Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis
Jonathan C.W. Edwards, M.D., Leszek Szczepanski, M.D., Ph.D., Jacek Szechinski, M.D., Ph.D., Anna Filipowicz-Sosnowska, M.D., Ph.D., Paul Emery, M.D., David R. Close, Ph.D., Randall M. Stevens, M.D., and Tim Shaw, B.Sc.
Background An open-label study indicated that selective depletionof B cells with the use of rituximab led to sustained clinicalimprovements for patients with rheumatoid arthritis. To confirmthese observations, we conducted a randomized, double-blind,controlled study.
Methods We randomly assigned 161 patients who had active rheumatoidarthritis despite treatment with methotrexate to receive oneof four treatments: oral methotrexate (10 mg per week) (control);rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide(750 mg on days 3 and 17); or rituximab plus methotrexate. Responsesdefined according to the criteria of the American College ofRheumatology (ACR) and the European League against Rheumatism(EULAR) were assessed at week 24 (primary analyses) and week48 (exploratory analyses).
Results At week 24, the proportion of patients with 50 percentimprovement in disease symptoms according to the ACR criteria,the primary end point, was significantly greater with the rituximab–methotrexatecombination (43 percent, P=0.005) and the rituximab–cyclophosphamidecombination (41 percent, P=0.005) than with methotrexate alone(13 percent). In all groups treated with rituximab, a significantlyhigher proportion of patients had a 20 percent improvement indisease symptoms according to the ACR criteria (65 to 76 percentvs. 38 percent, P0.025) or had EULAR responses (83 to 85 percentvs. 50 percent, P0.004). All ACR responses were maintained atweek 48 in the rituximab–methotrexate group. The majorityof adverse events occurred with the first rituximab infusion:at 24 weeks, serious infections occurred in one patient (2.5percent) in the control group and in four patients (3.3 percent)in the rituximab groups. Peripheral-blood immunoglobulin concentrationsremained within normal ranges.
Conclusions In patients with active rheumatoid arthritis despitemethotrexate treatment, a single course of two infusions ofrituximab, alone or in combination with either cyclophosphamideor continued methotrexate, provided significant improvementin disease symptoms at both weeks 24 and 48.
Rheumatoid arthritis is a systemic autoimmune disease that affectsapproximately 1 percent of the adult population.1 It is characterizedby chronic inflammation in the synovial membrane of affectedjoints that ultimately leads to loss of daily function due tochronic pain and fatigue. The majority of patients also havedeterioration of cartilage and bone in the affected joints,which may eventually lead to permanent disability. Rheumatoidarthritis is associated with increased morbidity and mortality.2
Although the precise pathogenesis of rheumatoid arthritis remainsunclear, it has been postulated that multiple exogenous or endogenousantigenic triggers, or both, act in the presence of a backgroundgenetic predisposition to initiate a self-perpetuating seriesof autoimmune responses in the synovial compartment.3,4 Manycell populations, including monocytes, macrophages, B cells,T cells, endothelial cells, and fibroblasts, participate inthe ongoing inflammatory process.3 The precise contributionof B cells to the immunopathogenesis of rheumatoid arthritisis not fully understood, although a number of mechanisms havebeen proposed.4,5,6 However, strong evidence for a criticalrole of B cells in rheumatoid arthritis came from a small open-labelstudy of rituximab in combination with cyclophosphamide andcorticosteroids.7
Rituximab is a genetically engineered chimeric anti-CD20 monoclonalantibody that is approved for the treatment of relapsed or refractory,low-grade or follicular, CD20+ B-cell non-Hodgkin's lymphoma.CD20 is a B-cell surface antigen that is expressed only on pre-Band mature B cells. It is not present on stem cells and is lostbefore differentiation of B cells into plasma cells. Therefore,rituximab causes a selective transient depletion of the CD20+B-cell subpopulation.7 To confirm the role of B cells in rheumatoidarthritis, we evaluated the effect of rituximab in patientswith active rheumatoid arthritis in a multicenter, randomized,double-blind, controlled study.
