophic scarring,
keloids extend beyond the borders of original injury and fail to
regress.8,9 Given their composition of haphazardly branched
and septal disorganized type I and III collagen bundles, keloids
are often symptomatic with accompanying pain and pruritus.10
Following disruption of skin integrity resulting from superficial
and deep injuries, keloids can form within months to years
psychological distress, and poor quality of life.10,11 A variety of
epidermal to dermal insults are implicated including iatrogenic
surgical incisions, burns, trauma wounds, body piercings, insect
bites, folliculitis, chickenpox, herpes zoster infection, vaccina-
tions, and acne.3 Keloid formation has also been observed fol-
lowing facial dermabrasion in patients on isotretinoin therapy.12
Indeed, apart from the hairless tissue of palms and soles, keloid
scar distribution occurs without topographic discrimination,
including on the cornea.13
Because of the complexity and mechanical forces at work
during the wound healing process, the exact pathophysiology
of keloid formation is still undetermined. Risk factors include
personal or family history of keloids, skin of color ethnic
groups, pregnancy, puberty, and skin injuries overlying osteo-
genic surfaces.14 The incidence of keloid scarring in the His-
panic and African-American population is 4.5–16%.15 In
African Americans, there is a significant association between
keloid scars, obesity, and hypertension.16,17 In a study exam-
ining systemic medical conditions and keloid formation, obe-
sity was present in 28.57% of the keloid population as
compared to 10.98% for the general population (P < 0.001).17
Hypertension was present in 44.29% of the keloid population
1

ª 2020 the International Society of Dermatology International Journal of Dermatology 2020

2 Review Keloids: a review of therapeutic management Ekstein et al.

as compared to 15.75% of the general population comparison. To date, the gold standard of treatment continues
(P < 0.001).2 to vary across academic institutions and independent private
Despite a firm understanding of the risk factors for keloid for- practitioners.7 Herein, we consolidate recently published narra-
mation, the lack of animal models limits investigational studies tive reviews, systematic reviews, and meta-analyses to provide
into the precise mechanism of keloid formation.18 The wound an overview of updated treatment recommendations for keloidal
healing process that leads to tissue repair and regeneration pro- scar formation.
ceeds in four time-sensitive phases: (i) hemostasis, (ii) inflam-
mation, (iii) proliferation, and (iv) remodeling.19 The early phase
Methods
of wound healing leads to the recruitment of inflammatory cells,
epithelial cells, and fibroblasts, which relocate into the wound This review explores current therapies available to treat keloids.
matrix and contribute to scar remodeling. Specifically, fibrob- The PubMed search engine was used to access the MEDLINE
lasts and myofibroblasts create a collagen-containing extracellu- database in order to search for studies pertaining to keloids.
lar matrix (ECM) that is in a delicate balance of synthesis and The following search phrases were used to refine results:
degradation.20 An imbalance associated with collagen produc- “Keloid/drug therapy” OR “Keloid/therapy” OR “keloid”. The
tion and ECM degradation, therefore, contributes to scar forma- article type was limited to review, publication dates were limited
tion.20 A proinflammatory microenvironment triggered by to January 1, 2016, to January 1, 2019, and species was
dysregulated levels of three TGF-b isoforms (TGF-b1, TGF-b2, limited to human. A total of 60 articles were identified with the
and TGF-b3) and other cytokines secreted by the type 2 T- above search criteria. Screening based on English language
helper cell (Th2) immune response (IL-4, IL-5, IL-10, and IL-13) (n = 4) and relevance (n = 16) excluded 20 articles (Fig. 1).
has been postulated to play a role in keloid formation.10,21 Fur-
thermore, increased expression of elastin and fibrillin-1 has
Results
been noted in scar elasticity.22 Recent studies suggest that
keloid fibroblasts displayed different actin filament stiffness and Medical therapies
force generation as compared to normal fibroblasts, which may
delineate keloid extension beyond original wound margin.2,23 Triamcinolone acetonide
Keloid fibroblasts also produce excess ECM when grown on a Triamcinolone acetonide (TAC; Kenalog), an intralesional corti-
stiff substrate,2 partly informing the increased risk of keloid for- costeroid injection, remains the most commonly used, first-line
mation in high-tension body surfaces, such as chest and upper choice treatment for keloid scarring.29 Corticosteroids affect
2
back. multiple key pathways in the formation of keloids by decreasing
Despite the fact that keloid formation is classified as a benign inflammation during the wound healing process.29 It also sup-
dermal growth, it can behave like a malignant tumor with regard presses collagen and glycosaminoglycan synthesis, reduces
to invasion and hyperproliferation. In contrast to a keloid, a fibroblast development, and augments collagen degradation.29
hypertrophic scar behaves differently and contains mainly type This treatment can be used as a monotherapy on a mature
III collagen arranged parallel to an epidermal surface. Studies keloid or as an adjuvant to surgical excision or laser therapy.
