Severe, ulcerative, lichenoid mucositis associated with secukinumab

Abstract

IntroductionSecukinumab is a new human monoclonal antibody targeting interleukin (IL)-17A, a cytokine involved in the pathogenesis of psoriasis. The US Food and Drug Administration approved secukinumab for psoriasis in 2015. Because the medication has been on the market for a short time, adverse events involving the oral mucosa are rarely reported. We report a case of severe, ulcerative, lichenoid mucositis associated with secukinumab use.Case reportA 62-year-old white man underwent follow-up for long-standing, intractable, erythrodermic psoriasis. He did not respond to tumor necrosis factor (TNF) inhibitors such as adalimumab and etanercept and could not tolerate cyclosporine. Because methotrexate was only mildly efficacious, secukinumab was added. Less than 1 week into secukinumab treatment, very painful erosions and ulcers developed on the lower lip (Fig 1). The patient was taking no other medications and had no history of recurrent orolabial herpes simplex virus infection or other oral disease such as aphthosis. Viral culture was negative for herpes simplex virus. A potassium hydroxide preparation and fungal culture were negative, and lesions did not respond to oral fluconazole.Because secukinumab was showing efficacy for his psoriasis, and in the absence of a clear etiology of the labial lesions, the patient elected to continue taking the drug. The lesions persisted and remained painful for 3 months, finally prompting discontinuation of secukinumab. Shave biopsy found ulceration with a dense lichenoid inflammatory infiltrate with scattered eosinophils, neutrophils, and plasma cells (Figs 2 and 3). The presence of eosinophils and deeper inflammatory infiltrate (Fig 2) suggested a lichenoid drug eruption. Direct immunofluorescence of perilesional mucosa found nonspecific basal epithelium staining for C3, IgG, and IgM. The patient started using 0.1% triamcinolone in Orabase paste. It was not until approximately 6 weeks from secukinumab discontinuation and 1 week of steroid paste use that the labial lesions showed substantial improvement.Fig 2Mucosal ulceration shows dense lichenoid infiltrate with focal intact epithelium. (Hematoxylin-eosin stain; original magnification: ×100.)View Large Image Figure ViewerDownload (PPT)Fig 3Eosinophils were noted throughout the inflammatory infiltrate, including in the deep inflammatory infiltrate. (Hematoxylin-eosin stain; original magnification, ×400.)View Large Image Figure ViewerDownload (PPT)DiscussionThere are sparse reports of oral adverse events associated with new anti–IL-17 drugs (Table I).1Baeten D. Baraliakos X. Braun J. et al.Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.Lancet. 2013; 382: 1705-1713Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 2McInnes I.B. Mease P.J. Kirkham B. et al.Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2015; 386: 1137-1146Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 3Purnell J.C. Williams B.A. Shalin S.C. Wong H.K. Mucocutaneous findings associated with interleukin (IL)-17 inhibition.JAAD Case Rep. 2016; 2: 92-94Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar However, oral adverse effects of other biologic agents such as TNF inhibitors, which have longer track records, are well described (Table I).4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Worsnop F. Wee J. Natkunarajah J. Moosa Y. Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus.Clin Exp Dermatol. 2012; 37: 879-881Crossref PubMed Scopus (24) Google Scholar, 6Ahdout J. Haley J.C. Chiu M.W. Erythema multiforme during anti-tumor necrosis factor treatment for plaque psoriasis.J Am Acad Dermatol. 2010; 62: 874-879Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 7Ford A.C. Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.Am J Gastroenterol. 2013; 108: 1268-1276Crossref PubMed Scopus (257) Google Scholar, 8Daulat S. Detweiler J.G. Pandya A.G. Development of pemphigus vulgaris in a patient with psoriasis treated with etanercept.J Eur Acad Dermatol Venereol. 2009; 23: 483-484Crossref PubMed Scopus (30) Google Scholar Mouth ulceration was reported in 2 patients in a phase 2 secukinumab trial, but specifics were not provided.1Baeten D. Baraliakos X. Braun J. et al.Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.Lancet. 2013; 382: 1705-1713Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar The differential diagnosis of our patient's labial lesions includes candidiasis, oral lichen planus (LP), drug-induced LP, lichenoid contact dermatitis, erythema multiforme (EM), major aphthae, complex aphthosis, pemphigus vulgaris (PV), and mucous membrane pemphigoid (MMP). Oral candidiasis, reported in 1.8% of patients at 52 weeks in a secukinumab trial,2McInnes I.B. Mease P.J. Kirkham B. et al.Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2015; 386: 1137-1146Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar was ruled out by negative potassium hydroxide preparation and fungal culture, and no response to oral fluconazole.Table IOral adverse effects associated with anti-IL-17 drugs and TNF-α inhibitorsDrug classAdverse effectAnti–IL-17 drugsUlcerative, lichenoid mucositis (current case)Mouth ulceration1Baeten D. Baraliakos X. Braun J. et al.Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.Lancet. 2013; 382: 1705-1713Abstract Full Text Full Text PDF PubMed Scopus (460) Google ScholarOral candidiasis2McInnes I.B. Mease P.J. Kirkham B. et al.Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2015; 386: 1137-1146Abstract Full Text Full Text PDF PubMed Scopus (603) Google ScholarSialadenitis3Purnell J.C. Williams B.A. Shalin S.C. Wong H.K. Mucocutaneous findings associated with interleukin (IL)-17 inhibition.JAAD Case Rep. 2016; 2: 92-94Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarTNF-α inhibitorsLichen planus–like reactions4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Worsnop F. Wee J. Natkunarajah J. Moosa Y. Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus.Clin Exp Dermatol. 2012; 37: 879-881Crossref PubMed Scopus (24) Google ScholarErythema multiforme6Ahdout J. Haley J.C. Chiu M.W. Erythema multiforme during anti-tumor necrosis factor treatment for plaque psoriasis.J Am Acad Dermatol. 2010; 62: 874-879Abstract Full Text Full Text PDF PubMed Scopus (25) Google ScholarOral candidiasis7Ford A.C. Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.Am J Gastroenterol. 2013; 108: 1268-1276Crossref PubMed Scopus (257) Google ScholarPemphigus vulgaris8Daulat S. Detweiler J.G. Pandya A.G. Development of pemphigus vulgaris in a patient with psoriasis treated with etanercept.J Eur Acad Dermatol Venereol. 2009; 23: 483-484Crossref PubMed Scopus (30) Google Scholar Open table in a new tab Unlike erosive oral LP that typically manifests with lesions on buccal mucosa, gingivae, and tongue that tend to run a chronic course, the lesions in our patient were located on the lip and noted during a short course of secukinumab. As highlighted in Table I, LP-like reactions have developed secondary to use of TNF inhibitors.4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Worsnop F. Wee J. Natkunarajah J. Moosa Y. Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus.Clin Exp Dermatol. 2012; 37: 879-881Crossref PubMed Scopus (24) Google Scholar These reactions arose most commonly within 2 months (range, 3 weeks to 16 months) of TNF inhibitor therapy. Oral LP in patients on TNF inhibitor therapy manifested with Wickham's striae, with only 3 reports of erosive disease.4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Worsnop F. Wee J. Natkunarajah J. Moosa Y. Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus.Clin Exp Dermatol. 2012; 37: 879-881Crossref PubMed Scopus (24) Google Scholar Wickham's striae were not noted in our patient. Unlike this case, most TNF inhibitor–associated cases presented also with cutaneous LP, and lesions were not exquisitely painful. TNF-α levels are elevated in saliva and serum of patients with LP; therefore, the appearance of oral LP in the context of TNF-α blockade is paradoxical. TNF-α inhibition leads to upregulation of interferon-α, a pro-inflammatory cytokine implicated in LP.4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar It is possible that anti–IL-17 drugs, which counteract the synergistic effects of IL-17 and TNF-α,9Wang C.Q. Akalu Y.T. Suarez-Farinas M. et al.IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis.J Invest Dermatol. 