What s already known about this topic? What does this study add?

Transcription

1 REVIEW ARTICLE BJD British Journal of Dermatology Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management* D.M. Saunte, 1 U. Mrowietz, 2 L. Puig 3 and C. Zachariae 4 1 Department of Dermatology, Zealand University Hospital, Roskilde, Denmark 2 Psoriasis Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany 3 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain 4 Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Linked Comment: Hay. Br J Dermatol 2017; 177:10 11 Summary Correspondence Ditte M. Saunte. disa@regionsjaelland.dk Accepted for publication 22 August 2016 Funding sources None. Conflicts of interest See Appendix 1 *Plain language summary available online DOI /bjd The recognition of the central role of interleukin (IL)-17A in the pathogenesis of psoriasis has led to the development of several monoclonal antibodies targeting this cytokine or its receptors for therapeutic purposes. IL-17A also plays an important role in immunological protection against infections, especially those due to Candida spp., as evidenced by findings in patients with genetic defects in IL-17-related immune responses. To assess the potential of anti-il-17 treatment to promote Candida infections, here we have systematically reviewed published clinical trials of patients with psoriasis or psoriatic arthritis. Candida infections were reported in 40% of patients treated with brodalumab, 17% with secukinumab and 33% with ixekizumab vs. 03%, 23% and 08% of those assigned to placebo, ustekinumab or etanercept, respectively. Although the incidence of Candida infection was found to be increased by only a small degree during anti- IL-17 therapy, patients undergoing such treatment should be monitored for fungal infection and treated as necessary. We propose adoption of the recently updated recommendations for the practical management of Candida infection in patients administered IL-17 inhibitors. What s already known about this topic? Interleukin (IL)-17A is involved in the inflammation process found in psoriasis/ psoriatic arthritis; furthermore, it plays an important role in immunological protection against infections, especially Candida infections. Inhibition of IL-17A during treatment is therefore expected to increase the incidence of Candida infections in patients treated with IL-17A. What does this study add? A systematic review of published data to get an overview of the incidence of Candida infections during treatment with IL-17A inhibitors and a practical management guide. Secukinumab and ixekizumab have been recently approved in many countries for the treatment of moderate-to-severe plaque psoriasis, as well as for psoriatic arthritis (PsA) in a small number of other countries. 1 Both of these monoclonal antibodies bind specifically to and inhibit the activity of interleukin (IL)-17A, a cytokine normally involved in immune-mediated protection from extracellular microbes; however, it is also implicated in the pathogenesis of psoriasis and PsA. 2 Brodalumab, an IL-17 receptor A antagonist, is in late-phase clinical development British Association of Dermatologists British Journal of Dermatology (2017) 177, pp

2 48 Candida infections during IL-17 treatment and practical management, Saunte et al. IL-17A has an important role in innate and adaptive responses against infections at mucosal and cutaneous interfaces, as exemplified by the occurrence of chronic mucocutaneous candidiasis (CMC), which presents clinically as recurrent or persistent Candida albicans infection of mucosae, nails and skin in patients with genetic defects impairing IL-17-related immune responses. 3 Thus, in patients treated with IL-17A antagonists, an increase in the incidence of Candida infections can be expected. 2 Other systemic biological agents such as tumour necrosis factor (TNF)-a antagonists are also associated with a wide spectrum of infections, including mycobacterial infections, reactivation of hepatitis infection and fungal infections such as histoplasmosis, aspergillosis, coccidioidomycosis, pneumocystosis, cryptococcosis and blastomycosis. Most of them are rare and the dimorphic fungi (Histoplasma, Coccidioides and Blastomyces) are not endemic in Europe. 4,5 This work reviews data from clinical trials about the risk of candidiasis in IL-17-targeted therapies for psoriasis and PsA (secukinumab, ixekizumab and brodalumab). Furthermore, we also consider the clinical implications, diagnostic methods and treatment options. IL-17-mediated immunity is essential for the protection of skin and mucous membranes against C. albicans. There are six members of the IL-17 family of cytokines (IL-17A through IL- 17F) and five receptors (IL-17RA through IL-17RE). 3 In mice IL-17A and IL-17F recruit granulocytes and induce the secretion of antimicrobial peptides from epithelial cells thereby contributing to the eradication of pathogens. 3 In humans, CMC is found in patients with primary immunodeficiencies in the IL-17 axis, such as loss-of-function mutations in IL17RA, ACT1 and IL17F, and gain-of-function mutations in STAT1. 3 Therefore, it is expected that the clinical use of IL-17 inhibitors will result in an increase in the occurrence of Candida infections in patients. Candida is a commensal yeast and part of the normal microflora of the skin and mucosal surfaces. Candida albicans is considered to be the most prevalent Candida species, but epidemiological trends may differ between countries. 6 Candida can act as a trigger for intertriginous psoriasis. 7,8 Some patients are more susceptible to infections than others owing to treatment (e.g. with therapeutic immunosuppression or broad-spectrum antibiotics), genetic defects (e.g. in the IL-17 axis) or other diseases (e.g. diabetes, HIV infection). 6 In patients with CMC, Candida infections are often persistent, hyperkeratotic and deep-seated. CMC presents as plaques on oral, oesophageal or genital mucosa, or as a thickening of the skin and nails. 9 CMC is rarely associated with disseminated systemic disease. 9 Methods Selection of data sources A PubMed search using the terms Candida and IL-17, Candida and anti IL-17, Candida and brodalumab, brodalumab, ixekizumab, Candida and ixekizumab, Candida and British Journal of Dermatology (2017) 177, pp47 62 secukinumab, Candida and interleukin 17, secukinumab, psoriasis arthritis and ixekizumab, psoriasis and ixekizumab, psoriasis arthritis and brodalumab, psoriasis and brodalumab, psoriasis and secukinumab and psoriasis arthritis and secukinumab was used to identify studies with IL-17 inhibitors used to treat patients with psoriasis. Studies published until 19 June 2016 were included. Single-dose studies were excluded. One study by Thacßi et al. reported 12 cases of nonserious mucosal or cutaneous Candida infection, 10 but no information was provided that allowed us to determine the incidence of infection in patients given secukinumab vs. ustekinumab and it was therefore excluded. Subanalyses of studies were excluded in order to not include the same patients twice in the analysis Results Details on how the diagnosis Candida infection was made in the cited literature could not be retrieved because of missing information. Candida infections are reported as Suspected Candida infection: included all adverse events (AEs) consistent with candidiasis infection, 15 Candida infections: included all AEs consistent with Candida infection 16 or simply stated as Candida infection/candidiasis. Overall frequencies of Candida infections during IL-17 inhibitor treatment of psoriasis/psa and incidence of Candida infections in reference biological and placebo of the included IL-17 inhibitor studies are presented in Table 1. Incidence of Candida infection during secukinumab treatment Thirteen studies were identified as using secukinumab for the treatment of psoriasis/psa and reporting Candida infections as AEs (Table 2). Studies that had groups given different doses of secukinumab revealed that the frequency of Candida infection was higher when 300 mg and 150 mg (range 00 50%) doses were administered than when lower doses of 75 mg (10%) were used. Two double-blind, 52-week, phase III trials (ERASURE and FIXTURE) reported a higher frequency of Candida infection in patients treated with secukinumab (08 47%) compared with etanercept (12%) or placebo (0 04%) (Table 2). 1 Candida infections were the only dose-related AE. In another randomized controlled trial (RCT) (SCULPTURE) 843 patients were given 300 mg or 150 mg secukinumab. At week 12 patients achieving more than a 75% reduction in Psoriasis Area and Severity Index (PASI 75) score were randomized to continue receiving treatment with the same dose as needed (with relapse defined as a loss of 20% or more of maximum PASI score improvement and loss of PASI 75 response) or at fixed intervals (every 4 weeks) for 52 weeks. Candida infections were reported in 13 (15%) patients (Table 2). 17 At week 12, 43 partial responders (PASI improvement 50% and < 75%) in the SCULPTURE study entered a new study (STATURE). They were randomized to an 8-week 2016 British Association of Dermatologists

