Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

A Systematic Review of Evidence Based

Treatments for Lichen Simplex Chronicus

Michelle C. Juarez & Shawn G. Kwatra

To cite this article: Michelle C. Juarez & Shawn G. Kwatra (2019): A Systematic Review of
Evidence Based Treatments for Lichen Simplex Chronicus, Journal of Dermatological Treatment,
DOI: 10.1080/09546634.2019.1708856

To link to this article: https://doi.org/10.1080/09546634.2019.1708856

Accepted author version posted online: 30

Dec 2019.

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 A Systematic Review of Evidence Based Treatments for Lichen Simplex Chronicus

Michelle C. Juarez, BS,1Shawn G. Kwatra, MD2

Affiliations
1. The Johns Hopkins School of Medicine, Baltimore, Maryland
2. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Corresponding Author:
Shawn G. Kwatra, MD
Cancer Research Building II, Johns Hopkins University School of Medicine
1550 Orleans Street
Baltimore, MD 21231

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Tel: 410-955-5922

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Email: swkatra1@jhmi.edu

Funding Sources: None

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Conflicts of Interest: Dr. Shawn G. Kwatra is an advisory board member for Pfizer, Menlo and Trevi Therapeutics
and has received grant funding from Kiniksa Pharmaceuticals. He is also the recipient of a Dermatology Foundation

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Medical Dermatology Career Development Award.

IRB status: Exempt

Patient Consent: Not required.

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Manuscript Word Count: 2539 words
Abstract Word Count: 148
References: 26
Figures: 1 (PRISMA flowchart)
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Tables: 1 (Treatment Studies)

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 A Systematic Review of Evidence Based Treatments for Lichen Simplex Chronicus

Abstract:

Lichen simplex chronicus (LSC) is a disorder characterized by thickened areas of skin from repeated rubbing or

scratching. The multifactorial nature of LSC makes management difficult and there are currently no evidence-based

guidelines for treatment. We conducted a systematic review of the literature to evaluate treatments for LSC and

provide an evidence-based summary of the current treatments as well as highlight novel therapies. A total of 21

studies were included which comprised 682 patients with LSC involving various areas. The most robust evidence

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was seen with the use of topical corticosteroids (n=7 RCTs) and limited data suggest benefit with other treatments

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such as topical immunomodulators, topical antipruritic agents, oral antihistamines, antiepileptics and

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antidepressants. We also discuss novel treatment approaches using transcutaneous electrical nerve stimulation,

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focused ultrasound, and phototherapy. Despite emerging evidence there remains a paucity of high-quality studies

supporting treatments for LSC and larger controlled trials are needed.
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Keywords: pruritus, lichen simplex, itch, neurodermatitis, neurodermatitis circumscripta
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Introduction:

Lichen simplex chronicus (LSC) is chronic pruritic condition characterized by areas of thickened skin

resulting from repeated rubbing or scratching. It may present with associated dryness, scaling, or erythema similar to

many other dermatologic conditions which can make diagnosis difficult. Commonly affected areas include the neck,

ankles, extremities, scalp, and genital region. While the incidence and prevalence are not well established, LSC

occurs more frequently in females during mid to late adulthood and disproportionately affects black patients.1 The

pathophysiology behind LSC remains unclear, but is thought to arise from a persistent itch-scratch cycle mediated

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by disturbances between central and peripheral neural tissue in the perception of itch. Emotional or psychological

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disturbances such as anxiety and depression have been associated with severely pruritic dermatoses, such as prurigo

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noduaris and LSC, and may contribute to the perpetuation of the itch-scratch cycle. 2,3

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Managing LSC can be difficult given the poorly understood and multifactorial nature of the condition.

There are a lack of studies that exclusively assess treatments in patients with LSC and as a result, few targeted
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therapies exist. Further, there are no evidence-based guidelines or summaries to guide treatment. This systematic

review evaluates the current literature on treatments for LSC and provides a summary of the evidence-based
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therapies in order to better characterize the quality of data supporting various interventions and highlight areas for

further research.
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Methods:
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We conducted a systematic review of the literature for clinical studies on medical treatments for LSC in
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accordance with the PRISMA guidelines (figure 1). With the help of a medical information specialist, we sought
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studies published after 1970 using the following databases: PubMed, Embase, Scopus, and the Cochrane Library.

