Proximal subungual onychomycosis (PSO) is a rare subtype of onychomycosis with a clinical presentation characterized by proximal leukonychia in the lunular area of the nail. PSO is associated with immunosuppression and regarded a sign of Human Immunodeficiency Virus (HIV) infection when caused by Trichophyton (T.) rubrum. We present two cases of PSO caused by T. rubrumdeveloped during treatment with TNF-α inhibitors combined with methotrexate (MTX). </p

Ditte Marie Saunte

Gregor Borut Ernst Jemec

Maiken Cavling Arendrup

Mattias Arvid Simon Henning

Pernille  Lindsø Andersen

Hrčak - Portal of scientific journals of Croatia

304Two Cases of Proximal Subungual Onychomycosis Caused by Trichophyton rubrum in HIV-negative  Patients During Treatment with TNF-α Inhibitors  Combined with MethotrexatePernille Lindsø Andersen1, Mattias Arvid Simon Henning1, Gregor B. E. Jemec1, Maiken Cavling Arendrup2, Ditte Marie L. Saunte11Department of Dermatology, Zealand University Hospital, Roskilde; Health Sciences Faculty, University of Copenhagen, Copenhagen, Denmark;2Unit of Mycology, De-partment of Microbiology and Research, Statens Serum Institut, Copenhagen, Den-markCorresponding author:Assist. Prof. Ditte Marie L. Saunte, MD, PhDDepartment of DermatologyZealand University Hospital; RoskildeSygehusvej 5DK-4000 RoskildeDenmark disa@regionsjaelland.dkReceived: August 28, 2018Accepted: November 16, 2018Acta Dermatovenerol Croat                              2018;26(4):304-306                                  CLiNiCAL ARtiCLeABSTRACT Proximal subungual onychomycosis (PSO) is a rare subtype of onychomycosis with a clinical presentation characterized by proximal leukonychia in the lunular area of the nail. PSO is associated with immuno-suppression and regarded a sign of Human immunodeficiency Virus (HiV) infection when caused by Trichophyton (T.) rubrum. We present two cases of PSO caused by T. rubrum developed during treatment with tNF-α inhibitors combined with methotrexate (MtX). KEY WORDS: onychomycosis, nail diseases, psoriasis, immunosuppresive agents, methotrexate, tumor necrosis factor-alphaINTRODUCTIONProximal subungual onychomycosis (PSO) is a rare subtype of onychomycosis found in 0.3% of cases (1). its clinical presentation is characterized by proximal leukonychia in the lunular area (2). PSO is associated with immunosuppression and regarded as a sign of Human immunodeficiency Virus (HiV) infection when caused by Trichophyton (T.) rubrum (1). PSO caused by T. rubrum has previously only been reported in a single patient treated with tumor necrosis factor-al-pha (tNF-α) inhibitors and in no patients treated with methotrexate (3). We present two cases of PSO caused by T. rubrum developed during treatment with tNF-α inhibitors combined with methotrexate (MtX).PATIENTSCase 1A 78-year-old man treated for psoriasis and psori-atic arthritis noted a toenail change during combina-tion treatment with etanercept 50 mg/week and MtX 10 mg/week. Figure 1 displays a timeline of his medi-cation. Medical history included mild nephropathy and a negative HiV test. Physical examination revealed proximal white nail changes on the left hallux, discrete scaling of planta pedis, and maceration of the lateral interdigital toe web. Direct microscopy of nail material displayed septate hyphae and a few arthroconidia. Culture and PCR confirmed T. rubrum infection. ACTA DERMATOVENEROLOGICA CROATICA305ACTA DERMATOVENEROLOGICA CROATICAthe patient was treated for three months with oral terbinafine 250 mg/day in combination with daily ap-plication of topical ciclopirox nail lacquer. Clinical im-provement was noted at four month follow-up with the nail at the proximal nail fold appearing normal. Direct microscopy displayed a few hyphae com-bined with a negative culture, indicating non-vital fungi. Mycological cure was observed eight months after treatment initiation and clinical cure after thir-teen months. Figure 2 illustrates the patient’s clinical course. Case 2A 55-year-old man with psoriatic and psoriasis ar-thritis was referred to the Dermatologic Outpatient Clinic with a facial rash potentially due to infliximab. Medical history included inflammatory bowel disease. the patient had received infliximab for eight months and MtX for fourteen months at the time of referral. tinea barbae caused by T. rubrum was diagnosed and treated with topical terbinafine. During clinical ex-amination a whitening of the nails the on left 1st and 3rd toe and right 2nd toe was noted, but interpreted as psoriasis nails. At three month follow-up, tinea barbae had clini-cally cleared, however progression of the proximal white nail changes was noted on the left hallux. A der-matophyte-specific PCR from the toenail confirmed T. rubrum infection. HiV test was negative. treatment