3 Candida infections during IL-17 treatment and practical management, Saunte et al. 49 Table 1 Overall frequencies of Candida infections during interleukin-17 inhibitor treatment of psoriasis/psoriatic arthritis and incidence of Candida infections in reference biological and placebo of the included IL-17 inhibitor studies a Treatment Total no. patients included Mild-to-moderate Candida infections Vulvovaginal/ genital Oral Skin Oesophageal Nail Severe Candida infections Overall Reference(s) Unknown infection site Total Secukinumab 4771 b 7(01) 15 (03) 2 (0) 2 (0) 0 (0) 56 (12) 1 (0) 83 (17) Langley et al., 1 Mrowietz et al., 17 Thacßi et al., 18 Paul et al., 19 Blauvelt et al., 20 Mease et al., 21 McInnes et al., 22 Rich et al., 23 van der Heijde et al., 24 Imafuku et al., 25 Kavanaugh et al., 26 McInnes et al. 27 Brodalumab (0) 7 (02) 0 (0) 1 (0) 0 (0) 169 (38) 0 (0) 177 (40) Papp et al., 15 Lebwohl et al., 16 Papp et al., 28 Nakagawa et al., 29 Papp et al., 30 Mease et al. 31 Ixekizumab (10) 63 (15) 20 (05) 2 (0) 1 (0) 9 (02) 0 (0) 135 (33) Leonardi et al., 32 Gordon et al., 34 Saeki et al., 35 Langley et al., 36 Griffiths et al., 45 Yamasaki et al. 46 Etanercept (04) 1 (01) 0 (0) 0 (0) 0 (0) 4 (04) 0 (0) 9 (08) Langley et al., 1 Saeki et al., 35 Griffiths et al. 45 Ustekinumab (0) 0 (0) 0 (0) 0 (0) 0 (0) 14 (23) 0 (0) 14 (23) Lebwohl et al. 16 Placebo (01) 2 (0) 1 (00) 0 (0) 0 (0) 1 (0) 0 (0) 7 (03) Langley et al., 1 Paul et al., 19 Blauvelt et al., 20 Mease et al., 21 McInnes et al., 22 Rich et al., 23 van der Heijde et al., 24 Kavanaugh et al., 26 McInnes et al., 27 Nakagawa et al., 29 Papp et al., 30 Mease et al., 31 Leonardi et al., 32 Gordon et al. 33 Data are n (%). a In studies with an introduction phase and a second treatment phase only cases reported during the longest observation period are included. b (from ERASURE/FIXTURE; see Table 2 where the placebo group were randomized to receive treatment or placebo from weeks 12 to 52) British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

4 50 Candida infections during IL-17 treatment and practical management, Saunte et al. Table 2 Incidence of Candida infections during interleukin (IL)-17 inhibitors treatment of patients with psoriasis and psoriatic arthritis Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Langley et al. 1 (ERASURE) Langley et al. 1 (FIXTURE) Phase III trial (738 included, one had protocol deviation) Phase III trial (1306) Psoriasis Two fixed secukinumab regimens; the placebo group was randomized to receive either secukinumab 300 mg or 150 mg or placebo at week 12 Psoriasis Full year examination of secukinumab vs. etanercept/placebo; the placebo group was randomized to receive either secukinumab 300 mg or 150 mg or placebo at week 12 (PASI 75 responders continued on placebo week 12) Weeks 0 12 Secukinumab 300 mg (245) NR Secukinumab 150 mg (245) NR Placebo (247) NR Weeks Secukinumab 300 mg (349) 20 (7) Oral or genital (not specified in detail) Mild or moderate (7) Secukinumab 150 mg ( (3) Oral or genital Mild or moderate (3) Introduction placebo, including 18 who 04 (1) Oral or genital Mild or moderate (1) continued to week 52 (247) Weeks 0 12 Secukinumab 300 mg (327) b NR Secukinumab 150 mg (327) NR Etanercept 50 mg (326) NR Placebo (326) NR Weeks Secukinumab 300 mg (467) b 47 (22) NR Mild or moderate (22) Secukinumab 150 mg (469) c 23 (11) NR Mild or moderate (11) Etanercept (323) 12 (4) NR Mild or moderate (2) Introduction placebo (week 0 12) and PASI 0 75 responders (327) d (continued) British Journal of Dermatology (2017) 177, pp British Association of Dermatologists