The following search terms were used: "neurodermatitis,” "dermatoneurosis," "lichen simplex," "neurodermatosis,”
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"neurodermatitides.” Bibliographies of relevant publications were also searched for additional studies meeting

inclusion criteria. We selected studies that concerned LSC, were written in the English language, and dealt with

human subjects. Randomized-controlled trials (RCTs), observational cohort studies, and multi-patient case series

were included. We excluded studies with fewer than 5 patients, studies that did not specify outcomes of the

treatment, studies that assessed non-medical treatments, and studies in which only abstracts were available or we

could not obtain access. Each article was assigned a level of evidence (LOE) according to the Oxford Center for

Evidence-based Medicine.4
Results:

Our initial literature search yielded 2,473 articles after removing duplicates. 2,402 were removed upon

screening of the title and abstract for relevance. Of the remaining 71 full text articles reviewed for eligibility, 50

were excluded for not fulfilling the inclusion criteria. Ultimately, a total of 21 original reports met the inclusion

criteria, including 11 RCTs, 8 observational studies, and 2 case series. These studies comprised 682 patients with

LSC involving the trunk, back, neck extremities, or genitalia. The characteristics and main findings of these studies

are summarized in table 1 and 2. Seven studies investigated topical corticosteroids, 3 studies assessed topical

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immunomodulators such as pimecrolimus and tacrolimus, 4 studies assessed topical antipruritics such as doxepin,

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capsaicin, and aspirin, and 2 studies assessed antiepileptics, antihistamines, and antidepressants. Five studies

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investigated emerging therapies, including 3 observational studies on transcutaneous electrical nerve stimulation, 1

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study on focused ultrasound, and 1 study on phototherapy. We discuss these findings below.

Topical Corticosteroids
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A total of 7 RCTs reported on the efficacy of several high potency steroids in the treatment of LSC, 2 of

which compared the efficacy of different corticosteroids against one another, and one of which assessed outcomes
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with variations in frequency of application. In all studies, short-term use of topical corticosteroids were generally

well-tolerated by patients. Common side effects included erythema, hyperpigmentation, burning, and dryness. Four
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out of 6 studies were rated a LOE of 1b or higher, one study was rated a LOE of 2b, and one study a LOE of 4.
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Two studies reported on the efficacy of halobetasol propionate in reducing disease severity in patients with
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LSC, noting a significant reduction in pruritus, erythema, scaling, and lichenification in treated patients compared to

controls. 5,6 In two separate double-blind multicenter RCTs comparing the efficacy of halobetasol propionate to
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diflucortolone valerate and clobetasol 17-propionate respectively, halobetasol had higher success rates and onset of
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action compared to diflucortolone, and higher healing rates than clobetasol, though these results were not

statistically significant.7,8 In a double-blind RCT to compare the efficacy of once daily application of fluprednidene-

21-acetate to thrice daily application of betamethasone 17-valerate, 9 no significant differences in the reduction of

symptomatology scores were noted in either group after 2 weeks of treatment (mean change in score 5.3 for

fluprednylidene-21-acetate and 3.8 for betamethasone p=.17) suggesting that fluprednylidene applied once daily was

as effective as thrice daily application of betamethasone, allowing for smaller quantities of a potent steroids to be

applied with potentially fewer side effects.

 Two RCTs examined the utility of occlusion as adjunctive therapy with topical corticosteroids, though

outcomes were conflicting.10,11 In one study, once weekly application of clobetasol propionate and duoderm

occlusive dressing led to complete remission of disease in 89% patients in two weeks. 11 However, in another study,

treatment with 0.3% diflucortolone valerate twice daily with plastic occlusion resulted in a significantly lower

improvement of lichenification and pruritus (p<.001 for both) and even led to development of more side effects.8

The authors hypothesized that this may have been due to ointment adhering to the occlusive dressing and resulting

in poorer absorption.

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Topical Immunomodulators: Tacrolimus, Pimecrolimus

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Given its reduced risk of skin atrophy and striae, studies on topical immunomodulators such as tacrolimus

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and pimecrolimus have been primarily limited to treating genital LSC. Three studies reported on the efficacy of

immunomodulators in treating genital LSC across 64 patients. There are no RCTs evaluating the efficacy of topical

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immunomodulators in LSC and all three studies were observational studies with a LOE of 4. In all studies,
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tacrolimus and pimecrolimus were well tolerated by patients. The most common side effect was burning which

occurred in 25% of patients and required discontinuation in 9% across all studies.

