Elsevier

Clinics in Dermatology

Volume 26, Issue 5, September–October 2008, Pages 448-459
Clinics in Dermatology

Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas

https://doi.org/10.1016/j.clindermatol.2007.10.026Get rights and content

Abstract

Psoriasis comprises a broad spectrum of different clinical courses among which the chronic stable psoriasis by far occurs most frequently. The clinical presentation ranges from mild disease to more serious forms involving large areas of skin and/or joint disease. A number of modifying factors may impact on treatment choice in individual cases (eg, location of the lesions, disease phase, treatment history, response to previous treatments, comorbidity). Aside from this consideration, there are special localizations that remain some of the most difficult regions to control. Such entities are the scalp, nails, and intertriginous areas. Topical treatment of such different-to-treat areas has to be considered as a first-line intervention strategy, at least in those patients who are presenting an exclusively isolated involvement. In some situations (eg, in severe psoriasis or in patients who are refractory to topical treatment), however, a systemic treatment is indicated. Most obvious difficulties in treating these locations are due to unrealistic expectations from the patients' perspectives, time-consuming applications, side effects, cosmetic injuries, and restricted bioavailability of active compounds. Aside from hair care, initial use of keratolytics for scalp psoriasis, corticosteroids, and vitamin D3 and analogues are currently standard treatments. Recently developed new formulations of both active ingredients such as foam or gel appear to be more acceptable to patients than traditional creams or ointments. Current treatment options for nail psoriasis are very often poorly efficacious, associated with undesirable effects, or time consuming. Success has to be measured in terms of months. Topical treatments (eg, corticosteroids, vitamin D analogues, tazarotene) are mainly used, but impressive improvement rates mostly will be achieved by systemic treatment of conventional and biologic agents. Finally, the usefulness of corticosteroids, vitamin D and analogues, and calcineurin inhibitors in treating intertriginous psoriasis clearly is demonstrated. Especially the use of calcineurin inhibitors exhibits efficacy in intertriginous regions and therefore may be seen as a promising treatment option in the future. Besides the important innovations in the last years, there is a need for new effective and well-tolerated treatment modalities, especially for long-term use in the 3 difficult-to-treat locations, which encompass cosmetic acceptability.

Introduction

Psoriasis is a genetically determined chronic immune-mediated inflammatory disease like rheumatoid arthritis, Crohn disease, ankylosing spondylitis (M. Bechterew), and others.1, 2 Psoriasis creates a significant stigma for patients and is a disease of major economic burden.3 The extent of skin involvement can vary widely from discrete, localized areas to generalized body involvement. At different stages of the disease, the whole range of morphological manifestations may present in an individual patient simultaneously or progressively with increasing age. Chronic plaque type of psoriasis is the most common form, being present in approximately 80% of patients. As shown in Table 1 the frequencies of affected areas in patients with chronic plaque psoriasis vary over a large range. Independent of the frequency, there are manifestations with special localizations that remain some of the most difficult areas to control. Such entities in psoriasis are the scalp, nails, and intertriginous areas. This article therefore will review shortly the clinical presentations and discuss current treatment modalities of these 3 particular localizations.

The scalp is one of the most common sites of psoriasis involvement at the onset and throughout the course of psoriasis. An epidemiological survey carried out in the Netherlands showed that 79% of all patients with psoriasis have involvement of scalp.4 Another Dutch questionnaire indicated that scalp psoriasis had existed already for more than 5 years in 81% of patients, and in 48% of the patients, psoriasis affected more than half of the scalp.5 Indeed, 50% to 80% of patients with psoriasis report scalp psoriasis or concomitant psoriasis of the body.6

The erythematosqamous lesions on the scalp are mostly asymmetrical, sharply demarcated, showing a silver-white scaling. Scalp psoriasis, however, can range from very mild disease to severe disease with thick, crusted plaques covering the entire scalp. An additional characteristic is that the psoriatic areas often advance beyond the hair border on the face, neck, or retroauricular regions (Fig. 1A-D).7 Sometimes, patients with scalp psoriasis complain of pruritus. One important question asked of patients very often is whether scalp psoriasis is inducing hair loss. As a rule, most patients experience no association with hair loss and observe a normal hair growth rate. In severe, recalcitrant, or prolonged disease, however, occurrence of alopecia to some degree is known. Analyses of trichograms of hairs taken from psoriatic lesions reveal a telogen effluvium.8 Scalp psoriasis is limited to the scalp alone or can be associated with type I and type II psoriasis, pustular psoriasis, erythrodermia, and psoriatic arthritis. In most cases, the condition is observed in patients with chronic plaque psoriasis. A special variant of scalp psoriasis is known as sebopsoriasis or seborrhiasis. The term describes an overlap with seborrheic dermatitis. In this condition, psoriasis mostly predominates, with associated facial involvement showing a greasy scaling with a yellowish color.7, 9, 10, 11 The pathogenic role of Malassezia species in this condition currently is under discussion.

