Al-Araji, SA

Chard, DT

Ciccarelli, O

Sahi, N

Trip, SA

English

UCL Discovery

Treatment refractory warts associated with fingolimod  Authors: Nitin Kumar Sahi1, Sarmad A Al-Araji1, Olga Ciccarelli1,2, Declan T Chard1,2, and S Anand Trip1,2   Affiliations: 1 Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, London, UK  2 National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, UK    *Correspondence to:  Nitin Kumar Sahi, UCL Department of Neuroinflammation, Russell Square House 10-12, WC1B 5EH London, UK E-mail: n.sahi@ucl.ac.uk   Keywords: Multiple sclerosis; Dermatology  Word count: 500    Case 1 - (Figure 1a) A 54-year-old woman with relapsing remitting multiple sclerosis (RRMS) on fingolimod since 2018 presented with periungual digital warts. She had previously switched from Natalizumab, due to JC virus seropositivity, and had relapsed on interferon beta-1a. Although her warts persisted despite topical treatment with salicylic acid, she wished to continue fingolimod therapy.    Case 2 - (Figure 1b) A 54-year-old woman with RRMS) commenced fingolimod in 2014, following relapse on interferon beta-1a. She developed digital warts in 2016, which became widespread despite treatment with salicylic acid and cryotherapy. Warts improved following dose reduction in 2019 but remained persistent.  Cutaneous warts are caused by the human papilloma virus (HPV).[1,2] Prevalence varies markedly in studies, but is highest during childhood (~5-30%) and falls significantly following the second decade of life.[1,2]  Salicylic acid or cryotherapy are the most evidenced treatments with cure rates around 50%, but multiple therapies exist and spontaneous resolution is common.[1] However, in the immunocompromised, warts are often refractory to standard treatments[1] with significant psychosocial impact.[3]   Both cases highlight treatment refractory warts in patients on fingolimod for MS, as previously reported.[4–6] We retrospectively identified warts in 7/336 patients (2.1%) receiving fingolimod at our centre between 2011-2019. Treatment was modified in four patients; Two patients discontinued fingolimod with either improvement or resolution, although one subsequently relapsed. Two patients were commenced on reduced dosing; warts improved in both, but one patient relapsed and restarted full dosing. Three patients did not change treatment and continued to have treatment refractory warts. Warts were unlikely to improve without either drug cessation or reduction, risking relapse and rebound disease.[7,8]    Causality between fingolimod and warts remains unproven, but is supported by the temporal relationship between treatment modification and improvement in warts.[4–6] Fingolimod may impair the immune response to HPV through lymphocyte sequestration, mediated by sphingosine-1-phosphate (S1P) receptor antagonism, and cause warts through chronic infection and clonal proliferation of keratinocytes. Fingolimod may also increase the risk of HPV-driven malignancy[1,6] through impaired T-cell mediated cancer surveillance.[9] As yet warts have not been reported with  other S1P receptor modulators (siponimod and ponesimod). Data on HPV lesions associated with siponimod may be of importance for female patients with secondary progressive MS, as cervical cancer mortality increases with age[10] and women over 65 do not have routine screening.  HPV vaccination is offered nationally to all children aged 12–13 years and is highly effective against cervical cancer in adolescents and young women. Unvaccinated individuals remain eligible until they are 25 years old, beyond which vaccination can be offered at clinician discretion. Vaccination and HPV screening prior to fingolimod should be strongly considered, whilst similar surveillance may be necessary for other S1P-receptor modulators. As more drugs causing lymphopenia are likely to be introduced for MS and other neuroinflammatory disorders, warts may become more commonly encountered in the neurology clinic.  Key Messages: • Warts are common in patients taking fingolimod and unlikely to improve without treatment modification, risking relapse or rebound disease • Consider HPV vaccination and screening before commencing fingolimod  Contributorship  N.K.S was involved in the patients’ care, collected data and obtained patient consent. He was responsible for writing the first draft and final manuscript.  S.A.A was involved in data collection, review and editing of the manuscript.  O.C was involved in data collection, review and editing of the manuscript.  D.C was involved in the patients’ care and was responsible for conceptualisation of the article, review and editing of the manuscript.  S.A.T was in charge of the patients’ care and was responsible for conceptualisation of the article, review and editing of the manuscript.  Competing Interests The author(s) declared the following potential competing interest with respect to the research, authorship and/or publication of this article:   N.K.S. is a clinical fellow at the National Hospital for Neurology and Neurosurgery, London, in a post which is supported by Merck.  S.A.A. reports no disclosures.   O.C. receives research funding from the National Institute for Health Research (NIHR), UK and National MS Societies, Rosetrees trust and NIHR University College London Hospitals (UCLH) Biomedical Research Centre; she has received speaker honoraria from Biogen and Merck during the past 12 months; and is the Deputy Editor of Neurology  D.C. is a consultant for Biogen and Hoffmann-La Roche. In the last three years he has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck.  S.A.T. receives support from the UCLH Biomedical Research Centre and has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck.  Funding  This project was supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The author(s) received no financial support for the research, authorship and/or publication of this article.  Figure 1 (A) Periungual wart on left little finger of case 1 with coexistent onychomycosis. (B) Persistent common digital wart on right index finger of case 2.     References  1  Sterling JC, Gibbs S, Haque Hussain SS, et al. British Association of Dermatologists’ guidelines for the management of cutaneous warts 2014. Br J Dermatol 2014;171:696–712. doi:10.1111/bjd.13310 2  Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev 2012;2012. doi:10.1002/14651858.CD001781.pub3 3  Munk NT, Agerskov H, Helldén K, et al. Care and treatment needs of immunosuppressive therapy patients with warts and impact on everyday life: a qualitative study. J Dermatolog Treat 2021;0:1–6. doi:10.1080/09546634.2020.1869146 4  Triplett J, Kermode AG, Corbett A, et al. Warts and all: Fingolimod and unusual HPV-associated lesions. Mult Scler J 2019;25:1547–50. doi:10.1177/1352458518807088 5  Jaafar N, Zeineddine M, Massouh J, et al. Skin warts during fingolimod treatment in patients with multiple sclerosis. Mult Scler Relat Disord 2019;36:1–2. doi:10.1016/j.msard.2019.101437 6  Mhanna E, Nouchi A, Louapre C, et al. Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination. Mult Scler J 2021;:1–5. doi:10.1177/1352458521991433 7  Zecca C, Merlini A, Disanto G, et al. Half-dose fingolimod for treating relapsing-remitting multiple sclerosis: Observational study. Mult Scler 2018;24:167–74. doi:10.1177/1352458517694089 8  Barry B, Erwin AA, Stevens J, et al. Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations. Neurol Ther 2019;8:241–50. doi:10.1007/s40120-019-00160-9 9  Lorvik KB, Bogen B, Corthay A. Fingolimod blocks immunosurveillance of myeloma and B-cell lymphoma resulting in cancer development in mice. Blood 2012;119:2176–7. doi:10.1182/blood-2011-10-388892 10  Hammer A, Kahlert J, Gravitt PE, et al. Hysterectomy-corrected cervical cancer mortality rates in Denmark during 2002-2015: A registry-based cohort study. Acta Obstet Gynecol Scand 2019;98:1063–9. doi:10.1111/aogs.13608  

Treatment-refractory warts associated with fingolimod

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Treatment-refractory warts associated with fingolimod

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