PEDIATRICS Vol. 123 No. 1 January 2009, pp. e159-e163 (doi:10.1542/peds.2008-2361)
ARTICLE |
B-Cell Depletion for Autoimmune Thrombocytopenia and Autoimmune Hemolytic Anemia in Pediatric Systemic Lupus Erythematosus
Divisions of a Rheumatology
c Hematology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
b Department of Health Policy Management and Evaluation and Public Health Sciences
d Department of Immunology, University of Toronto, Toronto, Ontario, Canada
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Our goal was to determine long-term efficacy and safety of B-cell–depletion therapy for children with autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus.
PATIENTS AND METHODS. A retrospective, single-center cohort study was conducted including all patients with pediatric systemic lupus erythematosus who were diagnosed with autoimmune thrombocytopenia and/or autoimmune hemolytic anemia and treated with rituximab. Treatment efficacy and safety parameters were monitored and recorded.
RESULTS. Nine patients with pediatric systemic lupus erythematosus were included in the study: 5 had autoimmune thrombocytopenia, 3 had autoimmune hemolytic anemia, and 1 had both. There were 5 female and 4 male patients; median age at diagnosis of pediatric systemic lupus erythematosus was 14 years (range: 8–16 years); and median pediatric systemic lupus erythematosus disease duration to time of rituximab treatment was 6 months (range: 2–30 months). Complete response was achieved in all 6 children with autoimmune thrombocytopenia (median time to complete response: 2 weeks [range: 1–12 weeks]). Two patients' conditions flared at 48 and 68 weeks, respectively, and were re-treated. The remaining 4 patients continued to be in remission at 24, 32, 36, and 88 weeks, respectively. All 4 children with autoimmune hemolytic anemia achieved complete response at a median time of 4 weeks (range: 4–32 weeks). All patients remained in complete response at 24, 44, 84, and 100 weeks of follow-up. Complete B-cell depletion was seen in all children after rituximab treatment. No serious infections occurred, but 1 patient had an infusion reaction.
CONCLUSIONS. Preliminary evidence suggests that B-cell–depletion therapy with rituximab is an efficacious and safe treatment for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Despite the prolonged effect on B-cell numbers and function, no serious infections were observed.
Key Words: B-cell depletion • rituximab • systemic lupus erythematosus • children
Abbreviations: SLE—systemic lupus erythematosus • pSLE—pediatric systemic lupus erythematosus • AITP—autoimmune thrombocytopenia • AIHA—autoimmune hemolytic anemia • Ig—immunoglobulin • IVIg—intravenous immunoglobulin • CR—complete response • PR—partial response
Pediatric systemic lupus erythematosus (pSLE) is an autoimmune disease characterized by B-cell activation and the production of autoantibodies. Autoimmune thrombocytopenia (AITP) and autoimmune hemolytic anemia (AIHA) are the most common hematologic manifestations of SLE and are found in 20% to 40% and 5% to 10% of patients, respectively.1 AITP results from accelerated platelet destruction mediated by autoantibodies to platelet glycoproteins.2 AIHA reflects autoimmune hemolysis caused by immunoglobulin G (IgG) with or without complement-fixing antibodies to erythrocytes that are detected by a direct antiglobulin (Coombs') test. The most common treatment for both of these disease manifestations is corticosteroids and/or intravenous immunoglobulin (IVIg). However, for many patients with SLE, the disease becomes either resistant to therapy or steroid-dependent requiring the use of second-line agents and/or splenectomy.3
Rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, has been shown to effectively deplete CD20+ cells and is effective in treatment of B-cell lymphomas.4 Investigators have used this therapy successfully to treat idiopathic thrombocytopenia in patients with steroid-dependent or steroid-resistant disease.5 Preliminary data have shown rituximab therapy to be effective in adults with SLE, likely as a result of the prolonged B-cell depletion induced by rituximab.6
To date, there have been few published series of the use of rituximab in patients with pSLE. The aim of this study was to determine long-term efficacy and safety of B-cell–depletion therapy with rituximab in patients with pSLE complicated by AITP and AIHA.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Design and Setting
Ours was a retrospective cohort study conducted at the pSLE clinic at the Hospital for Sick Children (Toronto, Ontario, Canada) between May 2003 and June 2007.
Inclusion Criteria
All children with pSLE with AITP and/or AIHA and treated with rituximab between May 2003 and June 2007 were included in this review. All patients fulfilled 
4 of 11 American College of Rheumatology classification criteria for SLE. The study was approved by the research ethics board at the Hospital for Sick Children.
Standardized assessments were performed and results were recorded according to the institutional protocol, including clinical features, laboratory markers, and treatment dosing and duration. "Last follow-up" was the last clinic visit.
Treatment
Rituximab was infused at a dose of 375 mg/m2 weekly for 4 doses (6 children) or 500 mg/m2 every 2 weeks for 2 doses (3 children). All patients were pretreated with acetaminophen, diphenhydramine, and hydrocortisone to limit infusion reactions.
