Journal of the Formosan Medical Association
Volume 111, Issue 4 , Pages 181-182, April 2012

An antibody treats almost all refractory autoimmune diseases: Fact and beyond

  • Kuender D. Yang

      Affiliations

    • Corresponding Author InformationCorresponding author. Department of Pediatrics, Show Chwan Memorial Hospital, Changhua, Taiwan.

Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan

Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Show Chwan Memorial Hospital, Changhua, Taiwan

Received 3 March 2011 published online 11 January 2012.

Article Outline

 

An antiCD20 monoclonal antibody (rituximab) has been shown to rescue almost all refractory autoimmune diseases. The chimeric antiCD20 antibody is one of the world’s most successfully therapeutic antibodies, with sales of approximately US$5.6 billion in 2009.1 Rituximab was first approved in 1997 by the US Food and Drug Administration (FDA) for treatment of B cell malignancies, and is now expanded to autoimmune indications, such as lupus nephritis, multiple sclerosis and vasculitis, particularly refractory autoimmune diseases that usually cause fatal outcomes.2, 3, 4, 5, 6, 7, 8 Autoimmunity is a complex process that involves the interaction of multiple immune cell types. B cells are thought to play a central role in the autoimmune disease serving as precursors to autoantibody-secreting plasma cells. In addition to producing antibodies, B cells are able to present antigen to T cells. Their depletion also results in the removal of antigen-presenting cells, reduced expression of molecules responsible for T cell costimulatory signals, and reduced levels of immune complexes formed between autoreactive antibodies and their antigen.

There are certain refractory autoimmune diseases successfully treated by rituximab including antiphospholipid syndrome (APS), thrombotic thrombocytopenic purpura (TTP), antineutrophil cytoplasmic antibody (ANCA) vasculitis, refractory rheumatoid arthritis, refractory juvenile dermatomyositis and refractory idiopathic thrombocytopenic purpura (ITP) (Table 1). In refractory APS, rituximab (100–375mg/m2) decreased anticardiolipin antibody levels from 20.6 standardized IgG antiphospholipid units (GPLU) to undetectable levels in six of seven patients 6 to 9 months after treatment, and caused a high response rate—more than 90%—in another report.2

Table 1. Favorable and unfavorable benefits and side effects of rituximab treatment for autoimmune diseases.
ResultsAutoimmune diseasesResponse rates
Favorable resultsRefractory APS290% Remission
Refractory TTP392% Complete response
Refractory ANCA vasculitis41% No response
Refractory rheumatoid arthritis after failure of etanercept treatment5RTX+MTX vs. placebo+MTX: ACR20 (51% vs. 18%)
Refractory juvenile dermatomyositis675% (3 out of 4 cases)
Refractory Sjögren’s syndrome7Significant improvement in fatigue visual analog scale in the rituximab group (p<0.001)
Refractory ITP811% therapeutic failure
Unfavorable resultsAdd-on therapy for SLE with conventional treatment2No better than conventional therapy
Macrophage Activation SyndromeRefractory lupus-associated macrophage activation syndrome (two cases)
Worsening psoriasis after Rituximab9Two case reports
Side effectsCommon side effects: Infections, infusion hypersensitivity, hypogammaglobulinemia
Rare side effects: reactivation of hepatitis B virus infection, tumor lysis syndrome, progressive multifocal leukoencephalopathy

In refractory TTP, which usually causes a fatal outcome, rituximab achieved 92% complete response rate associated with the disappearance of ADAMTS-13 inhibitors and no subsequent relapses in a median follow-up of 24 months (range, 13–84 months).3 In refractory ANCA vasculitis, a retrospective study showed that complete remission occurred in 49 of the 65 patients (75%), partial remission in 15 (23%), and no response only in one (2%) in UK.4 In refractory rheumatoid arthritis (RA), rituximab was approved by the FDA and European Medicine Agency for the treatment of RA after antiTNFα treatment failure.5 In refractory juvenile dermatomyositis, a case report showed that three of four patients showed clinical improvement.6 In refractory ITP, only two of the 18 patients treated with rituximab were classified as therapeutic failures (11%).7 In patients with refractory Sjögren’s syndrome, the first double-blind study of rituximab showed a favorable result from a randomized trial to receive either two infusions of rituximab or placebo along with steroids.8

