Blockade of the IL-17 signaling pathway increased susceptibility of psoriasis patients to superficial fungal infections

Blockade of the TNF-α or IL-23/IL-17 signaling pathway by biologics is highly effective against the cutaneous and joint symptoms of psoriasis; however, immunosuppression induced by these agents can lead to bacterial and fungal infections [ [1] Vallabhaneni S. Chiller T.M. Fungal infections and new biologic therapies. Curr. Rheumatol. Rep. 2016; 18: 29 Crossref PubMed Scopus (51) Google Scholar , [2] Saunte D.M. Mrowietz U. Puig L. et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br. J. Dermatol. 2017; 177: 47-62 Crossref PubMed Scopus (137) Google Scholar ]. We aimed herein to analyze the risk factors of superficial fungal infection associated with biologic use in patients with severe psoriasis. The present research was a retrospective, single-centre chart review enrolling 224 patients with psoriasis receiving biologics between January 2015 and March 2019 (Table 1). This study was approved by the ethics committee of Tokyo Medical University (permission no. 2017‐329). Superficial fungal infections in these patients were excluded by dermatological inspection at the time of their psoriasis diagnosis. Fungal infections were diagnosed clinically and confirmed by direct microscopy (KOH preparation). A culture using Sabouraud's dextrose agar was performed for some of the cases. Twenty-eight (12.5 %) patients showed a superficial fungal infection, including 19 cases of dermatophytosis, such as tinea pedis and onychomycosis, nine cases of mucocutaneous candidiasis, and three cases of pityriasis versicolor. The number of infections exceeded the number of patients due to the presence of both dermatophytosis and candidiasis in three patients. The average age of the infected group was higher than that of uninfected group (p = 0.021; Mann-Whitney U test). There was no difference in the gender ratio between the infected and uninfected groups. The risk of fungal infection was not influenced by the clinical manifestations of psoriasis or the PASI score (Table 1). The mean treatment duration with biologics was 118.7 months and 125.1 months in the infected and uninfected groups, respectively. The difference in treatment duration between the groups was not statistically significant. The average number of biologics prescribed for the infected and uninfected groups was 1.5 and 1.3, respectively. Anti-TNF-α agents, including infliximab and adalimumab, were prescribed for seven of 28 patients in the infected group and eighty of 196 patients in the uninfected group. Ustekinumab, a humanized monoclonal antibody against the p40 subunit of IL-12 and IL-23, was given to four of 28 infected patients and 49 of 196 uninfected patients. The prescription rate for anti-TNF-α and anti-p40 in the two groups did not differ significantly. In contrast, seventeen of 28 patients in the infected group and 67 of 196 patients in the uninfected group received IL-17 signal blocking agents. The proportion of patients treated with IL-17 or IL-17 receptor antibody was significantly higher among the infected patients than the uninfected patients (p = 0.011; Fisher’s exact test). The types of fungal infection were demonstrated below each psoriasis types. Several patients had dual fungal infection. The therapies before biologics treatment included ciclosporin, etretinate, MTX, and systemic steroid. Ciclosporin and systemic steroid were tapered, then stopped after the treatment with biologics was begun. In some patients, administration of etretinate and MTX continued during treatment with biologics. However, the previous treatments described above did not raise the risk of superficial fungal infection (Table 1). Most of the fungal infected cases were treated with topical antifungals, with the exception of administration of terbinafine tablets for a case of onychomycosis, miconazole gel for a case of oral candidiasis and itraconazole solution for two cases of oral and esophageal candidiasis. The present retrospective study demonstrated that the inhibition of IL-17 signaling by biologics enhanced the risk of superficial fungal infection in patients with psoriasis. Several reports have shown an increased risk of systemic infections, such as pneumocystis pneumonia, aspergillus pneumonia, and tuberculosis, in patients with psoriasis receiving a TNF-α inhibitor [ [3] Tragiannidis A. Kyriakidis I. Zündorf I. et al. Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors. Mycoses. 2017; 60: 222-229 Crossref PubMed Scopus (20) Google Scholar ]. In contrast, the present study demonstrated that the blockade of TNF-α or IL-23/IL-12 signaling in patients with psoriasis did not induce dermatophytosis or candidiasis. These findings might indicate that the inflammatory activation signal for the host defense against fungi differs by the site of the lesion, i.e., TNF-α is a crucial cytokine against visceral fungal infections while IL-17 signaling is essential for preventing superficial fungal infections. IL-17- or IL-17 receptor-deficient mice are susceptible to candidiasis [ [4] Saijo S. Ikeda S. Yamabe K. et al. Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity. 2010; 32: 681-691 Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar ]. Moreover, previous studies reported that chronic mucocutaneous candidiasis was associated with genetic mutations resulting in IL-17 signal transduction molecules [ [5] Puel A. Cypowyj S. Bustamante J. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011; 332: 65-68 Crossref PubMed Scopus (720) Google Scholar ]. These findings indicate that the IL-17 signaling pathway plays a crucial role in the immune response against candidiasis [ [6] Conti H.R. Gaffen S.L. IL-17-Mediated immunity to the opportunistic fungal pathogen Candida albicans. J. Immunol. 2015; 195: 780-788 Crossref PubMed Scopus (150) Google Scholar ]. In contrast, the function of IL-17 in the host defense against dermatophytes is still not understood [ [7] Heinen M.P. Cambier L. Fievez L. et al. Are Th17 cells playing a role in immunity to dermatophytosis?. Mycopathologia. 2017; 182: 251-261 Crossref PubMed Scopus (17) Google Scholar ]. The present study demonstrated that IL-17 signaling may also have a role in inhibiting dermatophyte infections. The average age was higher in the infected group than in the uninfected group. The incidence of dermatophytosis increases with aging [ [8] Gupta A.K. Daigle D. Foley K.A. The prevalence of culture-confirmed toenail onychomycosis in at-risk patient populations. J. Eur. Acad. Dermatol. Venereol. 2015; 29: 1039-1044 Crossref PubMed Scopus (49) Google Scholar ]. Thus, aging might contribute to the onset of superficial fungal infections in patients with psoriasis receiving biologics. Although we have investigated the risk factors of fungal infection in patients with psoriasis, the number of cases analyzed in this study was relatively small. Further investigation is needed to clarify the risk factors of fungal infection in similar patients. Table 1Characteristics of psoriatic patients treated by biologics associated with superficial fungal infection. Infected group Uninfected group Characteristics n = 28 n = 196 p a Fisher’s exact test for categorical and Mann-Whitney U test for continuous variables. Age (years), mean ± SD 53.5 ± 12.6 47.9 ± 14.0 0.021 * Statistically significant. Gender 0.493 Male 19 (67.9) 146 (74.5) PASI score, mean ± SD 10.0 ± 6.8 11.6 ± 10.5 0.878 Disease type 0.455 Psoriasis vulgaris 18 (64.3) 100 (51.0) TP/TC 13, TU 2, Can 5, TV 2 Pustular psoriasis 4 (14.3) 32 (16.3) TP/TC 3, TU 1, Can 1 Psoriatic arthritis 6 (21.4) 64 (32.7) TP/TC 4, Can 2 Treatment Duration of treatment with biologics (weeks), mean ± SD 118.7 ± 91.8 125.1 ± 127.8 0.345 No. of biologics received, mean ± SD 1.5 ± 0.6 1.3 ± 0.7 0.078 Biologics Anti TNF-α antibody 0.146 Recieved 7 (25.0) 80 (40.8) Anti p40 antibody 0.245 Recieved 4 (14.3) 49 (25.0) Anti IL-17 antibody or anti IL-17 receptor antibody 0.011* Recieved 17 (60.7) 67 (34.2) Previous therapy Ciclosporin 0.614 Recieved 4 (14.3) 41 (20.9) Etretinate 1.000 Recieved 5 (17.9) 38 (19.4) Methotrexate 0.492 Recieved 4 (14.3) 18 (9.2) Systemic steroid 1.000 Recieved 0 (0.0) 3 (1.5) Data are n (%) unless otherwise specified. TP/TC, tinea pedis or tinea corporis; TU, tinea unguium; Can, Candidiasis; TV, tinea versicolor. a Fisher’s exact test for categorical and Mann-Whitney U test for continuous variables. * Statistically significant. Open table in a new tab Data are n (%) unless otherwise specified. TP/TC, tinea pedis or tinea corporis; TU, tinea unguium; Can, Candidiasis; TV, tinea versicolor.