All patients had immune phenotyping and quantitative IgM, IgG, and IgA testing performed with B-cell numbers and Ig levels measured every 2 to 4 months after rituximab treatment. Complete blood counts were monitored weekly during the first 4 weeks; subsequent monitoring occurred at 1- to 4-week intervals, depending on response.
Outcome Measures
Clinical Response Criteria
Complete response (CR) was defined as the initial date on which a sustained platelet count of >150 x 109/L and/or a hemoglobin level of >120 g/L was reached from the day of first rituximab infusion and remained stable for a minimum of 12 weeks.
Partial response (PR) was defined as the initial date on which a platelet count of between 50 and 150 x 109/L and/or a hemoglobin level between 100 and 120 g/L was reached from the day of first rituximab infusion and remained stable for a minimum of 12 weeks.
Failure was defined as failure to meet the criteria for CR or PR.
Duration of response was calculated from the day of the initial infusion until the last clinic visit or the date of a flare.
Adverse Events
All patients were monitored for adverse events including infusion reactions and/or serious infections defined as (1) infections requiring the use of an antibiotic, antifungal, or antiviral agent and/or (2) infections requiring hospitalization.
Analysis
Descriptive analysis and frequencies were performed by using SPSS 11 (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
Nine patients with pSLE were included in the study: 5 had AITP, 3 had AIHA, and 1 had both. Five children were female and 4 were male, and the median age at pSLE diagnosis was 14 years (range: 8–16 years). The median disease duration from pSLE diagnosis to rituximab treatment was 6 months (range: 2–30 months). All the patients had been treated previously with corticosteroids before rituximab treatment. Five children had received IVIg and hydroxychloroquine before rituximab infusion, and 1 patient had also received azathioprine and methotrexate before rituximab treatment. The median hemoglobin level before rituximab treatment was 78 g/L (range: 46–110 g/L) for the 4 children with AIHA, and the median platelet count was 31 x 109 cells per L (range: 2–75 x 109 cells per L) for the 6 children with AITP.
Treatment Efficacy
Patients With AITP
A CR was achieved in all 5 children with AITP, with a median time to respond of 2 weeks (range: 1–12 weeks) (Table 1). Two of the patients' conditions flared at 48 and 68 weeks, respectively, whereas the other 3 children remained in remission at 24, 32, and 36 and 88 weeks, respectively. Both children whose conditions flared were re-treated with a second course of rituximab at a dose of 375 mg/m2 weekly for 4 doses. Both patients again achieved CR at 4 and 3 weeks, respectively, and remained in remission at 68 and 88 weeks, respectively. In patients 1 and 4, corticosteroids were successfully tapered and stopped at 17 and 24 weeks, respectively (Table 1). The other 3 children had intermittent intravenous pulses of high-dose prednisone for 4 days whenever their platelet levels dropped and never required daily corticosteroids before rituximab infusions. Patient 5 had AITP with central nervous system involvement before rituximab treatment. Patient 3 required oral prednisone at a dose of 15 mg because he developed arthritis 3 months after rituximab therapy; his platelet count was 107 x 109/L at the time of starting oral prednisone. Patient 4 was diagnosed with central nervous system lupus 3 months after rituximab therapy and required daily oral prednisone and pulse intravenous cyclophosphamide; her platelet count was 243 x 109/L at the beginning of this treatment.
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Patients With AIHA
All 4 children with AIHA had a CR at a median time of 4 weeks (range: 4–32 weeks) with a mean of 14.4 weeks (Table 1). All patients had a sustained CR at 24, 44, 84, and 100 weeks of follow-up. Corticosteroids were decreased in all patients after rituximab infusions and stopped at 16, 20, and 28 weeks for patients 6, 7, and 5, respectively (Table 1). Patient 1 was on 5 mg of prednisone at 100 weeks' follow-up.
Duration of B-Cell Depletion
The rate at which B-cell numbers were depleted and recovered varied among the patients. In 8 children in whom B cells were measured there was a complete absence of CD20 cells suggestive of B-cell depletion after rituximab infusions when measured 2 to 4 weeks after the initial infusion. The 2 children (patients 2 and 3) whose conditions flared had partial B-cell reconstitution before the flare, with CD20+ B-cell counts of 11 and 155 cells per µL (CD19+ B cells: 10 and 144 cells per µL), respectively. Patients 6 and 8 regained B cells at 20 and 60 weeks, respectively. However, they remained as complete responders. The other 3 children had not regained circulating B cells at last follow-up after a mean of 34 weeks. Patient 5 did not have B-cell estimations.
Five patients (patients 2–5 and 8) received IVIg as an immunomodulatory therapy before treatment with rituximab. Six patients (patients 1–4, 6, and 9) had low IgG levels, and 1 patient (patient 4) had a low IgM level after rituximab administration (Table 2) . The mean IgG level was 5.5 g/L at 18 weeks, with a mean level of IgG of 7.6 g/L (range: 3.2–9.5 g/L) at last follow-up after a mean follow-up of 57 weeks (range: 17–76 weeks).