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Topical pimecrolimus 1% applied twice daily for three months resulted in significant decrease in pruritus

and disease severity in 24 patients across two prospective observational studies. In one study with 12 female patients
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with moderate to severe vulvar LSC treated with 1% pimecrolimus, 75% of patients reported complete resolution of
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pruritus by week 4 of treatment with sustained resolution until the end of treatment at 12 weeks. 12 Additionally,
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disease severity scores as measured by the Investigators Global Assessment (IGA) decreased from a moderate-to-

severe baseline score to no disease by the end of treatment with concomitant improvements in erythema,
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excoriation, and lichenification for all patients. Kelekci et al reported similar results with significant decreases in

pruritus by 4 and 12 weeks of treatment compared to baseline (pruritus score 3.75 at baseline, 2.17 at 4 weeks p<.01,
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0.42 at 12 weeks p<.001) and complete cure of disease in 83% of treated patients. 13 In another study, 0.1% topical

tacrolimus significantly decreased mean itch scores, itch frequency, and overall affected surface area after treatment

(p<.001 for all) in 40 patients with scrotal LSC.14

Topical Antipruritics: Doxepin, Capsaicin, Aspirin

Four studies assessed topical antipruritic agents such as doxepin, capsaicin, and aspirin in treating patients

with LSC. All four studies were double-blind RCTs with LOE of 2b or higher; two studies investigated the utility of
topical doxepin, while single studies investigated topical aspirin and capsaicin. All agents were effective in treating

LSC-related pruritus except for capsaicin, which resulted in no clinical improvement in one small RCT. 15

Drake et al carried out a double-blinded multicenter RCT to assess the efficacy of doxepin cream applied

four times daily for one week in reducing pruritus in patients with LSC.16 Significantly more patients in the

treatment arm had improved pruritus severity scores compared to controls at 1 day and one week of treatment (45%

vs 23% respectively within 24 hrs, p=.01, and 76.5% vs 57% respectively within one week, p=.01) as well as a

significant improvement in physician global evaluation for pruritus relief scores (p=.003). A second study

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investigated the onset of action of topical doxepin and whether discontinuation of therapy would be associated with

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rebound worsening.17 Onset of action occurred within 15 minutes of application (p<.001) and sustained reductions

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in pruritus occured through one week of treatment. Additionally, no rebound effect was seen after discontinuing

therapy with doxepin cream (p<.001). The authors concluded that doxepin cream may be a useful adjunctive therapy

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to topical corticosteroids due to its rapid onset of action and lack of rebound effect that are often seen once
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discontinuing topical steroids, and may help in reducing overuse of steroids and potential adverse effects.

Topical 3% aspirin was similarly effective in reducing itch severity in a double-blind crossover RCT with
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29 patients with LSC.18 A higher percentage of patients in the treatment arm achieved therapeutic response as well

as a greater decrease in pruritus compared to the placebo group (p=.03). Treatment was overall well-tolerated, with
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three patients reporting burning as a side effect.

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Antiepileptics, Antihistamines, and Antidepressants

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Two studies investigated antiepileptics, antihistamines, and antidepressants in treating LSC, though sample

sizes in both of the studies were major limitations in the quality of evidence, with one study rating as a LOE of 2b
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and another a LOE of 4. One study investigated the utility of gabapentin in reducing pruritus in five patients with

LSC that had failed previous treatment.19 By 2 months of treatment, partial remission of disease occurred in all
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patients and complete remission in the majority of patients. Clinical improvement was sustained at 3 months follow

up. Interestingly, while lesions improved in all patients, pruritus was one of the side effects noted at the end of

therapy though it was never as severe in the beginning. Another side effect included sedation, which was tolerable in

all patients who experienced this.

Sanjana et al carried out a double-blind RCT to evaluate the efficacy of Chlorpheniramine and Imipramine

in 24 patients with LSC.20 In this study, patients were divided into three groups and randomly allocated to receive
placebo, 4 mg starting dose of chlorpheniramine, or 25 mg starting dose of imipramine in increasing doses weekly.

Treatment with chlorpheniramine and imipramine resulted in a significant decrease in pruritus severity between

baseline and at 2, 4, and 6 weeks of treatment, though a greater decrease was seen in the imipramine treated group.

Based on these findings, the authors concluded that imipramine was superior to the other medications in treating

pruritus in patients with LSC and may be considered in patients with recalcitrant pruritus who do not respond to

conventional therapies.

Emerging therapies: Phototherapy, Transcutaneous electrical nerve stimulation, Focused Ultrasound

While phototherapy has been used to treat many pruritic dermatologic conditions, data on its utility in LSC

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continues to be limited. Only one study included in our review investigates phototherapy for LSC, which was rated

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as a LOE of 4. In this study, authors investigated weekly treatments of NBUVB in patients with LSC resistant to

prior topical treatment.21 After a mean of 29 treatment sessions, complete response (>90% improvement) occurred in

