Clinical Reviews in Allergy & Immunology

, Volume 34, Issue 1, pp 103–110

Rituximab Off Label Use for Difficult-To-Treat Auto-Immune Diseases: Reappraisal of Benefits and Risks

Article

Abstract

Rituximab is increasingly used off label for difficult-to-treat auto-immune diseases. We reviewed the main case series or clinical studies to identify the best indications of rituximab and the situations at substantial risks for adverse events. Refractory immune thrombocytopenic purpura was the main indication. However, the long term benefit-to-risk ratio of rituximab treatment before or after splenectomy is unknown. A single 375 mg/m2 infusion may be as efficacious as the classical four infusions cycle. Rituximab is the best treatment for cold agglutinin disease. In warm agglutinin auto-immune anaemia, its efficacy has essentially been reported in chronic lymphocytic leukemia (CLL) patients and in children. In CLL patients, lethal adverse events occurred in patients also receiving cyclophosphamide. Rituximab seems to have an interesting benefit-to-risk ratio in Wegener granulomatosis (excepted in granulomatous lesions), HCV-associated symptomatic cryoglobulinemia in patients unresponsive to anti-viral therapy, pemphigus and thrombotic thrombocytopenic purpura. Efficacy and safety data in lupus are difficult to interpret. Serum sickness disease is not exceptional in immune thrombocytopenic purpura (ITP), lupus and sicca syndrome patients. A substantial infectious risk has been reported in pemphigus patients and in post-renal transplant cryoglobulinemia. Double-blind randomised controlled trials and phase IV studies are mandatory in most clinical settings to confirm the overall favourable perception of rituximab benefit to risk ratio.

