Genital and Inverse/Intertriginous Psoriasis: An Updated Review of Therapies and Recommendations for Practical Management

The current first-line recommendation for the short-term treatment of mild-to-moderate genital (grade of recommendation: B) and inverse psoriasis (grade of recommendation: C) is low- to mid-potency topical corticosteroids [10]. Fluticasone propionate 0.005%, a mid-strength topical steroid, used twice daily for 2 weeks has shown more than 50% improvement in facial and intertriginous psoriatic lesions [11]. These results were maintained for 8 more weeks with once-daily application for 2 consecutive days every week, suggesting gradual taper can help with long-term (> 4 weeks) management. The risk of side effects may be reduced with the use of low-potency steroids. They may also be used in conjunction with other topical therapies to enhance efficacy [10‐12].

Because the skin in the genital region is thin, there is an increased amount of percutaneous absorption [13, 14]. Also, due to the occlusive nature in the intertriginous areas, steroids have increased penetration and therefore are recommended for short-term therapy [15]. The recommended maximum duration of treatment is 4 weeks, which is set to reduce the risk of developing well-known side effects, including atrophy, telangiectasia, and striae.

While low- to mid-potency topical corticosteroids are generally more accepted to treat sensitive skin areas, such as the genital and intertriginous regions, topical corticosteroids with greater strength in shorter intervals may be needed to treat resistant or moderate-to-severe disease. A randomized clinical trial showed that 0.1% betamethasone valerate once daily for 28 days resulted in significant decrease in the Mean Psoriasis Area and Severity Index (M-PASI) score (86.4%) compared with 0.005% calcipotriol (62.4%) and 1% pimecrolimus (39.7%). [16] The study also reported a decrease in pruritus by 78% with 0.1% betamethasone compared with 57% for 0.005% calcipotriol and 35% for 1% pimecrolimus. Few studies have shown that mid- to high-potency corticosteroid therapy may be more effective and produce fewer side effects compared with other nonsteroid topical treatments [11, 17, 18].

Topical calcineurin inhibitors (TCI), such as tacrolimus and pimecrolimus, are alternative options for long-term topical therapy and are associated with milder and more manageable long-term side effects, such as skin atrophy (grade of recommendation: B). TCI blocks T-lymphocyte activation and formation of lymphokines, such as interleukin-2 and gamma interferon, by preventing the dephosphorylation and translocation of nuclear factor of activated T cells (NF-AT). [19] It is important to note that, because TCI does not affect collagen synthesis, there is a significantly lower risk of skin atrophy and related side effects compared with topical corticosteroids. [20] However, there is a risk of mild pruritus and local burning in the sensitive groin region.

TCI is indicated as second-line therapy for short-term chronic treatment of atopic dermatitis and is considered off-label for the treatment of psoriasis. However, the use of TCI for the treatment of inverse psoriasis has been supported by many studies, one of which demonstrated that applying tacrolimus ointment 0.1% twice daily achieved clearance or significant improvement after as early as 8 days of treatment [21]. After 8 weeks, the tacrolimus group showed greater improvement of Physician Global Assessment (PGA) (65.2%) compared with the placebo group (31.5%). Similarly, in another randomized clinical trial, 71% of patients who received pimecrolimus cream 1% twice daily for 8 weeks had an IGA score of 0 or 1, compared with 21% of patients who received placebo [22]. These differences could be seen as early as week 2 (54% versus 21%). In both studies, the adverse events were similar between the groups.

Topical vitamin D analogs, such as calcipotriol and calcitriol, are another long-term therapy recommended for genital and inverse psoriasis (grade of recommendation: C). Generally, studies have shown that topical calcipotriol and calcitriol are safe, but are less effective compared with topical corticosteroids or TCI. [23] One randomized head-to-head comparison between 3 μg/g calcitriol ointment and 50 μg/g calcipotriol ointment twice daily application found that calcitriol is better tolerated and more effective in the treatment of inverse psoriasis, with greater improvement of IGA (67% versus 33%). [24] The efficacy and safety of topical vitamin D analogs have been demonstrated in patients treated for 8 weeks. One head-to-head study showed that tacrolimus 0.3 mg/g is more effective compared with calcitriol 3 μg/g. [25] Topical vitamin D analogs are associated with more severe cutaneous irritation compared with TCI. [23, 26, 27].

Current evidence from clinical studies has shown that phosphodiesterase (PDE)-4 inhibitor is a safe and effective alternative to topical corticosteroids and TCI in both mild-to-moderate atopic dermatitis and psoriasis (grade of recommendation: C). [28‐31] More recently, the use of crisaborole, a topical PDE-4 inhibitor, was found to be well tolerated and effective in treating genital and inverse psoriasis. [32] A randomized, double-blinded, placebo-controlled trial showed that treatment with crisaborole 2% ointment (n = 14) twice daily for 4 weeks demonstrated 66% improvement compared with the 9% improvement with the placebo ointment (n = 7), measured by the Target Lesion Severity Scale (TLSS) [32]. After 8 weeks, patients in the crisaborole group continued to show improvement up to 81% lesional improvement and 71% lesional clearance. This study did not report any adverse event.

Roflumilast, another topical PDE-4 inhibitor, was studied in a phase IIb trial over a period of 12 weeks for the treatment of inverse psoriasis [33]. Psoriatic patients with intertriginous involvement were randomly assigned to receive roflumilast 0.3% cream (n = 16), roflumilast 0.15% cream (n = 18), or placebo (n = 17). At week 6, 73%, 44%, and 29% patients achieved Investigator Global Assessment (IGA) score indicating clear or almost clear and a two-grade improvement in the intertriginous-area IGA score in the roflumilast 0.3% group, roflumilast 0.15% group, and placebo group, respectively. At week 12, 93% had an intertriginous-area IGA score of 0 in roflumilast 0.3% group, compared with 18% in the placebo group.