Methods
Patients
Patients were recruited from 26 rheumatology centers in 11 countries(Australia, Canada, Israel, and 8 European countries). Eligiblepatients were at least 21 years of age, fulfilled the revised1987 American Rheumatism Association criteria,1 and had activedisease despite treatment with at least 10 mg of methotrexateper week. Active disease was defined by the presence of at leasteight swollen and eight tender joints and at least two of thefollowing: a serum C-reactive protein level of at least 15 mgper liter, an erythrocyte sedimentation rate of at least 28mm per hour, or morning stiffness lasting longer than 45 minutes.In addition, eligible patients were seropositive for rheumatoidfactor, as defined by a plasma rheumatoid factor level of atleast 20 IU per milliliter.
Patients were excluded if they had an autoimmune disease otherthan rheumatoid arthritis (except concurrent Sjögren'ssyndrome), American Rheumatism Association functional classIV disease, active rheumatoid vasculitis, a history of systemicdiseases associated with arthritis, chronic fatigue syndrome,serious and uncontrolled coexisting diseases, active infection,a history of recurrent clinically significant infection or ofrecurrent bacterial infections with encapsulated organisms,primary or secondary immunodeficiency, or a history of cancer(except basal-cell carcinoma of the skin that had been excised).
Patients were allowed to receive nonsteroidal antiinflammatorydrugs at stable doses or corticosteroids at doses that did notexceed 12.5 mg per day of prednisolone (or the equivalent).Concurrent treatment with any disease-modifying antirheumaticdrug or any anti–tumor necrosis factor therapy duringthe trial was prohibited.
The study was approved by the institutional review board orthe ethics committee at each study site. All patients gave writteninformed consent.
Study Protocol
At study entry, all patients had received methotrexate (as asingle disease-modifying antirheumatic drug) for at least 16weeks. Therapy with methotrexate during the last four weeksbefore baseline was at a stable dose. Patients were randomlyassigned to receive one of four treatments: oral methotrexateat a dose of 10 mg or more per week plus placebos for rituximaband cyclophosphamide (control group), rituximab plus placebosfor methotrexate and cyclophosphamide, rituximab plus cyclophosphamidein an intravenous infusion of 750 mg on days 3 and 17 plus placebofor methotrexate, and rituximab plus methotrexate at a doseof 10 mg or more a week plus placebo for cyclophosphamide. Inall three groups that received rituximab (MabThera, Roche; Rituxan,Genentech and IDEC Pharmaceuticals), rituximab was administeredas a 1000-mg intravenous infusion on days 1 and 15. Investigatorsand patients remained blinded to the assigned study medications.
All groups, including the control group, also received a 17-daycourse of treatment with corticosteroids. This consisted ofintravenous infusions of 100 mg of methylprednisolone beforeinfusions of either rituximab (or the placebo for rituximab)or cyclophosphamide (or the placebo for cyclophosphamide), togetherwith 60 mg per day of oral prednisone on day 2 and days 4 to7 and 30 mg per day on days 8 to 14. All patients also receivedleucovorin calcium (folinic acid) orally as a single 10-mg doseon day 1, to counter any undesired effects of methotrexate.During the course of the study, all treatments for rheumatoidarthritis remained stable.
To prevent potential unblinding due to nausea and vomiting associatedwith the use of cyclophosphamide, it was recommended that allpatients be administered an antiemetic agent (granisetron, 2mg orally) one hour before the infusions of cyclophosphamideor the placebo for cyclophosphamide.
Clinical assessments were performed at baseline (day 1) andat weeks 12, 16, 20, and 24 according to the American Collegeof Rheumatology (ACR) core set of disease-activity measures.These consisted of a count of swollen joints (66 joints evaluated),a count of tender joints (68 joints evaluated), patient's assessmentof pain on a scale from 0 (no pain) to 100 (unbearable pain),patient's global assessment of disease activity on a scale from0 (disease inactive) to 100 (maximal disease activity), physician'sassessment of disease activity, patient's assessment of physicalfunction (by means of a health-assessment questionnaire8), andlaboratory evaluation of acute-phase reactants (serum C-reactiveprotein level and erythrocyte sedimentation rate).