Most physicians underestimate the impact of scalp diseases on quality of life. Although most patients with scalp psoriasis routinely ask a physician for help, they will get at least partially a poor answer. These patients are dependent on information from pharmaceutical companies or cosmeticians. To develop a specific quality-of-life instrument for scalp dermatitis, Chen and coworkers12 have investigated 52 patients and constructed a 23-item instrument (so-called Scalpdex). The item analyses reveal that quality of life was most affected by the terms “my scalp itches,” “caring for my scalp condition is inconvenient for me,” or “I am frustrated by my scalp condition,” and that scalp dermatoses affect patients' quality of life on different levels: clinical symptoms, functioning, and emotions reflecting the whole spectrum of the psychosocial burden associated with scalp psoriasis.

Despite numerous available treatment modalities of scalp psoriasis, therapeutic experience of patients and physicians is disappointing, sometimes even frustrating. This statement is confirmed by a recent survey of 17,990 patients with psoriasis in 7 European countries.13 As 2 leading complaints, the terms time consuming and ineffective could be registered. The cause of the high level of dissatisfaction with existing therapies is based on several issues:

  • 1.

    In most cases, scalp psoriasis inflicts an emotional toll on affected patients because the visible lesions affect one's self-esteem and social ability. As a result, affected patients wish for a fast onset of treatment efficacy and an improved clearing in addition to lasting remissions and convenience.14, 15, 16 All currently available treatments for scalp psoriasis are not able to meet these expectations entirely, however. The contradiction between unrealistic expectations and feasibility sometimes is frustrating, with negative impact on compliance.

  • 2.

    Especially in scalp psoriasis, all topical therapeutic strategies finally affect cosmetic hair condition (eg, oily hair, brittle hair, dryness of skin, staining, unpleasant smell). As a result, willingness to accept such disadvantages of topical treatment modalities have to be seen as a strong determining factor for treatment success. The willingness to do that will not cover all patients, however.

  • 3.

    Because of the inevitable hair care, a perpetual so-called koebnerization effect of scalp psoriasis cannot be excluded. In this line, the patients' picking, scratching, and shampooing of the scalp may be seen as maintaining factors of disease activity.

  • 4.

    As a prerequisite for the efficacy of topical formulations used in scalp psoriasis, a sufficient bioavailability of the active drug after the process of liberation and percutaneous absorption is necessary.17 Otherwise, a treatment will fail to demonstrate efficacy. Pilosebaceous units are found in high density in the scalp region. Sebum content can be very high in determined patients, and therefore, a mixing of sebum with a topical formulation, for example, may change the availability of lipophilic components for absorption. In addition, considering the anatomical site, there is a large difference between the surface of the human scalp (about 700 cm2) and the mean surface of hair (female hair, 6 m2; male hair, 1 m2). If a preparation, for example, is evenly distributed to the hair and the scalp, the skin exposure is between 20 and 100 times lower than that of the hair surface.17 Thus, any patient will carefully make an effort to avoid hair exposure with a preparation for treatment. Nonetheless, determined amounts of any formulation will stay in the hair and not reach the scalp skin surface. It follows that there is a large extent of variation in the rate of percutaneous absorption between individuals. It is the experience of the author that in scalp treatment, the availability of the active compound on skin surface generally is a realistic problem.

Taken together, the outlined issues finally are of importance for compliance of patients. Thus, some authors state that the most common reason for patients declaring that topical formulations do not work is that they have not been compliant or have unreal expectations.18 A comparison between the number of references on treatment of scalp psoriasis and treatment of psoriasis in general reflects a proportion of about 1 to 60.

Considering the treatment options for scalp psoriasis recommended in the literature, there are some limitations.19

The evidence level for many therapeutic approaches does not meet the criteria of modern medicine. Common design deficiencies identified in studies of scalp psoriasis treatments are as follows:

  • lack of active control;

  • lack of placebo group;

  • open-label design;

  • small study population;

  • limited head-to-head trials, especially in comparison vs established treatments;

  • time lapse in crossover trials not sufficient to clear effect of initial treatment modalities; and

  • combination with systemic treatment modalities.

