Forgotten Remedies for Dermatology Is It Time to Drop the One-Size-Fits-All Approach and Consider Remedies of the Past?

COVER FOCUS A Brief Compendium of Some Long- Forgotten Remedies for Dermatology Is it time to drop the one-size-fits-all approach and consider remedies of the past?

BY KATHRYN ARNOLD, BA AND PETER A. LIO, MD

he pace of innovation in modern medicine is truly allows for a broad spectrum of treatment approaches, rang- extraordinary, with novel treatment modalities ing from natural oils to probiotics. helping revolutionize patient outcomes. However, Topical oils, which have anti-inflammatory and even with these impressive strides, physicians antimicrobial properties and are thought to replenish mayT need to reach back into history on occasion to find essential fatty acids that may be deficient in AD, hold promise a fitting therapy when the patient’s disease has not read as a therapy in this patient population. Sunflower seed oil the proverbial play book. Those treatments with the has been shown to preserve stratum corneum integrity and best evidence are not mentioned here; indeed, those are improve hydration in patients with AD after four weeks what we already know and use. Herein we focus on fringe of twice-daily application.3 A study of evening primrose therapies, most with little or mixed evidence, because oil cream showed significant improvement in patient- sometimes, as Celsus reminds us, “Satius est enim anceps reported symptoms after two weeks compared to placebo.4 auxilium experiri quam nullum” (It is better to try a Similarly, an investigation of borage oil, administered by doubtful remedy than to try none).1 We seek to expand coating children’s undershirts with the oil for two weeks, the clinician’s armamentarium beyond a one-size-fits-all demonstrated decreased erythema, itch, and transepidermal approach, presenting long-forgotten remedies as diverse water loss compared to controls.5 as the conditions and patients we treat. We realize that Vitamin B12 has likewise been used as a topical therapy this can be upsetting in an era where evidence is king, and and may work by inhibiting proinflammatory cytokine we in no way wish to impugn evidence-based medicine— production. In one study, application of vitamin B12 cream we’re simply here to dust off some older approaches twice daily for eight weeks led to significant improvement and explore, particularly for those cases where things are in an objective score of AD.6 Topical coal tar, one of the getting desperate. While this is clearly not an exhaustive oldest treatments for AD, also has been shown in numerous collection, we hope it will serve as a useful reference, studies to be a well-tolerated and effective remedy.7 Recent inspiring further investigation and application of these work suggests it may act to restore skin barrier function, therapies and perhaps sparking ideas for new ones. promoting expression of proteins, such as filaggrin, that are deficient in this disease.8 In addition, caffeine, a naturally ATOPIC DERMATITIS occurring methylxanthine, has proven to be a useful adjunct A common, chronic inflammatory disease, atopic derma- to topical steroids in AD. A study of 83 patients comparing titis (AD) is thought to be caused by immune dysregulation topical caffeine 30% and hydrocortisone 0.5% in hydrophilic and skin barrier dysfunction.2 This multi-faceted etiology ointment to hydrocortisone 0.5% in hydrophilic ointment