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30% of patients, and 73.8% of patients showed moderate or better (>50% improvement) responses. Additionally,

there was a 75% improvement in mean pruritus scores. Side effects were minimal and primarily included erythema.
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Three prospective observational studies, all rated a LOE of 4, evaluated the utility of transcutaneous
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electrical nerve stimulation (TENS) in ameliorating pruritus in 50 patients with LSC across all studies. TENS uses a

pulsed electric current to send impulses across large diameter afferent nerves that inhibit nociceptive A delta and C
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fibers that play a role in pain and pruritus. Its utility in relieving pruritus has been reported in other pruritic
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conditions such as prurigo nodularis, generalized pruritus, and mycosis fungoides. 22,23 In 22 patients with treatment-
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resistant LSC, TENS treatment resulted in an average of 4.50 point reductions in VAS score(95% CI 3.65-5.34) at

the end of 4 weeks of treatment.24 Mohammed-Ali et al reported similar results with statistically significant
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decreases in VAS scores at 2 and 4 weeks of treatment compared to baseline as well as during follow up one month

after the completion of treatment (p<.001 for all). 25 Additionally, the significant reduction of pruritus led to
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improvement of inflammatory lesions and 45% of patients with LSC had physician reported outcomes of clinical

efficacy. Side included mild erythema, irritation, and numbness. In another study, treatment with TENS resulted in

improvement in quality of life as early as two weeks of treatment.26 The authors concluded that TENS was a

promising and safe therapeutic for treating pruritus and should be considered as an adjuvant for therapy.

Focused ultrasound therapy has emerged as a novel modality for treating non-neoplastic disorders of the

vulva. Focused ultrasound therapy provides ultrasound beams to directed areas resulting in destruction of specific
tissue which then improve growth and promote reconstruction of the tissue while sparing surrounding areas. In one

study, 85 patients with LSC were treated with focused ultrasound therapy with 48% of patients reporting complete

cure of the disease, which included complete resolution of signs and symptoms such as itch, disappearance of skin

discoloration, and restoration of skin elasticity.27 At 5 years of follow up, 22.35% of patients with LSC reported

recurrence. Adverse effects included transient hyperemia and edema and no long-term complications were noted at

follow up.

Discussion:

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The number of studies assessing treatment options for LSC have increased over the past several years,

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however, there remains a paucity of high-quality evidence assessing the utility and efficacy of these treatments in

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patients with LSC. Of the 21 studies, 11 were RCTs focused mainly on topical corticosteroid treatment, and only 9

studies included a sample size greater than 25 patients. Further, there is mixed data concerning the efficacy of some

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of the aforementioned treatment modalities which may be due in part to the unclear etiology and pathophysiology
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behind LSC. Additionally, while other treatment modalities such as intralesional steroids and immunosuppressants

have been historically used in the treatment of LSC, no large studies have evaluated their use. It should be noted that
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this systematic review is limited by its inclusion of English-only studies, as foreign studies have investigated other

treatment modalities not included in this review. Although the evidence remains limited, the results of this study
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suggest that symptoms of LSC may be managed successfully with topical corticosteroids as first line therapy and
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other treatment modalities may be considered as adjunctive therapy in more resistant forms of the disease. Novel
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treatments with transcutaneous electrical nerve stimulation and focused ultrasound appear promising, but further

research is needed to validate their use. Nevertheless, treatment selection should be largely patient-directed in order
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to delivery optimal therapy.

While systemic treatment has been useful in other pruritic conditions, there is a lack of evidence on
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systemic agents for treatment in LSC. This may be because these agents have increased risk of side effects and are

indicated for more severe and widespread forms of pruritus and would not be indicated for isolated LSC.28,29

Similarly, data on novel treatment approaches with biologics, neurokinin receptor antagonists, and opioid receptor

antagonists that have been successful treatment in other pruritic diseases are lacking in patients with LSC.30,31

Studies investigating these emerging treatments would be useful in adding to the repertoire of treatment options for

this condition.
 References:

1. Whang KA, Kwatra SG. Gender and racial differences in patient perception of pruritus: Evidence from a

single institution and National Ambulatory Medical Care Survey data. Journal of Investigative

Dermatology. 2018;138(5):S220.

2. Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients.

Journal of the American Academy of Dermatology. 2018;79(4):714-719.e713.

3. Huang AH CJ, Khanna R, Khang S, Kwatra SG. Real-World Prevalence of Prurigo Nodularis and Burden

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of Associated Diseases. Journal of Investigative Dermatology. 2019.

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4. Howick J CI, Glasziou P et al. The Oxford 2011 Levels of Evidence. 2011;

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https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/.

5. Guzzo CA, Weiss JS, Mogavero HS, et al. A review of two controlled multicenter trials comparing 0.05%

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halobetasol propionate ointment to its vehicle in the treatment of chronic eczematous dermatoses. Journal
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of the American Academy of Dermatology. 1991;25(6):1179-1183.