A recent meta-analysis of topical agents used for the treatment of plaque-type psoriasis revealed a total of only 42 well-designed placebo-controlled trials in this area; of these studies, only 7 focused specifically on the treatment of scalp psoriasis.20 More importantly, this analysis identified only marginal efficacy benefits with most agents with the exception of topical corticosteroids, vitamin D analogues, and a combination of potent corticosteroids and calcipotriol. Despite this notification, in the following, the most frequently used topical agents for treating scalp psoriasis should be discussed in a systematic order.

It is widely known from clinical experience that most topical treatments fail to resolve scalp lesions until thick, hyperkeratotic scales have been removed. The rationale for this observation is the reduced bioavailability of antipsoriatic drugs in viable epidermis. Measurements of the transepidermal water loss of involved skin exhibited a decrease in skin barrier function but, conversely, a 5-fold increase of transepidermal water loss, if scales were removed before measurement.17 Therefore, after removal of scales by salicylic acid, the influx of active drug in inflammatory skin is more easy to manage. Salicylic acid likely acts by disrupting desmosomes in the stratum corneum and may reduce scaling.18 Another effect due to salicylic acid is an enhanced penetration and efficacy of corticosteroids.21 Salicylic acid 5% to 10% formulated in a solution, gel, ointment, or in an oily preparation, which can be washed off easily, has a significant keratolytic effect. The formulation should be applied a few times for about 2 or 4 days. The patient should be informed that in most cases, such preparations are “leave-on” products associated with restrictions to cosmetic acceptance. There are some commercially available combinations of salicylic acid and corticosteroids in Europe (eg, Diprosalic, Elosalic).

Coal tar may help to inhibit the epidermal proliferation and especially to reduce pruritus of scalp. Despite its wide use, the exact mechanism of action in psoriasis is not known. Because of the potential toxicologic risk, guidelines on the use of tar products differ between countries. Mostly, coal tar as 2% solution incorporated in shampoo or in a lotion is prescribed. There are no evidence-based randomized controlled trials on its efficacy in scalp psoriasis, however. Nevertheless, the patient's acceptance especially of tar shampoos is high because of its “rinse-off” character. When coal tar preparation is used as a sole treatment, it is often insufficient to solve the therapeutic problem. Thus, coal tar formulations may support other therapeutic regimens. Some patients are unable to tolerate the unpleasant smell, and others will note staining of their light hair after prolonged use. Combinations of coal tar and other agents such as salicylic acid or corticosteroids are available. In view of the mutagenic potential of tar, applying in pregnant or lactating women is contraindicated.5 Coal tar and tar-containing products can cause folliculitis and phototoxicity and may act as a local irritant.

Since the pioneering work of Galewsky22 in 1916, the topical treatment of psoriasis has been improved dramatically. Despite its side effects, anthralin as a single agent can be characterized as an effective topical remedy in psoriasis therapy. Anthralin in its usual petrolatum base is, however, difficult to remove when used on the scalp. Thus, several special formulations for scalp psoriasis have been recommended. Micanol with 1% or 3% anthralin is a temperature-sensitive vehicle that, when activated at skin temperature, prevents staining of clothes and furniture. A special vehicle for anthralin in treating scalp psoriasis is the so-called bio-wash-oil, which was designated for cleaning the heavily soiled hands of factory workers. It can be easily applied to the scalp and washed off with water.23 There is the possibility to combine anthralin with coal tar or liquor carbonis detergens. The cutaneous side effect of anthralin includes erythema, edema, and staining. It can discolor blond hair, especially turning it yellowish. Clothing or other household fabrics can also be affected by anthralin-induced staining. From the perspective of patients, the most important one is to avoid any contact of anthralin with the eyes (eg, by hanging down of hairs). Patients selected for treatment with anthralin should be highly motivated and able to follow detailed instructions. In some countries, especially in Europe, proprietary preparations with anthralin are available (eg, Micanol, Psoralon-MT, Psoradexan).

