title: Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis.
abstract: Severe recurrent aphthous stomatitis (SRAS) is a rare, disabling disorder of unknown etiology. Thalidomide is an effective second-line therapy for SRAS, but is suppressive rather than curative, and adverse events limit its use. Few reports describe the efficacy, tolerance, and safety of thalidomide, and how it is actually used as long-term (maintenance) therapy for SRAS. Therefore, we conducted this study to describe thalidomide use in the real-life management of a cohort of patients with SRAS. This multicenter retrospective cohort study covered a period of 5 years and 5 months (January 2003-May 2008). Patients who had started thalidomide monotherapy for SRAS during the 2003-2006 period were eligible. Data were collected from patients' medical charts and supplemented by patients' responses during a targeted telephone interview. Ninety-two patients followed at 14 centers were included: 76 had oral or bipolar aphthosis, and 16 had Behçet disease. Thalidomide was rapidly effective: 85% (78/92) entered complete remission (CR) within a median of 14 days. Response time was independent of the initial thalidomide dose (r = 0.04). Thalidomide was continued for > or =3 months (maintenance therapy) by 77/92 (84%) of the patients on 1 of 2 maintenance regimens: continuous therapy with regular intake (60/77) or intermittent therapy in response to attacks (17/77). Although intermittent therapy was less restrictive than continuous therapy, medical supervision under the former was less rigorous. The median maintenance dose was 100 mg/week, and did not reflect the initial dose (r = 0.18). The intermittent-treatment group's median dose was significantly lower and its median duration of thalidomide intake significantly longer than for patients on continuous therapy (19 vs. 150 mg/wk; p < 0.0001, and 32 vs. 19 mo; p = 0.002, respectively). Adverse events were reported by 84% (77/92) of patients. They were mostly mild (78% of patients), but sometimes severe (21%). Nevertheless, after 40 months of follow-up, 60% of patients were still receiving continuous or intermittent maintenance therapy with favorable efficacy/tolerance ratios. Despite its retrospective nature, this detailed study provides novel information on the different ways thalidomide is used as SRAS maintenance therapy in a large and unselected cohort of patients. Low-dose maintenance regimens appear to be widely used, effective, and relatively well tolerated. These observations suggest the value of undertaking a randomized trial to assess various maintenance regimens.
authors.affiliation: From Department of Dermatology (MH, SB), CHU Hôtel-Dieu, Nantes; Department of Dermatology (OC), Hôpital Henri-Mondor, AP-HP, Créteil, and Université Paris 6-Pierre-et-Marie-Curie, Paris; Department of Clinical Research and Public Health (SBG), Hôpital Henri-Mondor, AP-HP, Université Paris 12, LIC EA 4393, Créteil; and 11 Chaussée de la Muette, Paris (JR);France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Hello
authors.forename: Sébastien
authors.initials: S
authors.lastname: Barbarot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bastuji-Garin
authors.forename: Jean
authors.initials: J
authors.lastname: Revuz
authors.forename: Olivier
authors.initials: O
authors.lastname: Chosidow
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012008:Recurrence; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013281:Stomatitis, Aphthous / Q000188:drug therapy*; D013792:Thalidomide / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D013792:Thalidomide
references.citation: Allen PF. Assessment of oral health related quality of life. Health Qual Life Outcomes. 2003;1:40.
references.citation: Bastuji-Garin S, Ochonisky S, Bouche P, Gherardi RK, Duguet C, Djerradine Z, Poli F, Revuz J. Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol. 2002;119:1020-1026.
references.citation: Bonnetblanc JM, Royer C, Bedane C. Thalidomide and recurrent aphthous stomatitis: a follow-up study. Dermatology. 1996;193:321-323.
references.citation: Chattopadhyay A, Chatterjee S. Risk indicators for recurrent aphthous ulcers among adults in the US. Community Dent Oral Epidemiol. 2007;35:152-159.
references.citation: Flageul B, Wallach D, Cavelier-Balloy B, Bachelez H, Carsuzaa F, Dubertret L. Thalidomide et thromboses. Ann Dermatol Venereol. 2000;127:171-174.
references.citation: Gardner-Medwin JM, Smith NJ, Powell RJ. Clinical experience with thalidomide in the management of severe oral and genital ulcerations in conditions such as Behcet's disease: use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis. 1994;53:828-832.
references.citation: Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol. 1985;12:85-90.
references.citation: Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128:443-450.
references.citation: Jenkins JS, Powell RJ, Allen BR, Littlewood SM, Maurice PD, Smith NJ. Thalidomide in severe orogenital ulceration. Lancet. 1984;2:1424-1426.
references.citation: Letsinger JA, McCarty MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol. 2005;52:500-508.
references.citation: Ochonisky S, Verroust J, Bastuji-Garin S, Gherardi R, Revuz J. Thalidomide neuropathy incidence and clinicoelectrophysiologic findings in 42 patients. Arch Dermatol. 1994;130:66-69.
references.citation: Perri AJ III, Hsu S. A review of thalidomide's history and current dermatological applications. Dermatol Online J. 2003;9:5.
references.citation: Revuz J, Guillaume JC, Janier M, Hans P, Marchand C, Souteyrand P, Bonnetblanc JM, Claudy A, Dallac S, Klene C, et al. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol. 1990;126:923-927.
references.citation: Rogers RS III. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg. 1997;16:278-283.
references.citation: Scully C. Aphthous ulceration. N Engl J Med. 2006;355:165-172.
references.citation: Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg. 2008;46:198-206.
references.citation: Torras H, Lecha M, Mascaro JM. Thalidomide treatment of recurrent necrotic giant mucocutaneous aphthae and aphthosis [letter]. Arch Dermatol. 1982;118:875.
references.citation: Verpilleux MP, Bastuji-Garin S, Revuz J. Comparative analysis of severe aphthosis and Behcet's disease: 104 cases. Dermatology. 1999;198:247-251.
references.citation: de Wazieres B, Gil H, Magy N, Berthier S, Vuitton DA, Dupond JL. Traitement de l'aphtose recurrente par thalidomide: etude pilote chez 17 patients. Rev Med Interne. 1999;20:567-570.