suggest a greater genetic predisposition in keloids compared to Response to TAC injections varies widely with a reported 50–
hypertrophic scars.24 Four single-nucleotide polymorphisms
(SNPs) across three loci on chromosome bands 1q41, 3q22.3-
23, and 15q21.3 associated with keloid pathogenesis have been
identified, although the mechanisms by which these SNPs con-
tribute to keloid formation are poorly understood.25 MicroRNA-
21 signaling pathways also contribute to keloid formation.24 Fur-
thermore, epigenetic signaling involving histone modification,
regulatory RNA alterations, and DNA methylation are also impli-
cated in keloid pathogenesis.26
Keloidal pathophysiology therefore remains multimodal and
complex. There are a wide range of therapies used in treating
keloids with various degrees of success graded by time to
recurrence. Keloid treatment can be classified into medical and
surgical interventions as well as a combination including topical
agents, intralesional injections, radiation, and laser therapy.27,28
Numerous clinical trials have reported the effectiveness of vari-
ous treatments on keloid scarring. Yet, variability in quality and
other limitations render it difficult to ascertain intra-trial Figure 1 Flowchart of study identification in literature review

International Journal of Dermatology 2020 ª 2020 the International Society of Dermatology

Ekstein et al.
100% regression.30 One year posttreatment, the recurrence rate
is an estimated 33%.30 After 5 years, the recurrence rate
increases to 50%.30 TAC is injected at a dosage of 10–40 mg/
ml into the mid-dermis every 4–6 weeks until the scar has
resolved.29 Side effects include skin atrophy and hypopigmenta-
tion.
Triamcinolone acetonide in combination with 5-Fluo-
rouracil
The addition of 5-fluorouracil (5-FU) to TAC is postulated to
lower the side effect profile because of a decreased dose
requirement of each agent. Several studies have reported on
this combination treatment; however, the number of reported
cases is low.31 Ren et al. report the effectiveness of intrale-
sional TAC alone compared to TAC in combination with 5-FU in
a systematic review and meta-analysis.31 While hypertrophic
scars were not analyzed separately from keloid scars, the com-
bination of TAC and 5-FU was more effective than TAC alone.
Effectiveness was measured in terms of patient assessment
after treatment (odds ratio [OR], 2.92; 95% CI, 1.63–5.22,
P < 0.001), observer assessment following treatment (OR, 4.03;
95% CI, 1.40–11.61; P < 0.01), scar height after treatment
(mean differences [MD], 0.14; 95% CI, 0.23 to –0.05;
P < 0.01), and erythema score (MD, 0.20; 95% CI, 0.34 to –
0.06; P < 0.01).31 Data from Alexandrescu et al. support these
findings.32
Mitomycin C
Mitomycin C (MMC), a derivative of Streptomyces caespitosus,
is an antibiotic agent with antineoplastic and antiproliferative
activities, which has been used as a topical agent following
keloid surgical excision. By inhibiting DNA, RNA, and protein
synthesis, MMC prevents cell division and fibroblast prolifera-
tion.27 In a meta-analysis, Shin and colleagues determined the
recurrence rate for topical MMC to be 16.5% (95% CI, 7.9–
31.1). Treatment consisted of 1 mg/ml MMC applied to the sur-
gical wound for 3–5 minutes every 3 weeks.27 No adverse
effects at the 1 mg/ml dose were noted.
Bleomycin
Bleomycin is a cytotoxic agent that induces sclerosis and is
commonly used in the treatment of various malignancies.33 The
first reported use of this intralesional treatment for keloids was
in 1996 and achieved a 47% remission rate.30 Illustrating the
difficulty of assessing treatment efficacy, subsequent studies
report widely varying degrees of recurrence. The lowest recur-
rence rate noted for this treatment is 0% at a mean duration of
19 months follow-up.34 However, another group reported recur-
rence rates in a Vietnamese population of 3.8%, 15.4%, 45.5%,
and 50% at 6, 12, 15, and 18 months follow-up, respectively.35
The wide range of recurrence rates based on follow-up time is
also seen in intralesional TAC treatment as discussed previ-
ously. In a study comparing intralesional bleomycin to TAC in
ª 2020 the International Society of Dermatology
Keloids: a review of therapeutic management Review 3
patients with Fitzpatrick skin types III to V, both treatments were
comparable with no significant difference in efficacy between
the two groups.36 However, there was a high rate of bleomycin-
induced hyperpigmentation (71.4%).36 A meta-analysis to stan-
dardize the efficacy of intralesional bleomycin is warranted.