Topical corticosteroids have been widely used as treatment for scalp psoriasis. Like in other involved areas of psoriasis, the corticosteroid therapy aims at the strong antiinflammatory and antiproliferatory action on the skin and minor (if any) systemic and local side effects.24 Topical corticosteroids are categorized by numerous classification systems based on different measurements (eg, vasoconstrictor assays, UV-B–induced erythema test, psoriasis plaque test, atrophogenicity potential).25, 26, 27, 28 The Cornell-Stoughton25 classification, for example, ranges from the superpotent class I corticosteroids, such as clobetasol dipropionate, halobetasol propionate, and others, to the weaker class VII corticosteroids, such as hydrocortisone 1%. Notably, this is in contrast to some European classification systems, which start with class I as the group with the weakest-potential corticosteroids.26 All topical corticosteroids reduce clinical inflammation but vary in strength, concentration, vehicle, and last but not least, cost. The antiinflammatory steroids can be incorporated into almost any vehicle including oils, ointments, cremes, sprays, tapes, lotions, gels, solutions, and foams. In addition, topical steroids generally are suitable components of combination treatment modalities (eg, urea, salicylic acid, coal tar, calcipotriol) in corresponding 2-component products or as single complementary application in a determined treatment schedule. The efficacy of topical corticosteroids in the treatment of plaque psoriasis is well established.29 Clobetasol 17–propionate and betamethasone dipropionate produced clearance or marked improvement in 75% and 80% of patients, respectively.18 Recently, Mason et al20 analyzed data from all randomized placebo-controlled trials involving topical psoriasis treatments. The statistically pooled data spanned 3380 patients randomized in 41 placebo-controlled studies and 4898 patients in head-to-head trials. As a result, the very potent steroids were found to be the most efficacious.

Used as a single agent, recent studies have clearly shown topical corticosteroids to be more effective than vehicle alone in the treatment of scalp psoriasis.30 For treating scalp psoriasis, in particular, the formulation used is relevant. As a rule, a cream, lotion, solution, or shampoo is preferred to an ointment. In one study, clobetasol scalp solution resulted in more than 50% clearance in 81% of patients compared with placebo, with 26% of patients achieving complete clearance.31 Betamethasone valerate foam, originally developed especially for treatment of scalp involvement, cleared or nearly cleared scalp psoriasis in 72% of patients and was preferred by patients over the lotion vehicle.32 In one study, clobetasol foam resulted in clearance or nearly clearance of scalp psoriasis in 74% of patients.33 It is the impression of the author that patients with scalp psoriasis appreciate the use of foams in day-to-day practice. These preparations belong now to the therapeutic armamentarium in treating scalp psoriasis because patients find them more acceptable and are thus more likely to comply with treatment.34, 35, 36 Brand-name preparations of betamethasone valerate 0.1% and clobetasol propionate 0.05% have become available in Europe and the United States (eg, Deflatop, Clarelux, Luxiq, Olux).

Cutaneous side effects are the most common and usually occur when corticosteroids are used with excessive frequency or duration or on steroid-sensitive areas such as the face or intertriginous areas. Therefore, application frequency and duration of treatment should be done in accordance with recommendations of the manufacturers. Because of the lower percutaneous absorption of corticosteroids, however, the scalp is more resistant to atrophy, but it does occur (eg, percutaneous absorption of cortisol: 6% on forehead, 3.5% on the scalp).37 Thus, continuous twice-daily application of a superpotent corticosteroid should be limited to a 2-week course. As a rule, once-a-day application of a potent corticosteroid is sufficient. After clearance, application on 1 or 2 consecutive days each week sometimes provides adequate maintenance. Despite high efficacy, topical corticosteroid use is limited to the short-term treatment of scalp psoriasis. Prolonged treatment of scalp psoriasis with topical corticosteroids is not recommended because of the lack of data available to support safety and efficacy of topical steroids during prolonged use.19