5 Candida infections during IL-17 treatment and practical management, Saunte et al. 51 Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Rich et al. 23 Phase II RCT induction phase (404); maintenance phase (379) Blauvelt et al. 20 (FEATURE) Paul et al. 19 (JUNCTURE) Thacßi et al. 18 (STATURE) Phase III trial (177) Phase III trial (220) Phase III trial partial responders from SCULPTURE (43) Psoriasis Secukinumab induction and maintenance Induction week 12 Maintenance week 44 Secukinumab 150 mg single dose (66) NR Secukinumab 150 mg early (weeks 0, 1, 2, NR 4) (133) Secukinumab 150 mg monthly (weeks 0, 4, NR 8) (138) Placebo (67) NR Secukinumab 150 mg weeks 12 and 24) NR (65) Secukinumab 150 mg when relapse (67) NR Secukinumab 150 mg monthly to week 32 NR (247) Mild or moderate (2) Psoriasis 12-week treatment 12 weeks Secukinumab 300 mg (59) 34 (2) Oral (1); vulvovaginal (1) Secukinumab 150 mg (59) 17 (1) Vulvovaginal (1) Placebo (59) 0 Mild or moderate (1) Psoriasis 12-week treatment 12 weeks Secukinumab 300 mg (60) 0 Secukinumab 150 mg (61) 16 (1) Vulvovaginal Mild or moderate (1) (1) Placebo (61) 16 (1) Oral (1) Mild or moderate (1) Psoriasis Induction weeks weeks Secukinumab 300 mg at baseline and week 4 (21) Maintenance period weeks 8 36 IV secukinumab 10 mg/kg, baseline, weeks 2 and 4 (22) Secukinumab 300 mg (40) 48 (1) Oral Mild or moderate (1) 0 (0) NR (continued) 2016 British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

6 52 Candida infections during IL-17 treatment and practical management, Saunte et al. Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Mrowietz et al. 17 (SCULPTURE) Mease et al. 21 Phase III trial FUTURE 1 study group (606) Kavanaugh RCT et al. 26 FUTURE 2 (397) McInnes Phase III trial et al. 22 (397) RCT Psoriasis Introduction weekly from baseline until week 4 and at week 8 Maintenance PASI 75 responders (843) PsA Induction phase 10 mg/ kg until week 4; week 8 16 placebocontrolled; week patients on placebo switched to 150 mg or 75 mg PsA Weeks 1, 2, 3 and 4, and then monthly PsA Once a week from baseline and from week 4 once per month Week 12 Secukinumab 300 mg (484) Secukinumab 150 mg (482) Week 52 Secukinumab 300 mg retreatment as needed (217) Secukinumab 300 mg fixed interval (216) Secukinumab 150 mg retreatment as needed (206) NR NR Maintenance 18 (4) Oral or genital Mild or moderate (4) 19 (4) Oral or genital Mild or moderate (4) 10 (2) Oral or genital Mild or moderate (2) Secukinumab 150 mg fixed interval (203) 15 (3) Oral or genital Mild or moderate (3) Week 52 At week 52 secukinumab 150 mg (295) 20 (6) Oral (4); oesophageal (1); skin (1) Severe oral (1); less than severe (5) At week 52 Secukinumab 75 mg (292) 14 (4) Oral (4) Less than severe (4) At week 16 placebo (202) 0 (0) Week 52 Secukinumab 300 mg (100) NR Secukinumab 150 mg (100) NR Secukinumab 75 mg (99) NR Placebo (98) NR Week 52 Secukinumab 300 mg (100) 50 (5) Oral (2); vulvovaginal (1); oesophageal (1); skin (1) Secukinumab 150 mg (100) 50 (5) Oral (2); vulvovaginal (2); concurrent oral and vulvovaginal (1) Mild or moderate (5) Mild or moderate (5) Secukinumab 75 mg (99) 10 (1) Oral (1) Mild or moderate (1) Placebo (98) 0 (0) (continued) British Journal of Dermatology (2017) 177, pp British Association of Dermatologists

7 Candida infections during IL-17 treatment and practical management, Saunte et al. 53 Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) McInnes Phase II RCT et al. 27 (42) Imafuku Phase III, open et al. 25 label (12) van der Phase III Heijde 24 double-blind RCT (606) Lebwohl Phase III trial et al. 16 AMAGINE-2 (1831) PsA Two IV doses 3 weeks apart Pustular psoriasis Weeks 0, 2, 3 and 4, and then monthly PsA Introduction secukinumab 10 mg/kg IV weeks 0, 2 and 4, and then monthly Week 6 Secukinumab 10 mg/kg IV (28) NR Placebo (14) NR Week 52 Secukinumab 150 mg (10) NR Nonresponders at week 16 secukinumab NR 300 mg (2) Week 52 Secukinumab 150 mg (202) NR Secukinumab 75 mg (202) NR Placebo (202) NR Psoriasis Induction phase 12 weeks Brodalumab 140 mg (607) 13 (8) NR Mild or moderate (8) until week 12 Brodalumab 210 mg (612) 16 (10) NR Mild or moderate (10) Ustekinumab (300) 07 (2) NR Mild or moderate (2) Placebo (309) 06 (2) NR Mild or moderate (2) Until week weeks Constant dose brodalumab 140 mg Q2W 48 (5) NR Mild or moderate (5) (104) Constant dose brodalumab 210 mg Q2W (486) 33 (16) NR Mild or moderate (16) Combination of brodalumab 140 mg Q2W/ 64 (27) NR Mild or moderate 210 mg Q2W (423) (27) Mixed dosing brodalumab (503) 42 (21) NR Mild or moderate (21) Brodalumab 210 mg Q2W after 39 (2) NR Mild or ustekinumab (51) moderate (2) Ustekinumab (300) 33 (10) NR Mild or moderate (10) (continued) 2016 British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