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demonstrated superior improvement in lichenification, In addition to symptomatic relief, cannabinoids may excoriation and global impression in the combined group promote skin healing and modulate local inflammation. compared to hydrocortisone alone.9 Several mechanisms An in vitro assessment of topical cannabinoid receptor 1 ago- have been proposed for this effect. As a phosphodiesterase nists demonstrated anti-inflammatory activity in models of inhibitor, caffeine increases levels of cAMP, which may be both acute and chronic inflammation as well as enhanced deficient in AD.10 Further, caffeine is thought to regulate cell recovery of epidermal barrier function.18 Though our death, promoting apoptosis and inhibiting necrosis, thereby knowledge of this topic is far from complete, cannabinoids decreasing local inflammation.11 are a promising treatment for AD, as well as other inflam- Additionally, supplements including vitamin D and probi- matory and pruritic skin conditions, and merit additional otics have been singled out as adjunct therapies. Vitamin D studies to elucidate their role in the dermatologic pharma- is inversely correlated with AD severity, perhaps explaining copeia.19 why some patients experience flares of their disease with decreased sun exposure.12 In keeping with this effect, one PSORIASIS study showed that treatment with 1,000 IU of vitamin D2 Psoriasis is an inflammatory condition characterized by daily for one month led to disease improvement in children increased proliferation of keratinocytes and inflamma- whose AD worsened in the winter.13 Probiotics, another tory infiltration of the epidermis. Because this disease may potential therapy, may work in part by shifting the immune involve dysregulated interactions between immune and system from a Th2 to Th1 response, thereby protecting cutaneous cells, many treatments function to decrease against atopy. Lactobacillus therapy for children and adoles- inflammation or modulate keratinocyte turnover.20 cents with AD has been shown to significantly decrease dis- Balneotherapy, or treatment of disease by bathing, is a ease severity and enhance quality of life after two months, remedy dating back centuries that is gaining appreciation an effect that persisted for several months after discontinua- for its role in symptomatic control of psoriasis.21 A variety of tion of probiotics.14 different baths, including sodium bicarbonate, tar, and sele- Lastly, cannabis and its related compounds may be useful nium, have shown efficacy in improving psoriatic symptoms tools for management of AD. Henry Granger Piffard, author such as pruritus and irritation.22–24 Sunlight, as a natural of the first textbook of dermatologic therapeutics, noted source of ultraviolet (UV) radiation, has also been associated in his book: “a pill of cannabis indica at bedtime has at my with improvement in psoriasis.25 Fittingly, the combination hands sometimes afforded relief to the intolerable itching of UV light with bathing may be even more effective than of eczema.”15 Supporting this therapeutic potential, palmi- either component alone. Dead Sea climatotherapy, which toylethanolamine (PEA), an endogenous cannabinoid, dem- involves daily bathing and sun exposure, provides a natural onstrated improved pruritus, lichenification, and excoriation case study for this synergistic treatment.26 When six weeks when applied topically in patients with mild to moderate of UVB therapy alone was compared to UVB plus saline AD.16 Cannabinoids have been shown to modulate mast baths, reduction in an index of psoriasis severity was signifi- cell degranulation in an animal model, suggesting a possible cantly higher in the combination group, lending support to mechanism for this effect.17 this phenomenon.27

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Additional therapies for psoriasis include antibiotics, weight loss, and topical caffeine. Initial evidence for antibiotics as a remedy was drawn from the observation that “Sunlight, as a natural source streptococcal pharyngitis is a common antecedent to guttate psoriasis, and elimination of the bacteria often leads to of ultraviolet (UV) radiation, disease resolution.28 Consequently, it is advisable to examine has also been associated with the patient for infection and treat accordingly. The concept of “occult infection” was very much en vogue a generation improvement in psoriasis. Fittingly, ago. The Doctors Shelley suggested that even if there is no the combination of UV light with evidence of infection, treatment with erythromycin (250mg qid), an oral antifungal, or metronidazole (250mg tid) may bathing may be even more effective resolve occult infection and consequently improve psoria- than either component alone.” sis.29 Another therapy, calorie restriction, may have derived from observation of the correlation between obesity and psoriasis.30 This effect has been confirmed in a randomized controlled trial showing significant improvement of psoriasis and may significantly impact psychological well- in obese patients following long-term weight loss (mean being. Its pathogenesis involves hyperkeratinization weight loss was 10.1kg from mean baseline BMI of 34 kg/ of follicles, increased sebum production, proliferation m2).31 Lastly, caffeine has shown promise in the treatment of of Propionibacterium acnes, and inflammation of the psoriasis. When topical caffeine 10% applied three times a pilosebaceous unit, each of which offers a unique day was compared to placebo, more significant reduction in therapeutic target.33 Psoriatic Area and Severity Index (PASI) scores was observed Tea tree oil (prepared in a 5% gel) has been shown in in the caffeine group after eight weeks, with mild itch as the several studies to decrease both noninflammatory and only side effect.32 inflammatory acne lesions as well as associated erythema, with treatments ranging from once or twice daily for four to ACNE eight weeks.34 While contact allergy can be a problem, it is The most common skin condition in the United States, generally well-tolerated.35 Purified bee venom (PBV) has also acne vulgaris affects up to 90 percent of adolescents been investigated for the treatment of acne. In one study, PBV showed concentration-dependent in vitro antibacterial effects against P. acnes, and a significant decrease in both