Since the appearance of the results of the pilot study on patients with psoriasis38 in 1986, vitamin D3 and analogues have been a mainstay in topical treatment of chronic plaque psoriasis.39, 40 One of the best investigated compound is calcipotriol (syn calcipotriene). Calcipotriol is a vitamin D3 analogue, that binds to vitamin D receptor found in keratinocytes, halting proliferation and causing terminal differentiation.29, 41, 42 In placebo-controlled studies and comparative studies against other treatments, the efficacy and safety of calcipotriol have been clearly demonstrated. Directly comparative studies with calcipotriol have revealed that calcipotriol is more effective than anthralin, tazarotene 0.05%, or 0.1% gel, calcitriol, and tacalcitol.43 Calcipotriol formulations are characterized by paucity of side effects, aesthetic acceptability, and therapeutic advantages over anthralin and coal tar. In scalp psoriasis, calcipotriol solution twice daily for 8 weeks reduced the scalp severity index from 18.4 to 5.6 in a large cohort of patients.44 Generally, calcipotriol solution has been found to be effective as short-term treatment for scalp psoriasis in controlled trials and has demonstrated efficacy equivalent to that of betamethasone valerate.45, 46 Also, in long-term treatment of scalp psoriasis, calcipotriol has shown efficacy with no evidence of tachyphylaxis.47 The maximum efficacy of calcipotriol solution is achieved in about 8 weeks. Clinical investigations using new formulations of calcipotriol/betamethasone dipropionate currently are ongoing.48 In addition to calcipotriol solution, the topical application of tacalcitol emulsion was investigated in scalp psoriasis. The once-daily application was effective and well tolerated.

Despite the frequent use of systemic therapies of psoriasis, especially of moderate to severe plaque-type psoriasis, little is known about exact efficacy of these approaches in scalp psoriasis. Conventional systemic drugs, such as methotrexate, cyclosporine, fumaric acid esters, leflunomide, acitretin, and biologic agents (alefacept, efalizumab, etanercept, infliximab, adalimumab) are approved by the regulatory bodies for treatment of moderate to severe chronic plaque psoriasis, psoriatic arthritis, or other severe clinical presentations of psoriasis. It is evident that in such conditions, scalp psoriasis is located only in one localized area of the whole body surface. For affected patients, mostly the major portion of the body surface area outside the scalp is of urgent priority. Moreover, for the assessment of severity, validated instruments such as Psoriasis Area and Severity Index (PASI), body surface area, or physician global assessment are used. This means that for PASI or body surface area, the scalp area, by the rule of 9, is calculated by only 4% to 5% of the whole body surface. As a result, instead, a global PASI response (eg, PASI 75 response), an isolated efficacy calculation of the scalp in clinical trials and in day-to-day practice, will not regularly be used.

Clinical experience with the broad range of systemic treatments including biologic agents reveals that in most patients, the general improvement is accompanied also by a satisfactory amelioration or even complete clearing of scalp psoriasis.

A review of past and current medical literature reveals that numerous alternative therapeutic approaches for scalp psoriasis have been used including, for example, dermatome shaving, grenz rays, aloe vera extract, antifungals, retinoids, topical methotrexate, and UV phototherapy. The evidence levels for these therapeutic modalities, however, do not meet the criteria of evidence-based medicine because data of randomized controlled clinical trials are lacking. From theoretical point of view, for example, the use of the synthetic acetylenic retinoid tazarotene as gel or cream in special areas of the scalp may be helpful because the same preparations are indicated for acne and photoaging, even on the entire face. Some authors recommend the application of tazarotene gel 0.1% in combination with topical corticosteroids and calcipotriol.18 The common adverse effects (eg, pruritus, erythema, burning/stinging, skin pain, increased sun sensitivity) have to be considered very strictly, however. To date, no trials have assessed efficacy or safety of topical retinoids in scalp psoriasis.

The frequency of nail psoriasis varies between 10% and 55%.49, 50 In patients with psoriatic arthritis, a frequency of about 85% is found.51 Only in 1% to 3% of patients, nail psoriasis can occur without any cutaneous or joint involvement. The clinical manifestations may range from minimal, for example, in the form of simple pitting, to extensive changes involving virtually the entire nail units with destruction and interference with normal function (Fig. 2A-D). Characteristics of nail psoriasis are as follows:

  • pitting of the nail plate,

  • oil drop discoloration,

  • subungual hyperkeratosis,

  • onycholysis (distal or total),

  • transverse ridging, and

  • splinting hemorrhages.

For measurement of nail psoriasis severity, a scoring system has been developed (nail psoriasis severity index).52 The most common findings are discrete onycholysis and/or pitting.51 A special entity is the pustular psoriasis of nail apparatus (syn acrodermatitis continua suppurativa Hollpeau), characterized by periungual pustules and generally poor response to treatment.

Current treatment options for nail psoriasis are very often poorly efficacious, associated with undesirable systemic effects, being time consuming, or impracticality.49, 50, 53 There are several reasons because of restricted therapeutic efficacy.

  • 1.