Laboratory assessments (including complete blood counts andserum biochemical analyses) were performed at screening (threeweeks before baseline), on days 1, 3, 15, and 17, and at weeks4, 8, 12, 16, 20, and 24. At selected visits, levels of CD19+B cells and CD3+, CD4+, and CD8+ T cells were measured by fluorescence-activatedcell sorting, and immunoglobulin (IgG, IgA, and IgM) concentrationsand rheumatoid factor levels were measured by nephelometry.Once rituximab is present in the plasma, it interferes withthe flow cytometry in the assessment of CD20. Consequently,in order for the levels of B cells to be assessed, a separatemarker is required. CD19 is a surface antigen and is presenton B cells and was the marker used for B cells after the exposureof plasma to rituximab. To investigate the effect of selectiveB-cell depletion on acquired immunity, antitetanus antibodytiters were assessed at baseline and at week 24. Samples weretaken at baseline (before the dose of study medication, on day1) and at week 24 for analysis of human antichimeric antibodiesagainst rituximab with the use of an enzyme-linked immunosorbentbridging assay (Genentech).
Adverse events were recorded at each visit. A serious adverseevent was defined as an event that was fatal, was life-threatening,required hospitalization or prolongation of existing hospitalization(with the exception of hospitalization for exacerbations ofarticular or periarticular manifestations of rheumatoid arthritis),resulted in persistent or substantial disability or incapacityor in a congenital anomaly or birth defect, or was medicallysignificant or required intervention to prevent any of the outcomesmentioned.
Additional follow-up of patients, including assessments of efficacy,laboratory values, and safety, was conducted at regular intervalsup to 48 weeks. Personnel at all sites remained blinded to treatmentduring this follow-up.
Clinical Outcome Measures
The primary end point of the study was the proportion of patientswith an ACR 50 response at week 24. An ACR 50 response was definedas an improvement of at least 50 percent from baseline in countsof both tender and swollen joints, as well as in three of thefive remaining disease-activity measures of the ACR core set:physician's assessment of disease activity, patient's assessmentof disease activity, patient's assessment of pain, patient'sassessment of physical function (by means of the health-assessmentquestionnaire), and the value for one acute-phase reactant (eitherserum C-reactive protein level or erythrocyte sedimentationrate).9
Secondary outcomes included ACR 20 and ACR 70 responses (20percent and 70 percent improvement, respectively, accordingto the ACR criteria), a change in the disease-activity score(which includes the physician's assessment of 28 joints andthe patient's self-assessment of disease activity),10 and theresponse according to the criteria of the European League againstRheumatism (EULAR response).11
Statistical Analysis
Sample-size calculations were based on the assumption that theproportion of patients continuing to receive only methotrexateand achieving an ACR 50 response at week 24 would be 5 percentand that the proportion of patients in any of the rituximabtreatment groups would be 30 percent. On the basis of theseassumptions and with the use of Fisher's exact test with a two-sidedsignificance level of 0.05, we calculated that a sample of 40patients per treatment group would provide the study with 82percent power to detect a difference between the two proportions.
The primary analyses were based on the intention-to-treat principle.For patients who withdrew before week 24, a last-observation-carried-forwardmethod of imputation was applied. Statistical analyses (withthe two-sided Fisher's exact test) were performed only for comparisonsof each rituximab group with the control group. Exploratorysecondary analyses were performed for ACR response rates atweek 48 with use of a nonresponder imputed rule for all patientswho withdrew before that time.
Roche was the study sponsor and was responsible for data collection.Statistical analyses were conducted by suitably qualified statisticianswho were employees of the sponsor. The trial protocol was designedjointly by the lead clinical investigator (Dr. Edwards) andthe sponsor. All the authors had access to and involvement inthe interpretation of the data, as well as input into and controlover the content of this manuscript (supervised by Dr. Edwards).
Results
Characteristics of the Patients
A total of 161 patients were recruited into the study. The baselinecharacteristics and measures of disease activity were similarin the four treatment groups (Table 1). The patients had long-standingand highly active disease, as shown by a high mean number ofswollen and tender joints, elevated values for acute-phase reactants,and a high mean disease-activity score. The median dose of methotrexateat study entry was 12.5 to 15 mg per week.