©istockphoto ASSESSING HYPNOTHERAPY inflammatory and noninflammatory lesions was observed in patients receiving PBV-containing cosmetics for two weeks.36 In addition, Vleminckx’s solution is a centuries-old remedy derived by boiling sulfur with lime, which confers greater bioavailability than sulfur’s elemental form. It has been shown to be effective in treating acne, with significantly fewer lesions observed after two weeks of every-other-day application. Though its odor and appearance initially pre- vented widespread use, Vleminckx’s solution was combined with a mask vehicle in this study, minimizing these unpleas- ant properties and making treatment more palatable to patients.37 Warts 10 of 14 patients attained the desired depth of Turning to systemic therapies, both non-steroidal anti- hypnosis, and 80 percent of these experienced com- inflammatory drugs (NSAIDs) and azole antifungals have plete treatment response—only on the side of the body demonstrated promise in managing acne. In a study of suggested by the practitioner to resolve. patients with resistant acne, ibuprofen (600mg qid) was shown to be as effective as erythromycin (250mg qid), with Molluscum 8 children, all <4 years old, have been compounding effects when the two were combined.38 A successfully treated. similar study using combination minocycline (50mg tid) and See body for full discussion. ibuprofen (400mg tid) resulted in significant improvement in all patients, as measured by number of nodulocystic

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Focus on Yeast Candida albicans, a dimorphic fungus that typically func- Castellani’s paint is predated by Gentian violet (GV), a ther- tions as a commensal organism to humans, can become apy developed in 1861 by French chemist Charles Lauth and pathogenic when the local microbiome is disturbed and historically used as an antibacterial and antifungal agent.110 GV various predisposing features allow for overgrowth. The skin, has strong in vitro data to support its efficacy against Candida, mouth, throat, and genitals are most commonly affected, with lower minimal inhibitory concentration and superior though systemic infections are not infrequent in immunocom- antimycotic activity compared to other topical agents.111,112 promised patients. Effective topical therapies for candidiasis, Moreover, in an in vitro comparison of Gentian violet and such as Castellani’s paint and gentian violet, have existed for Castellani’s paint, GV was found to possess far more potent centuries, and correction of a nutritional deficiency may be fungistatic properties.113 GV is most commonly used for oral effective in clearing chronic infections. candidiasis. In a study comparing GV to nystatin and ketocon- Castellani’s paint is a remedy dating back to the early 20th azole in patients with thrush, cure rate after 14 days was com- century, developed by Italian physician Aldo Castellani. The solu- parable between GV and ketoconazole and superior to nystat- tion is comprised of fuchsin, ethyl alcohol, boric acid, phenol, in. As with Castellani’s paint, there is concern for staining acetone, resorcinol, and water, with fuchsin as an undesirable side effect of treatment, but imparting its characteristic magenta GV 0.00165% solution used as a mouth rinse color.106 It is effective for treatment of (bid for 14 days) has been shown to intertriginous candidiasis and is a use- act as a potent antifungal without ful alternative to long-term topical staining the oral mucosa.114 corticosteroids.107,108 Historically, In a study of 31 patients with Castellani’s paint has been chronic mucocutaneous candidiasis, prescribed for daily application nearly 75 percent were found to over seven days, though clinical be iron deficient. The majority experience suggests a single appli- experienced disease improvement when cation may be a powerful adjunct supplemented with one-time intravenous to standard medical therapy. The iron followed by ferrous fumarate (200mg most common adverse effect is skin stain- tid) for two months.115 ing secondary to fuchsin, which can be avoided by utilizing alternative preparations that omit this compo- Gentian violet takes its name from the violet 109 plant, though it is not derived from these flowers.

