B Cell Depletion: On the Rise
Article Outline
Abbreviations: BAFF, B cell activating factor of the tumor necrosis factor family, SLE, Systemic lupus erythematosus
B cell depletion using rituximab, initially developed as a treatment modality for B cell neoplasms and US Food Drug Administration-approved for that purpose in 1997, is a rising therapy for various immune-mediated diseases. In this issue of The Journal, El-Hallak et al retrospectively describe their experience with B cell depletion therapy in the treatment of pediatric autoimmune diseases in a single pediatric institution.1 Their 10 patients had a variety of conditions. Some of these conditions, such as Evans syndrome or systemic lupus erythematosus (SLE), are well known to respond to rituximab. Several other patients had less well categorized autoimmune conditions for which there has been no previous experience with B cell depletion. Although the literature on the use of rituximab in immune-mediated diseases is expanding, the data on pediatric patients are still very limited; therefore, this report is important. Multiple clinical trials are currently underway studying a wide variety of diseases (Table).2 In addition, case reports suggest that B cell depletion therapy is effective in many other immune-mediated conditions, such as myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, renal transplantation, or ABO-mismatched transplantation, to name just a few. Rituximab is currently Food and Drug Administration-approved only for 1 autoimmune condition, moderately to severely active rheumatoid arthritis in adults. Unfortunately, controlled clinical trials for pediatric patients are much harder to perform because of the small number of eligible patients. Therefore, the interpretation for the safety and efficacy of B cell depletion therapy in pediatric autoimmune disease largely relies on the analysis of case series and extrapolation from adult studies.
See related article, p 376
Table. Immune-mediated conditions studied for their response to B cell depletion therapy
| Rheumatic diseases |
•Systemic lupus erythematosus •Rheumatoid arthritis •Sjögren syndrome •Inflammatory myopathy (dermatomositis, polymyositis, juvenile dermatomyositis) •ANCA-associated vasculitis •Systemic sclerosis |
| Hematologic diseases |
•Cold agglutinin disease •Aplastic anemia •Acquired pure red cell aplasia •Idiopathic thrombocytopenic purpura •Thrombotic throbocytopenic purpura •Evans syndrome •Acquired hemophilia •Hemophilia with high titer inhibitor |
| Neurologic diseases |
•Chronic focal encephalitis (Rassmussen’s encephalitis) •Multiple sclerosis •Opsoclonus myoclonus syndrome •Polyneuropathy with immunoglobulin M autoantibodies •Stiff person syndrome |
| Renal diseases |
•Lupus nephritis •Membranoproliferative glomerulonephritis |
| Gastrointestinal diseases |
•Ulcerative colitis •Primary biliary cirrhosis |
| Endocrine diseases |
•Graves disease •New onset type I diabetes mellitus |
| Other diseases |
•Pemphigus •Bullous pemphigoid •Chronic urticaria •Chronic graft versus host disease |
Rituximab is a chimeric anti-CD20 monoclonal antibody, comprising a human IgG1κ constant region and a murine variable region. CD20 is a signature B cell differentiation antigen that is expressed on the surface of pre-, naive, mature, and memory B cells, but not on plasma, early pro-B, or stem cells.3 Depletion of B cells is thought to be mediated by the induction of antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. B cells are not only precursors of antibody-producing plasma cells, but also highly effective antigen-presenting, cytokine-producing, and regulatory cells. The effects of rituximab probably rely on interference with all these functions. Rituximab not only depletes B cells, but can also alter B cell homeostasis and improve B cell abnormalities.4 Although plasma cells are not depleted, a reduction in pathogenic autoantibodies is seen. One example is a decrease in rheumatoid factor titers in rheumatoid arthritis.5 This is presumably caused by interference with activation and differentiation of B cells toward the effector plasma cell. Total immunoglobulin levels usually remain within reference range. The effect obtained by rituximab is transient in most cases. El-Hallak et al reported that B cell repopulation occurred at a mean of 8 months, although 2 patients continued to have prolonged B cell depletion 5 years and 17 months after initial treatment. This observation is consistent with earlier studies that showed B cell repopulation at a mean of 8 months after rituximab therapy.6 Ng et al report that repeat treatment with rituximab is effective; their series included 7 adult patients with refractory SLE who responded to as many as 3 separate cycles of rituximab.7
Is rituximab safe? Overall, rituximab appears to be a well-tolerated treatment with a modest toxicity profile, although data are very limited for pediatric patients. More than 540,000 patients worldwide have received rituximab, most for the treatment of B cell malignancies.8 Accordingly, most of the safety information stems from the treatment of malignancies rather than autoimmune disease; this makes the safety assessment somewhat difficult, because the concomitant aggressive chemotherapeutic regimens often have significant toxicities in their own right. El-Hallak et al also reported an acceptable toxicity profile for a prolonged follow-up period in their study. One death was reported, but was probably caused by the severity of the underlying disease process. Serious infections occurred, but at the same rate as before rituximab therapy. Interpretation of their data is limited by the small number of patients. According to the literature, the most common adverse effects observed with rituximab are infusion-related and relatively easy to manage, similar to those seen with other chimeric monoclonal antibodies. Infusion-related adverse effects