Table 1. Baseline Characteristics of the Patients.
All patients who underwent randomization received at least onedose of their assigned medication and had at least one follow-upassessment after baseline. Therefore, the intention-to-treatand safety populations were identical and consisted of all 161patients who entered the study. Ten patients withdrew from thestudy before week 24 (Figure 1). Nine of these 10 patients didnot have ACR responses; 1 patient in the rituximab–cyclophosphamidegroup had an ACR 20 response before an adverse event led toearly withdrawal.
Figure 1. Disposition of All Randomized Patients at 24 and 48 Weeks.
Patients who did not complete the study for unknown reasons or for reasons other than an adverse event, lack of response, or withdrawal of consent are classified as "other."
Clinical Efficacy
On the basis of the primary end point of an ACR 50 responseat week 24, the regimens of rituximab in combination with eithermethotrexate or cyclophosphamide resulted in levels of responsethat were significantly higher (P=0.005) than the levels inthe control group (Figure 2). The ACR 50 response in the rituximab-monotherapygroup was numerically higher than the response in the controlgroup (which received only methotrexate) but the differencedid not reach statistical significance (P=0.059). The proportionsof patients with ACR 20 and ACR 70 responses at week 24 werehigher in the rituximab groups than in the control group, withstatistically significant increases in the frequency of ACR20 responses in all rituximab groups (P0.025) and ACR 70 responsesin the rituximab–methotrexate group (P=0.048).
Figure 2. American College of Rheumatology Clinical Responses at Weeks 24 and 48.
ACR 20 denotes at least a 20 percent improvement in disease symptoms according to the American College of Rheumatology (ACR) core set of outcome measures, ACR 50 a 50 percent improvement, and ACR 70 a 70 percent improvement. P values are for comparisons with the methotrexate-monotherapy (control) group.
The mean change from baseline in the disease-activity scoreat week 24 showed significant improvement over methotrexatealone in all rituximab groups (P0.002) (Table 2). Furthermore,a significantly higher proportion of patients in the rituximabgroups than in the control group responded to treatment, asdefined by EULAR criteria (P0.004). In addition, 20 to 24 percentof patients receiving rituximab had a good EULAR response atweek 24, as compared with 5 percent of patients receiving methotrexatealone.
Table 2. Changes from Baseline in Disease-Activity Score, Rates of Response According to the European League against Rheumatism (EULAR) Criteria, and Pharmacodynamic Outcomes at Week 24.
Exploratory analyses of ACR responses at week 48 (Figure 2)showed ACR 70, ACR 50, and ACR 20 responses in 0 percent, 5percent, and 20 percent of patients in the methotrexate controlgroup, respectively, as compared with 15 percent, 35 percent,and 65 percent of patients in the rituximab–methotrexategroup (P=0.03, P=0.002, and P<0.001, respectively). In therituximab–cyclophosphamide group, 27 percent and 49 percentof patients had ACR 50 and ACR 20 responses, respectively (P=0.01for both comparisons). All other comparisons of ACR responsesat week 48 favored rituximab therapy but did not reach statisticalsignificance.
Pharmacodynamic Outcomes at Week 24
Rituximab treatment was associated with nearly complete depletionof peripheral-blood B cells, which lasted throughout the 24-weekstudy period (Figure 3A). Conversely, numbers of B cells (CD19+cells) first declined and then remained stable in the controlgroup. An initial decline and subsequent rebound were also seenin T-cell populations (CD3+, CD4+, and CD8+) in all treatmentgroups. Such effects are most likely associated with the useof corticosteroids during the initial phase of the study.7 Despitedepletion of B cells, levels of immunoglobulins did not changesubstantially (mean values remained within normal ranges forIgG, IgM, and IgA isotypes), and there was no effect on antitetanusantibody titers (Table 2).
Figure 3. Median Levels of Peripheral CD19+ B Cells and Median Changes in Levels of Total Rheumatoid Factor during the 24-Week Study Period.
Panel A shows the levels of peripheral CD19+ B cells during the study period, and Panel B shows the median change in total rheumatoid factor.