Emollients and topical coal tar preparations have shown significant efficacy in both adults and children with genital lesions without causing significant adverse events. Currently, the mechanism of action of coal tar is unclear and still under investigation. It is proposed that coal tar can suppress keratinocyte proliferation and differentiation in psoriatic lesions and may also have an antiinflammatory role [34]. Coal tar 2% and topical salicylate preparations twice daily to the affected area showed significant improvement at week 8 for one patient, with some residual postinflammatory hyperpigmentation [35]. This formulation provides a favorable alternative to crude coal tar, coal tar ointment, and coal tar solution because it is easy to spread, dries relatively quickly, and can be obtained without a prescription. While there are not many clinical trials that have investigated the efficacy and safety of tar prep in genital and inverse psoriasis specifically, the National Psoriasis Foundation (NPF) recommends topical coal tar preparations as second-line therapy in the treatment of inverse psoriasis, either alone or in combination with topical steroids (grade of recommendation: B) [36].

Topical antiseptic treatments, such as chlorhexidine and chloroxylenol, have been used previously in the treatment of inverse psoriasis flares to prevent bacterial and fungal colonization in these areas (grade of recommendation: D). [17, 37, 38] While antifungal therapies may help with intertrigo, a differential diagnosis of inverse psoriasis, it has not been strongly suggested to alleviate clinical symptoms of inverse psoriasis.

Currently, there are no large clinical trials that evaluate the efficacy and safety of oral systemic therapies for genital and inverse psoriasis. There are two reports on methotrexate (grade of recommendation: C) and one case report on mycophenolate mofetil [13]. Methotrexate was associated with several side effects including headache, insomnia, urinary tract infections, and gastrointestinal symptoms [13]. Thus, the use of methotrexate should be limited to patients with debilitating quality-of-life impairment [23].

Tofacitinib, a Janus kinase (JAK) 1/3 inhibitor used in rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, has been used successfully to treat a patient who had a combination of inverse psoriasis, alopecia areata, and vitiligo [40]. The patient was treated with 5 mg twice daily with narrowband ultraviolet-B (NB-UVB) phototherapy three times per week. This combination therapy has been supported by studies that demonstrated that JAK inhibitors may be more effective when used with phototherapy [41, 42]. Adverse events reported were few episodes of headache and flu-like symptoms, which led the patient to self-discontinue tofacitinib after 1 month only.

There are also reports on the use of oral antifungals [18, 20], oral antibiotics [43], dapsone [44, 45], pramoxine [46], doxepin [47], antihistamines [12], and antipsychotics [48] for the treatment of genital and inverse psoriasis. However, the benefits have not been studied extensively.

Currently, there is a phase III randomized clinical trial (DISCREET) that is evaluating the efficacy and safety of apremilast, an oral PDE-4 inhibitor, in patients with moderate-to-severe genital psoriasis (NCT03777436). Patients receive either apremilast 30 mg or placebo twice daily for 16 weeks.

Currently, ixekizumab, a high-affinity monoclonal antibody targeting interleukin (IL)-17A, is the only drug that contains data on genital psoriasis in its Food and Drug Administration (FDA) label (grade of recommendation: B) [49]. Several papers have demonstrated significant improvement in genital lesion appearance, itch, sexual health, and quality of life in resistant genital psoriasis treated with ixekizumab. [49‐52] A randomized, placebo-controlled, phase III clinical trial demonstrated the long-term efficacy and safety of ixekizumab for up to 52 weeks [51]. Patients received either ixekizumab 80 mg (n = 75) or placebo (n = 74) every 2 weeks up to week 12, then entered an open-label period where all patients received ixekizumab 80 mg every 4 weeks up to week 52. In total, 73% of patients in the initial treatment arm were reported to achieve clear or almost clear genital skin (sPGA-G 0/1) by the end of week 12, and 75% by the end of week 52. Similarly, 79% of patients who were in the initial placebo group also achieved sPGA-G0/1 at the end of week 52, showing rapid improvement. The number and severity of adverse events remained the same as previous studies of ixekizumab in patients with moderate-to-severe plaque psoriasis. The dosing recommendation of ixekizumab for the treatment of psoriasis is 160 mg subcutaneously at week 0, 80 mg every 2 weeks up to week 12, and finally 80 mg every 4 weeks. For plaque psoriasis or genital psoriasis with minimal disease severity, dosing recommendation is 80 mg subcutaneously every 2 weeks [53].

There are two other biologic therapies that have been reported in the literature, one case report for each, for the treatment of inverse psoriasis [54, 55]. There is a single case report of successful treatment of inverse psoriasis with adalimumab, a fully humanized monoclonal antibody against TNF-alpha [54]. The patient was treated with 40 mg every 14 days for 90 days, and experienced complete regression of psoriatic lesions and psoriatic arthritis. In another case report of recalcitrant psoriasis, a patient was treated with ustekinumab, an IL-12/23 inhibitor, 45 mg every 4 weeks for the first 4 weeks, then 45 mg every 12 weeks [55]. After the first injection, the patient had an adverse event of external otitis with tympanic perforation that interrupted the treatment. The patient was restarted on ustekinumab 3 months later and completed three injections that resulted in significant improvements of pruritus, erythema, and quality of life.

Currently, there is one actively recruiting clinical trial studying the effectiveness of guselkumab in moderate facial and genital psoriasis (GULLIVER study) (NCT04439526).