Rituximab in Autoimmune Hematologic Diseases: Not Just a Matter of B Cells Roberto Stasi Rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cellsurface antigen, has been investigated extensively in autoimmune disorders. Following the encouraging results in immune thrombocytopenia (ITP), the use of this agent was explored in other autoimmune hematologic diseases, most notably autoimmune hemolytic anemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), characterized by the presence of pathogenetic autoantibodies. Although randomized clinical trials are lacking, the cumulative data would suggest that rituximab has a beneficial role in their treatment. Response to B-cell– depleting therapy is actually associated with a significant decrease of circulating autoantibodies. However, several lines of evidence indicate that the T-cell compartment may also be modulated by these interventions. The doses and the duration of rituximab treatment in patients with autoimmune diseases are still unclear. The incidence of severe side effects is low but not insignificant. In particular, the risk of systemic infections and viral reactivation is a major concern. Semin Hematol 47:170 –179. © 2010 Elsevier Inc. All rights reserved.
T
he pathogenesis of autoimmune disorders involves an ongoing interaction of numerous types of cells and cell mediators.1 B cells are thought to play a central role in supporting the development and perpetuation of autoimmunity as a result of research in both mice and humans.2 It has now become apparent that in addition to the antibody-producing function, B cells serve many other purposes within the immune system (Figure 1). In the process of undergoing activation and maturation into memory B cells and plasma cells, they are very efficient antigen-presenting cells (APCs) to T cells of soluble antigens that are bound specifically by the B-cell antigen receptor (surface immunoglobulin).3 They are actually 100 to 1,000 times more potent in antigen presentation than the other APCs, such as macrophages or dendritic cells, and are especially effective at presenting low concentrations of antigen.4 In addition to presenting the antigen, B cells also provide costimulatory signals for T cells that lead to T-cell activation.1,5 This process involves molecules such as B7/CD28, CD40/CD40 ligand (CD40L), and OX40 ligand/OX40 on the surface of B Department of Haematology, St George’s Hospital, London, United Kingdom. Address correspondence to Roberto Stasi, MD, PhD, Department of Haematology, St George’s Hospital, Blackshaw Road, SW17 0QT London, UK. E-mail:
[email protected] 0037-1963/10/$ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2010.01.010
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cells and T cells, respectively, and appears to determine the extent of primary expansion of CD4⫹ T cells both in mice6,7 and in humans.8 B cells can respond to or secrete cytokines such as interleukin (IL)-1, IL-10, IL-6, interferon (IFN)-␥, and tumor necrosis factor (TNF)-␣, thereby establishing or enhancing a pro-inflammatory environment.9 In fact, these mediators modulate the migration of dendritic cells, activate macrophages, exert a regulatory role on T-cell functions, and provide feedback stimulatory signals for further B-cell activation.10 Finally, B cells also seem to play an important role in promoting normal follicular dendritic cell function11 and normal lymphoid architecture in the development of secondary lymphoid tissues.12 Derangement of B-cell functions can actually lead to a breach of tolerance and to the development of autoimmune diseases, characterized not only by the presence of pathogenetic autoantibodies but also by dysregulation of multiple aspects of cellular immunity.1 On these grounds a rational approach to treatment of autoimmune diseases involves targeting B cells. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been the first and by far most investigated agent in this setting. It has been licensed for use in rheumatoid arthritis (RA), but it is also widely used off-label in a number of other autoimmune disorders. This review will focus on the results of B-cell depletion therapy based on rituximab in autoimmune hematological diseases. Seminars in Hematology, Vol 47, No 2, April 2010, pp 170 –179
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Figure 1. Mechanism of B-cell functions. The figure shows the main functions of B cells through which they contribute to the pathology of immune-mediated hematological disorders. (A) Production of autoantibodies. These can cause cytopenia either via complement activation or antibody-dependent-cell mediated cytotoxicity. They can also bind to and inhibit coagulation factors such as FVIII (congenital hemophilia with inhibitors and acquired hemophilia) or proteases such as ADAMTS13 (thrombotic thrombocytopenic purpura). (B) APC function. This results in clonal expansion of cytotoxic T cells and cytokine production. (C) Production of proinflammatory cytokines, such as IL-6, TNF, and IL-10, which activate macrophages and dendritic cells, as well as various stages of immunoregulatory T cells.
