Correspondence
Rituximab in Relapsing–Remitting Multiple Sclerosis
N Engl J Med 2008; 358:2645-2647June 12, 2008
- Article
To the Editor:
Hauser et al. (Feb. 14 issue)1 report positive results of a phase 2 trial of rituximab in relapsing–remitting multiple sclerosis. I wish to draw attention to the Food and Drug Administration (FDA) public health advisory concerning rituximab.2 This advisory was recently updated after the reported deaths from progressive multifocal leukoencephalopathy of two patients who were treated with rituximab for systemic lupus erythematosus. Keeping pace with the use of more potent and specific immunosuppressant agents, the incidence of opportunistic infections such as progressive multifocal leukoencephalopathy seems to be increasing. In clinical trials of natalizumab for the treatment of Crohn's disease and multiple sclerosis, progressive multifocal leukoencephalopathy developed in three patients, two of whom died.3 Natalizumab was withdrawn from the market, and after a large postexposure evaluation, it was allowed back on the market with extensive safety instructions. Hence, despite the promising results of the newer generation of immunosuppressive drugs, their safety profiles raise concern. In order to optimize the balance between the risks and benefits of treatment, future trials should both incorporate rigorous safety monitoring and target those patients who have a great risk of disability.
3 ReferencesHans M. Schrijver, M.D.
Westfries Gasthuis, 1620 AR Hoorn, the Netherlands
h.schrijver@westfriesgasthuis. nl 1
Hauser SL ,Waubant E ,Arnold DL , et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358:676-688
Full Text | Web of Science | Medline2
FDA public health advisory: life-threatening brain infection in patients with systemic lupus erythematosus after Rituxan (rituximab) treatment. (Accessed May 23, 2008, at http://www.fda.gov/cder/drug/advisory/rituximab.htm.)
3
Berger JR ,Koralnik IJN . Progressive multifocal leukoencephalopathy and natalizumab -- unforeseen consequences. N Engl J Med 2005;353:414-416
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To the Editor:
The use of rituximab, an anti-CD20 antibody, in the treatment of autoimmune diseases, including multiple sclerosis, is surely promising. In their article, Hauser et al. report that CD19 and CD20 have similar expression profiles, and therefore they monitored CD19 cells in the patients with multiple sclerosis who were treated with rituximab. CD19 and CD20 expression is not the same in different stages of B-cell development and function.1 CD20− autoreactive B-cell clones could, in some cases, mediate the damage in autoimmune diseases.2 Therefore, the monitoring of CD19-expressing and CD20-expressing cells could perhaps improve our understanding of the efficacy of rituximab in patients with autoimmune diseases. Analysis of CD20 expression in peripheral blood could also allow us to establish the relationship between the presence of CD20+ B cells and the immune-mediated damage as shown, for instance, in idiopathic autoimmune hemolytic anemia.3 Finally, this approach may contribute to a better selection of patients who are likely to have a good response to treatment with rituximab.
3 ReferencesRaffaele De Palma, M.D., Ph.D.
Second University of Naples, 80131 Naples, Italy
raffaele.depalma@unina2. it Adelina Sementa, M.D.
Moscati Hospital, 83100 Avellino, Italy1
Levesque MC ,St Clair EW . B cell-directed therapies for autoimmune disease and correlates of disease response and relapse. J Allergy Clin Immunol 2008;121:13-21
CrossRef | Web of Science | Medline2
Wiestner A ,Cho HJ ,Asch AS , et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood 2002;100:3426-3428
CrossRef | Web of Science | Medline3
D'Arena G ,Califano C ,Annunziata M , et al. Rituximab for warm-type idiopathic autoimmune hemolytic anemia: a retrospective study of 11 adult patients. Eur J Haematol 2007;79:53-58
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To the Editor:
The monoclonal antibody described in the article by Hauser et al. is another addition to the growing list of immunotherapies that improve magnetic resonance imaging (MRI) findings and relapse rates in multiple sclerosis. Previous studies have shown that the use of antilymphocytic globulin and total lymphoid irradiation in multiple sclerosis is futile.1 In multiple sclerosis, acute demyelination can evolve without B cells,2 and one third of lesions have no lymphocytes.1 There is no disease-specific antibody in multiple sclerosis, unlike other autoimmune diseases in which rituximab is effective.
Previous lessons from trials of multiple sclerosis suggest that there is a huge gap between the treatment effect, as assessed by changes on MRI and relapse rates, and the long-term outcome, as assessed by disability measures such as the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite Scale. The gap is bridged, as in this trial, by statistical extrapolation rather than by longitudinal follow-up data. Inflammatory changes in multiple sclerosis (e.g., enhancing lesions on contrast-enhanced MRI and relapses) are probably tissue reactions to neurodegeneration rather than autoimmune in nature. The timeline of MRI changes in the rituximab trial suggests that the effect was probably antiinflammatory and not due to B-cell depletion. Unless neurodegeneration in multiple sclerosis is arrested, no form of immunotherapy, however well directed, will contain the long-term progression of disability.
2 ReferencesAbhijit Chaudhuri, D.M., Ph.D.
Queen's Hospital, Romford RM7 0AG, United Kingdom
chaudhuria@gmail.com Peter O. Behan, D.Sc., M.D.
University of Glasgow, Glasgow G12 8QQ, United Kingdom1
Chaudhuri A ,Behan PO . Multiple sclerosis is not an autoimmune disease. Arch Neurol 2004;61:1610-1612
CrossRef | Web of Science | Medline2
Barnett MH ,Prineas JW . Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004;55:458-468
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Author/Editor Response
Schrijver raises an important cautionary point. Rituximab has been in use since 1997 for the treatment of B-cell lymphoma and since 2006 for rheumatoid arthritis. Three cases of progressive multifocal leukoencephalopathy have been reported in patients with autoimmune diseases (two with systemic lupus erythematosus and one with vasculitis) who were treated with multiple immunosuppressive agents, including rituximab. The preliminary studies of rituximab reported to date, including the phase 2 study and the recently published phase 1 trial,1 were not designed to assess long-term safety or to detect uncommon adverse events. Rituximab is not currently approved by the FDA for use in multiple sclerosis.
The expression profiles of CD19 and CD20 are similar, although they are not identical. Both markers are expressed on all mature circulating B cells; however, the CD19 antigen is expressed somewhat earlier in the B-cell lineage pathway (e.g., on pro-B cells). For this reason, CD19 is a reliable surrogate for the presence of residual B cells after treatment with an anti-CD20 antibody. The near-absence of CD19+ cells observed after treatment clearly indicates that the B-cell pool was effectively depleted from the circulation.
The comments by Chaudhuri and Behan highlight the gaps that exist in our current understanding of the pathogenic cascade leading to chronic multiple sclerosis. The relationship among focal inflammation, clinical relapses, and late progression is certainly one of the most important unresolved questions in the field. The ongoing trial of rituximab in primary progressive multiple sclerosis may shed some light on this question. It is often through bedside experiments — such as the trials of rituximab in multiple sclerosis — that our fundamental concepts of disease causation receive real-life tests.
1 ReferencesStephen L. Hauser, M.D.
Emmanuelle Waubant, M.D., Ph.D.
University of California at San Francisco, San Francisco, CA 94143
hausers@neurology.ucsf. edu Amit Bar-Or, M.D.
Montreal Neurological Institute, Montreal, QC H3A 2B4, Canadafor the HERMES Trial Group
1
Bar-Or A ,Calabresi PA ,Arnold D , et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008;63:395-400
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