Abstract
Pemphigus foliaceus (PF) and Behçet’s disease (BD) are immune-mediated conditions which are usually treated with corticosteroids, immunosuppressants, and, when refractory, with biologic agents. In both diseases, interleukin (IL)-6 serum levels are increased driving the immune-mediated inflammatory process. Tocilizumab is a humanized monoclonal antibody, targeting IL6-receptor, used in the treatment of rheumatoid arthritis. Besides the current indication, it has been recently administered to patients with refractory immune inflammatory diseases as an off-label treatment. Here, we report the case of a woman affected with PF and BD, who did not respond to corticosteroids, immunosuppressants, and biologic agents including adalimumab, anakinra, and infliximab. A complete, long-lasting, clinical, and serological remission was achieved only with tocilizumab. To the best of our knowledge, the association between PF and BD has never been reported. Moreover, only two cases of BD and no cases of PF treated with tocilizumab have been described to date. A literature review on the use of biologic agents on patients with PF and BD was also carried out.
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References
Nousari HC, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet. 1999;354:667–72.
Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev. 2010;10:84–9.
Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012;11:226–30.
James KA, Culton DA, Diaz LA. Diagnosis and clinical features of pemphigus foliaceus. Dermatol Clin. 2011;29:405–12.
Tampoia M, Giavarina D, Di Giorgio C, Bizzaro N, Diagnostic accuracy of enzyme-linked immunosorbent assays (ELISA) to detect anti-skin autoantibodies in autoimmune blistering skin diseases: a systematic review and meta-analysis. Autoimmun Rev. 2012. doi:10.1016/j.bbr.2011.03.031.
Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. 2007;34:503–11.
Leshem YA, Katzenelson V, Yosipovitch G, David M, Mimouni D. Autoimmune diseases in patients with pemphigus and their first-degree relatives. Int J Dermatol. 2011;50:827–31.
Sáez-de-Ocariz M, Granados J, Yamamoto-Furusho JK, López-Martínez A, Vega-Memije ME. Rheumatoid arthritis associated with pemphigus foliaceus in a patient not taking penicillamine. Skinmed. 2007;6:252–4.
Malik M, Ahmed AR. Concurrence of systemic lupus erythematosus and pemphigus: coincidence or correlation? Dermatology. 2007;214:231–9.
Calebotta A, Cirocco A, Giansante E, Reyes O. Systemic lupus erythematosus and pemphigus vulgaris: association or coincidence. Lupus. 2004;13:951–3.
Hidalgo-Tenorio C, Sabio-Sánchez JM, Tercedor-Sánchez J, León-Ruíz L, Pérez-Alvarez F, Jiménez-Alonso J. Pemphigus vulgaris and systemic lupus erythematosus in a 46-year-old man. Lupus. 2001;10:824–6.
Narbutt J, Torzecka JD, Sysa-Jedrzejowska A, Pas HH. Pemphigus foliaceus in an 11-year-old boy with dermatomyositis: simple coincidence or familial immunological background? Br J Dermatol. 2003;148:838–9.
Black M, Marshman G. Dermatomyositis and pemphigus vulgaris: association or coincidence? Australas J Dermatol. 2011;52:e11–4.
Saadoun D, Wechsler B. Behcet’s disease. Orphanet J Rare Dis. 2012;7:20.
International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet. 1990;335:1078–80.
Pipitone N, Olivieri I, Salvarani C, Italian Society of Rheumatology. Recommendations of the Italian society of rheumatology for the treatment of the primary large-vessel vasculitis with biological agents. Clin Exp Rheumatol. 2012;30:S139–61.
Goebeler M, Herzog S, Bröcker EB, Zillikens D. Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab. Br J Dermatol. 2003;149:899–901.
Arin MJ, Engert A, Krieg T, Hunzelmann N. Anti-CD20 monoclonal antibody (rituximab) in the treatment of pemphigus. Br J Dermatol. 2005;153:620–5.
Joly P, Mouquet H, Roujeau JC, D’Incan M, Gilbert D, Jacquot S, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med. 2007;357(9):545–52.
Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol. 2007;143:1033–8.
Marzano AV, Fanoni D, Venegoni L, Berti E, Caputo R. Treatment of refractory pemphigus with the anti-CD20 monoclonal antibody (rituximab). Dermatology. 2007;214:310–8.
Fernando SL, O’Connor KS. Treatment of severe pemphigus foliaceus with rituximab. Med J Aust. 2008;189:289–90.
Prodanovic EM, Korman NJ. A case of non-Hodgkin’s lymphoma-associated pemphigus foliaceus and use of rituximab for treatment. J Dermatolog Treat. 2008;19:1–3.