Imiquimod
Imiquimod 5% cream (Aldara) is a topical immunomodulatory
treatment, which increases the expression of tissue necrotic fac-
tor alpha (TNF-a), gamma and alpha interferons (IFN-c and -a),
and interleukin 1, 6, 8, and 12. It also acts as a toll-like receptor
(TLR) agonist. A meta-analysis of topical 5% imiquimod cream
applied for 6–8 weeks post-keloid excision showed that the rate
of recurrence was 24.7% (95% CI, 3.2–76.4); variable outcomes
were reported.27
Botulinum A
Use of botulinum toxin-A (BoNT-A) in keloid treatment is based
on its ability to reduce muscle tension and thereby wound ten-
sion.37 BoNT-A has been reported to decrease TGF-b expres-
sion, reduce fibroblast proliferation, and alter collagen activity
during pathologic scar formation.38 A meta-analysis of treating
keloids with BoNT-A remains to be conducted; however, Sch-
lessinger and colleagues reviewed several small studies that
have been performed to date.39 Efficacy of BoNT-A in keloid
treatment is not definitive with studies showing mixed results.39
Interestingly, a meta-analysis of randomized controlled trials
has been conducted on hypertrophic scars in the maxillofacial
area and neck, which showed a statistically significant differ-
ence in scar width, patient satisfaction, and visual analysis
scores in the treatment of hypertrophic scars.40 While BoNT-A
has been reported to be effective in hypertrophic scar preven-
tion, its use in keloid treatment remains uncertain.
Interferons
Immune-response modifiers, interferon alpha and gamma (IFN-a
and IFN-c), are observed at decreased concentrations in
keloids.41 Interferons exert antiviral, antiproliferative, and antifi-
brotic properties.42 Indeed, IFN-c and IFN-a antagonize TGF-b-
stimulated collagen metabolism in vitro.43 Treating keloids with
intralesional interferon injections has had varying levels of suc-
cess with adverse reactions, including systemic flu-like symp-
toms, pain at the injection site, edema, and erythema
reported.42,44 IFN-a-2b did not demonstrate efficacy in treating
keloids.45 Al-Khawajah et al. reported the cases that withdrew
because of local pain (7 of 22 patients) during injection and
because of severe systemic symptoms following the first injection
(2 of 22 patients).45 Other studies demonstrate more favorable
results. Berman et al. found that intralesional IFN-a-2b injections
into a keloid resulted in a 41% reduction in area.46 In a larger
study (n = 124) on interferon injections following keloid excision,
IFN-a-2b demonstrated a lower recurrence rate (18.7%) com-
pared to TAC (58.5%) and excision alone (51.2%).47
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4 Review Keloids: a review of therapeutic management
Onion extract (Allium cepa)
Onion extract (Allium cepa) has been shown to significantly
improve dermal collagen organization in animal model
scars.48 Additionally, the derivative of Allium cepa, quercetin,
48
displays antiproliferative and antihistamine effects.
majority of trials, to date, tested this treatment on non-keloi-
dal scars. In a study by Wananukul and colleagues, 10%
onion extract in silicone derivative gel significantly decreased
the incidence of hypertrophic scar formation from median
sternotomy.49 However, no significant difference in keloid
incidence between treatment and placebo groups was
observed.49 The use of onion extract may be better suited
for combination therapy. When intralesional TAC alone was
compared to TAC with onion extract to treat keloid and
hypertrophic scars, the TAC with onion extract group demon-
strated a statistically significant improvement in pain sensi-
tiveness, pruritus, and elevation at week 20,50 although no
significant difference in erythema or induration was seen
between treatment groups.50 An additional study examining
keloid and hypertrophic scars compared the following three
treatment arms: onion extract alone, silicone
sheet alone, and combination of onion extract and silicone
51
sheet. While onion extract alone was more effective in
improving scar color, the silicone gel sheet was more effec-
tive in reducing scar height.51 The combination of these
treatments provided the best response.51
Laser-based devices
Forbat and colleagues reviewed the effectiveness of light-,
laser-, and energy-based devices in the management of keloid
scars.28 Laser-based devices can be divided into ablative and
nonablative categories. Ablative lasers remove the epidermal
layer and include erbium-doped yttrium aluminium garnet (Er:
YAG) and carbon dioxide (CO2) lasers. Nonablative lasers tar-
get the dermis and include potassium titanyl phosphate (KTP),
pulsed dye laser (PDL), and neodymium-doped yttrium garnet
(Nd:YAG) lasers.28,52 For CO2 laser treatments, keloid recur-
rence was noted between 2 weeks and 3 years post laser.