nent while preserving efficacy. ©istockphoto

lesions and patient self-assessment.39 Further, though acne. A landmark paper from Plewig and Kligman looked at antibiotics are considered a cornerstone of acne therapy, 65 patients with acne and randomized them to eating two antifungal medications also deserve consideration. It has “enriched” bars of chocolate daily against a placebo group. been suggested that antibiotics eliminate P. acnes but They concluded, “This excessive intake of chocolate and fat simultaneously allow Malassezia to proliferate, preventing did not alter the composition or output of sebum. A review complete treatment response. However, ketoconazole is of studies purporting to show that diets high in carbohydrate effective against both P. acnes and Malassezia, and a paper or fat stimulate sebaceous secretion and adversely affect by the late dermatologist William Danby, MD suggests that acne vulgaris indicates that these claims are unproved.”41 patients with acne refractory to standard antibiotics may Since then, however, multiple studies have confirmed that respond to a trial of ketoconazole (400mg weekly for six maintaining a low glycemic load diet over several months to eight weeks). Given concern for ketoconazole-induced significantly decreases acne lesion counts.42,43 One trial hepatotoxicity, reasonable alternatives include miconazole showed reduction in free androgen index and elevation of and itraconazole, which have demonstrated in vitro activity insulin-like growth factor binding protein-1, suggesting a against P. acnes.40 possible mechanism for this effect.43 Lastly, there is the slightly ironic update to the old notion that “chocolate doesn’t cause acne.” A series of papers in the ROSACEA late 1960s and early 70s debated the effect of chocolate on Rosacea, a skin disorder characterized by central facial red-

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ness, inflammatory lesions, and flushing, is thought to stem from dysregulation of the innate immune system, vascular dysfunction, and microorganism-provoked inflammation.44 “Both pumpkin seed oil and As vascular reactivity is thought to play a role in rosacea, melatonin have shown promise clonidine, an alpha-2 adrenergic agonist, has been studied in this population. Though it does not alter the overall dis- in the treatment of androgenetic ease process, oral clonidine (0.05mg bid) has demonstrated efficacy in minimizing flushing and thus may be a useful alopecia. Pumpkin seed oil, which adjunct for patients whose primary feature is flushing.45 has been shown to inhibit 5-alpha Other treatments, including dapsone and salicylic acid, target the inflammatory component of this disease. Dapsone, reductase and thus decrease an antibiotic with anti-inflammatory properties, may be androgen levels, led to significant helpful in patients refractory to tetracyclines.46 Topical salicylic acid, which modulates inflammation through inhibi- increases in mean hair count and tion of prostaglandin synthesis, has also proven effective in rosacea.47 patient self-satisfaction when taken In addition, sulfur, benzyl benzoate, and crotamiton are at doses of 400mg daily for six topical therapies thought to act as sarcopticides, eliminating populations of Demodex folliculorum that exacerbate rosa- months.” cea. In a trial comparing topical sulfur to oral lymecycline, treatment with sulfur cream 10% resulted in significantly fewer papules and pustules than lymecycline (150mg daily) (daily for seven to 10 days), demonstrated near-complete after four weeks, and these results persisted for six months repigmentation in 64 percent of patients after two after completion of therapy. Thus, sulfur may be an equiva- months. Controls received either 5-FU cream or epidermal lent or superior therapy to tetracycline antibiotics, with abrasion alone, and none of these patients experienced fewer long-term adverse effects.48 Crotamiton and benzyl improvement of their disease.53 benzoate may also be effective in these patients with mite- Several oral therapies, including ginkgo biloba, aspirin, and excerbated illness, though the data is less robust than for a variety of vitamins, have demonstrated promise in manag- sulfur.49 ing vitiligo. A natural supplement with antioxidant properties, ginkgo biloba (40mg tid) has been shown to halt pro- VITILIGO gression of depigmentation and, in a subset of patients, to An acquired disorder of depigmentation, vitiligo is charac- produce near-complete repigmentation.54 Additionally, low terized by complete loss of melanocytes in the affected skin. dose aspirin may be an effective therapy, due to its immu- Its complex pathophysiology has not been fully established nomodulatory and antioxidant properties. Treatment with but is thought to involve genetics, autoimmunity, oxidative aspirin (300mg daily) for 12 weeks led to arrest of disease stress, and neural mechanisms, among other influences.50 By activity in patients with active vitiligo.55 Further, after docu- targeting these many etiological facets, vitiligo therapies act mentation of decreased levels of folate, vitamin B12, and to recruit new melanocytes to depigmented patches or miti- ascorbic acid in patients with vitiligo, it was demonstrated gate the loss of existing melanocytes. that supplementing these vitamins may slow disease pro- Topical remedies for vitiligo include tar and gression and promote repigmentation, even in patients with 5-fluorouracil (5-FU). In one study, crude coal tar solution normal serum levels.56 Vitamin administration in combina- (300mg/ml applied weekly) coupled with betamethasone tion with sun exposure induces pigmentation to a greater cream (0.1% bid) induced significant repigmentation after extent than either therapy alone, suggesting a synergistic 10 to 20 treatments; areas treated with betamethasone effect.57 alone did not demonstrate any effect.51 Topical 5-FU In a study of dermatomally-distributed vitiligo, treatment likewise has been shown to be effective in restoring with the monoamine oxidase inhibitor nialamide (50mg tid) pigmentation. One trial, which combined one-time resulted in 50 percent repigmentation in more than half dermabrasion with 5-FU 5% cream (daily for seven days), of patients. This form of vitiligo is thought to be a unique showed a response rate of nearly 75 percent at six months process secondary to sympathetic nerve dysfunction rather after treatment.52 A second study, which examined the than autoimmune destruction of melanocytes, a theory combination of epidermal abrasion and topical 5-FU supported by the lack of efficacy of topical corticosteroid