MECHANISMS OF ACTION OF RITUXIMAB IN AUTOIMMUNE DISORDERS The proposed mechanisms for the elimination of B cells by rituximab are reviewed elsewhere in this issue of Seminars in Hematology (see article by Weiner). Rituximab given at lymphoma-like doses induces a rapid (usually within 1 week) and marked depletion of circulating B cells in the majority of patients with autoimmune diseases.13,14 B-cell numbers in the blood remain low for about 6 –12 months, until hematopoietic stem cells (which do not express CD20) produce recovery of lymphopenia.13,14 Disorders such as systemic lupus erythematosus (SLE) and idiopathic inflammatory myopathy seem to be associated with a less pronounced or shorter depletion in the peripheral blood,15,16 which may partly be explained by pharmacokinetics and pharmacodynamic differences. Interestingly, rituximab can be detected in circulation for months following its administration, and it is not clear whether the initial depletion is followed by a period of continued depletion.17 A bone marrow study in patients with RA suggested that there is continuing depletion of B-cell precursors probably until rituximab is cleared.18 The long-lived plasma cell compartment does
not appear to be substantially affected by anti-CD20 therapy, as only modest decreases in IgG levels occur during repeated courses.13,14,19,20 Nevertheless, reduced antibody titers after vaccination against pneumococcal and other antigens in patients receiving rituximab suggest that a clear diminution occurs in the induction of new long-lived plasma cells. By contrast, titers of autoantibodies such as anti– glycoprotein IIB/IIIA in immune thrombocytopenia (ITP),21 anti-erythrocyte antibodies in autoimmune hemolytic anemia (AIHA),22 antiADAMTS13 in thrombotic thrombocytopenic purpura (TTP),23 rheumatoid factor in RA,24 antineutrophil cytoplasmic antibodies in vasculitis,25,26 and anti– double-stranded DNA (dsDNA) antibodies in SLE,27 can drop dramatically or even become undetectable after B-cell depletion. Although some patients can achieve sustained clinical remission despite persistence of detectable autoantibodies, in many of these studies clinical improvement following rituximab therapy was associated with a significant decrease in autoantibody serum levels. Such findings suggest that autoreactive antibodies are produced by short-lived plasma cells or plasmablasts, which are not replenished after B-cell depletion.
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Peripheral blood B-cell reconstitution after rituximab therapy has been investigated in detail in patients with RA. These studies show an increased frequency of detectable transitional B cells and CD5⫹ B cells,14,28 similarly to B-cell reconstitution after bone marrow transplantation.29 At the start of repopulation, an increased number of circulating plasmablasts/plasma cells can be seen, in which the complementarity-determining regions in the immunoglobulin genes display the characteristics of a T-cell–induced mutational pattern.30 In this regard, CD4⫹ T-cell– depletion studies have demonstrated that an intact CD4⫹ T-cell compartment is required for induction of strong antibody responses.31 On the other hand, activated B cells are thought to be fundamental for coordinating T-cell functions, as B-cell– depleted mice exhibit a dramatic decrease in numbers of CD4⫹ and CD8⫹ T cells and a 10-fold inhibition of memory CD8⫹ T cells.32,33 These observations may explain some of the findings in patients with ITP, in whom response to rituximab was associated with the clearance, and refractoriness to therapy with the persistence, of pathogenetic antibodies21 and oligoclonal/clonal T cells in the peripheral blood.34 Successful B-cell depletion in ITP also results in normalization of the type 1 T-helper (Th)1–Th2 ratio,34 an effect that may be mediated by reduced expression of molecules responsible for T cell costimulatory signals.35 The normalization of the defective suppressive capacity of regulatory T cell (Treg) following rituximab therapy is intriguing,36 as a central deficiency of Tregs can break the immune tolerance and allow for unchecked activation of autoreactive Th1 cells and B cells. However, Treg changes have not been consistently observed after rituximab in other autoimmune diseases37,38 and it is not yet clear whether the Treg derangement is a primary event or simply the consequence of other abnormalities of the immune system. The effects of rituximab on other cellular compartments remain unknown, although it has been speculated that B-cell depletion in RA also affects macro-
phages and other invasive cells by reorganizing them in the synovium.39 In summary, the rationale for the use of B-cell depletion in autoimmune diseases has been confirmed by both clinical and experimental data. One of the main effects of rituximab is actually to decrease the production of pathogenic autoantibodies by short-lived plasma cells derived from CD20⫹ B cells. However, rituximab also reduces the critical mass of antigen-presenting cells (APCs) to pathogenic autoreactive T cells, thereby blocking the B cell–T cell interaction. The effects on the Treg compartment may play an important role in the response to rituximab, but how rituximab modulates Treg function is unknown. The mechanisms of disease recurrence also remain unclear. Taking into account the findings in ITP, we can speculate that rituximab therapy is effective only when T-cell subsets can be modulated. In some patients clonal autoreactive memory T cells are not depleted and provide decisive help for activation of newly generated autoreactive B cells.