Treatment with the Er:YAG laser resulted in a 22% recurrence
rate at 8 months post laser. Nd:YAG laser exhibited recurrence
rates that differed based on keloid site at 6 months post laser:
52.9% recurrence for anterior chest, 35.7% recurrence for upper
arms, and 25% for scapula keloids. While these data are
promising for the use of multiple laser subcategories, additional
randomized controlled trials are warranted to determine the
effectiveness. Khansa et al. reported a similar conclusion that
laser-based devices produced variable results.53 Higher Fitz-
patrick skin types are at a greater risk of adverse effects from
laser therapy, and thus the efficacy of laser-based devices to
treat keloids in skin of color ethnic groups is not widely stud-
ied.28 In one study evaluating the 1064 nm Nd:YAG laser on
patients with Fitzpatrick skin types I to VI, postinflammatory pig-
mentation changes were not observed.54 The Nd:YAG laser
International Journal of Dermatology 2020
Ekstein et al.
may, therefore, be an acceptable option for patients with darker
skin types IV to VI.54
Laser-based devices in combination with TAC
Pulsed dye laser is a nonablative laser that can attenuate keloi-
The
dal pain and pruritus53 but is limited in its ability to decrease
scar size. PDL alone appears to downregulate TGF-b1 expres-
sion with no impact on type I collagen formation.53,55 Therefore,
PDL in combination with TAC may provide a synergistic effect
as corticosteroids also contribute to reducing collagen synthesis
and increasing collagen degradation.29,53 Combination of these
modalities yielded a 60% improvement in height, 40% improve-
ment in erythema, and 75% improvement in pruritus; however,
the sample size was small (n = 7).56
Improved results with the CO2 and Nd:YAG lasers in combina-
tion with TAC have also been noted.30 Specifically, Stucker et al.
demonstrated that intralesional TAC halts early recurrences of
keloids treated with the CO2 laser.57 Another study using CO2 laser
with intralesional TAC over 6 months noted a significant increase
in recurrence of keloids in patients who did not follow-up regularly
gel for TAC injections.58 Kumar et al. noted an additive effect of TAC
and Nd:YAG laser; keloids that persisted following Nd:YAG laser
therapy were subsequently treated with intralesional TAC, resulting
in complete resolution over 18 months to 5 years of follow-up.59
Cryotherapy
Traditional cryotherapy involves using freeze-thaw cycles to
damage scar tissue. Consequent damage to the surrounding
skin surface gave rise to a more targeted approach of intrale-
sional cryotherapy in which a specialized needle probe freezes
the scar from the inside.60,61 A comprehensive review of eight
studies found this approach favorable in reducing scar volume,
pain, and pruritis.62 However, persistent hypopigmentation in
Fitzpatrick IV to VI skin types was observed, and recurrence
rates varied widely between 0% and 24%.62
Surgical therapy
Excision
Excising keloids without secondary intervention generally results
in a poor outcome. Excision alone results in a recurrence rate
of greater than 50%.63 While certain wound closure techniques
reduce tension at the wound site, no data support whether a
specific wound closure technique reduces the likelihood of
keloid recurrence. However, a tensionless closure following
excision is considered important in reducing scar hypertrophy
and scar widening.64
Combined medical and surgical therapies
Triamcinolone acetonide following excision
A recent meta-analysis reported whether triamcinolone intrale-
sional injection following surgical excision prevented the
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Ekstein et al.