8 54 Candida infections during IL-17 treatment and practical management, Saunte et al. Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Lebwohl AMAGINE-3 Psoriasis Induction phase 12 weeks Brodalumab 140 mg Q2W (626) 05 (3) NR Mild or moderate (3) et al. 16 (1881) e Brodalumab 210 mg Q2W(622) 13 (8) NR Mild or moderate (8) Ustekinumab (313) 03 (1) NR Mild or moderate (1) Placebo (313) 03 (1) NR Mild or moderate (1) Weeks Week 52 Constant dose brodalumab 140 mg Q2W 18 (2) NR Mild or moderate (2) (113) Papp et al. 28 Phase II, OLE study (included 181, completed 144) Nakagawa Phase II RCT et al. 29 (151) Papp et al. 30 Phase II, randomized double-blind, placebocontrolled, dose-ranging study (198) Constant dose brodalumab 210 mg Q2W (489) Psoriasis Initial enrolment Week 12 Brodalumab 210 mg every 2 week (Q2W) (181) Amendment 2/3 Week 120 Weight < 100 kg: brodalumab 140 mg Q2W, when inadequate response increased to 210 mg again (119) Weight > 100 kg brodalumab 210 mg Q2W (62) Discontinued 204% (37) Psoriasis Weeks 1, 2, 4, 6, 8, and 10 Psoriasis Day 1, weeks 1, 2, 4, 6, 8 and (27) NR Mild or moderate (27) Combination of Brodalumab 140 mg Q2W/ 65 (28) NR Mild or moderate 210 mg Q2W (428) (28) Mixed dosing Brodalumab (515) 41 (21) NR Mild or moderate (21) Brodalumab 210 mg Q2W after 29 (2) NR Mild or moderate (2) ustekinumab (68) Ustekinumab (313) 13 (4) NR Mild or moderate (4) Overall 28% (5); oral candidiasis: mild or moderate (5) (it is not mentioned which patient group had candidiasis) Week 12 Brodalumab 70 mg (38) 0 (0) Brodalumab 140 mg (37) 0 (0) Brodalumab 210 mg (37) 27 (1) Oral Moderate (grade 2) candidiasis Placebo (38) 0 (0) Week 12 Brodalumab 70 mg (39) NR Brodalumab 140 mg (39) NR Brodalumab 210 mg (40) NR Brodalumab 280 mg (42) NR Placebo (38) NR (continued) British Journal of Dermatology (2017) 177, pp British Association of Dermatologists

9 Candida infections during IL-17 treatment and practical management, Saunte et al. 55 Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Mease et al. 31 Phase II RCT followed by open phase (168) Papp et al. 15 Phase III RCT (661) Yamasaki Phase III study et al. 46 (30) Leonardi Phase II doubleblind, et al. 32 RCT (142) Gordon et al. 34 Open-label extension (120) Saeki et al. 35 Open-label (91) PsA Phase II RCT day 1, weeks 1, 2, 4, 6, 8 and 10 (week 12) followed by an open phase (weeks 12 52) Psoriasis Introduction phase to week 12 Open phase (weeks 12 52) Psoriasis Open label day 1, weeks 1 and 2, and then monthly; psoriasis type: erythrodermic (18); generalized pustular (12) Psoriasis Weeks 0, 2, 4, 8, 12 and 16 Psoriasis Minimum 52 weeks if treatment Psoriasis Psoriasis type: plaque (78); erythrodermic (8); generalized pustular (5) Week 12 Brodalumab 140 mg (57) NR Brodalumab 280 mg (56) NR Placebo (55) NR Week 52 Brodalumab 140 mg Q2W (57) NR Week 12 Brodalumab 140 mg Q2W (219) 05 (1) NA Mild or moderate Brodalumab 210 mg Q2W (222) 23 (5) NA Mild or moderate Placebo (220) 14 (3) NA Mild or moderate Week 52 Mixed dosing Brodalumab (143) 21 (3) NA Mild or moderate Combination 30 (3) NA Mild or moderate brodalumab 140 mg Q2W/210 mg Q2W (99) Brodalumab 140 mg 16 (1) NA Mild or moderate Q2W (61) Brodalumab 210 mg 32 (11) NA Mild or moderate Q2W (345) Week 52 Brodalumab 140 mg (30) 67 (2) Oesophageal Moderate (1); oral (1) Week 20 Ixekizumab 10 mg (28) NS Ixekizumab 25 mg (30) NS Ixekizumab 75 mg (29) NS Ixekizumab 150 mg (28) NS Placebo (26) NS Week 52 Ixekizumab 120 mg monthly (120) NR Week 12 Ixekizumab 160 mg (week 0), thereafter 80 mg Q2W to week 12; week monthly NR (continued) 2016 British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