6. Kantor I, Cook PR, Cullen SI, Willis I, Gibson JR, Stanfield JW. Double-blind bilateral paired comparison
M
of 0.05% halobetasol propionate cream and its vehicle in patients with chronic atopic dermatitis and other

eczematous dermatoses. J Am Acad Dermatol. 1991;25(6 Pt 2):1184-1186.

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7. Datz B, Yawalkar S. A double-blind, multicenter trial of 0.05% halobetasol propionate ointment and 0.05%
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clobetasol 17-propionate ointment in the treatment of patients with chronic, localized atopic dermatitis or
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lichen simplex chronicus. Journal of the American Academy of Dermatology. 1991;25(6 II SUPPL.):1157-

1160.
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8. Brunner N, Yawalkar S. A double-blind, multicenter, parallel-group trial with 0.05% halobetasol

propionate ointment versus 0.1% diflucortolone valerate ointment in patients with severe, chronic atopic
Ac

dermatitis or lichen simplex chronicus. Journal of the American Academy of Dermatology. 1991;25(6 II

SUPPL.):1160-1163.

9. Rajan VS. Controlled double blind trial with supracortin cream. Singapore Medical Journal.

1976;17(4):216-218.
10. Geraldez MCB, Carreon‐Gavino M, Hoppe G, Costales A. Diflucortolone Valerate Ointment With and

Without Occlusion in Lichen Simplex Chronicus. International Journal of Dermatology. 1989;28(9):603-

604.

11. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid

occlusive dressing. Acta Dermato-Venereologica. 1992;72(1):69-71.

12. Goldstein AT, Parneix-Spake A, McCormick CL, Burrows LJ. Pimecrolimus cream 1% for treatment of

vulvar lichen simplex chronicus: An open-label, preliminary trial. Gynecologic and Obstetric Investigation.

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2007;64(4):180-186.

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13. Kelekci HK, Uncu HG, Yilmaz B, Ozdemir O, Sut N, Kelekci S. Pimecrolimus 1% cream for pruritus in

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postmenopausal diabetic women with vulvar lichen simplex chronicus: A prospective non-controlled case

series. Journal of Dermatological Treatment. 2008;19(5):274-278.

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14. Tan E, Tey HL, Tan ES, Tan AS. Tacrolimus ointment 0.1% in the treatment of scrotal lichen simplex
an
chronicus: An open-label study. Annals of the Academy of Medicine Singapore. 2013;42(9):S284.

15. Kantor GR, Resnik KS. Treatment of lichen simplex chronicus with topical capsaicin cream. Acta Derm
M
Venereol. 1996;76(2):161.

16. Drake LA, Millikan LE. The antipruritic effect of 5% doxepin cream in patients with eczematous
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dermatitis. Doxepin Study Group. Arch Dermatol. 1995;131(12):1403-1408.

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17. Breneman DL, Dunlap FE, Monroe EW, Schupbach CW, Shmunes E, Phillips SB. Doxepin cream relieves
pt

eczema-associated pruritus within 15 minutes and is not accompanied by a risk of rebound upon

discontinuation. Journal of Dermatological Treatment. 1997;8(3):161-168.

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18. Yosipovitch G, Sugeng MW, Chan YH, Goon A, Ngim S, Goh CL. The effect of topically applied aspirin
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on localized circumscribed neurodermatitis. Journal of the American Academy of Dermatology.

2001;45(6):910-913.

19. Gencoglan G, Inanir I, Gunduz K. Therapeutic Hotline: Treatment of prurigo nodularis and lichen simplex

chronicus with gabapentin. Dermatologic Therapy. 2010;23(2):194-198.

20. Sanjana VD, Fernandez RJ. Evaluation of an antihistamine and antidepressant for the treatment of lichen

simplex chronicus. Indian journal of dermatalogy, venereology and leprology. 1992;58(6):384‐387.

21. Esen Salman K, Kivanc Altunay I, Salman A. The efficacy and safety of targeted narrowband UVB

therapy: a retrospective cohort study. Turkish journal of medical sciences. 2019;49(2):595-603.

22. Greaves MW. Recent advances in pathophysiology and current management of itch. Annals of the Academy

of Medicine Singapore. 2007;36(9):788-792.

23. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalized pruritus. Clin Exp

Dermatol. 1993;18(1):67-68.

24. Engin B, Tufekci O, Yazici A, Özdemir M. The effect of transcutaneous electrical nerve stimulation in the

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treatment of lichen simplex: A prospective study. Clinical and Experimental Dermatology. 2009;34(3):324-

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328.