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Focus on Pruritus ©istockphoto Pruritus may be seen as a manifestation of a number of medical conditions or as a primary condition. In the words of John Savin, “Itching lies neglected in the shadow of pain. It is just as intolerable and an every-day problem in all skin clinics… The similarities between the physiology of itching and pain are very close.”116 The prevalence of this symptom, its impact on patients’ well being, and the absence of a widely effective cure call for an evaluation of long-forgotten remedies for itch. While many itch therapies are etiology-specific, others may be applied regardless of the underlying condition. Simple cooling of the skin or topical application of menthol may also be effective in reducing intensity of pruritus.117 Though histamine Aspirin is an overlooked option for the short-term receptors are mainly implicated in urticarial itch, an antihis- management of itch induced by hot baths or showers. tamine trial is often warranted in patients with unexplained general pruritus. Sedating antihistamines may be more effective ing after two to 10 days. The authors caution that treatment than peripherally acting drugs.118 should continue only for several weeks after the cessation of For psychogenic itch, a wide variety of psychotropic medica- symptoms to avoid further increasing hemoglobin concentra- tions are available. H1-antihistamines, doxepin, mirtazapine, tions.123 selective serotonin reuptake inhibitors, pimozide, topiramate, Another treatment for pruritus in PV is aspirin (500mg tid and alprazolam have demonstrated efficacy in managing this for seven days), which partially relieves itch triggered by hot form of pruritus and can be selected so as to treat both the bath or shower.124 Turning to aquagenic pruritus, antihista- symptom and any comorbid psychiatric disorder.119 These mines have been investigated with some promise after early treatments overlap with the therapy for neurogenic pruritus studies suggested the condition is associated with local mast as seen in multiple sclerosis (MS) and stroke. MS may present cell degranulation. A trial of two patients demonstrated com- with paroxysmal itching, and carbamazepine (200-400mg tid) plete resolution of symptoms with cimetidine (200mg qid) has been shown in a small study to be effective in eliminating and chlorpheniramine (8mg qid) treatment.125 In another case these pruritic attacks.120 In addition, unilateral itch can be seen report, a patient who had failed multiple therapies, includ- in the aftermath of stroke. One early study points to topical ing antihistamines, was successfully managed with naltrexone glycerin and olive oil as well as carbamazepine and amitripty- 25mg daily for six weeks, which was later tapered to 25mg line as useful treatments for post-stroke pruritus.121,122 every other day.126 Lastly, for patients undergoing hemodialysis, Effective therapies are also available for other etiologies of oral activated charcoal (6g/day for eight weeks) relieved itch itch, including polycythemia vera (PV), primary aquagenic pru- in over 90 percent of those studied. This therapy presumably ritus, and hemodialysis. One study of iron-deficient PV patients worked by decreasing enteric absorption of pruritogenic sub- demonstrated that supplementation with ferrous gluconate stances, though no significant changes in standard laboratory (300mg tid) or ferrous sulfate (300mg daily) abolished itch- variables were noted.127