    Nail psoriasis is a very visible and exposed disease and therefore may cause significant negative impact on quality of life (eg, in profession). Thus, most affected patients do wish for a rapid improvement. Despite availability of modern biologics, however, no currently available treatment is able to meet the patients' demand. As a result, a number of patients are showing decreased compliance because of long-term treatment and/or insufficient convenience of therapeutic realization, especially of topical treatment. Patients must understand that response to therapy is measured in terms of months and that sometimes, there is no instant gratification.

  • 2.

    In view of the anatomical structure of the nail unit, generally, it is difficult to achieve sufficient concentrations of antipsoriatic active drugs in the involved nail, nail bed, or matrix by topical application. Therefore, aiming for an increased penetration of agents, occlusion device, or intralesional application is recommended. Such procedures, however, sometimes are painful (eg, corticosteroid injection). Thus, some patients will refuse determined treatment modalities.

Whatever has to be done for treating nail psoriasis, already existing psoriatic nail changes, in particular, of the nail plate, depend on the normal nail growth rate determined physiologically (fingernails, 0.1 mm/d; toenails, 0.04 mm/d). Also seen from this point of view, treatment success has to be measured in terms of months.

With regard to topical treatments of nail psoriasis, the use of the following agents is recommended:50, 51, 53, 54, 55, 56, 57, 58

  • corticosteroids (open application, occlusion technique, intralesional),

  • calcipotriol,

  • tazarotene,

  • anthralin, and

  • 5-fluorouracil.

The disadvantage of intralesional corticosteroid application is the risk of atrophy, and sometimes, it is associated with pain during injections. There are no clinical trials that give the answer as to how often an intralesional corticosteroid application is really safe.

In a randomized controlled trial, 58 patients with a long history of the disease were treated with betamethasone dipropionate (64 mg/g) in combination with salicylic acid ointment (0.03%/g) and calcipotriol ointment twice a day for 3 to 5 months. Both treatments resulted in a similar reduction of nail thickness after 3 and 5 months: 3 months, calcipotriol 26.5% and betamethasone 30.4%, and 5 months, calcipotriol 49.2% and betamethasone 51.7%.57 Other markers of nail psoriasis and outcome criteria, for example, completely free of symptoms, were not defined in the study. Therefore, the conclusion is restricted to both drugs being able to reduce thickness of nails by about 50% in 5 months of treatment. Another study compared occlusion and nonocclusion technique using tazarotene 0.1% gel vs vehicle gel in 31 patients.56 In terms of the criteria, onycholysis and pitting tazarotene significantly reduced both symptoms compared with vehicle after 24 weeks. Furthermore, 1% or 5% fluorouracil in different vehicles (eg, propylene glycol, special penetration enhancer in lotion formulation or cream) has been used in nail psoriasis.59, 60, 61 Because of the small number of patients, no definite recommendations can be made. Despite the difficulties with topical cyclosporine application, some success has been reported with oil-dissolved 70% solution of cyclosporine used over 12 months in 16 patients.62, 63 Moderate improvement could also be achieved after 5 months with 0.4% to 2% anthralin in petrolatum using daily short-contact therapy.64 The use of phototherapy with or without acitretin also has proven effective in some patients.

Summarizing the data on topical treatment modalities in nail psoriasis, there is still a lack of efficient, safe, and patient-accepted modalities. Because most patients with nail psoriasis complain of the difficulties of topical treatment procedures, the question to treatment alternatives remains to be answered. Of course, in patients with severe psoriasis, especially involving large skin areas or joints, clearly, a systemic treatment is indicated. Only a limited number of reports about the effect of systemic treatment of nail psoriasis exist, however. Mostly, uncontrolled studies with small patient cohorts, case reports, or combined treatments with additional topical application of antipsoriatic drugs are restricting issues for giving general recommendations. Some recently published treatment results include cyclosporine,65, 66 acitretin,66, 67 and methotrexate.50, 53

Because of the appearance of biologic agents in treating chronic plaque psoriasis and psoriatic arthritis, the awareness of unsatisfactory treatment modalities of nail psoriasis was renewed. In comparison with topical treatment, the use of biologic agents as long-term treatment results, in most patients, in a complete and long-lasting remission. In a multicenter, double-blind, placebo-controlled clinical trial with measurement of the effect of infliximab in 378 patients with moderate-to-severe plaque psoriasis, in addition, the improvement of nail psoriasis was evaluated using the nail psoriasis severity index.68 In about 300 patients, the nail psoriasis severity index could be observed from baseline to week 50. Improvement of nail psoriasis continued between weeks 10 and 24 and was generally maintained at week 50 (improvement of nail psoriasis severity index score: week 10, 26.0 (42.3%); week 24, 56.3 (43.4%); week 50, 56.3 (52.0%); vs placebo: week 10, −5.9 (54.3%); week 24, −3.2 (62.3%), week 50, n. a.). Because nail growth is quite slow, the delayed response of nail signs in comparison with skin response is explicable.