RESULTS OF CLINICAL TRIALS We focus here on the three conditions that comprise most of the published literature: primary immune thrombocytopenia (previously referred to as idiopathic thrombocytopenic purpura or ITP), autoimmune hemolytic anemia (AIHA), and thrombotic thrombocytopenic purpura (TTP). The results in less common autoimmune hematologic diseases are reviewed in recent articles to which the reader is referred.40 – 42 A search of PubMed was conducted with each disease name and abbreviation combined with “rituximab” up to June 2009. Additional published studies identified from the text of any of the publications identified on PubMed were also included. A summary of clinical trial results is provided in Table 1, with details reported below.
Primary Immune Thrombocytopenia ITP is characterized by isolated thrombocytopenia in the absence of obvious causes of thrombocytopenia such as infections, liver diseases, systemic autoimmune
Table 1. Summary of Treatment Results of Autoimmune Haematologic Disorders With Rituximab
Disease
No. of Studies
No. of Patients
ITP ITP AIHA TTP
1943* 251,52 104 541
313 35 116 61
Rituximab Regimen 375 100 375 375
mg/m2/wk ⫻ 4 mg/wk ⫻ 4 mg/m2/wk ⫻ 4 mg/m2/wk ⫻ 4
Response ORR (%)
CR (%)
Response Duration
62 71 71 98
46 46 29 NA
1–360⫹ 1–16⫹ 1–96⫹ 2–37
*Studies including five or more patients. Abbreviations: ORR, overall response rate; CR, complete response; ITP, primary immune thrombocytopenia (idiopathic thrombocytopenic purpura); AIHA, autoimmune hemolytic anemia: TTP, thrombotic thrombocytopenic purpura; NA, not available.
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disorders, etc. The mechanisms of the thrombocytopenia in ITP involve both an increased destruction of platelets in the reticuloendothelial system (notably the spleen), and an antibody-mediated suppression of megakaryocyte production.43 The clinical manifestations of ITP are highly variable and range from complete lack of symptoms to frank hemorrhage from any site, the most serious of which is intracranial. For patients with severe thrombocytopenia (platelet counts ⬍20 –30 ⫻ 109/L) who do not recover spontaneously or after corticosteroids and go on to develop chronic ITP, there is a long list of available approaches. The first prospective trial of rituximab for the treatment of an autoimmune disorder was actually conducted in ITP, and its results published in 2001.13 In that study, 25 individuals with chronic ITP and platelet counts ⬍30 ⫻ 109/L received rituximab according to the lymphoma protocol (375 mg/m2 once weekly for 4 weeks). A complete response (platelet count ⬎100 ⫻ 109/L) was observed in five cases, a partial response (platelet count 50 –100 ⫻ 109/L) in five cases, and a minor response (platelet count ⬍50 ⫻ 109/L, with no need for continued treatment) in three cases, for an overall response rate of 52%. In seven cases, responses were sustained (ⱖ6 months or longer). Much of the subsequent literature about rituximab in ITP is made of very small series or anecdotal reports. To eliminate this “publication bias,” meaning the known tendency to report positive rather than negative results, a systematic review published in 2007 has restricted the analysis of efficacy results to studies enrolling five or more patients with chronic ITP.44 The final analysis included 19 eligible reports on efficacy (313 patients).44 The pooled response rate (platelet count ⱖ50 ⫻ 109/L) was 62.5%, the complete response rate (platelet count ⱖ150 ⫻ 109/L) was 46.3%, and the median duration of response was 10.5 months. There was no significant difference in the response rates between splenectomized and nonsplenectomized patients for either adults or children and