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Treatment Safety
One child (patient 7) developed an infusion reaction during the second course of rituximab that was characterized by fever, an erythematosus itchy rash, and hypotension. Her condition improved with intravenous fluid resuscitation and diphenhydramine. Despite the B-cell depletion and resulting hypogammaglobulinemia, there were no infections that required hospitalization or the use of antibacterial, antifungal, or antiviral agents.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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B-cell depletion with rituximab has been proven to be a useful therapy for pediatric autoimmune diseases and, in particular, the immune-mediated cytopenias of AIHA and AITP.7 Its efficiency in pSLE has been reported in only 3 children with AIHA,8 1 with AITP,9 and 7 with active SLE resistant to standard immunosuppressive agents.10 However, all pediatric patients previously reported received concomitant immunosuppressive therapy consisting of prednisone and second-line agents, which may have influenced the response to B-cell depletion. In this report we have shown that rituximab was efficacious in inducing a complete remission in children with AIHA and AITP secondary to pSLE without the use of a second-line immunosuppressive agent, although some patients were on prednisone at the time of treatment.
All 4 children with AIHA secondary to SLE had a CR at a median time of 4 weeks after B-cell depletion with rituximab. All the children's conditions had previously failed treatment with, or were dependent on, corticosteroid therapy, and 1 patient's condition had failed IVIg, azathioprine, and methotrexate therapy. These results are consistent with the previous reports of 3 pediatric patients and 1 adult patient with AIHA secondary to SLE.11,12 At the time of this writing, none of our children have had a relapse of AIHA after rituximab therapy, and only 1 patient remained on low-dose prednisone.
All 6 patients with AITP secondary to SLE had a CR to rituximab therapy, with a median time of 2 weeks to CR. Patients 2, 3, and 4 were diagnosed with AITP and treated with intermittent steroids and IVIg by a hematologist. They later developed SLE and were referred to a rheumatologist. Those patients were treated with rituximab during their next episode of purpuric rash with thrombocytopenia without steroids. Two patients' conditions flared with a recurrence of AITP at 48 and 68 weeks but again responded rapidly with completion remission after a second course of B-cell depletion. There have been very few reports of the use of rituximab in either adult or pediatric patients with AITP secondary to SLE. However, there has been extensive use of rituximab for idiopathic thrombocytopenic purpura, with >150 patients reviewed by Franchini et al,13 who reported a CR or PR rate of 60% that persisted for a mean of 52 weeks (range: 12–154 weeks).
In our study we found complete depletion of all circulating B cells within 4 weeks of treatment in all the children treated with rituximab in whom B cells were measured. The B-cell depletion persisted in all 5 patients who remained in remission at last follow-up, but a return of circulating B cells preceded a relapse of the thrombocytopenia in 2 children who required re-treatment. A return of circulating B cells preceding relapse was noted previously in adult patients with rheumatoid arthritis14 and SLE,6 with a mean time to relapse of 10 months in patients with SLE and 11 months in patients with rheumatoid arthritis. It is notable that in 2 previous studies of adult SLE, the median depletion duration was short at 4 and 7 months, with a mean time to flare of 10 and 18 months in the 60% and 43% of patients whose conditions flared.6,13
We observed rituximab-induced hypogammaglobulinemia in 6 children. One patient (patient 8) received monthly IVIg after rituximab because his IgG levels were low before starting rituximab. It has been suggested that monthly infusions of IVIg may be required for patients who develop persistently low IgG levels.15 Ng et al6 reported 1 patient who died of pneumococcal septicemia after B-cell–depletion therapy, but this patient was treated with hydroxychloroquine, methotrexate, sulfasalazine, azothioprine, and mycophenolate mofetil before rituximab. However, in our study, despite the persistence of low IgG levels, we did not see any infection requiring either intravenous or oral anti-infective agents, suggesting that routine IVIg may not be required. Our only patient who received routine IVIg after rituximab had a low serum IgG level before rituximab treatment and a history of recurrent infections that required antibiotic therapy. We suggest that, in the absence of immunosuppressive agents other than prednisone, routine IVIg may not be required.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We suggest that rituximab therapy was a safe and efficacious therapy that was associated with long-term CR in our pediatric patients with AIHA and/or AITP secondary to SLE whose conditions had failed previous therapies. We believe that these results warrant a large prospective trial to confirm the safety and efficacy of rituximab in severe AIHA and/or AITP secondary to pSLE.
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FOOTNOTES |
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Accepted Oct 8, 2008.
Address correspondence to Earl D. Silverman, MD, FRCPC, Hospital for Sick Children, Division of Rheumatology, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: earl.silverman{at}sickkids.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject B-cell depletion is currently used in the management of SLE in adults. It is efficacious and safe in adults. However, its efficacy and safety in children are not known.
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| What This Study Adds We describe the effectiveness, safety, and long-term follow-up in children with SLE who were treated with rituximab.
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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