recurrence of keloids.65 Researchers analyzed four studies
comprising 254 patients and found that surgery combined with
TAC was not effective in lowering the rate of keloid recurrence
with a pooled risk difference of 0.06 (95% CI, 0.16 to 0.28; P,
not significant).65 However, the location of the keloid may be
associated with the success of TAC following excision. Ear
keloids exhibited increased responsiveness to TAC following
excision.66 In a meta-analysis examining the use of TAC follow-
ing excision of ear keloids, the recurrence rate was 15.4% (95%
CI, 9.4–24.1%; P < 0.001), proving to have similar efficacy as
radiotherapy following excision.66
5-Fluorouracil following excision
5-Fluorouracil is an antineoplastic pyrimidine analog that has
an inhibitory effect on fibroblasts.65 Shin and Kim conducted
a meta-analysis on whether 5-FU prevents keloid recurrence
following surgical excision.65 Following analysis of two studies
with a total of 107 patients, keloid recurrence was statistically
lower in patients treated with 5-FU (risk ratio, 0.18; 95% CI,
0.04–0.75; P = 0.02). 65
Most studies injected 50–150 mg of 5-
FU to the excision border and wound bed following keloid
removal.65
Radiotherapy following excision
Use of radiotherapy for keloid treatment was first described in
1906.5 Radiotherapy disrupts the normal wound healing pro-
cess and can therefore be administered directly to a mature
keloid or following surgical excision to prevent keloid re-for-
mation. Mankowski and colleagues conducted a meta-analysis
systematic review on radiation-based treatments involving 72
studies and 9048 keloids.63 Their data demonstrated that pos-
texcisional radiotherapy was more effective in preventing
recurrence than radiotherapy alone (22% and 37% recurrence
rate, respectively, P = 0.005).63 However, radiation as a
monotherapy may be recommended when treating elderly
patients for whom surgical removal may not be a viable
option because of location or size. Additionally, radiotherapy
applied to mature keloid has been reported to reduce pain
67
and pruritus. In comparing radiation modalities, postopera-
tive brachytherapy had the lowest recurrence rate of 15%,
compared to a 23% recurrence rate for x-ray and 23% recur-
rence rate for electron beam radiation.63 In a separate meta-
analysis examining ear keloids, radiotherapy following surgical
excision proved to be effective with a recurrence rate of
14.0% (95% CI, 9.6–19.9%; P < 0.001).66
Furthermore, several studies have reported that excision fol-
lowed by radiation is safe and practical.1,63 The most common
side effect reported for radiotherapy treatment was alterations
in skin pigmentation including erythema, transient hyperpigmen-
tation, hyperpigmentation, hypopigmentation, and unspecified
pigmentation changes with a total occurrence of 32.5%.63
ª 2020 the International Society of Dermatology
Keloids: a review of therapeutic management Review 5
Mankowski and colleagues also found that chest keloids have
the highest recurrence rate.63
Pressure therapy following excision
Pressure therapy involves the use of specialized garments or
devices, such as Zimmer splints or magnets, to apply a pro-
longed state of pressure to the skin.68,69 It is hypothesized that
the added pressure modifies wound tension and causes local-
ized hypoxia.68,70 A meta-analysis examining trials using pres-
sure garments to prevent scar formation in burn patients did
not report a difference in global scar assessment between
pressure garment-treated scars and nonpressure-treated
scars.71 However, several observational studies using pressure
therapy following surgical excision for ear keloids demonstrate
favorable results with a recurrence rate of 6.7% to
10.6%.68,69,72 One trial reported a 0% recurrence rate; how-
ever, a corticosteroid injection was combined with pressure
therapy following surgical excision, and the study population
was small (n = 7).73
Topical silicone following excision
Silicone for prevention of keloids is a pragmatic form of at-home
treatment. Its exact mechanism of action is yet to be elucidated;
however, postulated explanations include decreased skin
stretching, occlusion, and hydration.7,74 While early studies of
silicone gel sheeting suggested high success rates in treating
keloids and hypertrophic scars, meta-analyses conclude that sil-
icone is not an effective treatment modality for the prevention of
keloids.30,75,76 Hsu and colleagues reviewed the effectiveness
of silicone for prevention of keloid scarring in patients with new