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25. Mohammad Ali BM, Hegab DS, El Saadany HM. Use of transcutaneous electrical nerve stimulation for

chronic pruritus. Dermatologic Therapy. 2015;28(4):210-215.

us
26. Yuksek J, Sezer E, Aksu M, Erkokmaz U. Transcutaneous electrical nerve stimulation for reduction of
an
pruritus in macular amyloidosis and lichen simplex. The Journal of dermatology. 2011;38(6):546-552.

27. Wu C, Zou M, Xiong Y, et al. Short- and long-term efficacy of focused ultrasound therapy for non-
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neoplastic epithelial disorders of the vulva. BJOG: An International Journal of Obstetrics and

Gynaecology. 2017;124:87-92.
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28. Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of
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chronic pruritus. Journal of the American Academy of Dermatology. 2016;75(3):619-625.e616.

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29. Sharma D KS. Thalidomide for the treatment of chronic refractory pruritus. Journal of the American

Academy of Dermatology. 2016;74(2):363-369.

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30. He A AJ, Sweren RJ, Kwatra MM, Kwatra SG Aprepitant for the Treatment of Chronic Refractory

Pruritus. BioMed Research International. 2017.

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31. Kwatra SG SS, Kang H PD-1 Blockade-Induced Pruritus Treated with a Mu-Opioid Receptor Antagonist.

New England Journal of Medicine. 2018;379(16):1578-1579.

Figure 1. Summary of the process of article selection for studies included in the systematic review

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 Table 1. Treatments for Lichen Simplex Chronicus (LSC)
Oxford
Measured
Study N Study Design Intervention Dosage/Frequency Outcomes Level of AE
Endpoints
Evidence
Once daily
Once daily
application of
application of Significant reduction in
fluprednylidene- Regression of
fluprednylidene-21- symptomatology score in both
Rajan, 58 total, 40 Double-blind 21-acetate vs signs and
1976 (7) with LSC RCT thrice daily acetate vs thrice symptoms of groups, no statistically significant 1b Not reported
application of daily application of disease superiority of one modality over
betamethasone 17- the other
betamethasone valerate
17-valerate
Statistically significant No side effects in
improvement in median pruritus group treated
Pruritus and lichenification at week 2 of without occlusion;
Diflucortolone 0.3% diflucortolone
severity, treatment in group treated pustular lesions,
Geraldez Valerate ointment valerate twice daily
60 RCT lichenification without occlusion than in group 1b erythema, and
, 1989 (8) with and without with or without
, therapeutic treated with occlusion (p<.001). hyperpigmentation
occlusion occlusion
efficacy Proportion of healed cases were

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observed in group
lower in patients treated with treated with

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occlusion. occlusion
Success rate was 91.5% in
patients treated with halobetasol

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and 83.6% in those treated with
diflucortolone valerate; early
onset of therapeutic effect
Success rate reported in a higher percentage Burning and
(described as
.05% Halobetasol of patients treated with erythema with

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Double-blind Halobetasol healed and
120 total, propionate or 0.1% halobetasol than in those treated halobetasol;
Brunner, multicenter propionate vs marked
45 patients diflucortolone with diflucortolone (70% vs 1b vesiculation,
1991 (6) with LSC parallel -group diflucortolone valerate 2x daily for improvement) 59%); higher percentage oozing, pruritus,
RCT valerate 21 days , early onset reporting healing of disease and dryness in
of therapeutic
an effect within 17 days in those treated diflucortolone group
with halobetasol vs diflucrtolone
(40.7% vs 32.8% respectively),
though no statistically significant
differences in any of these
measures.
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Healing reported in a higher
percentage of patients treated
with halobetasol than those
Onset of treated with clobetasol (65% vs Pruritus, erythema,
Double-blind Halobetasol .05% Halobetasol therapeutic 55%) but not statistically numbness of finger
Datz, 127 total, 9 multicenter Propionate vs propionate or .05% action, global different. Success rates tips, telangiectasia
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patients clobetasol 17- 1b

1991 (5) with LSC parallel group Clobetasol 17- propionate 2x/daily assesment of (described as healed and in halobetasol
RCT Propionate for 21 days therapetuic marked improvement) were group; skin irritation
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effect identical in the two treatment in clobetasol group

groups (93.7 vs 92.2%) as well
as early onset of therapeutic
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effect within 2 days of treatment.