Rituximab treatment was associated with a large and rapid decreasein rheumatoid factor levels (Figure 3B). This reduction waspronounced and was maintained at week 24. Conversely, treatmentwith methotrexate alone was initially associated with a modestdecrease in rheumatoid factor level. However, this decreasewas transient, and values returned to baseline by week 24. Theinitial decrease may be related to the short course of corticosteroidsgiven during the initial phase of the study.
Adverse Events
During the primary 24-week trial period, six patients withdrewearly owing to adverse events. Two of these withdrawals weredue to an exacerbation of rheumatoid arthritis (one in the controlgroup and one in the rituximab–cyclophosphamide group).The other four events were hypotension and bronchopneumoniain the rituximab-monotherapy group, staphylococcal septicemiain the rituximab–cyclophosphamide group, and renal impairment(a focal lesion on the left kidney of a patient with preexistingnephrolithiasis) in the rituximab–methotrexate group.
The treatment groups had a similar overall incidence of adverseevents, with 73 to 85 percent of patients reporting at leastone event; 30 to 45 percent of patients in each group had eventsassociated with the first infusion (Table 3). The majority (85to 90 percent) of adverse events associated with rituximab infusionswere characterized as mild or moderate. The following adverseevents generally occurred during or within 24 hours after thefirst infusion of rituximab and tended to be less frequent withthe subsequent infusion: transient hypotension or hypertension,cough, pruritus, and rash.
During the initial 24 weeks, a total of 16 serious adverse eventswere reported in 14 patients, with the highest incidence amongpatients receiving rituximab plus cyclophosphamide (Table 3).Serious infections occurred in one patient (2.5 percent) inthe control group and in a total of four patients (3.3 percent)in the rituximab groups (two patients in the rituximab-monotherapygroup and two in the rituximab–cyclophosphamide group).Of these four patients, two had septic arthritis, one of whomalso had septicemia owing to Staphylococcus aureus infection.The third patient, who had a history of pseudomonas infectionand bronchiectasis, had two episodes of Pseudomonas aeruginosapneumonia. Fatal bronchopneumonia developed in the fourth patient,who received rituximab alone. No causative organism was isolatedin this patient, who had a concomitant cardiac condition (ischemicor vascular heart disease) that may have contributed to thepatient's death. The infection in the patient in the controlgroup was a corneal abscess.
During the extended observation to week 48, a further threepatients withdrew owing to adverse events: one in the controlgroup (the nature of the adverse event was not recorded) andtwo in the rituximab monotherapy group (exacerbation of rheumatoidarthritis in one patient and rash in the other). The profileof adverse events reported remained consistent with those observedduring the initial 24 weeks (Table 3). There were six additionalserious adverse events, including two serious infections (gastroenteritisin a patient who had received rituximab alone, and pyelonephritisin a patient receiving rituximab with methotrexate).
Human antichimeric antibodies developed in only 5 of 117 patients(4.3 percent) in the rituximab groups. No specific clinicalmanifestations were observed in those patients.
Discussion
In this multicenter, randomized, double-blind, controlled studyof a selective depletion of B cells in the treatment of activerheumatoid arthritis, a single short course of rituximab (twoinfusions, on days 1 and 15), either alone or in combinationwith cyclophosphamide or continuing methotrexate, provided patientswith significant improvements in disease symptoms. At 24 weeks,the proportion of patients who had at least a 50 percent improvementin disease symptoms (ACR 50, the primary end point) was substantiallygreater in all the rituximab regimens than in the methotrexate(control) group. All the rituximab groups also had a significantlyhigher proportion of patients who had ACR 20 responses thanin the control group, and a significantly higher percentageof patients treated with rituximab plus methotrexate had anACR 70 response. Furthermore, 83 to 85 percent of patients treatedwith rituximab had a moderate or good response according toEULAR criteria, as compared with 50 percent of patients in thecontrol group (P0.004). The mean decline from baseline in thedisease-activity score and the rheumatoid factor level at week24 was also significantly greater in the rituximab groups. Subsequentexploratory analyses12 with use of data from an extended observationperiod showed that pronounced ACR responses remained evidentin the rituximab groups 48 weeks after a single course of treatment.