10 56 Candida infections during IL-17 treatment and practical management, Saunte et al. Table 2 (continued) Reference (study name) Study type (no. of patients) Disease Study description Follow-up period Treatment regimen (no. of patients) % Candida infections (no. of patients) Candida Disease severity infections a (no. of patients) Langley et al. 36 Phase II trial RCT (142) followed by OLE Gordon et al. 33 (UNCOVER- 1/2/3) Phase III trial RCT (3866) Psoriasis Initiation administration weeks 0, 2, 4, 6, 12 and 16 Week 20 Ixekizumab 10 mg (13) NR Ixekizumab 25 mg (10) NR Ixekizumab 75 mg (10) NR Ixekizumab 150 mg (10) NR Placebo (15) NR OLE Week 48 PBO-IXE (12) NR IXE-IXE (39) NR Mild or moderate Psoriasis Induction phase week 0 12: placebo vs. ixekizumab 80 mg Q2W/monthly (vs. etanercept in UNCOVER 2 and 3) UNCOVER-1/2/3 maintenance phase week 60: b either ixekizumab 80 mg every 4 or 12 weeks Week 12 Etanercept twice weekly (739) 07 (5) Genital/ vulvovaginal (4); oral (1) Week 60 Patients with ixekizumab exposure (3736) 36 (135) Oral (63); genital/ vulvovaginal (40); skin/ intertrigo (20); oesophageal (2); nail (1); unspecified (9) Week 60 Placebo (791) 05 (4) Genital/ vulvovaginal (3); skin (1) Mild or moderate Mild or moderate NR, not reported; RCT, randomized controlled trial; IV, intravenous; PASI 75, 75% reduction in Psoriasis Area and Severity Index; PsA, psoriatic arthritis; Q2W, every second week; OLE, open-label extension; NA, not applicable; NS, not specified; PBO-IXE, RCT placebo OLE ixekizumab; IXE-IXE, RCT ixekizumab OLE ixekizumab. a Oral (includes terms oral candidiasis and oral fungal infection) and genital/vulvovaginal (includes terms genital candidiasis, vulvovaginal candidiasis and vulvovaginal mycosis). b In the paper (Table 4), the number of patients on any secukinumab 300 mg was 467 (22/467; 47%). c In the paper (Table 4) the number of patients on any secukinumab 150 mg was 469 (11/469; 23%). d As placebo includes the placebos from the introduction phase and PASI 75 responders, the total numbers of patients are higher than the 1306 included. e Different numbers in the paper compared with the supplementary appendix. British Journal of Dermatology (2017) 177, pp British Association of Dermatologists

11 Candida infections during IL-17 treatment and practical management, Saunte et al. 57 treatment of secukinumab 300 mg or secukinumab 10 mg per kg intravenously. This was followed by a maintenance period from week 8 to week 36 with secukinumab 300 mg (n = 40). 18 Only one patient treated with secukinumab 300 mg had oral candidiasis (48%) in the introduction period. In a 12-week, phase III RCT (JUNCTURE) comparing autoinjector and pen administration of secukinumab 300 mg, secukinumab 150 mg or placebo for the treatment of patients with moderate-to-severe psoriasis, vulvovaginal candidiasis was reported in one (16%) patient in the 150-mg group and oral candidiasis in one patient (16%) in the placebo group. 19 Blauvelt et al. randomized 177 patients to secukinumab 300 mg, 150 mg or placebo (FEATURE study). 20 Treatment was administered once weekly until week 4 and again at week 8. At week 12 two patients (34%) in the secukinumab 300 mg group and one patient (17%) in the secukinumab 150 mg group were diagnosed with Candida infection (Table 2). In a phase III study, 606 patients with PsA were randomized to receive intravenous secukinumab 10 mg per kg at weeks 0, 2 and 4 followed by subcutaneous injections of either 150 mg, 75 mg or placebo every 4 weeks. 21 At weeks 16 24, patients from the placebo group were switched to subcutaneous 150 mg or 75 mg depending on the clinical response. Candidiasis was reported in 10 patients receiving secukinumab (17%). In another phase III RCT (FUTURE 2), 397 patients with PsA were randomly assigned to receive either secukinumab 300 mg (n = 100), 150 mg (n = 100), 75 mg (n = 99) or placebo (n = 98) once a week from week 0 and then monthly from week Candida infections were detected in 11 patients (37%) (Table 2), all of whom were on secukinumab. All of the reported Candida infections were mild or moderate in severity, localized and self-resolved, or were responsive to standard therapy (Table 2). In four of the identified studies there were no reports of Candida infections during the study period (Table 2), and in one study the frequency and type of infections were comparable in secukinumab and placebo-controlled patients. However, it was not mentioned whether these infections were bacterial or fungal in nature. 27 Treatment with brodalumab and the prevalence of Candida infection In eight studies, 4431 patients with psoriasis or PsA were treated with brodalumab and 177 (40%) patients developed Candida infections, with rates ranging from 0% to 67% (Tables 1 and 2). In two phase III studies by Lebwohl et al. (AMAGINE-2 and AMAGINE-3) brodalumab (210 mg or 140 mg every 2 weeks) was compared with ustekinumab (45 mg or 90 mg according to weight) or placebo over a 12-week period (induction phase). Between weeks 12 and 52, patients receiving brodalumab were randomly assigned to receive maintenance doses of 210 mg or 140 mg every 2, 4 or 8 weeks. Patients receiving placebo in the induction phase received 210 mg brodalumab every 2 weeks and patients receiving ustekinumab continued to receive ustekinumab every 12 weeks. At week 52, Candida infections were suspected in 48% (n = 147) of patients treated with brodalumab and 23% (n = 14) treated with ustekinumab as monotherapy, respectively. 16 In a study on the safety and efficacy of brodalumab for the treatment of psoriasis, after 120 weeks of therapy five of 181 (28%) patients developed oral candidiasis (Table 2). 28 The patients were initially treated with brodalumab 210 mg every second week (Q2W) until week 12 and then according to weight (< 100 kg: 140 mg Q2W, 100 kg or inadequate response to 140 mg increased to 210 mg Q2W). 28 Nakagawa et al. performed a brodalumab RCT in Japanese patients with moderate-to-severe psoriasis. 29 The patients were randomized to receive 70 mg, 140 mg or 210 mg of brodalumab, or placebo at baseline and weeks 1, 2, 4, 6, 8 and 10. At week 12 one patient (27%) receiving brodalumab 210 mg had oral candidiasis. 29 In a prospective phase III RCT of brodalumab treatment in 661 patients with moderate-to-severe plaque psoriasis a total of 18 patients were suspected of having candidiasis during the 52-week trial period. 15 During the induction phase (12 weeks) patients were randomized 1: 1: 1 to receive brodalumab 210 mg, brodalumab 140 mg or placebo at week 0 and then Q2W, with an additional dose at week 1. During this induction period Candida infection was suspected in five patients in the 210-mg group, one in the 140-mg group and three in the placebo group. From week 12 to 52 patients with inadequate responses who were originally randomized to receive brodalumab or placebo were given brodalumab 210 mg Q2W, and patients originally randomized to brodalumab 210 mg or 140 mg Q2W with a static Physician Global Assessment score < 2 were re-randomized to receive their induction dose of brodalumab or placebo. Beginning at week 16, re-randomized patients who experienced return of disease qualified for retreatment, and after at least 12 weeks of treatment with inadequate responses patients qualified for rescue and received open-label brodalumab 210 mg Q2W. During this period a total of 18 patients (28%) were suspected to have Candida infection (Table 2). All infections were mild to moderate in severity and responded to antifungal therapy. In two of the identified brodalumab studies there were no reports of Candida infection during the study period (Table 2). 30,31 The occurrence of Candida infection during ixekizumab therapy In five studies selected, 4113 patients were treated with ixekizumab for psoriasis and 135 (33%) of the patients had a Candida infection (Table 1). In one phase II RCT 142 patients were randomly assigned to receive 10 mg, 25 mg, 75 mg or 150 mg ixekizumab or placebo at weeks 0, 2, 4, 8, 12 and 16. Candida infections were 2016 British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