for overall response or complete response.45 In most studies, there were two patterns of response: the majority of responders (⬃72%) responded to rituximab within 4 weeks, whereas the rest did not achieve a complete response until several weeks or even months after the start of rituximab therapy.21 These distinct patterns of response suggest that rituximab may operate through at least two separate mechanisms. The rituximab response in early responders is too rapid to be explained by the depletion of autoantibodies. Instead, it has been proposed that in these patients, opsonized B cells block the macrophage Fc-receptor function, reducing the sequestration of platelets in the spleen.13,46 Further, it has been speculated that the late and sustained responses are more likely to result from the actual removal of B cells as precursors of autoantibody-producing plasmablasts, and subsequent reduction in autoantibody levels.13
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However, the lack of direct correlation between antiplatelet antibody levels and clinical response in some patients suggests that additional mechanisms involving T cells may also be at work.34,36 The point at which rituximab should be used, prior to or after splenectomy, has been much debated.45 A phase II multicenter trial has assessed the safety and efficacy of rituximab as an alternative to splenectomy in adults with chronic ITP (duration ⬎6 months) who were potential candidates for splenectomy.47 The result indicates that the immunotherapy can actually prevent or delay splenectomy, although only 40% of patients had platelet counts ⱖ30 ⫻ 109/L at 2 years. In addition, the follow-up time was too short to assess the real impact of this approach on the outcome of patients as well as the long-term safety profile of rituximab. As far as children are concerned, Mueller et al have recently described a response duration in excess of one year in a subset of nonsplenectomized children with chronic ITP who were treated with rituximab.48 This follows their initial report of a phase I–II trial in which 31% of children with chronic ITP (11 of 36) achieved sustained platelet counts of ⬎50 ⫻ 109/L.49 The rate of durable responses after treatment with rituximab in this report is similar to those reported in other pediatric series.50,51 While most studies using rituximab in ITP employed the same dose as is used to treat lymphoma (375 mg/m2 weekly for 4 weeks), more recent reports suggest that treatment with four once-weekly doses of 100 mg (fixed-dose) rituximab can produce the same results.52,53 The use of rituximab as upfront therapy in patients with newly diagnosed ITP has been investigated recently in a prospective randomized study.54 The addition of rituximab to a therapeutic pulse of dexamethasone significantly improved the long-term rate of sustained response (platelets ⬎50 ⫻ 109/L at 6 months) at 85%, more than double the rate of dexamethasone alone (39%). Even after failure of dexamethasone alone (defined as platelets ⬍20 ⫻ 109/L within 6 months) in 27 patients, the administration of rituximab and dexamethasone was effective with a sustained response in more than half of the latter group. Because of the efficacy of rituximab as salvage therapy, and because the long-term side effects of rituximab in ITP remain a concern, the anti-CD20 strategy does not appear to be indicated as standard first-line therapy.55
Autoimmune Hemolytic Anemia Based on the characteristic temperature reactivity at which the red blood cell (RBC) autoantibodies show maximal binding, AIHA is classified as either warm AIHA or cold AIHA. In rare cases, patients can have both warm and cold autoantibodies (mixed AIHA).