In this study, all patients, including those in the controlgroup, received a short course of corticosteroids, which areknown to have strong antiinflammatory effects in patients withrheumatoid arthritis. In the original open-label study, in whichrituximab was given in combination with cyclophosphamide andcorticosteroids, it was found that corticosteroids may contributeto B-cell death by encouraging apoptosis or direct cytolysis.7As shown in previous studies,7,13 the corticosteroids were unlikelyto have affected the disease outcomes at week 24 in our trial;however, determining the need for concomitant corticosteroidsrequires further study.
These data clearly identify B cells as key contributors to theimmunopathogenesis of rheumatoid arthritis. Although their preciserole is not clear, there are several mechanisms that could profoundlyinfluence the disease process.4,5,6,14,15 B cells may functionas antigen-presenting cells and provide important costimulatorysignals required for CD4+ T-cell clonal expansion and effectorfunctions.16,17 In addition, it is known that the synovial membranein patients with rheumatoid arthritis contains an abundanceof plasma cells (derived from B cells) that produce rheumatoidfactor and that positivity for rheumatoid factor is associatedwith more aggressive articular disease, a higher frequency ofextraarticular manifestations, and increased mortality.18,19Immune complexes that contain rheumatoid factor bind to Fc receptorson macrophages in the synovial membrane, inducing the releaseof proinflammatory cytokines, such as tumor necrosis factor.4,20 Rheumatoid factor may also be a self-perpetuating stimulusfor B cells, potentially leading to activation of and antigenpresentation to T helper cells, which could be mechanisticallyresponsible for further production of rheumatoid factor.4 Finally,although T-cell activation is considered to be a key componentof the pathogenesis of rheumatoid arthritis, recent evidenceindicates that such activation depends on the presence of Bcells.16
The overall safety profile observed in this study was consistentwith that reported previously with rituximab in patients withlymphoma.21 Adverse events occurred most frequently with thefirst infusion. Although the events that occurred during infusionswere similar to those that occur in non-Hodgkin's lymphoma,the incidence and severity of these adverse events seem to bereduced in patients with rheumatoid arthritis. From 70 to 80percent of patients with non-Hodgkin's lymphoma report adverseevents during their first infusion,21 as compared with just36 percent of patients in this study. The reasons for this differenceare unknown but could be due to either lower levels of CD20+lymphocytes in patients with rheumatoid arthritis or premedicationwith corticosteroids.
The groups receiving rituximab had profound and prolonged depletionof peripheral-blood B cells, which raises the question of whetherthese patients may be more susceptible to infection. However,at weeks 24 and 48, the overall incidence of infection was similarin the control group and the rituximab groups, with no obviouspattern in types of causative organism. Immunoglobulin levelsappeared to be only minimally affected, and antitetanus antibodytiters (as a measure of previously acquired immunity) were unaffected.By week 24, serious infections had occurred in one patient (2.5percent) in the control group and in a total of four patients(3.3 percent) in the rituximab groups. Two additional seriousinfections were reported during the extended observation periodof 48 weeks. Fatal bronchopneumonia developed in one patientin the rituximab monotherapy group, who had a concomitant cardiaccondition (no causative organism was isolated). The incidenceof infection will require careful monitoring in future studies,as will long-term effects on acquired immunity.
In conclusion, this study provides clear evidence that a singleshort course of rituximab provides significant, clinically meaningfulbenefits to patients with active rheumatoid arthritis. Ratesof ACR responses were maintained over a prolonged observationperiod. This finding provides valuable insight into the roleof B cells in this progressively disabling disease.
Supported by Roche.
Drs. Edwards, Szczepaski, Szechiski, Filipowicz-Sosnowska, andEmery report having received grant support from F. Hoffmann–LaRoche. Drs. Edwards and Emery report having served as consultantsto F. Hoffmann–La Roche. Dr. Szechiski reports havingserved as a consultant to Schering-Plough and having been amember of a speakers' bureau sponsored by Aventis. Dr. Filipowicz-Sosnowskareports having been a member of speakers' bureaus sponsoredby Aventis, Merck, and Wyeth. Dr. Close and Mr. Shaw are employeesof Roche Products. Dr. Stevens is employed by Roche.