Pruritus,
By one week and two weeks of
scaling,
treatment, severity scores of
erythema,
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Multicenter lichenification erythema, scaling, pruritus,

double-blind .05% Halobetasol scores, lichenification were lower in
Guzzo, Halobetosol halobetasol treated sites Local adverse
1991 (3) 23 paired Propionate propionate twice overall compared to vehicle ( p<.0013, 2b effects
comparison daily for two weeks disease and p<.0001 respectively).
RCT severity,
Patient reported effectiveness
Ac

patient
was higher in halobetasol
perceptions
treated sites.
of efficacy
No significant difference in VAS
VAS score scores between capsaicin
Double-blind Capsaicin .075% and degrees treated and placebo treated
Kantor, 7 placebo- Topical cream and vehicle of erythema, sites. No significant difference in 2b Not reported
1991 (4) controlled RCT Capsaicin four times daily lichenification degree of erythema,
, and scale lichenificaiton, and scale
between two sites
 4 mg Decrease in pruritus at 2, 4, and
Antihistamine
chlorpheniramine 6 weeks of treatment seen with
(Chlorpheniramin
Sanjana, Double-blind maleate, 25 mg Pruritus chlorpheniramine and
24 e) and 2b Not reported
1992 (23) RCT imipramine in severity imipramime, though statistically
Antidepressant
increasing doses significant decrease seen with
(Impramine)
weekly imipramime.
Clobetasol
Once weekly
Prospective Propionate and Complete remission in 89% of
Volden, treatment on affected Overall
19 observational Hydrocolloid patients 4 Mild folliculitis
1992 (9) areas Improvement
study Occlusive Mean time to remission: 2 weeks
Dosage not specified
Dressing
Within 24 hrs of treatment, 45%
of patients with LSC had
improvied pruritus vs 23% in
control group (p=.01); within one
week, 76.5% of doxepin treated
patients reported improvement in

t
pruritus vs 57% in control group
(p=.01).

ip
Reduction in
5% Doxepin
Hydrochloride cream VAS score, 52% reduction in VAS score
Drake, Multicenter or vehicle cream to pruritus within 24 hours in the treated Transient stinging,

cr
136 double-blind Topical Doxepin severity, and group vs 27.5% reduction in 1b drowsiness, dry
1995 (14) RCT affected areas four physician control group (P=.001); 62.6% mouth
times/day for one global reduction in VAS score after one
week
evaluation week in treated group vs 53%

us
reduction in control group
(p=.001)

Significant improvement in
an physician global evaluation for
pruritus relief in treated patients
vs controls at 24 hours and one
week (p=.003)
M
Double-blind, Pruritus,
Significant differences in
vehicle .05% halobetasol erythema,
Kantor, controlled, Topical propionate cream or scaling, pruritus, erythema, scaling, and
1996 (13) 13 bilateral paired Halobetasol vehicle twice daily for lichenification lichenification seen in areas 2b Burning, stinging
Proprionate treated with halobetasol vs
comparison 14 days severity
vehicle (p<.001).
d

RCT scores
e

Onset of
action of Significant decrease in pruritus
pt

therapy in within 15 minutes (p<.001) in

achieving
5% Doxepin treated areas. Decreasing Burning, stinging,
Brenema Single and pruritus relief
hydrochloride or pruritus severity and relief dryness,
n, 1997 48 Double-blind Topical Doxepin and 1b
vehicle cream four continued through day 7 of somnolence, dry
ce

(15) RCT times daily evaluation of treatment. No rebound effect mouth,

disease after discontinuation of doxepin
course after
cream (p<.001).
cessation of
therapy
Ac

46% of patients achieved

5 ml of 3% Aspirin
sgnificant therapeutic response
Yosipovi dissolved in
Double-blind, compared to 3% in placebo.
tch, 2001 29 Topical Aspirin dichloromethane or VAS score 2b Burning
crossover RCT Decrease in VAS score of 2.18
(16) placebo twice daily
in treatment arm vs 0.69 in
for two weeks
control group (p=.03).
Decrease in median VAS score
VAS score, from 6 to 0 by week 4 and
Goldstei 1% Pimecrolimus Investigator's sustained until week 12. Median
Prospective Topical
n, 2007 12 twice daily for 3 Global IGA decreased 2.5 points from 4 None
open-label trial Pimecrolimus
(10) months Assesment baseline to week 12. Erythema,
(IGA) score excoriation, lichenification, and
pruritus improved for all patients
 Reduction in Significant decrease in pruritus
1% Pimecrolimus pruritus, after 4 weeks and 3 months of
Kelekci, 12 Prospective Topical twice daily for 3 overall treatment from baseline scores. 4 Burning
2008 (11) case series Pimecrolimus
months disease Complete cure in 83.3% of
improvement patients at follow up
3x/week for 4 weeks, Mean reduction in VAS from 0 to
for total of 12 4 weeks was 4.50 for all
Engin, Prospective Transcutaneous sessions patients. By the end of the study,
2009 (19) 22 observational electrical nerve >100 Hz, <100 VAS score 80% of patients experienced a 4 Slight erythema
study stimulation
microsecond pulse reduction in pruritus intensity of
width >50%
Gabapentin 300
mg/day gradually Overall Partial remission by 2 months in
Mild pruritus
Gencogl increased to 900 disease all patients. Complete remission
Retrospective responsive to
an, 2010 5 Gabapentin mg/day for 3 or 4 improvement, in majority of patients. At 3 4
case series topical lubriants and