The good results of biologic agents on nail psoriasis are confirmed by alefacept and etanercept69, 70, 71 in addition to experience from clinical practice (Fig. 3A and B). Despite these patients' perspective, impressive improvement rates on nail psoriasis by biologic or conventional systemic agents, the main pivotal question in psoriasis therapy, is the clear-cut indication for treatment with systemics because of isolated nail psoriasis. In any case, this decision has to be an individualized one. On balance, treatment of nail psoriasis still remains a challenge for dermatologists.

A subset of patients with psoriasis exhibit intertriginous involvement (syn inverse psoriasis or flexural psoriasis). By contrast to scalp psoriasis, involvement of intertriginous areas is only estimated at 2% to 6% of patients with psoriasis.4 The psoriasis manifestation occurs in the armpits, groin, under the breasts, and in skin folds around the genitals and buttocks, including retroauricular folds. In view of the clinical presentations, inverse psoriasis appears as smooth, mostly very inflamed skin areas, typically with less or no scaling than seen in scalp or plaque psoriasis on the body (Fig. 4). The lesions are well demarked. Therefore, mycotic infections should be excluded. Sometimes, patients with psoriasis inversa exhibit a high comorbidity with conditions such as obesity, diabetes, and/or hypertension. Patients with intertriginous psoriasis often complain about intense itching, irritation from sweating, and soreness, with emotional consequences. Because infections can be a trigger and an aggravating factor in psoriasis, antifungal or antibacterial agents are commonly used for treating intertriginous psoriasis. Results from pilot studies investigating microorganisms, however, reveal that Candida seems not to play an important role in intertriginous psoriasis,72 whereas bacterial pathogens were found in body folds and rectal psoriasis.9

In line with this, a decreased quantity of lesional CD161+ cells in the dermis of flexural psoriasis, which could be caused by chronic microbial challenge, has been found.73 Moreover, a common problem seen with inverse psoriasis is irritation from rubbing or sweating. Thus, compared with common psoriasis, the intertriginous psoriasis has unique characteristics in terms of the frequency, affected areas, and clinical symptoms.

Regarding the treatment modalities of intertriginous psoriasis, a special issue has to be considered:

Most patients in a high degree are showing a permanent direct skin-to-skin contact of involved intertriginous areas. From a pharmacologic point of view, the situation is comparable with skin occlusion technique resulting in alteration of numerous skin functions including skin physiology.74 For treatment, conversely, an enhanced hydration and an increased percutaneous absorption of drugs should be noted. It is well known, for example, that skin occlusion enhances percutaneous absorption of compounds such as steroids, phenols, or alcohols.17 Thus, the general requirements for treatment strategies or corresponding formulations in intertriginous areas should be as follows: odorless, tasteless, cosmetically accepted, chemically and physically stable, not provoking irritation, and having no systemic absorption. Looking at these demands, tar preparations, anthralin, and tazarotene do not offer first-line therapy in patients with flexural psoriasis because of their irritation-inducing potential.

A review of past and current literature about treatment modalities in intertriginous psoriasis clearly exhibits the usefulness of 3 classes of topical compounds:75

  • corticosteroids (with some restrictions),

  • vitamin D3 and vitamin D3 analogues, and

  • calcineurin inhibitors (tacrolimus, pimecrolimus).

In general, intertriginous psoriasis may be seen as a corticosteroid-sensitive entity. Clinical experience reveals, in most cases, a rapid onset of action due to the increased percutaneous absorption as a result of the occlusionlike effect. Class IV to VI corticosteroids are the most suitable choice for initial treatment of intertriginous areas, whereas lower-potency corticosteroids are indicated in the maintenance treatment phase. The duration of maintenance treatment should not exceed 4 weeks, when used once daily. How long a treatment period can be carried out safely has never been clearly established in inverse psoriasis, however. For benefit/risk ratio of treatment with topical corticosteroids, exact guidelines for administration modalities are weak. Recommendations mostly are based on clinical experience.