12 58 Candida infections during IL-17 treatment and practical management, Saunte et al. not reported in any of the groups until week 20. Infection or infestation was reported in 26% (n = 7) of the placebo group and in 29 43% of the ixekizumab groups. 32 In three RCTs (UNCOVER-1/UNCOVER-2/UNCOVER-3) the effect of ixekizumab (every 2 or 4 weeks) was compared with etanercept and/or placebo at week Overall, 128 (34%) patients had suspected or confirmed mucocutaneous Candida infection [n.b. In the Gordon et al. paper, 128 (34%) are the data mentioned; however, it is also mentioned that the number of patients with candidiasis were as follows: oral (n = 63); vulvogenital (n = 40), skin (n = 20), oesophageal (n = 2), nail (n = 1) and unspecified (n = 9), giving an actual total of 135 (36%)]. Oral and genital/vulvovaginal candidiasis were the most commonly reported manifestations (Table 2). The overall frequency of Candida infection did not differ significantly between the ixekizumab and placebo groups, although they were numerically higher in the former (owing to the larger number of patients in the treatment group). However, most Candida events resolved on standard oral or topical therapy and were not recurrent. 33 Four of the selected ixekizumab studies reported no incidences of Candida infection over their duration (Table 2). 32,34 36 Discussion In this review data from clinical trials of anti-il-17a therapies for psoriasis and PsA (secukinumab, ixekizumab and brodalumab) have been reviewed to explore the incidence of Candida infection during the treatment period. A consensus on how to diagnose and treat patients on IL-17A antagonists with candidiasis is missing from these studies. Thus, development of a guide for the practical management and treatment of Candida infection is suggested in order to help standardize future research and medical care. When Candida infection is suspected in patients taking therapeutic IL-17 blockers, the diagnosis should always be confirmed by culture or molecular diagnostics in order to rule out non-albicans Candida species as some of these have intrinsic resistance to azoles (Table 3). Thus, a proposed screening algorithm for routine use is shown in Figure 1. The majority of Candida infections in patients with psoriasis or PsA were mild to moderate in severity. The authors did not consider these infections as a reason to discontinue IL-17 antagonist treatment as most of the infections resolved after treatment with conventional therapy. From the review of literature data and our own experience a treatment algorithm is suggested (Fig. 2): in uncomplicated mild cases, topical antifungal treatment is preferred over systemic therapy. In general, the systemic absorption of the topical antifungals is low, but some prefer the use of polyenes, including nystatin or amphotericin B, which are not absorbed through the skin or mucous membranes. Other antifungals such as azoles, morpholine or ciclopirox olamine can be considered (Fig. 2). In refractory cases of, for example, periungual or vulvovaginal candidiasis gentian violet solution or British Journal of Dermatology (2017) 177, pp47 62 Table 3 Antifungal susceptibility patterns of the major Candida spp. for mucocutaneous infections Antifungal C. albicans C. glabrata C. krusei Topical Nystatin S S S S Miconazole S S-DD R S-DD Econazole S S-DD R S-DD Clotrimazole S S-DD to R S-DD S Amphotericin B S S S S Systemic Fluconazole S S-DD to R R S Itraconazole S S-DD to R S-DD to R S Voriconazole S S to R S to R S Posaconazole S S to R S to R S C. parapsilosis/ C. tropicalis S, susceptible; S-DD, susceptible dose-dependent; R, resistant. boric acid may be helpful. However, the latter is not approved for use in all countries. In cases of moderate-to-severe infection or if the disease is refractory to topical therapy, a systemic antifungal treatment may be necessary. Fluconazole is the first choice of therapy when C. albicans is isolated as it is considered a narrow-spectrum antifungal. Broad-spectrum antifungals should be avoided as they promote the development of general antifungal resistance. The fluconazole treatment recommendations are shown in Table 4. If the infections persist despite treatment, (re-) confirmation of the Candida infection and a susceptibility test is recommended, as selection of Candida species with intrinsic (Table 3) or acquired antifungal resistance may occur. Very rarely, and only in selected cases, should broad-spectrum antifungals such as posaconazole, voriconazole or echinocandins be used. 6 It is advisable to check for potential drug interactions before initiating antifungal therapy, as well as consulting current drug information for possible AEs. A proposed treatment algorithm is shown in Figure 2. IL-17A is an important cytokine for host homeostasis, particularly regarding Candida. A failure to produce IL-17A results in an increased susceptibility to infection by Candida. This is exemplified by gain-of-function mutations in signal transducer and activator of transcription (STAT) 1, which have been reported as key factors in conferring an increased risk for the development of CMC. 37,38 This is due to an impairment of STAT3 activity in a STAT1-dependent manner, resulting in a reduction in the development of T cells producing IL-17A, IL- 17F and IL-22. Furthermore, in a mouse model of acute oropharyngeal candidiasis IL-17A was shown to be the most important cytokine for protection from Candida infection. Hence, blocking the biological activity of IL-17A or IL-17RA with the aim to treat autoimmune inflammation may always carry the risk of increasing the susceptibility of patients to Candida infection British Association of Dermatologists