wounds by evaluating 10 trials that were designed with a treat-
ment and placebo arm.74 Topical silicone did not provide a sig-
nificant difference in the prevention of keloids in patients who
have a history of abnormal scarring.74 Furthermore, Cochrane
systematic review analyzing 20 clinical trials concluded that
there is weak evidence supporting the use of silicone gel sheet-
ing as a means of prevention of abnormal scarring; however,
improvements in scar color and thickness were observed.77 Sili-
cone can be applied to the skin in the form of a silicone gel
sheet or a topical silicone gel for 12–24 hours per day with
twice daily washing for a minimum of 1 month.78
New therapeutic developments
Verapamil, a calcium channel blocker which alters fibroblast
gene expression resulting in reduced collagen synthesis and
increased collagenase, has been utilized in keloidal treatment.4
Studies using intralesional verapamil following surgical excision
or alone reported a wide efficacy range from 1.4 to 48% recur-
rence.79 Its efficacy has been reported similar to TAC injections;
high-quality trials are needed to define the role of verapamil in
keloid treatment.80
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6 Review Keloids: a review of therapeutic management
Ultraviolet A1 (UV-A1) phototherapy in the spectral range of
340–400 nm induces increased collagenase activity.4 Evidence
supports its use for fibrosing disorders, including localized scle-
roderma, lichen sclerosus et atrophicus, and graft-versus-host
disease.81 Only a few studies to date have tested UV-A1 pho-
totherapy in treating keloids in a total of six patients with mixed
results.82-84
Other agents that may have a potential role in keloid treat-
ment include tamoxifen and calmodulin inhibitors. Tamoxifen
citrate is a nonsteroidal antiestrogen that downregulates TFG-b,
fibroblast, and collagen expression.85 Similarly, calmodulin inhi-
bitors may also result in scar degradation and warrant further
study.4
Angiotensin-converting enzyme inhibitors (ACEIs) affect
wound healing by reducing collagen synthesis, TGF-b1 expres-
sion, and fibroblast proliferation.86 Topical enalapril significantly
reduced the mean size of hypertrophic scars in a double-blinded
clinical trial.87 One case report observed improvement in keloid
scarring following oral enalapril.88 Topical captopril used in a
separate case report on a postburn keloid demonstrated
improvement in the lesion and reduced redness, scaling, and
itchiness.89
A new alternative to topical silicone is a combination of sili-
cone oil with hypochlorous acid (HOCL); it is a gel or spray that
can be applied twice daily.90 HOCL has an antimicrobial,
antipruritic, and anti-inflammatory role by increasing oxygena-
tion and disrupting biofilm formation.90 Anecdotal reports sug-
gest that HOCL gel performed better than 100% silicone gel in
the management of keloid and hypertrophic scars.90
Apligraf is a living, human, bilayered skin substitute that
promotes wound healing.91 FDA approved its use for venous
leg ulcers and diabetic foot ulcers.91 The potential of using neo-
dermal products for restructuring keloids continues to be an
area of exploration with few case reports available in the litera-
ture and a pilot study with a small number of participants.92
Mammalian target of rapamycin (mTOR) is a potential thera-
peutic target for keloids.93 Research suggests mTOR plays a
role in the regulation of collagen expression and decreases
ECM deposition when inhibited.93 It is therefore postulated that
targeting mTOR with rapamycin therapy may block excess fibro-
proliferation leading to abnormal scarring.94 Indeed, rapamycin
treatment of human fibroblasts in vitro blocks collagen synthesis
pathways that are significantly increased in keloid scarring.94
TGF-b1, TGF-b2, and TGF-b3 isoforms appear to have inter-
95
related roles in keloid pathogenesis. The TGF-b3 isoform, in
particular, has been studied in clinical trials.95 Intradermal
avotermin (recombinant TGF-b3) was administered prophylacti-
cally to improve scarring in three double-blind, placebo-con-
96
trolled, phase I/II studies. However, it appears that the phase
3 clinical trial in 2011 did not accomplish its endpoints leading
the company to conclude that avotermin may not provide signifi-
cant benefit for scar revision.97 Efficacy of targeting other TGF-
b isoforms remains to be further investigated.95
International Journal of Dermatology 2020
Ekstein et al.