t
(22) months of until reduction in months follow up, clinical sedation

ip
desired effect pruritus improvement sustained.
achieved
At 2 weeks of therapy, there was

cr
a significant decrease in median
3x/week for 4 weeks
Dermatology VAS score from baseline
Prospective Transcutaneous for total of 12
Yuksek, 8 observational electrical nerve sessions; 50-100 Hz, quallity of life (p=.007). 4 Transient local
2011 (20) index (DQLI), Significant improvement in erythema

us
study stimulation 40-75 microsecond
VAS score median DLQI total scores as
pulse width
early as 2 weeks of treatment
compared to baseline (P=.006)
Improvement
an
in disease Statistically significant decrease
severity, in mean itch score, itch Burning which
Prospective twice daily treatment
Tan, Topical difference in frequency, improvement in required
40 observational with 0.1% tacrolimus 4
2013 (12) Tacrolimus mean itch quality of life and slep, and in discontinuation of
study ointment for 6 weeks score pre and
M
overall severity of lesions treatment
post (p<.001 for all).
treatment
3 treatments/week 1) patient Statistically significant decrease
d

for max of 12 reported VAS in VAS score between baseline

Mohamm Prospective Transcutaneous sessions or until score and at 2,4, and follow up after 1 Mild erythema,
ad-Ali, 20 observational electrical nerve symptomatic cure 2) physician month of the end of sessions 4 irritation, and
e

2015 (21) study stimulation 50-100Hz, pulse reported (p<.001 for all). Overall 67% numbness
width 40-75 clinical improvement in VAS score at 4
pt

microseconds improvement weeks of treatment.

Complete response (>90%
improvement) in 30% of patients,
ce

2-3 times/week
moderate or better response
Esen Mean number of VAS score,
Retrospective (>50% response) in 73.8% of
Salman, 26 Narrowband UVB sessions: 29 Overall 4 Erythema
2019 (24) cohort study Mean cum dose: Improvement patients who were previously
23.7 j/cm2 unresponsive to topical
Ac

treatment. 75% decrease in VAS

score post-treatment
48.24% of patients with LSC
were cured of disease (restored
Propsective skin elasticity, disappearance of Transient
Wu, 2017 84 observational Focused 3.5 W, 10 MHx, 100 Overall itch, restoration of skin color), 4 hyperemia and
(25) ultrasound Hz pulse Improvement overall effective in 94.12% of edema, superficial
study
patients with LSC. Recurrence skin burn
rate at 5 year follow up was
22.35%
Table 2. Summary of treatment modalities and level of evidence
Oxford Level of
Modality Study Treatment
Evidence
Once daily application of fluprednylidene-21-acetate
Topical Corticosteroid Rajan (7) vs thrice daily application of betamethasone 17- 1b
valerate
Diflucortolone Valerate ointment with and without
Geraldez (8) 1b
occlusion

Brunner (6) Halobetasol propionate vs diflucortolone valerate 1b

Datz (5) Halobetasol Propionate vs Clobetasol 17-Propionate 1b

Guzzo (3) & Kantor (13) Halobetosol Propionate 2b

t
Clobetasol Propionate and Hydrocolloid Occlusive

ip
Volden (9) Dressing 4

cr
Goldstein (10) & Kelekci
Topical Immunomodulator (11) Topical Pimecrolimus 4

Tan (12) Topical Tacrolimus 4

us
Topical Antipruritic Agent Kantor (4) Topical Capsaicin 2b
Drake (14) & Breneman
(15)
an
Topical Doxepin 1b

Yosipovitch (16) Topical Aspirin 2b

M
Antiepileptic, Antihistamine, Antihistamine (Chlorpheniramine) and Antidepressant
or Antidepressant Sanjana (23) (Impramine) 2b
d

Gencoglan (22) Gabapentin 4

e

Engin (19), Yuksek (20),

Emerging Therapies
pt

& Mohammad-Ali (21) Transcutaneous electrical nerve stimulation 4

Wu, 2017 (25) Focused ultrasound 4

ce

Esen Salman (24) Narrowband UVB 4

Ac