13 Candida infections during IL-17 treatment and practical management, Saunte et al. 59 Fig 1. Proposed screening algorithm for Candida infections in patients to be treated with anti-interleukin (IL)-17 drugs. Fig 2. Proposed treatment algorithm for Candida infections during treatment with antiinterleukin-17 drugs. Our understanding of immunity to Candida infections is largely based upon studies of the most common species, C. albicans, and has been shown to involve a dectin/caspase recruitment domain-containing protein 9 (CARD9)/IL-17 pathway. 40 However, CARD9 also mediates other antifungal activities, such as reactive oxygen species production and neutrophil-mediated killing, which are also important in combating fungal pathogens. Furthermore, TNF-a, rather than IL-17, might be involved in the immune defence against non-albicans Candida infections. 41 Unfortunately, species identification and susceptibility assays have not been done routinely in the studies we analysed. Thus, we cannot make any inference regarding the relative frequency of non-albicans Candida or azole-resistant isolates. Most infections recorded in published clinical trials of patients with psoriasis and PsA receiving IL-17 inhibitors were superficial and mild to moderate in severity (Table 1). These mild-to-moderate infections responded to conventional 2016 British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62

14 60 Candida infections during IL-17 treatment and practical management, Saunte et al. Table 4 Fluconazole treatment recommendations 50,51 Candidiasis Fluconazole dose (mg) Duration Oropharyngeal daily 7 14 days Oesophageal Acute daily days Recurrent Three times weekly Vulvovaginal Acute 150 Single dose Severe acute 150 Every 72 h for a total of 2 3 doses Recurring 150 Induction therapy by a topical agent or oral fluconazole, thereafter weekly for 6 months therapy and did not lead to treatment discontinuation. One of the highest infection rate (65%) was found in the brodalumab studies using a combination of brodalumab 140 mg Q2W/210 mg Q2W in a total of 428 patients. 16 The overall incidence of candidiasis during brodalumab, ixekizumab or secukinumab treatment was 40%, 33% and 17%, respectively. Thus, IL-17 blockade presents only a small increase in risk for the development of candidiasis when compared with infection rates in patients with controlled psoriasis and PsA treated with ustekinumab, etanercept or placebo (which were 23%, 08% and 03%, respectively). It is interesting to note that an antibody targeting IL-17RA (brodalumab) causes the highest incidence of Candida infection. This is likely owing to the fact that IL-17RA is involved in not only IL-17A, but also IL-17F and IL-17E recognition and signalling. 42 Thus, blockade of IL-17RA will likely have a broader impact on antifugal immunity than targeting IL-17A alone. Unfortunately, we have not been able to find a systematic review of the incidence of Candida infections during treatment with other biologicals (e.g. adalimumab, infliximab, ustekinumab, etanercept). We expected to see a higher incidence of Candida infections during anti-il-17a treatment, as patients with a congenital deficits in IL-17 function are known to develop CMC characterized by recurrent or persistent C. albicans infections of the skin, nails and mucosae. 3 A possible explanation for this low rate of candidiasis might be that congenital deficits result in broader defects in immune function that hinder the development of immune response to Candida, which are not mirrored by postnatal blockade targeting IL-17A specifically. It is also notable that only a few studies report dermatophyte infections, as the defence against dermatophytes is dependent upon IL-17-mediated induction of epithelial defensins and chemokines for immunosurveillance and fungicidal activity. 13 A future surveillance of dermatophytosis in IL-17-treated patients is warranted. It has previously been reported that psoriasis is associated with an increased rate of colonization by Candida spp. in the oral cavity, as well as in other anatomical areas such as gastrointestinal tract, the intertriginous areas and the nails. 7,8,43,44 The isolation of Candida alone does not necessarily imply disease, which is usually characterized by the presence of concomitant clinical signs and symptoms. Candida may, indeed, represent part of the normal microflora of the skin and mucosal surfaces. In theory, a patient with a higher burden of Candida colonization is also exposed to a higher risk of infection when receiving an immunosuppressive therapy. Interestingly, Picciani et al. did not find an association between the presence of Candida and treatment. 8 In immunosuppressed patients neutropenia is frequently reported, and it has also been reported as an AE in patients treated with IL-17 inhibitors ,23,28,30,32,35,45 In patients with neutropenia serious infections would be expected, but in the published trials the majority of infections reported were mild to moderate. Furthermore, no confirmation is available that patients with neutropenia are also the ones with Candida infection in the published clinical trials of IL-17A inhibitors and brodalumab. In clinical trials patients must fulfil inclusion and exclusion criteria and this selection may bias the data summarized in this study. To obtain an insight into infection rates with Candida during anti-il-17 therapies, registry data are necessary with confirmed cases. In addition, the follow-up time of the studies was between 12 and 52 (60) weeks with the exception of one study with a follow-up time of 120 weeks. A prospective study of long-term use of IL-17 inhibitor treatment may be needed to assess more accurately the risk of Candida infections in the wider community of patients. In the future antifungal prophylactic therapy may be helpful in patients with a previous history of recurrent candidiasis or predisposing factors including diabetes or immunosuppression. Acknowledgments We thank Peter John Morrison, PhD, Kiel, for English writing support. References 1 Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in plaque psoriasis results of two phase 3 trials. N Engl J Med 2014; 371: Yiu ZZ, Griffiths CE. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol 2016; 12: Ling Y, Puel A. IL-17 and infections. Actas Dermosifiliogr 2014; 105 (Suppl.): Ahn CS, Dothard EH, Garner ML et al. To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis. J Am Acad Dermatol 2015; 73: Salt E, Wiggins AT, Rayens MK et al. Risk factors for targeted fungal and mycobacterial infections in patients taking tumor necrosis factor inhibitors. Arthritis Rheumatol 2016; 68: Ruhnke M, Rickerts V, Cornely OA et al. Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. Mycoses 2011; 54: British Journal of Dermatology (2017) 177, pp British Association of Dermatologists