MicroRNAs (miRNAs) are noncoding RNAs that silence
genes at the posttranscriptional level.98 The expression of miR-
NAs in keloidal fibroblasts is expressed at different concentra-
tions compared to normal fibroblasts.99 A growing body of
research suggests that specific miRNAs, such as miRNA-29
and miRNA-21-5p, appear to play key roles in keloid develop-
ment providing additional targets for novel therapeutics.100,101
Discussion
Understanding fibroproliferative process of keloid pathogenesis
and achieving scar resolution through treatment modalities have
behooved clinical investigators for decades. Herein we have cat-
egorized treatment options into medical, surgical, or combination
therapies. In this review, excision alone was the least effective
method of treatment (Table 1). While TAC is a current mainstay
of keloid management, it is not effective in lowering the rate of
recurrence when administered following excision.65 However,
effectiveness may depend on the location of the keloid as exci-
sion followed by TAC was effective for ear keloids.66 Anatomical
location also influences the responsiveness to laser-based
devices and pressure therapy. TAC appears to be effective in
the management of mature keloids; however, repeated injec-
tions may be needed as the recurrence rate increased to 27%
from 1 year posttreatment to 5 years posttreatment.30
Chemotherapeutics and immunomodulatory agents, 5-FU,
MMC, imiquimod, and bleomycin are each effective for keloid
management (Table 1). Yet, long-term follow-up to 5 years
posttreatment is lacking. MMC may reduce recurrence rates
compared to imiquimod. In the meta-analysis conducted com-
paring MMC to imiquimod, MMC proved to have greater efficacy
in terms of recurrence rates.27 Furthermore, TAC in combination
with 5-FU was more effective in reducing hypertrophic and
keloid scar recurrence compared to TAC alone.31,32 One mech-
anism could involve 5-FU inhibiting the expression of type I col-
lagen gene that is induced by TGF-b, thereby inhibiting excess
collagen synthesis similar to corticosteroids.102
Laser-based devices and forms of radiotherapy have also
been effective in the treatment of keloids (Table 1). Efficacy
varied by laser type. CO2 laser is least effective, while the Er:
YAG laser resulted in a 22% keloid recurrence rate.28 The Nd:
YAG laser shows varying results based on keloid location with
a recurrence rate ranging from 25% for scapular keloids to
52.9% for keloids located on the anterior chest.28 Radiotherapy
showed promising results following excision. Recurrence rates
varied based on radiation type with electron beam and x-ray
resulting in a 23% recurrence rate and brachytherapy resulting
1,63,67
in a 15% recurrence rate (Table 1).
Future areas of interest include the use of stem cells in pre-
venting keloid formation. Certain stem cell types, such as mes-
enchymal stem cells and umbilical cord blood stem cells, can
provide antioxidant effects and reduce inflammation during the
wound healing process.103 However, their translation into
ª 2020 the International Society of Dermatology
Ekstein et al. Keloids: a review of therapeutic management Review 7

Table 1 Efficacy of medical and surgical treatments on keloid scars

Mean Recurrence
Category Treatment Rate (%) Mean Follow-up (months) References

Medical Triamcinolone acetonide 33 12 Morelli Coppola et al., 2018 30

50 60 Morelli Coppola et al., 2018 30
Er:YAG laser 22 8 Forbat et al., 2017 28
Nd:YAG laser 25–52.9 6 Rossi et al., 2013 42
Mitomycin C 16.5 ≥6 Shin et al., 2017 27
Rossi et al., 2013 42
Imiquimod 24.7 ≥6 Shin et al., 2017 27
Bleomycin 0–50 6 to 19 Morelli Coppola et al., 2018 30
Saray et al., 2005 34
Hu et al., 2019 35
Intralesional cryotherapy 0–24 6 to 21.5 van Leeuwen et al., 2015 51
Surgical Excision >50 6 to 12 Mankowski et al., 2017 52
Combined Triamcinolone acetonide after excision 15.4 12 to 35 Shin et al., 2016 54,55
(Medical and Surgical) Brachytherapy after excision 15 14.4 Mankowski et al., 2017 52
X-ray after excision 23 14.4 Mankowski et al., 2017 52
Electron beam after excision 23 14.4 Mankowski et al., 2017 52
Pressure therapy after excision 6.7–10.6 18 Park et al., 2011 57
Park et al., 2013 61

Er:YAG, erbium-doped yttrium aluminium garnet; Nd:YAG, neodymium-doped yttrium garnet.

clinical application continues to be limited because of unre-
solved concerns related to safety, potential tumorigenicity, and
effects on fibroblasts.103 Autologous fat grafting is another
method that is being tested because of the lack of adequate
results with the current treatments available.104 Silva and col-
leagues reviewed the studies of this treatment for hypertrophic
scars and keloids.104 Because of the limited number of studies
and hypertrophic scars being grouped with keloids, more data
are needed to determine the efficacy of this therapy.
Conclusion
As keloid pathogenesis becomes better understood, additional
mechanistic targets will be elucidated paving the way for more
effective treatments. Further research into tumor growth and
metastasis may provide further insight into keloid pathogenesis.
Similarities between keloid scar formation, tumor growth, and
metastasis have been observed, including overexpression of
collagen triple helix repeat containing-1 (CTHRC1), fibroblast
activation protein alpha (FAP-a), and dipeptidyl peptidase-IV
(DPP-IV).105,106 For now, keloid management remains a multi-
modal approach. There continues to be no single treatment
available that provides a consistently low recurrence rate. An
increasing number of studies are examining the combination of
existing treatments for a synergistic effect. This includes laser-
based devices in combination with TAC and 5-FU in combina-
tion with TAC. These combinations are providing favorable out-
comes when compared to monotherapy.