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Warm autoantibody AIHA accounts for about 80% of all of the AIHA cases, and can be either idiopathic (60% of cases) or secondary to lymphoproliferative and autoimmune disorders or infections (40% of cases).56 Warm antibodies react strongly with RBC antigens at about 37°C and their affinity for RBCs decreases at lower temperatures. Antibodies involved in warm autoantibody AIHA are polyclonal and they react with self-antigens that are common to all RBCs except those that lack Rh antigen.56 Most of them are from the IgG class, whereas IgM and IgA are rarely involved. Cold autoantibody AIHA constitutes approximately 20% of all AIHA cases, and is subdivided into cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH). CAD usually develops in elderly individuals as a result of the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on RBCs. Cold autoantibodies bind to RBCs most efficiently at 0 – 4°C and typically show little affinity at physiologic temperature. The presence of these antibodies may result in hemolytic anemia due to complement-mediated RBC destruction in the reticuloendothelial system. Slowing of blood flow with occlusion of superficial blood vessels by agglutinated RBCs can cause a Raynaud-like syndrome (acrocyanosis). The causative antibody in PCH, also referred to as Donath-Landsteiner antibody, is an IgG immunoglobulin with specificity for the P blood group system, although other targets have been reported. The DonathLandsteiner antibody fixes the first two components of complement in the cold and completes the cascade on warming to 37°C. PCH occurs most frequently in children, and is commonly associated with an upper respiratory tract infection. Rituximab has been demonstrated to be useful in treating warm and cold AIHA refractory to conventional therapies, although comparisons of response rates are difficult owing to a lack of universal agreement on the variable definitions of a response. Responses were assessed based on the following: an increase of hemoglobin concentrations; a reduction in reticulocyte counts; reduction or absence of hemolysis (based on lactate dehydrogenase [LDH] and bilirubin levels); and decreased need of transfusion. In nine studies in warm AIHA including five or more patients, six in adults and three in children, the use of rituximab produced a clinical response in 87 of 103 (85%) patients.22,57– 64 Patients typically received three to four infusions at a dose of 375 mg/m2 at weekly intervals, often in combination with other therapies. The rapidity of response to rituximab treatment varied considerably (2–16 weeks), but most of the responses were seen between 4 and 8 weeks from the first rituximab infusion. The association of AIHA with chronic lymphocytic leukemia did not affect the response rate
R. Stasi
to rituximab.59,62 In this setting, one particularly effective protocol combined dexamethasone and cyclophosphamide with rituximab, leading to a response in eight of eight patients.62 With regard to CAD, a few prospective series have been published. In the largest one, Berentsen et al reported on rituximab single-agent therapy administered according to the lymphoma protocol to 27 patients with primary CAD.65 A response was defined as improvements in hemoglobin levels of at least 2 g/dL, reduction of serum IgM levels by at least 50% of the initial level or to the normal range, improvement of clinical symptoms, and transfusion independence. Fourteen of 27 patients responded to their first course of rituximab, and six of 10 relapsed patients responded to re-treatment, resulting in an overall response rate of 54%. Responders achieved a median increase in hemoglobin levels of 4.0 g/dL and a median decrease in IgM levels by 54%. Interestingly, four patients classified as nonresponders achieved increases in hemoglobin level from 2.0 to 4.3 g/dL, suggesting a clinical benefit that may not be detected by standard criteria. Median time to response was 1.5 months (range, 0.5– 4.0) and median observed response duration was 11 months (range, 2– 42). The results of a similar trial in 20 patients (13 with primary CAD and seven with CAD associated with a malignant B-cell lymphoproliferative disease) by Schöllkopf et al were in agreement with these findings (response rate of 45%), although a shorter response duration was reported (median, 6.5 months; range, 2–10 months).66 The potential value of rituximab for the treatment of this condition is reinforced by the results of a Norwegian population-based retrospective study of 86 patients with primary CAD.67 Rituximab was the only treatment to induce a complete response in any patient, with an overall response rate of 60%. Conventional treatment with alkylating agents (with or without corticosteroids) gave a response rate of 16%, with no complete responses. The evidence on the use of rituximab for the treatment of PCH is confined to a single anecdotal report in a 64-year-old woman who was successfully treated with rituximab according to the lymphoma regimen.68
Thrombotic Thrombocytopenic Purpura TTP is a life-threatening multisystem disorder that in its most typical form is characterized by microangiopathic hemolysis, thrombocytopenia, neurological abnormalities, fever, and renal dysfunction.69 Most cases of TTP are caused by a deficiency in a plasma metalloprotease, ADAMTS13, which cleaves a specific peptide bond in plasma von Willebrand factor (vWF). In fact, unusually large multimers of vWF (ULVWF) can be demonstrated in the plasma of patients with TTP.70 These ULVWF multimers mediate platelet clumping in
