Cammelli, Daniele

Palterer, Boaz

Parronchi, Paola

Vitiello, Gianfranco

English

Florence Research

Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]Contents lists available at ScienceDirectSeminars in Arthritis and Rheumatismhttp://d0049-01journal homepage: www.elsevier.com/locate/semarthritTocilizumab-induced mucosal ulcers in apatient with relapsing polychondritis: Anadverse drug reaction?Dear Editor,We have read with interest, the article by Deroux et al. [1],describing the use of tocilizumab (TCZ) in refractory Behçet'sdisease (BD), in which four female patients were treated success-fully without any adverse event. In particular, mucocutaneouslesions responded well to TCZ administration.In addition to the letter to Editor written by Emmi et al. [2], themucocutaneous paradoxical effect of TCZ is well reported in otherdiseases, such as rheumatoid arthritis and ankylosing spondylitis,and in different portions of the gastrointestinal tract, involving oralmucosa as well as small and large intestine [3,4]. In this regard wereport herein a patient affected by relapsing polychondritis (RP)resistant to corticosteroid treatment that developed recurrentmucosal ulcers after the second infusion of TCZ.B.F. is a 46-year-old-man in which RP was diagnosed in 2009for the presence of recurrent auricular and nasal chondritis, drycough, hoarseness, pain at proximal trachea and larynx, and a non-erosive peripheral arthritis involving both hands and wrists andthe left knee. Acute phase reactants resulted highly elevated andboth rheumatoid factor and anti-citrullinated protein antibodywere negative. The patient had never suffered from mucosalulceration. The patient was at first treated with repeated boluscorticosteroids and intramuscular methotrexate 15 mg/weekly,with a weak control of the symptomatology. For this reason, in2010 he started a therapy with infliximab (350 mg every 8 weeks,Fig. Major oral ulcers involving the oral mucosx.doi.org/10.1016/j.semarthrit.2016.03.01672/& 2016 Elsevier Inc. All rights reserved.augmented to 350 mg every 5 weeks) till June 2015, whenthe drug was suspended for loss of efficacy and reappearance ofthe symptomatology above mentioned. TCZ was started at a doseof 8 mg/kg every 4 weeks in August, with a good initial response.Since the second infusion, the patients started suffering fromrecurrent major oral ulcers (Fig.); ulcers swabs twice demon-strated the absence of Herpes viruses. An empirical 1-weektreatment with valaciclovir 1000 mg/tid did not amelioratethe ulcers. Due to the persistence of oral ulcerations and,since the 13th infusion, the onset of peripheral arthritis involvingboth hands, the shoulders and the hips, TCZ was suspendedand ulcers progressively disappeared during the following15 days.In addition to the conflicting data about TCZ efficacy inmucocutaneous manifestations of BD patients well summarizedby Emmi and colleagues and already reported by Diamantopoulos[5], this biological agent seems to be associated independentlywith gastrointestinal ulceration, and mouth ulcerations arereported as common adverse reactions in TCZ data sheet. In fact,several trials (STREAM, TOWARD, SATORI, SAMURAI, and OPTION)reported a variable percentage ranging from 2% to 11.5% of “oralulcerations” and “stomatitis” in patients treated with TCZ, withoutany clinical description or correlation with infections [6–10](Table). In addition to this, TCZ was associated with gastrointest-inal perforation and Iwasa et al. [3] speculated that this conditionmay be preceded by mucosal ulceration. The mechanism isnot clear, but it is probably mediated by inhibiting STAT3, whichpromotes injury and impaired regeneration of intestinalepithelium [11]. For this reason, TCZ-related mucosal ulcers seemto be a general adverse effect more than an exacerbation ofmucocutaneous involvement as it can happen in BD. Ad hoca (A), the tongue (B) and the lower