A pilot study using fluticasone propionate ointment 0.005% in 20 patients with psoriasis of the face and intertriginous psoriasis revealed good response. Patients were treated once daily for 2 weeks, then once daily for 2 consecutive days every week for 8 more weeks.76 As result, intertriginous and facial sites responded more quickly to topical fluticasone propionate ointment than nonintertriginous or nonfacial skin. More than 50% improvement occurred after 2 weeks in 100% of lesions and was maintained during the following 8 weeks' treatment phase. More recently, in a double-blind randomized controlled study, the efficacy and the safety of 3 active compounds (0.1% betamethasone valerate, 0.005% calcipotriol, 1% pimecrolimus) and vehicle were investigated in a total of 80 patients with intertriginous psoriasis.77 During the active treatment phase of 4 weeks, the study medication was applied once daily with a 6-week follow-up without active therapy. From baseline to the end of treatment (day 28), the modified PASI decreased by 86.4% for betamethasone valerate, 62.4% for calcipotriol, 39.7% for pimecrolimus, and 21.1% for vehicle control. This trial confirmed the high efficacy of a topical corticosteroid but gives no answer about the potential of adverse effects in long-term treatment. Today, no exact data are available on safety of topical corticosteroid therapy in intertriginous psoriasis for more than 4 to 10 weeks. For patients, therefore, a limited application of topical steroids or a combination with calcipotriol is recommended.

Vitamin D3 and congeners such as calcipotriol are effective in treating chronic plaque psoriasis.39 Experience in the therapy of intertriginous areas is not well established in the literature, however. So far, only a few pilot studies have been reported to examine the effectiveness of calcipotriol in intertriginous psoriasis.78, 79, 80, 81 Despite the ability to induce skin irritation, however, calcipotriol generally was well tolerated in these studies and effective in a treatment period of 6 weeks for intertriginous psoriasis. Ortonne and coworkers82 investigated the efficacy and safety of calcitriol compared with calcipotriol in a multicenter, randomized trial with 75 patients with chronic stable psoriasis localized in facial, hairline, retroauricular, or flexural areas. After a treatment period of 6 weeks, both compounds led to clearing of at least 1 target lesion in 21 subjects (28%); perilesional erythema, edema, and stinging/burning were all significantly less severe with calcitriol than with calcipotriol. Thus, calcitriol ointment was found to be better tolerated and would appear to be more effective than calcipotriol in sensitive skin areas.82 As in the trial, patients were treated additionally in localizations other then flexural psoriasis, and the mentioned conclusions have to be interpreted with caution. Nevertheless, calcitriol and vitamin D3 analogues are able to treat intertriginous areas of patients with psoriasis.83, 84

Corresponding head-to-head trials comparing the formulations of the active form of vitamin D3 (calcitriol), tacalcitol, and calcipotriol in intertriginous psoriasis remain to be initiated in future. Possibly, a combination consisting of initial treatment with topical corticosteroids and maintenance treatment with calcipotriol or other vitamin D3 congeners will result an optimum of efficacy and low risk of unwanted side effects.

In addition to these 3 drug-based treatment options for intertriginous psoriasis in clinical practice, there are a few patients in whom these drugs are inadequately effective, poorly tolerated, produce toxicity, or in whom they are contraindicated; narrow-band UV-B therapy is possible.85 Phototherapy, although effective, presents a major logistic problem for many patients.

Calcineurin inhibitors approved for treatment of atopic dermatitis selectively block T lymphocytes and cytokine production. They do not alter collagen synthesis, however, and therefore exhibit no skin atrophy.86 In the last years, numerous reports have been published about the efficacy of topical tacrolimus in chronic plaque psoriasis.87, 88, 89, 90, 91, 92 Because of its mechanism of action, calcineurin inhibitors are an interesting treatment option for sensitive skin areas such as in intertriginous psoriasis. In Table 2, the most important data of clinical trials using calcineurin inhibitors in intertriginous psoriasis are summarized:

As a conclusion of the results of these trials, calcineurin inhibitors may be seen as a promising treatment option in intertriginous psoriasis. Some limitations for generalization, however, are the small number of patients, the short duration of the active treatment phase, and partially, the lack of separate calculation of treatment response between facial and intertriginous areas. Further investigations therefore have to confirm the efficacy and safety of both calcineurin inhibitors especially in a long-term treatment schedule in patients with intertriginous psoriasis.

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