with terbinafine 250 mg/day for three months com-bined with topical amorolfine applied once a week was initiated.DISCUSSIONthese two cases represent the rare manifestation of PSO caused by T. rubrum in HiV-negative patients treated with tNF-α inhibitors in combination with MtX. Patients with psoriasis have an increased sus-ceptibility to dermatophyte infections (4). A study on onychomycosis in 315 patients with psoriasis treated with tNF-α inhibitors (infliximab, etanercept, and adalimumab) found a prevalence of 13-33% com-pared with 14% in patients with psoriasis not treated with biologics. None of these patients presented with PSO (4). tNF-α inhibitors may reduce the inflammatory response to fungal infection. the cytokine is mainly secreted by macrophages and prevents the actions of iL-12 and interferon-γ and the migration of dendritic cells (5). tNF-α inhibitors mainly suppress monocytes and dendritic cells, while MtX inhibits activation and Figure 1. Patient 1: timeline of psoriasis medication and onset of proximal subungual onychomycosis. *tNF-α inhibi-torsFigure 2. Clinical course of the patient 1: A) Presentation. B) three months after treatment. C) Nine months after treatment.Andersen et al. Acta Dermatovenerol CroatSubungual onychomycosis   2018;26(4):303-306306proliferation of lymphocytes (6). the combination of tNF-α inhibitors with MtX may further suppress the immune response by targeting different immune cells.CONCLUSIONthis is the first time PSO caused by T. rubrum has described in patients receiving tNF-α inhibitors com-bined with MtX, a frequent treatment strategy. this condition may therefore be under-diagnosed. We suggest screening for onychomycosis before treat-ment initiation and clinical follow-up during combi-nation treatment with tNF-α inhibitors and MtX.AcknowledgementsWe thank the patients for providing informed consent to share their cases in this paper.Conflict of interestsM.A.S.H. and P.L.A. have no conflicts of interests to declare. G.B.e.J. has received honoraria from AbbVie, Colo-plast, Pfizer, Pierre Fabre, inflarx, MSD, Novartis, and UCB for participation on advisory boards, and grants from Abbvie, Leo Pharma, Novartis, Janssen-Cilag, Regeneron, UCB, and Sanofi for participation as an in-vestigator, and received speaker honoraria from Ab-bVie, Galderma, and Leo Pharma. D.M.S. has received honoraria from Sanofi and Jannsen for participation on advisory boards, speaker honoraria from Abbvie, Leopharma, and Astella and travel grants from Abbvie, Sanofi, and Pfizer. M.C.A. has received personal speaker’s honoraria in the past five years from Astellas, Basilea, Gilead, MSD, Pfizer, t2Candida, and Novartis. She has re-ceived research grants and contract work paid to the Statens Serum institute from Astellas, Basilea, Gilead, MSD, Pfizer, t2Candida, F2G, Cidara, and Amplyx.References:1. Gupta AK, taborda P, taborda V, Gilmour J, Rach-lis A, Salit i, et al. epidemiology and prevalence of onychomycosis in HiV-positive individuals. int J Dermatol. 2000;39:746-53.2. Piraccini BM, Alessandrini A. Onychomycosis: A Review. J Fungi (Basel). 2015;1:30-43.3. Gonzalez-Lopez L, Monteagudo-Sanchez B, Mos-quera-Fernandez A, Gonzalez-Vilas D, Ordonez P. Proximal subungual onychomycosis in a patient treated with tumor necrosis factor alpha blockers. Semergen. 2017;43:245-6.4. Al-Mutairi N, Nour t, Al-Rqobah D. Onychomyco-sis in patients of nail psoriasis on biologic therapy: a randomized, prospective open label study com-paring etanercept, infliximab and Adalimumab. expert Opin Biol ther. 2013;13:625-9.5. Lowther AL, Somani AK, Camouse M, Florentino Ft, Somach SC. invasive Trichophyton rubrum infection occurring with infliximab and long-term prednisone treatment. J Cutan Med Surg. 2007;11:84-8.6. Witte t. Methotrexate as combination partner of tNF inhibitors and tocilizumab. What is reasona-ble from an immunological viewpoint? Clin Rheu-matol. 2015;34:629-34.Andersen et al. Acta Dermatovenerol CroatSubungual onychomycosis   2018;26(4):303-306ACTA DERMATOVENEROLOGICA CROATICA

Two cases of proximal subungual onychomycosis caused by Trichophyton rubrum in HIV negative patients during treatment with TNF-α inhibitors combined with methotrexate.

Andersen, Pernille Lindsø

Henning, Mattias Arvid Simon

Jemec, Gregor B E

Arendrup, Maiken Cavling

Saunte, Ditte Marie

Copenhagen University Research Information System

Two Cases of Proximal Subungual Onychomycosis Caused by Trichophyton rubrum in HIV-negative Patients During Treatment with TNF-α Inhibitors Combined with Methotrexate

Two cases of proximal subungual onychomycosis caused by Trichophyton rubrum in HIV negative patients during treatment with TNF-α inhibitors combined with methotrexate.

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