Based on the most recent evidence, brachytherapy following
excision provides the lowest rate of recurrence. For ear keloids,
specifically, pressure therapy following excision is the most effi-
cacious based on observational studies. However, in clinical
practice, the patient and physician may opt to a minimally inva-
sive, cost-effective treatment initially. In these circumstances,
multiple TAC injections may be first line, followed by combina-
tion therapies if adequate results with TAC alone are not
achieved. Treatment options may be limited to physician prefer-
ence and resources available. Radiotherapy is limited to larger,
well-funded medical establishments. Low-cost and minimally
invasive TAC injections may explain why TAC, while less effec-
tive than other modalities, is the most common form of treat-
ment today.
There continues to be a need for randomized studies with
larger sample sizes and longer follow-up time. Robust keloid
patient registries could help assess additional risk factors,
systemic medical conditions associated with keloid formation,
and effectiveness of various treatments. As discoveries in
keloid pathogenesis unfold, targeted treatment can be
designed to halt mechanistic checkpoints implicated in this
type of scar formation. Keloids continue to have no gold
standard of treatment; however, the increasing number of
treatments available and synergistic combinations of these
treatments are showing favorable results. Future studies
could target the efficacy of novel treatment modalities and
the use of combination therapies for the management of
keloids.

ª 2020 the International Society of Dermatology International Journal of Dermatology 2020

8 Review Keloids: a review of therapeutic management
Educational Challenge (answers provided
after references)
1 The following is true about keloids:
a Keloids are benign fibroproliferative skin tumors growing
beyond the site of original dermal injury
b Keloids are malignant fibroproliferative skin tumors growing
beyond the site of original dermal injury
c Keloids are benign fibroproliferative skin tumors limited to
the site of original dermal injury with high rates of recur-
rence
2 Keloids are benign fibroproliferative skin tumors limited to the
site of original dermal injury with low rates of recurrence
3 True or false: Given their composition of haphazardly
branched and septal disorganized type I and III collagen bun-
dles, keloids are often symptomatic with accompanying pain
and pruritus.
4 Which of the following is considered to be a risk factor asso-
ciated with keloids?
a Personal or family history of keloids
b Skin of color ethnic groups
c Pregnancy
d Puberty
e Skin injuries overlying osteogenic surfaces
f All of the above
5 True or false: Proinflammatory microenvironment triggered
by excess TGF-b and elevated production of certain
cytokines has been postulated to play a role in keloid for-
mation.
6 What is the correct order of four time-sensitive wound healing
phases?
a (1) Inflammation (2) Hemostasis (3) Proliferation (4)
Remodeling
b (1) Inflammation (2) Hemostasis (3) Remodeling (4) Prolif-
eration
c (1) Hemostasis (2) Inflammation (3) Proliferation (4)
Remodeling
d (1) Hemostasis (2) Inflammation (3) Remodeling (4) Prolif-
eration
7 How do corticosteroids (i.e., intralesional triamcinolone) affect
keloid formation?
a Decrease inflammation during wound healing process
b Increases collagen and glycosaminoglycan synthesis
c Reduces fibroblast development
d Augments collagen degradation
e A, C, and D are correct
f A, B, and C are correct
8 Which of the following lasers is a potential option for keloid
treatment in patients with darker skin types (Fitzpatrick IV to
VI)?
a Ablative erbium-doped yttrium aluminium garnet laser (Er:
YAG)
International Journal of Dermatology 2020
Ekstein et al.
b Ablative yttrium-scandium-gallium-garnet laser (YSGG)
c Ablative carbon dioxide laser (CO2)
d Nonablative neodymium-doped yttrium garnet laser (Nd:
YAG)
9 True or false: Excising keloids without secondary intervention
generally results in a good outcome with minimal recurrence
rate.
10 Recent studies have proposed that mesenchymal stem cells
and umbilical cord blood stem cells affect wound healing
and reduce scar formation. What is the proposed mecha-
nism?
a Reduces antioxidant and anti-inflammatory effects during
wound healing
b Improves antioxidant and anti-inflammatory effects during
wound healing
c It is unknown
11 True or false: There continues to be no gold standard of
keloid treatment that provides a consistently low recurrence
rate.
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Answers
1 A
2 True
3 F
4 True
5 C
6 E
7 D
8 False
9 B
10 True
International Journal of Dermatology 2020