treatment. In this subset of patients, modulating the frontal hairline and thinning of the vertex.59 Alopecia area- catecholamine metabolism may hold promise for reversing ta is an autoimmune disease of the hair follicles with a preva- dermatomal depigmentation.58 lence of 0.1-0.2%. In contrast to hormone-mediated alopecia, hair loss occurs in round patches on the scalp and may affect ALOPECIA other parts of the body.60 Chemotherapy-induced alopecia is Hair loss comprises a variety of conditions, including andro- the result of cytotoxic drugs that target rapidly dividing cells, genetic alopecia, alopecia areata, and chemotherapy-induced including hair follicles. Total scalp alopecia typically occurs hair loss. Androgenetic alopecia affects up to 80 percent of and may have tremendous negative psychological impact on men over their lifetime and results from the effects of dehy- patients.61 Fortunately, promising treatment modalities are drotestosterone (DHT) on androgen-sensitive hair follicles. available for many etiologies of alopecia. Characteristically, hair loss occurs as bitemporal recession of Both pumpkin seed oil and melatonin have shown prom-

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ise in the treatment of androgenetic alopecia. Pumpkin seed oil, which has been shown to inhibit 5-alpha reductase and thus decrease androgen levels, led to significant increases in “Other resourceful topical wart mean hair count and patient self-satisfaction when taken at doses of 400mg daily for six months.62 Likewise, studies of therapies include banana skin, topical melatonin (0.0033% solution applied daily for three household cleaners, and hot water. months) have demonstrated increased hair density, reduced hair loss as measured by hair pull test, and improved An early case report detailed the patient- and investigator-rated alopecia severity.63 cure of a young patient’s plantar A diverse variety of treatments has been studied for alopecia areata (AA), including topical onion and garlic, aroma- warts after six weeks of treatment therapy, and cryotherapy. Topical raw onion juice (bid for two months) led to hair regrowth in nearly 87 percent of with banana skin, in which the inner patients in one study, significantly more than the tap water skin of the fruit was secured over control.64 Another pungent remedy, topical garlic gel, has been examined as an adjunct therapy to corticosteroids. After warts with tape and replaced daily.” three months of twice daily application, enhanced treatment response was observed with combination garlic gel and betamethasone cream compared to betamethasone alone.65 trauma, insect bites, viral infection, and vaccinations. Additionally, aromatherapy, performed by massaging essential Lymphohistiocytic infiltrate and collagen degeneration are oils into the scalp, may promote hair regrowth in AA patients. characteristic histologic features, suggesting GA may be When essential oils in a carrier oil mixture were compared caused by a delayed-type hypersensitivity reaction in which to carrier oil alone, 45 percent of patients in the essential oil macrophages are activated to express proinflammatory group showed improvement at seven months, compared cytokines and collagenase.71 The mechanisms of many to 15 percent in the control group. Patients applied the oils treatments for GA are as uncertain as its pathogenesis, themselves and no adverse effects were reported, suggesting though they may function to suppress the immune system aromatherapy may be more tolerable and accessible than cur- through various pathways. rent mainstays of AA treatment.66 Chlorambucil and methotrexate, medications with Further, superficial cryotherapy, in which liquid nitrogen immunosuppressive potential, have been examined in the is briefly applied to patches of hair loss, is a safe, simple management of GA. Chlorambucil acts as an alkylating and effective treatment for AA. Liquid nitrogen is applied agent, decreasing immune function by damaging lymphocyte for several seconds three to four times per treatment, with DNA. It has shown efficacy in patients with generalized GA, treatments repeated over the course of three months. In one including those with severe or refractory disease, when given study, 60 percent of patients experienced either partial or at low doses (2mg tid) over two to four months. Careful full response; superior response correlated with first disease monitoring is required, however, to ensure therapeutic occurrence and treatment intervals of two weeks or less.67 effect is balanced against the complication of bone marrow Lastly, for prevention of chemotherapy-induced alopecia, suppression.72,73 Methotrexate, an antimetabolite that inhibits scalp cooling prior to and during intravenous administration synthesis of purine and pyrimidine bases, may be similarly of a cocktail of doxorubicin, vincristine, and 5-FU has been efficacious. A case report of a patient with generalized GA shown to significantly decrease hair loss.68 The mechanism refractory to dapsone, cyclosporine, and photochemotherapy is thought to be localized vasoconstriction, which prevents noted dramatic improvement in response to 15mg chemotherapy agents from reaching the hair follicle. methotrexate weekly. The patient’s lesions recurred when Since the initial description of this phenomenon in 1977, treatment was held for a surgical procedure and promptly scalp cooling devices have been invented to simplify the resolved when the drug was resumed post-surgery.74 treatment process, and these devices have been validated in Additional therapies that have shown benefit in GA large clinical trials.69,70 include dapsone, niacinamide, and potassium iodide. Dapsone, an antibiotic with anti-inflammatory properties, GRANULOMA ANNULARE has been reported to cure generalized GA when given Granuloma annulare (GA), an idiopathic skin lesion, orally (100-200mg daily) for six weeks.75 Topical dapsone presents as a skin-colored or erythematous annular plaque 5% gel applied twice daily over a similar time frame and may be provoked by a variety of factors including may be useful for localized GA in cosmetically sensitive