Keywords

Rituximab Auto-immune disease Benefit-to-risk ratio 

References

  1. 1.
    Franchini M et al (2006) The efficacy of rituximab in the treatment of inhibitor-associated hemostatic disorders. Thromb Haemost 96:119–125PubMedGoogle Scholar
  2. 2.
    Kimby E (2005) Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 31:456–473PubMedCrossRefGoogle Scholar
  3. 3.
    Vianelli N et al (2005) Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases. Haematologica 90:72–77PubMedGoogle Scholar
  4. 4.
    Bennett CM et al (2006) Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura. Blood 107:2639–2642PubMedCrossRefGoogle Scholar
  5. 5.
    Saleh MN et al (2000) A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 27:99–103PubMedGoogle Scholar
  6. 6.
    Godeau B et al (2006) Rituximab is an alternative to splenectomy in adults with chronic immune thrombocytopenic purpura: results of a multicenter prospective phase 2 study. Blood 108,145a, abstract 478.Google Scholar
  7. 7.
    Kojouri K et al (2004) Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 104:2623–2634PubMedCrossRefGoogle Scholar
  8. 8.
    Taube T et al (2005) Effect of a single dose of rituximab in chronic immune thrombocytopenic purpura in childhood. Haematologica 90:281–283PubMedGoogle Scholar
  9. 9.
    D’Arena G et al (2006) Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol 81:598–602PubMedCrossRefGoogle Scholar
  10. 10.
    Zaja F et al (2003) Anti-CD20 therapy for chronic lymphocytic leukemia-associated autoimmune diseases. Leuk Lymphoma 44:1951–1955PubMedCrossRefGoogle Scholar
  11. 11.
    Narat S et al (2005) Rituximab in the treatment of refractory autoimmune cytopenias in adults. Haematologica 90:1273–1274PubMedGoogle Scholar
  12. 12.
    Trape G et al (2003) Rituximab chimeric anti-CD20 monoclonal antibody treatment for refractory hemolytic anemia in patients with lymphoproliferative disorders. Haematologica 88:223–225PubMedGoogle Scholar
  13. 13.
    Shanafelt TD et al (2003) Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc 78:1340–1346PubMedCrossRefGoogle Scholar
  14. 14.
    Zecca M et al (2003) Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood 101:3857–3861PubMedCrossRefGoogle Scholar
  15. 15.
    Berentsen S et al (2006) Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica 91:460–466PubMedGoogle Scholar
  16. 16.
    Schollkopf C et al (2006) Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma 47:253–260PubMedCrossRefGoogle Scholar
  17. 17.
    Berentsen S et al (2004) Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood 103:2925–2928PubMedCrossRefGoogle Scholar
  18. 18.
    Tokunaga M et al (2007) Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis 66:470–475CrossRefGoogle Scholar
  19. 19.
    Vallerskog T et al (2006) Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther 8:R167PubMedCrossRefGoogle Scholar
  20. 20.
    Leandro MJ et al (2005) B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44:1542–1545CrossRefGoogle Scholar
  21. 21.
    Smith KG et al (2006) Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum 54:2970–2982PubMedCrossRefGoogle Scholar
  22. 22.
    Willems M et al (2006) Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 148:623–627PubMedCrossRefGoogle Scholar
  23. 23.
    Vigna-Perez M et al (2006) Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 8:R83PubMedCrossRefGoogle Scholar
  24. 24.
    Sfikakis PP et al (2005) Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum 52:501–513PubMedCrossRefGoogle Scholar
  25. 25.
    Marks SD et al (2005) B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 52:3168–3174PubMedCrossRefGoogle Scholar
  26. 26.
    Looney RJ et al (2004) B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 50:2580–2589PubMedCrossRefGoogle Scholar
  27. 27.
    Gottenberg JE et al (2005) Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 64:913–920PubMedCrossRefGoogle Scholar
  28. 28.
    Ginzler EM et al (2005) Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353:2219–2228PubMedCrossRefGoogle Scholar
  29. 29.
    Seror R et al (2007) Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjogren's syndrome. Ann Rheum Dis 66:351–357PubMedCrossRefGoogle Scholar
  30. 30.
    Pijpe J et al (2005) Rituximab treatment in patients with primary Sjogren's syndrome: an open-label phase II study. Arthritis Rheum 52:2740–2750PubMedCrossRefGoogle Scholar
  31. 31.
    Levine TD (2005) Rituximab in the treatment of dermatomyositis: an open-label pilot study Arthritis Rheum 52:601–607PubMedCrossRefGoogle Scholar
  32. 32.
    Noss EH et al (2006) Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol 33:1021–1026PubMedGoogle Scholar
  33. 33.
    Stasi R et al (2006) Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford) 45:1432–1436CrossRefGoogle Scholar
  34. 34.
    Aries PM et al (2006) Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 65:853–858PubMedCrossRefGoogle Scholar
  35. 35.
    Keogh KA et al (2006) Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 173:180–187PubMedCrossRefGoogle Scholar
  36. 36.
    Eriksson P (2005) Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab. J Intern Med 257:540–548PubMedCrossRefGoogle Scholar
  37. 37.
    Sansonno D et al (2003) Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 101:3818–3826PubMedCrossRefGoogle Scholar
  38. 38.
    Roccatello D et al (2004) Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 19:3054–3061PubMedCrossRefGoogle Scholar
  39. 39.
    Zaja F et al (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834PubMedCrossRefGoogle Scholar
  40. 40.
    Bryce AH et al (2006) Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma 7:140–144PubMedCrossRefGoogle Scholar
  41. 41.
    Basse G et al (2006) Rituximab therapy for mixed cryoglobulinemia in seven renal transplant patients. Transplant Proc 38:2308–2310PubMedCrossRefGoogle Scholar
  42. 42.
    Lake-Bakaar G et al (2007) Hepatitis C virus and alanine aminotransferase kinetics following B-lymphocyte depletion with rituximab: evidence for a significant role of humoral immunity in the control of viremia in chronic HCV liver disease. Blood 109:845–846PubMedCrossRefGoogle Scholar
  43. 43.
    Schmidt E et al (2006) Rituximab in refractory autoimmune bullous diseases. Clin Exp Dermatol 31:503–508PubMedCrossRefGoogle Scholar
  44. 44.
    Schmidt E et al (2007) Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol 156:352–356PubMedCrossRefGoogle Scholar
  45. 45.
    Ahmed AR et al (2006) Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355:1772–1779PubMedCrossRefGoogle Scholar
  46. 46.
    Bohm M et al (2005) The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 129:644–652PubMedCrossRefGoogle Scholar
  47. 47.
    Scully M et al (2007) Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol 136:451–461PubMedCrossRefGoogle Scholar
  48. 48.
    Fakhouri F et al (2005) Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 106:1932–1937PubMedCrossRefGoogle Scholar
  49. 49.
    Heidel F et al (2007) Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia. Thromb Haemost 97:228–233PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Service de Pharmacologie Clinique, Unité de PharmacoépidémiologieCHU de ToulouseToulouseFrance
  2. 2.Service de Médecine Interne, Salle Le Tallec, Pavillon Dieulafoy, Hôpital PurpanCHU de ToulouseToulouseFrance

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