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the microvasculature, ultimately resulting in the formation of hyaline microthrombi in different organs, microangiopathic hemolytic anemia, and thrombocytopenia. The ADAMTS13 deficiency in patients with sporadic TTP usually results from the presence of inhibitory IgG autoantibodies, which have been detected in 70% to 80% of such patients.71 Since the early 1990s, plasma exchange has become the treatment of choice for TTP. However, many TTP patients need additional immunosuppressive therapy with corticosteroids, vincristine, cyclophosphamide, splenectomy or a combination of the these therapies.69 The successful use of rituximab to treat patients with a variety of autoimmune diseases has led to a number of small case series and two prospective uncontrolled trials23,72 in patients with immune-mediated TTP. Patients were refractory to at least one of the following: plasma exchange, corticosteroids, vincristine, splenectomy, immunosuppressive agents, intravenous immunoglobulin. Most patients were treated with rituximab at lymphoma doses and all received plasma exchange concurrently, at least until disease symptoms stabilized. How long plasma exchange should be delayed after rituximab infusion is a controversial issue. Some have recommended delaying plasma exchange for 72 hours after rituximab administration to maximize the effect of the drug73; others maintain that an interval of 24 hours between rituximab treatment and plasma exchange is adequate.74,75 In six studies each including five or more cases, rituximab therapy was effective in achieving a clinical remission in 65 of 67 (97%) patients.23,72,76 –79 The median time to response ranged between 11 and 26 days from the first rituximab infusion. The objective parameters to measure response included improvements in hemoglobin levels, platelet counts, LDH elevation, ischemic signs and need for plasma exchange. Patients with longstanding TTP appeared to respond as well to rituximab treatment as those being treated during their first acute episode, and a decrease in ADAMTS13 antibody titers after rituximab therapy has been consistently reported.23,72,77 Because all of these reports with small numbers of patients might suffer from a publication bias, a larger phase II study assessing the safety, efficacy and tolerability of rituximab in combination with plasma exchange was started in March 2006 and is due to be completed in June 2010 (ClinicalTrials.gov identifier: NCT00937131). One of the limitations of the cited studies is that the median duration of follow-up was only 10 months. Relapses in three of eight patients have been reported only by Heidel et al, with a median progression free survival upon rituximab of 45.8 months (range, 2.4 – 50.9 months).78 With regard to subsequent outcome of patients who relapsed, re-treatment with rituximab resulted in durable responses achieved again in the majority of those so treated.80
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Finally, a small case series has suggested that rituximab used as pre-emptive treatment may be effective in maintaining a sustained remission in patients with antiADAMTS13 antibodies in whom other treatments failed to limit the production of inhibitors, and suggests that re-treatment with rituximab should be considered when ADAMTS13 activity decreases and inhibitors reappear into the circulation, to avoid a new relapse.81
SAFETY Infusion-related reactions, which occur mainly with the first infusion and are very common in patients with non-Hodgkin lymphoma (NHL),82 have been infrequently reported in autoimmune diseases.40 Moreover, they were generally mild in nature and did not warrant the discontinuation of rituximab. One life-threatening adverse event has been reported during the use of rituximab for refractory TTP. A 20-year-old female patient developed acute biventricular cardiogenic shock in response to treatment with a single dose of rituximab.83 The use of paracetamol, antihistamines, and corticosteroids are recommended as pretreatment to help control infusion reactions.82 Rapid infusions of rituximab (90-minute infusion schedule; 20% of the dose administered in the first 30 minutes, remaining 80% administered over 60 minutes) with corticosteroid premedication appear to abrogate severe infusion reactions in patients with NHL,84,85 but no studies with this modality have been reported in autoimmune diseases. However, the use of low-dose rituximab in autoimmune cytopenias has produced minimal infusion-related side effects.52,86 Rituximab-associated infections and viral reactivation are reasonable concerns due to the depletion of the B-cell component of the immune system. In randomized phase III trials in RA, the infection rate was 35% to 41%,19,20,87 with serious infections occurring in 1.2% to 3.7% of patients. A review of the use of rituximab in other autoimmune disorders found that in 25 studies involving 389 patients the incidence of serious infections varied from 2.8% to 45% (mean, 12.5%).41 However, patients were frequently on concomitant immunosuppressive therapies, which also enhanced or contributed to susceptibility to infection. A recent study described 57 cases of progressive multifocal leukoencephalopathy (PML) for US Food and Drug Administration–approved or off-label use of rituximab in patients receiving or having received other immunosuppressive therapies.88 Only five of these patients had an autoimmune disorder. PML is caused by reactivated JC virus, which is present in latent form in about 80% of adults. Reactivation of the hepatitis B virus (HBV) is also considered to be associated with immunosuppression caused by rituximab treatment. Among HBsAg-negative/anti-HBc–positive patients with aggressive lymphoma treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), 25% developed HBV reactivation.89 Finally, increase of