2013; 133: 2741-2752Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar can provoke a similar reaction.Our patient was not on any other drugs known to cause oral LP-like reactions.10Schlosser B.J. Lichen planus and lichenoid reactions of the oral mucosa.Dermatol Ther. 2010; 23: 251-267Crossref PubMed Scopus (83) Google Scholar Methotrexate can cause mucositis, which typically affects several sites and is associated with cutaneous involvement, hematologic abnormalities, and keratinocyte dystrophy.11Delyon J. Ortonne N. Benayoun E. et al.Low-dose methotrexate-induced skin toxicity: Keratinocyte dystrophy as a histologic marker.J Am Acad Dermatol. 2015; 73: 484-490Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar These features were absent in our case. Our patient was on methotrexate long before the lesions developed, and lesions resolved after discontinuation of secukinumab despite continued methotrexate treatment. Our patient was not using any topical medications that could have caused lichenoid contact dermatitis at the time that the labial lesions developed.Additional diagnoses considered include EM, aphthae, PV, and MMP. Features of EM such as white pseudomembranes and targetoid and necrotic lesions were missing in our case, and the 3-month duration without periods of healing was not consistent with EM. Furthermore, EM diagnosis was not supported by the histopathologic findings. Typical features of major aphthae, such as a large, discrete, deep ulcers with yellow cratered base and healing with scarring were not noted in this case.12Letsinger J.A. McCarty M.A. Jorizzo J.L. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide.J Am Acad Dermatol. 2005; 52: 500-508Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Histopathologic features of major aphthae such as necrosis, presence of neutrophils below the ulcer, and involvement of salivary glands were absent. Furthermore, our case did not show features of complex aphthosis, such as almost constant presence of ≥3 oral aphthae. Our patient had no vesiculobullous lesions affecting the skin or other mucosal surfaces, and direct immunofluorescence ruled out immunobullous disease such as PV and MMP.An association between secukinumab and labial lesions in this case is supported by the onset of lesions shortly after secukinumab administration and resolution after discontinuation of the drug. The underlying mechanism of our patient's labial lesions may be similar to that proposed for TNF inhibitor–associated oral LP (upregulation of interferon-α),4Asarch A. Gottlieb A.B. Lee J. et al.Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor-alpha antagonists.J Am Acad Dermatol. 2009; 61: 104-111Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar because IL-17 inhibitors downregulate the synergy of IL-17 with TNF-α.9Wang C.Q. Akalu Y.T. Suarez-Farinas M. et al.IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis.J Invest Dermatol. 2013; 133: 2741-2752Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Furthermore, decreased IL-17–positive cells are seen in oral LP when compared with nonspecifically inflamed mucosa,13Firth F.A. Friedlander L.T. Parachuru V.P. Kardos T.B. Seymour G.J. Rich A.M. Regulation of immune cells in oral lichen planus.Arch Dermatol Res. 2015; 307: 333-339Crossref PubMed Scopus (27) Google Scholar and it is possible that drugs such as secukinumab may enhance a similar disturbance in local immune regulation, causing oral lichenoid reactions. As additional anti–IL-17 drugs are approved, it is important to further characterize such adverse events. Clinicians must be aware of this possible class effect, as early diagnosis helps decrease morbidity, given the extended time to recovery in our patient and the potential for significant quality-of-life disruption with these painful labial lesions. IntroductionSecukinumab is a new human monoclonal antibody targeting interleukin (IL)-17A, a cytokine involved in the pathogenesis of psoriasis. The US Food and Drug Administration approved secukinumab for psoriasis in 2015. Because the medication has been on the market for a short time, adverse events involving the oral mucosa are rarely reported. We report a case of severe, ulcerative, lichenoid mucositis associated with secukinumab use.