15 Candida infections during IL-17 treatment and practical management, Saunte et al Bedair AA, Darwazeh AMG, Al-Aboosi MM. Oral Candida colonization and candidiasis in patients with psoriasis. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 114: Picciani BLS, Michalski-Santos B, Carneiro S et al. Oral candidiasis in patients with psoriasis: correlation of oral examination and cytopathological evaluation with psoriasis disease severity and treatment. J Am Acad Dermatol 2013; 68: Huppler AR, Bishu S, Gaffen SL. Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy. Arthritis Res Ther 2012; 14: Thacßi D, Blauvelt A, Reich K et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 2015; 73: Papp K, Menter A, Strober B et al. Efficacy and safety of brodalumab in subpopulations of patients with difficult-to-treat moderate-to-severe plaque psoriasis. J Am Acad Dermatol 2015; 72:e1. 12 Gottlieb AB, Langley RG, Philipp S et al. Secukinumab improves physical function in subjects with plaque psoriasis and psoriatic arthritis: results from two randomized, phase 3 trials. J Drugs Dermatol 2015; 14: Ohtsuki M, Morita A, Abe M et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol 2014; 41: Mease PJ, Genovese MC, Mutebi A et al. Improvement in psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory with brodalumab treatment in patients with psoriatic arthritis. J Rheumatol 2016; 43: Papp KA, Reich K, Paul C et al. A prospective phase 3, randomised, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 2016; 175: Lebwohl M, Strober B, Menter A et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 2015; 373: Mrowietz U, Leonardi CL, Girolomoni G et al. Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: a randomized, double-blind, noninferiority trial (SCULPTURE). J Am Acad Dermatol 2015; 73:e1. 18 Thacßi D, Humeniuk J, Frambach Y et al. Secukinumab in psoriasis: randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE). Br J Dermatol 2015; 173: Paul C, Lacour J-P, Tedremets L et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol 2015; 29: Blauvelt A, Prinz JC, Gottlieb AB et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol 2015; 172: Mease PJ, McInnes IB, Kirkham B et al. Secukinumab Inhibition of interleukin-17a in patients with psoriatic arthritis. N Engl J Med 2015; 373: McInnes IB, Mease PJ, Kirkham B et al. Secukinumab, a human anti-interleukin-17a monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet 2015; 386: Rich P, Sigurgeirsson B, Thaci D et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol 2013; 168: van der Heijde D, Landewe RB, Mease PJ et al. Secukinumab provides significant and sustained inhibition of joint structural damage in a phase III study of active psoriatic arthritis. Arthritis Rheumatol 2016; 68: Imafuku S, Honma M, Okubo Y et al. Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: a 52-week analysis from phase III open-label multicenter Japanese study. J Dermatol 2016; 43: Kavanaugh A, McInnes IB, Mease PJ et al. Efficacy of subcutaneous secukinumab in patients with active psoriatic arthritis stratified by prior tumor necrosis factor inhibitor use: results from the randomized placebo-controlled FUTURE 2 study. J Rheumatol 2016; 43: McInnes IB, Sieper J, Braun J et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17a monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-ofconcept trial. Ann Rheum Dis 2014; 73: Papp K, Leonardi C, Menter A et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol 2014; 71:e3. 29 Nakagawa H, Niiro H, Ootaki K. Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study. J Dermatol Sci 2015; 81: Papp KA, Leonardi C, Menter A et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366: Mease PJ, Genovese MC, Greenwald MW et al. Brodalumab, an anti-il17ra monoclonal antibody, in psoriatic arthritis. N Engl J Med 2014; 370: Leonardi C, Matheson R, Zachariae C et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012; 366: Gordon KB, Blauvelt A, Papp KA et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med 2016; 375: Gordon KB, Leonardi CL, Lebwohl M et al. A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin- 17A monoclonal antibody, in patients with chronic plaque psoriasis. J Am Acad Dermatol 2014; 71: Saeki H, Nakagawa H, Ishii T et al. Efficacy and safety of openlabel ixekizumab treatment in Japanese patients with moderate-tosevere plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis. J Eur Acad Dermatol Venereol 2015; 29: Langley RG, Rich P, Menter A et al. Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2015; 29: van de Veerdonk FL, Plantinga TS, Hoischen A et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 2011; 365: Liu L, Okada S, Kong X-F et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208: Conti HR, Gaffen SL. IL-17-mediated immunity to the opportunistic fungal pathogen Candida albicans. J Immunol 2015; 195: Plato A, Willment JA, Brown GD. C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathways. Int Rev Immunol 2013; 32: Whibley N, Jaycox JR, Reid D et al. Delinking CARD9 and IL-17: CARD9 protects against Candida tropicalis infection through a TNF-adependent, IL-17-independent mechanism. J Immunol 2015; 195: British Association of Dermatologists British Journal of Dermatology (2017) 177, pp47 62