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hepatitis C virus (HCV) RNA levels during or after rituximab-combination chemotherapy has also been described,22,90 although the clinical significance of these findings is uncertain. The use of rituximab has been directly attributed as a cause of death in eight studies representing 147 patients with various autoimmune diseases.41 The death rate in these eight studies varied from 2.8% to 33% (mean, 7.4%). Of course, there are many more reports including hundreds of patients altogether in which rituximab appears to be safe, and in which no fatality could be attributed to its use. Besides, the accurate interpretation of the deaths reported in the eight studies is very difficult, because patients had a wide spectrum of diseases and the time at which rituximab was used in the course of the disease, the severity of the disease, and the concomitant therapies that contributed to profound immune suppression were different in each study. The incidence of human anti-chimeric antibodies (HACA) is very low in patients with NHL and does not influence the efficacy or toxicity of rituximab therapy.82 On the other hand, in some patients with autoimmune disease studies have reported the appearance of significantly high titers of HACA, which were associated with failure to deplete B cells.41 Serum sickness, characterized by fever, rash, and arthralgias, can occur in a minority of patients, particularly in those with autoimmune conditions, who receive rituximab and develop HACA. The rates of serum sickness ranged from 6% to 20% in patients receiving rituximab for pediatric chronic ITP or Sjögren’s syndrome.91 The following tests are recommended before initiating rituximab therapy: complete blood cell count with differential, and CD19 counts, AST, ALT, HBV and HCV, human immunodeficiency virus, electrocardiogram, tuberculin purified protein derivative (PPD) reaction, and chest x-ray. These tests will identify subclinical infections that could flare on rituximab, and patients with borderline cardiac function that would be more likely to experience severe infusion adverse events. Also, no vaccine should be administered just before administration of the drug. It is unclear whether the immune response to vaccine after rituximab has been administered is sufficient. Therefore, when vaccinations are contemplated, these should be done at least 1 month before drug administration. After therapy has been administered, the number of CD19⫹ cells can be monitored every 3 months to follow the return of B-cell counts. Some investigators use this marker to decide on when to retreat. It is still unclear how often rituximab should be administered in patients with autoimmune diseases.
CONCLUSIONS AND FUTURE DIRECTIONS Over the last decade, the use of rituximab has transformed the treatment algorithm of many autoimmune
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hematologic disorders. Optimizing the use of the rituximab and developing new agents will be critical to continuing these advances. At this time, remarkable efforts are produced to improve on the rituximab molecule. Attempts include modifications that permit binding to a better epitope, binding more tightly to CD20, increasing activation of antibody-dependent cellular cytotoxicity, and facilitating apoptosis. The product furthest along in clinical development is ofatumumab, a fully human IgG1-kappa monoclonal antibody that targets a novel epitope of CD20.92 Preclinical studies indicate that ofatumumab is associated with greater complement-dependent cytotoxicity than rituximab, presumably because of a slower rate of dissociation from its antigen (“off rate”) and greater interaction with the complement component C1q.81 Other humanized anti-CD20 antibodies, veltuzumab and ocrelizumab, have produced promising preliminary results.93 It is likely that these new antibodies will be first developed to occupy the therapeutic niches where rituximab is used in an off-label setting. The value of B-cell-targeted therapy for immune modulation clearly needs to be further delineated. In particular, additional research is needed to investigate whether blocking members of the tumor necrosis factor cytokine family, such as B-cell–activating factor (BAFF) and a proliferation ligand (APRIL), can inhibit long-lived plasma cells. Also, areas of investigation include blockade of costimulation, and induction of regulatory T cells. Finally, long-term observations of protective immunity are needed to further evaluate the rate of infections.
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