include transient fever, chills, nausea, headache, and less common allergic reactions, such as bronchospasm, urticaria, pruritus, rash, flushing, and angioedema. More severe reactions, such as hypotension, or frank anaphylaxis, occur rarely. Infusion-related adverse effects are more common with the initial infusion. Edwards et al reported that in adult patients with autoimmune diseases, delayed respiratory reactions occur as long as 10 days after rituximab infusion, with symptoms suggestive of bronchitis, pneumonitis, or serositis; those reactions are hard to differentiate from infections.9 Severe adverse effects include hematologic toxicity, such as thrombocytopenia and neutropenia. Many of those cases may have been caused by the concomitant use of myelosuppressive agents rather than rituximab itself. However, cases of severe neutropenia and thrombocytopenia have also been reported in childhood autoimmune hemolytic anemia when rituximab was used as a single agent.10 The pathogenesis of this complication is unclear. Clearly, there is a lower incidence and severity of adverse events in the treatment of autoimmune diseases when compared with malignancies, presumably because of the lack of a tumor lysis and cytokine release syndrome. According to Bennett et al, one exception may be the occurrence of serum sickness, which occurred at a rate of 12% in pediatric subjects who were treated for chronic idiopatic throbocytopenic purpura.11 Infectious complications, particularly opportunistic infections, have been described, but it is unclear how significant this risk is, because patients often receive concomitant immunosuppressive medications. Long-lasting effects of rituximab on the developing immune system are not known. In 1 case report of the use of rituximab during pregnancy, complete B cell depletion was noted in the newborn. B cell repopulation occurred by the age of 4 months, leading to a normal immune status at the age of 20 months.12 To what extent this observation can be extrapolated to pediatric patients is not clear.
How should rituximab therapy be monitored? In addition to disease-specific clinical and laboratory markers, are there rituximab-specific monitoring parameters that can help to fine tune the therapy? An obvious monitoring parameter is the number of circulating B cells with flow cytometry. A low number of circulating B cells is indicative of successful B cell depletion. However, re-population of B cells is not necessarily associated with clinical relapse. Leandro et al report that approximately 50% of their patients with rheumatoid arthritis experience a relapse of disease with the return of B cells, and the other 50% at a variable time thereafter, often after prolonged periods,6 similar to this study’s findings.1 What differentiates these patients is unclear. Patients who relapse early tend to repopulate with memory B cells, rather than with naïve B cells.6 This might help in identifying patients who are at high risk for relapse after B cell depletion. The assessment of changes in B cell abnormalities and recurrence of specific B cell subtypes requires specific studies and assessment of B cell panels. Primary B cell abnormalities are also common. In SLE, an expansion of memory B cells and CD27+ plasmablasts is often seen and may correct with rituximab therapy.4 Other specific markers useful in rituximab therapy may include the B cell activating factor of the tumor necrosis factor family (BAFF), also known as B lymphocyte stimulator.13 BAFF plays a major role in B cell activation and survival. It is produced mostly by monocytes/macrophages and acts on B cells through different receptors. BAFF levels have been shown to be elevated in many autoimmune diseases, most prominently in SLE. BAFF levels are not increased in all patients with SLE, but only in approximately 50% of these patients.14 BAFF levels increase after rituximab therapy.15 Presumably, this increase occurs by different mechanisms: An early increase simply by a decrease in corresponding receptors, therefore increasing free BAFF levels, and by a delayed upregulation of BAFF through transcriptional mechanisms. After rituximab therapy, BAFF levels initially rise sharply, but then decrease with B cell repopulation.16 On one hand, it remains to be seen whether monitoring of BAFF is helpful in determining which patients are at risk for disease relapse. However, the co-administration of rituximab and anti-BAFF therapy is, at least theoretically, a very tempting approach for obtaining long-term depression of B cell function, and, thus, disease remission. A BAFF antagonist, belimumab, has already been used in phase II clinical trials.17
In summary, B cell depletion therapy is a very promising treatment modality for a wide spectrum of immune mediated diseases, but larger controlled trials are needed. Much remains to be learned about the appropriate monitoring of therapy.
Added while in print: A recent report by the FDA indicates that patients treated with rituximab may be at an increased risk for progressive multifocal leukoencephalopathy (http://www.fda.gov/cder/drug/infopage/rituximab/default.htm).
References
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- . B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus. 2006;15:570–576
- . Increase of B-cell activating factor of the TNF family (BAFF) after rituximab: insights into a new regulating system of BAFF production. Ann Rheum Dis. 2006;[Epub ahead of print]
- Differential effects on BAFF and APRIL levels in rituximab treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2006;8:R167
- . Belimumab Human Genome Sciences/Cambridge Antibody Technology/GlaxoSmithKline. Curr Opin Investig Drugs. 2006;7:464–472
PII: S0022-3476(07)00006-6
doi:10.1016/j.jpeds.2006.12.050
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Clinical Effects and Safety of Rituximab for Treatment of Refractory Pediatric Autoimmune Diseases
