Skip to main content

Advertisement

Log in

Refractory pemphigus foliaceus and Behçet’s disease successfully treated with tocilizumab

  • Treatment of Autoimmunity
  • Published:
Immunologic Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Nousari HC, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet. 1999;354:667–72.

    Article  PubMed  CAS  Google Scholar 

  2. Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev. 2010;10:84–9.

    Article  PubMed  CAS  Google Scholar 

  3. Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012;11:226–30.

    Article  PubMed  CAS  Google Scholar 

  4. James KA, Culton DA, Diaz LA. Diagnosis and clinical features of pemphigus foliaceus. Dermatol Clin. 2011;29:405–12.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

  6. Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. 2007;34:503–11.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Malik M, Ahmed AR. Concurrence of systemic lupus erythematosus and pemphigus: coincidence or correlation? Dermatology. 2007;214:231–9.

    Article  PubMed  Google Scholar 

  10. Calebotta A, Cirocco A, Giansante E, Reyes O. Systemic lupus erythematosus and pemphigus vulgaris: association or coincidence. Lupus. 2004;13:951–3.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Black M, Marshman G. Dermatomyositis and pemphigus vulgaris: association or coincidence? Australas J Dermatol. 2011;52:e11–4.

    Article  PubMed  Google Scholar 

  14. Saadoun D, Wechsler B. Behcet’s disease. Orphanet J Rare Dis. 2012;7:20.

    Article  PubMed  Google Scholar 

  15. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet. 1990;335:1078–80.

    Google Scholar 

  16. 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.

    PubMed  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Fernando SL, O’Connor KS. Treatment of severe pemphigus foliaceus with rituximab. Med J Aust. 2008;189:289–90.

    PubMed  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. Kim MR, Kim HC, Kim SC. Long-term prognosis of pemphigus in Korea: retrospective analysis of 199 patients. Dermatology. 2011;223:182–8.

    Article  PubMed  Google Scholar 

  27. 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.

    PubMed  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Horváth B, Huizinga J, Pas HH, Mulder AB, Jonkman MF. Low-dose rituximab is effective in pemphigus. Br J Dermatol. 2012;166:405–12.

    Article  PubMed  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. Grekin SJ, Fox MC, Gudjonsson JE, Fullen DR. Psoriasiform pemphigus foliaceus: a report of two cases. J Cutan Pathol. 2012;39:549–53.

    Article  PubMed  Google Scholar 

  36. 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.

    Google Scholar 

  37. 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.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    PubMed  Google Scholar 

  39. 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.

    Article  PubMed  Google Scholar 

  40. 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.

    PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. van Vollenhoven RF. Rituximab—shadow, illusion or light? Autoimmun Rev. 2012;11:563–7.

    Article  PubMed  Google Scholar 

  43. Isenberg DA. Rituximab—it was the best of times, it was the worst of times. Autoimmun Rev. 2012;11:790–1.

    Article  PubMed  CAS  Google Scholar 

  44. Kasperkiewicz M, Schmidt E, Zillikens D. Current therapy of the pemphigus group. Clin Dermatol. 2012;30:84–94.

    Article  PubMed  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    Article  PubMed  CAS  Google Scholar 

  47. Vojáčková N, Fialová J, Vaňousová D, Hercogová J. Pemphigus vulgaris treated with adalimumab: case study. Dermatol Ther. 2012;25:95–7.

    Article  PubMed  Google Scholar 

  48. 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.

    PubMed  Google Scholar 

  49. 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.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. 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.

    Article  PubMed  Google Scholar 

  52. Shapiro LS, Farrell J, Haghighi AB. Tocilizumab treatment for neuro-Behçet’s disease, the first report. Clin Neurol Neurosurg. 2012;114:297–8.

    Article  PubMed  Google Scholar 

  53. Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA. Resistant Behçet disease responsive to anakinra. Ann Intern Med. 2008;149:284–6.

    Article  PubMed  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  55. Sadreddini S, Noshad H, Molaeefard M, Noshad R. Treatment of retinal vasculitis in Behçet’s disease with rituximab. Mod Rheumatol. 2008;18:306–8.

    Article  PubMed  CAS  Google Scholar 

  56. 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.

    Article  PubMed  Google Scholar 

  57. 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.

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. 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.

    Article  PubMed  CAS  Google Scholar 

  60. 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.

    PubMed  Google Scholar 

  61. 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.

    Article  Google Scholar 

  62. Chriguer RS, Roselino AM, de Castro M. Glucocorticoid sensitivity and proinflammatory cytokines pattern in pemphigus. J Clin Immunol. 2012;32:786–93.

    Article  PubMed  CAS  Google Scholar 

  63. Zhou ZY, Chen SL, Shen N, Lu Y. Cytokines and Behcet’s disease. Autoimmun Rev. 2012;11:699–704.

    Article  PubMed  CAS  Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. Grando SA. Pemphigus autoimmunity: hypotheses and realities. Autoimmunity. 2012;45:7–35.

    Article  PubMed  CAS  Google Scholar 

  67. Direskeneli H. Autoimmunity vs autoinflammation in Behçet’s disease: do we oversimplify a complex disorder? Rheumatology (Oxford). 2006;45:1461–5.

    Article  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. Arakawa M, Dainichi T, Yasumoto S, Hashimoto T. Lesional Th17 cells in pemphigus vulgaris and pemphigus foliaceus. J Dermatol Sci. 2009;53:228–31.

    Article  PubMed  CAS  Google Scholar 

  70. Hamzaoui K. Th17 cells in Behçet’s disease: a new immunoregulatory axis. Clin Exp Rheumatol. 2011;29:S71–6.

    PubMed  Google Scholar 

  71. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40:1830–5.

    Article  PubMed  CAS  Google Scholar 

  72. Langier S, Sade K, Kivity S. Regulatory T cells: the suppressor arm of the immune system. Autoimmun Rev. 2010;10:112–5.

    Article  PubMed  CAS  Google Scholar 

  73. Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012;52:199–219.

    Article  PubMed  CAS  Google Scholar 

  74. 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.

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrea Doria.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-013-8411-1

Keywords

Navigation