Serrão VV, Martins A, Páris FR, Lopes MP. Successful treatment of recalcitrant pemphigus foliaceus with rituximab. J Eur Acad Dermatol Venereol. 2008;22:768–70.
Shimanovich I, Nitschke M, Rose C, Grabbe J, Zillikens D. Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins. Br J Dermatol. 2008;158:382–8.
Kim MR, Kim HC, Kim SC. Long-term prognosis of pemphigus in Korea: retrospective analysis of 199 patients. Dermatology. 2011;223:182–8.
Carvalho R, Maio P, Cunha D, Freitas I, Afonso A, Cardoso J. Rituximab in pemphigus foliaceous with autoantibodies against both Desmoglein 1 and Desmoglein 3. Eur J Dermatol. 2011;21:415–6.
Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C, Zillikens D, Schmidt E. Rituximab for treatment-refractory pemphigus and pemphigoid: a case series of 17 patients. J Am Acad Dermatol. 2011;65:552–8.
Kim JH, Kim YH, Kim MR, Kim SC. Clinical efficacy of different doses of rituximab in the treatment of pemphigus: a retrospective study of 27 patients. Br J Dermatol. 2011;165:646–51.
Kanwar AJ, Tsuruta D, Vinay K, Koga H, Ishii N, Dainichi T, Hashimoto T. Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol. 2013;27:e17–23.
Horváth B, Huizinga J, Pas HH, Mulder AB, Jonkman MF. Low-dose rituximab is effective in pemphigus. Br J Dermatol. 2012;166:405–12.
Kasperkiewicz M, Shimanovich I, Meier M, Schumacher N, Westermann L, Kramer J, et al. Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of 23 patients. Br J Dermatol. 2012;166:154–60.
Reguiai Z, Tabary T, Maizières M, Bernard P. Rituximab treatment of severe pemphigus: long-term results including immunologic follow-up. J Am Acad Dermatol. 2012;76:623–9.
Matsukura S, Knowles SR, Walsh S, Shear NH. Effect of a single-cycle alternative dosing regimen for rituximab for recalcitrant pemphigus: a case series of 9 patients. Arch Dermatol. 2012;148:734–9.
Grekin SJ, Fox MC, Gudjonsson JE, Fullen DR. Psoriasiform pemphigus foliaceus: a report of two cases. J Cutan Pathol. 2012;39:549–53.
Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients adjuvant rituximab therapy of pemphigus. Arch Dermatol. 2012;18:1–6.
Paradisi A, Cianchini G, Lupi F, Di Pietro C, Sampogna F, Didona B, et al. Quality of life in patients with pemphigus receiving adjuvant therapy. Clin Exp Dermatol. 2012;37:626–30.
Kasperkiewicz M, Eming R, Behzad M, Hunzelmann N, Meurer M, Schulze-Koops H, et al. Efficacy and safety of rituximab in pemphigus: experience of the German Registry of Autoimmune Diseases. J Dtsch Dermatol Ges. 2012;10:727–32.
Gubinelli E, Bergamo F, Didona B, Annessi G, Atzori F, Raskovic D. Pemphigus foliaceus treated with etanercept. J Am Acad Dermatol. 2006;55:1107–8.
McLaughlin P, White CA, Grillo-Lopez AJ, Maloney DG. Clinical status and optimal use of rituximab for B-cell lymphomas. Oncology. 1998;12:1763–9.
Furst DE, Keystone EC, Fleischmann R, Mease P, Breedveld FC, Smolen JS, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009. Ann Rheum Dis. 2010;69:i2–29.
van Vollenhoven RF. Rituximab—shadow, illusion or light? Autoimmun Rev. 2012;11:563–7.
Isenberg DA. Rituximab—it was the best of times, it was the worst of times. Autoimmun Rev. 2012;11:790–1.
Kasperkiewicz M, Schmidt E, Zillikens D. Current therapy of the pemphigus group. Clin Dermatol. 2012;30:84–94.
Pardo J, Mercader P, Mahiques L, Sanchez-Carazo JL, Oliver V, Fortea JM. Infliximab in the management of severe pemphigus vulgaris. Br J Dermatol. 2005;153:222–3.
Jacobi A, Shuler G, Hertl M. Rapid control of therapy-refractory pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol. 2005;153:448–9.
Vojáčková N, Fialová J, Vaňousová D, Hercogová J. Pemphigus vulgaris treated with adalimumab: case study. Dermatol Ther. 2012;25:95–7.
Shetty A, Marcum CB, Glass LF, Carter JD. Successful treatment of pemphigus vulgaris with etanercept in four patients. J Drugs Dermatol. 2009;8:940–3.
Pineton de Chambrun M, Wechsler B, Geri G, Cacoub P, Saadoun D. New insights into the pathogenesis of Behçet’s disease. Autoimmun Rev. 2012;11:687–98.
Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum. 2011;41:61–70.
Hirano T, Ohguro N, Hohki S, Hagihara K, Shima Y, Narazaki M, et al. A case of Behçet’s disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol. 2012;22:298–302.
Shapiro LS, Farrell J, Haghighi AB. Tocilizumab treatment for neuro-Behçet’s disease, the first report. Clin Neurol Neurosurg. 2012;114:297–8.
Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA. Resistant Behçet disease responsive to anakinra. Ann Intern Med. 2008;149:284–6.
Bilginer Y, Ayaz NA, Ozen S. Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behçet’s disease. Clin Rheumatol. 2010;29:209–10.
Sadreddini S, Noshad H, Molaeefard M, Noshad R. Treatment of retinal vasculitis in Behçet’s disease with rituximab. Mod Rheumatol. 2008;18:306–8.
Davatchi F, Shams H, Rezaipoor M, Sadeghi-Abdollahi B, Shahram F, Nadji A, et al. Rituximab in intractable ocular lesions of Behçet’s disease; randomized single-blind control study (pilot study). Int J Rheum Dis. 2010;13:246–52.
Iaccarino L, Gatto M, Bettio S, Caso F, Rampudda M, Zen M, et al., Overlap connective tissue disease syndromes. Autoimmun Rev. 2012. doi:10.1016/j.autrev.2012.06.004.
Fonseca JE, Santos MJ, Canhão H, Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev. 2009;8:538–42.
Doria A, Zen M, Bettio S, Gatto M, Bassi N, Nalotto L, et al. Autoinflammation and autoimmunity: bridging the divide. Autoimmun Rev. 2012;12:22–30.
D’Auria L, Bonifati C, Mussi A, Agosto GD, Simone CD, Giacalone B. Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity. Eur Cytokine Netw. 1997;8:383–7.
López-Robles E, Avalos-Díaz E, Vega-Memije E, Hojyo-Tomoka T, Villalobos R, Fraire S, et al. TNFα and IL-6 are mediators in the blistering process of pemphigus. Inter J Dermatol. 2001;40:185–8.
Chriguer RS, Roselino AM, de Castro M. Glucocorticoid sensitivity and proinflammatory cytokines pattern in pemphigus. J Clin Immunol. 2012;32:786–93.
Zhou ZY, Chen SL, Shen N, Lu Y. Cytokines and Behcet’s disease. Autoimmun Rev. 2012;11:699–704.
Sun A, Wang YP, Chia JS, Liu BY, Chiang CP. Treatment with levamisole and colchicine can result in a significant reduction of IL-6, IL-8 or TNF-alpha level in patients with mucocutaneous type of Behcet’s disease. J Oral Pathol Med. 2009;38:401–5.
Akman-Demir G, Tüzün E, Içöz S, Yeşilot N, Yentür SP, Kürtüncü M, et al. Interleukin-6 in neuro-Behçet’s disease: association with disease subsets and long-term outcome. Cytokine. 2008;44:373–6.
Grando SA. Pemphigus autoimmunity: hypotheses and realities. Autoimmunity. 2012;45:7–35.
Direskeneli H. Autoimmunity vs autoinflammation in Behçet’s disease: do we oversimplify a complex disorder? Rheumatology (Oxford). 2006;45:1461–5.
Briani C, Doria A, Marcolongo R, Tognon S, Ruggero S, Toffanin E, et al. Increased titres of IgM anti-heparansulfate antibody in Behçet’s disease. Clin Exp Rheumatol. 2006;24:S104–7.
Arakawa M, Dainichi T, Yasumoto S, Hashimoto T. Lesional Th17 cells in pemphigus vulgaris and pemphigus foliaceus. J Dermatol Sci. 2009;53:228–31.
Hamzaoui K. Th17 cells in Behçet’s disease: a new immunoregulatory axis. Clin Exp Rheumatol. 2011;29:S71–6.
Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40:1830–5.
Langier S, Sade K, Kivity S. Regulatory T cells: the suppressor arm of the immune system. Autoimmun Rev. 2010;10:112–5.
Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012;52:199–219.
Zen M, Gatto M, Domeneghetti M, Palma L, Borella E, Iaccarino L, Punzi L, Doria A. Clinical guidelines and definitions of autoinflammatory diseases: contrasts and comparisons with autoimmunity—a comprehensive review. Clin Rev Allergy Immunol. 2013. doi:10.1007/s12016-013-8355-1.
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Caso, F., Iaccarino, L., Bettio, S. et al. Refractory pemphigus foliaceus and Behçet’s disease successfully treated with tocilizumab. Immunol Res 56, 390–397 (2013). https://doi.org/10.1007/s12026-013-8411-1
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DOI: https://doi.org/10.1007/s12026-013-8411-1