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areas.76 Niacinamide, a form of vitamin B3, may be cum contagiosum is characterized by skin-colored umbili- effective in generalized GA at doses of 1500mg daily for cated papules that often resolve with time. Its unsightly six months. The vitamin is thought to inhibit delayed-type appearance, however, prompts surveillance for more hypersensitivity reactions by suppressing antigen-induced expedient cures than the unaided immune system can pro- lymphocyte transformation and cytokine production.77 vide. Potassium hydroxide (KOH) solution 10% has been Lastly, saturated solution of potassium iodide (1ml daily found to be effective in treatment of molluscum when for three months) has led to resolution of generalized applied twice daily for four weeks, with minimal local side GA in some patients.78 Iodine exerts immunomodulatory effects.90 When KOH solution was compared to weekly properties by inhibiting neutrophil chemotaxis and cryotherapy, efficacy at four weeks was equivalent between reactive oxygen species production, though its specific groups, and KOH led to improved cosmetic results.91 In mechanism in GA is unclear.79 addition, cimetidine, a histamine2-receptor antagonist, has been investigated as a potential therapy for patients with SCABIES molluscum refractory to standard treatment. Histamine Scabies is a skin infestation by the Sarcoptes scabei mite that receptors are present on suppressor T-cells and serve an manifests as papules and burrows with intense pruritus and activating function; thus, cimetidine is thought to boost commonly affects the finger webs, wrists, and axillae. Multiple cell-mediated immunity by decreasing the activity of these therapies, including naturally occurring oils and neem and regulatory cells. In one study of patients with refractory turmeric paste, have demonstrated ability to eradicate these disease, oral cimetidine (40mg/kg daily) for two months problematic organisms. Though clinical trials are lacking, resulted in full clearance in 70 percent of patients and halt- in vitro studies of 5% tea tree oil have shown acaricidal ing of disease progression in 23 percent.92 properties comparable to lindane and ivermectin.80,81 Further, hypnotherapy, which harnesses the power of Clinical data is available for lippia tree oil, however. In suggestion, holds promise in treatment of molluscum. one study, 100 percent of patients were cured of infestation Successful treatment of eight children has been reported; all after treatment with topical lippia oil 20% for five days, were younger than four years old, hinting that age may influ- compared to 87.5 percent of patients treated with benzyl ence response.93 Interestingly, research on hypnotherapy benzoate 20%. This finding is supported by in vitro evidence points to immune modulation as the likely mechanism in of lippia oil’s superior scabicidal activity.82 In addition, a treating virally-mediated disease, suggesting this function paste of neem and turmeric, long used in Indian traditional may unite a diverse array of molluscum therapies.94 medicine for treatment of scabies, produced a 97 percent cure rate within three to 15 days in a study of 814 patients. WARTS One disadvantage of this therapy, however, is the duration Warts, or verrucae, are stubborn HPV-mediated lesions of treatment, which could hinder compliance and thereby with a predilection for the hands, feet, face, and muco- decrease efficacy.83 sal surfaces. Long a source of frustration to clinicians and Additional therapies include benzyl benzoate and sulfur. patients alike, they have yielded a breadth of therapies for Benzyl benzoate, which acts by inducing mite neurotoxicity, lesions refractory to standard management. has been shown to cause complete eradication after a single Several common medications, including cidofovir, podo- application, an impressively brief duration of treatment.84 phyllin, and colchicine, have been used as topical thera- Subsequent studies have validated this finding and shown pies due to their ability to impede rapid cell proliferation. benzyl benzoate’s efficacy is comparable to ivermectin in Cidofovir, which inhibits DNA polymerase and thus DNA the management of scabies.85,86 Lastly, topical sulfur is a replication, has been shown to be effective for treatment remedy dating back centuries, thought to cause toxicity of viral warts in children and adults. Localized lesions can via its metabolites and to dislodge mites from burrows be cleared after six to seven weeks of nightly application via its keratolytic properties.87 One study showed that of cidofovir ointment 1%, but intravenous administration topical sulfur ointment 10% applied at bedtime for three may be required for disseminated or recalcitrant verrucae.95 consecutive days was more than 90 percent effective in Similarly, podophyllin, which antagonizes topoisomerase eradicating mites.88 Sulfur can be used safely in pregnancy II, has been used for management of condyloma acumina- and childhood, suggesting a unique role when clinicians tum. When applied twice a day for three days, podophyllin hope to spare the adverse effects of first line therapies.89 resin 0.5% yielded an 82 percent cure rate at one week and 61 percent cure rate at three months.96 Another therapy, MOLLUSCUM colchicine, prevents cell division by disabling the mitotic A virally-mediated disease common in children, mollus- spindle apparatus. One to two applications of colchicine