lip (C).TableReported rates of tocilizumab-related stomatitis and/or oral ulcerations during some clinical trialsStudy Patients Drugs Stomatitis/oral ulcersSTREAM [5] 54 Placebo 3.7%54 TCZ 4 mg 5.6%53 TCZ 8mg 7.3%TOWARD [6] 414 Placebo þ DMARD Mouth ulceration 1%/stomatitis 0%802 TCZ 8 mg þ DMARD Mouth ulceration 2%/stomatitis 1%SATORI [7] 61 MTX 8 mg 0%66 TCZ 8 mg 11.5%SAMURAI [8] 148 DMARD 9.0%158 TCZ 8 mg 5.7%OPTION [9] 204 Placebo 0.5%212 TCZ 4 mg 2%206 TCZ 8 mg 2%Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]2clinical studies are needed to clarify the linkage between mucosalulceration and TCZ administration.Gianfranco Vitiello, MDa,n,1, Boaz Palterer, MDa,1Department of Experimental and Clinical Medicine, University ofFlorence, AOU Careggi, Largo Brambilla 3, 50134 Florence, ItalyE-mail address: gianfranco.vitiello@stud.unifi.it (G. Vitiello)Paola Parronchi, MD, PhDbDepartment of Experimental and Clinical Medicine, Unit ofInternal Medicine, University of Florence, Florence, ItalyDaniele Cammelli, MDcRheumatology Section, Immunoallergology Unit, AOU CareggiFlorence, ItalyReferences[1] Deroux A, Chiquet C, Bouillet L. Tocilizumab in severe and refractory Behcet'sdisease: four cases and literature review. Semin Arthritis Rheum 2015:1–5,http://dx.doi.org/10.1016/j.semarthrit.2015.11.012 (in press).[2] Emmi G, Silvestri E, Squatrito D, Emmi L, Cantarini L, Prisco D. Tocilizumab-induced exacerbation of mucosal ulcers in a patient with multi-refractoryBehçet's disease. Semin Arthritis Rheum 2016:6–11.nCorresponding author.1 Both authors equally contributed to this work.[3] Iwasa T, Nakamura K, Ogino H, et al. Multiple ulcers in the small and largeintestines occurred during tocilizumab therapy for rheumatoid arthritis.Endoscopy 2011;43:70–2.[4] Samimi M, Lauferon F, Hüttenberger B, Vaillant L, Goupille P, MacHet L.Ulcérations buccales aphtoïdes persistantes associées au tocilizumab: Deuxcas. Ann Dermatol Venereol 2013;140:120–4.[5] Diamantopoulos AP, Hatemi G. Lack of efficacy of tocilizumab in mucocuta-neous Behcet's syndrome: report of two cases. Rheumatology (Oxford)2013;52:1923.[6] Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonalantibody, in monotherapy, in patients with rheumatoid arthritis (the STREAMstudy): evidence of safety and efficacy in a 5-year extension study. Ann RheumDis 2009;68:1580–4.[7] Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibitionwith tocilizumab reduces disease activity in rheumatoid arthritis withinadequate response to disease-modifying antirheumatic drugs: the tocilizu-mab in combination with traditional disease-modifying antirheumatic drugthe. Arthritis Rheum 2008;58:2968–80.[8] Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlledtocilizumab monotherapy for rheumatoid arthritis patients with an inade-quate response to methotrexate (SATORI): significant reduction in diseaseactivity and serum vascular endothelial growth factor by IL-6 receptorinhibition t. Mod Rheumatol 2009;19:12–9.[9] Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlledmonotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI):evidence of clinical and radiographic benefit from an X-ray reader-blindedrandomised controlled trial of tocilizumab. Ann Rheum Dis 2007;66:1162–7.[10] Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptorinhibitionwith tocilizumab in patients with rheumatoid arthritis (OPTION study): adouble-blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97.[11] Calabrese L, Rose-John S. Il-6 biology: implications for clinical targeting inrheumatic disease. Nat Rew Rheumatol 2014;2:720–7.

Tocilizumab-induced mucosal ulcers in a patient with relapsing polychondritis: An adverse drug reaction?

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Tocilizumab-induced mucosal ulcers in a patient with relapsing polychondritis: An adverse drug reaction?

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