These promising results have shared a light to treat all autoimmune diseases by the antiCD20 strategy, particularly the most prevalent autoantibody disease, systemic lupus erythematosus (SLE). Unfortunately, the antiCD20 treatment added on the conventional treatment did not show a significant benefit over conventional treatments.2 Moreover, not all refractory autoimmune diseases responded to the antiCD20 therapy. Some case reports showed that rituximab failed to rescue autoimmune associated macrophage activation syndrome (MAS), and caused a worsening psoriasis.9 In fact, psoriasis and MAS are known to be mediated by cell-mediated diseases, and patients with psoriasis responded to anticell immunity monoclonal antibody (Ustekinumab: antiIL12/23 monoclonal antibody). The antiB cell strategies may be suitable for autoantibody-mediated diseases but not cell-mediated diseases. Another strategy is to specifically target the receptors of autoantigen (self-deoxynucleic acid, self-DNA), such as TLR7 and TLR9 which could initiate autoantibodies directed against self-DNA. Evidence has recently shown that abnormal recognition of TLR7 and TLR9 was involved in the pathogenesis of SLE, and inhibitors of TLR7 and TLR9 could improve lupus manifestations. Antagonists of TLR7 and/or TLR9 share the highlight for better specific target therapy of SLE and other autoimmune diseases.10

There are some other antiB cell monoclonal antibodies which have been developed, such as antiCD19 (Blinatumomab), antiCD22 (Epratuzumab), and antiCD52 (Alemtuzumab). The results of several large clinical trials using antiB cell surface markers to nonrenal or renal lupus patients has surprisingly not been successful.2 Recently, another type of monoclonal antibody directed against soluble B cell activation molecule, called antiBLyS/BAFF (Belimumab), which targets mature B cells but not precursor B cells, has shown promising clincial trials for SLE patients.2

Depletion of B cells by rituximab (chimeric monoclonal antibodies) causes a minimal-to-moderate decrease in total immunoglobulin levels during a few courses of treatment. Most of the common side effects of rituximab on the patients with autoimmune disease are minimal and tolerable, including drug-infusion reaction, infections and other rare side effects, such as reactivation of hepatitis B virus infection in patients with nonHodgkin lymphoma (NHL), tumor lysis syndrome in lymphoma patients, and rituximab-induced mucocutaneous reactions and progressive multifocal leukoencephalopathy. The next generation of antiB cell antibodies will be fully humanized monoclonal antibodies, which may induce less side effects and be suitable for making formulations for subcutaneous use instead of intravenous use. These trends will benefit autoimmune patients and increase the convenience of medication in the future.

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References 

  1. Arndt P. Spectrum Pharmaceuticals to develop biosimilar Rituximab. [accessed 01.01.11]. Available from: http://www.businesswire.com/news/home/20110105005774/en/Spectrum-Pharmaceuticals-Develop-Biosimilar-Rituximab.
  2. Looney RJ. B cell-targeted therapies for systemic lupus erythematosus: an update on clinical trial data. Drugs. 2010;70:529–540
  3. George JN, Woodson RD, Kiss JE, Kojouri K, Vesely SK. Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the transfusion medicine/hemostasis clinical trials network with a systematic review of rituximab therapy for immune-mediated disorders. J Clin Apher. 2006;21:49–56
  4. Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009;60:2156–2168
  5. Devine EB, Alfonso-Cristancho R, Sullivan SD. Effectiveness of biologic therapies for rheumatoid arthritis: an indirect comparisons approach. Pharmacotherapy. 2011;31:39–51
  6. Cooper MA, Willingham DL, Brown DE, French AR, Shih FF, White AJ. Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Arthritis Rheum. 2007;56:3107–3111
  7. Garcia-Chavez J, Majluf-Cruz A, Montiel-Cervantes L, Esparza MG, Vela-Ojeda J. Mexican Hematology Study Group. Rituximab therapy for chronic and refractory immune thrombocytopenic purpura: a long-term follow-up analysis. Ann Hematol. 2007;86:871–877
  8. Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomized, double-blind, placebo-controlled pilot study. Ann Rheum Dis. 2008;67:1541–1544
  9. Olivieri I, D’Angelo S, Leccese P, Vertone D, Olivieri A. Worsening of psoriasis with rituximab therapy. Clin Exp Rheumatol. 2011;28:926
  10. Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 2010;465:937–941

PII: S0929-6646(11)00171-9

doi:10.1016/j.jfma.2011.05.004

Journal of the Formosan Medical Association
Volume 111, Issue 4 , Pages 181-182, April 2012

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