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solution 8% have been shown to result in wart clearance, medications quickly before their effectiveness runs out.” In though this effect was much more pronounced in patients an era of rapidly developing and increasingly sophisticated who had previously been cured of condyloma compared to therapies, the astute clinician should not hesitate to reach those experiencing their first genital wart.97 for forgotten remedies that have stood the test of time. In Other resourceful topical wart therapies include banana this way, though the efficacy of newer medications may run skin, household cleaners, and hot water. An early case out, a patient’s treatment options need not. n report detailed the cure of a young patient’s plantar warts after six weeks of treatment with banana skin, in which the Kathryn Arnold, BA is a medical student at University of inner skin of the fruit was secured over warts with tape Chicago Pritzker School of Medicine, Chicago. and replaced daily. No recurrence was observed after two Peter A. Lio, MD is a Clinical Assistant Professor years of follow-up.98 One study examined the therapeutic of Dermatology and Pediatrics at Northwestern properties of liquid ammonia-containing cleaning solu- University Feinberg School of Medicine and a partner tions, such as Ajax. When diluted with three parts water at Medical Dermatology Associates of Chicago. and applied for 10 minutes weekly, these solutions led to 1. Spivack, B. S. A. C. Celsus: Roman medicus. J. Hist. Med. Allied Sci. 46, 143–157 (1991). clearance of a variety of warts, including verrucae vulgaris 2. Boguniewicz, M. & Leung, D. Y. M. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol. Rev. and condyloma acuminatum, within five weeks.99 242, 233–246 (2011). 3. Danby, S. G. et al. Effect of olive and sunflower seed oil on the adult skin barrier: implications for neonatal skin care. Pediatr. Dermatol. 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