Source Information
From University College London, London (J.C.W.E.); Medical University School of Lublin, Lublin, Poland (L.S.); University School of Wroclaw, Wroclaw, Poland (J.S.); the Institute of Rheumatology, Warsaw, Poland (A.F.-S.); Leeds Royal Infirmary, Leeds, United Kingdom (P.E.); Roche Products, Welwyn Garden City, Hertfordshire, United Kingdom (D.R.C., T.S.); and Roche, Nutley, N.J. (R.M.S.).
Address reprint requests to Professor Edwards at the Centre for Rheumatology, University College London, 4th Fl., Arthur Stanley House, 40-50 Tottenham St., London W1P 9PG, United Kingdom, or at jo.edwards{at}ucl.ac.uk.
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Appendix
In addition to the authors, the following investigators andinstitutions participated in the study: M. Nahir (Rambam MedicalCenter, Haifa, Israel), H.-D. Stahl (University of Leipzig,Leipzig, Germany), K. Pavelka (Institute of Rheumatology, Prague,Czech Republic), T. Sheeran (Cannock Chase Hospital, Cannock,United Kingdom), I. Rosner (Bnei-Zion Medical Center, Haifa,Israel), R. Cattaneo (Spedali Civili and University of Brescia,Brescia, Italy), J.L. Marenco (Valme University Hospital, Seville,Spain), I. Zimmermann-Górska (Medical University of Pozna,Pozna, Poland), B. Seriolo (University Hospital of Genoa, Genoa,Italy), C. Mussini (Azienda Ospedaliera Policlinico di Modena,Modena, Italy), E. Martín-Mola (Hospital UniversitarioLa Paz, Madrid), L. Carreño (Hospital Universitario GregorioMarañón, Madrid), S. Bustabad (University Hospitalof the Canary Islands, Tenerife, Spain), P. Dawes (Haywood Hospital,Stoke-on-Trent, United Kingdom), R. Day (Clinical Trials Centre,Darlinghurst, Australia), M. Malaise (University of Liège,Liège, Belgium), E.M. Veys (University Hospital of Ghent,Ghent, Belgium), B. Haraoui (University of Montreal, Montreal),W. Bolten (Rheumatology Clinic, Wiesbaden, Germany), F.C. Breedveld(Leiden University Medical Center, Leiden, Germany), and R.Marcolongo (University of Siena, Siena, Italy).
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Owczarczyk, K, Hellmann, M, Fliedner, G, Rohrs, T, Maizus, K, Passon, D, Hallek, M, Rubbert, A
(2008). Clinical outcome and B cell depletion in patients with rheumatoid arthritis receiving rituximab monotherapy in comparison with patients receiving concomitant methotrexate. Ann Rheum Dis
67: 1648-1649
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Jacob, A., Weinshenker, B. G., Violich, I., McLinskey, N., Krupp, L., Fox, R. J., Wingerchuk, D. M., Boggild, M., Constantinescu, C. S., Miller, A., De Angelis, T., Matiello, M., Cree, B. A. C.
(2008). Treatment of Neuromyelitis Optica With Rituximab: Retrospective Analysis of 25 Patients. Arch Neurol
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(2008). Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis
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Quartuccio, L, Salvin, S, Fabris, M, Sacco, S, De Vita, S
(2008). Disappearance of bone marrow B cell clonal expansion in patients with type II hepatitis C virus-related cryoglobulinemic glomerulonephritis after clinical efficient rituximab therapy. Ann Rheum Dis
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Godeau, B., Porcher, R., Fain, O., Lefrere, F., Fenaux, P., Cheze, S., Vekhoff, A., Chauveheid, M.-P., Stirnemann, J., Galicier, L., Bourgeois, E., Haiat, S., Varet, B., Leporrier, M., Papo, T., Khellaf, M., Michel, M., Bierling, P.
(2008). Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood
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Lovric, S., Erdbruegger, U., Kumpers, P., Woywodt, A., Koenecke, C., Wedemeyer, H., Haller, H., Haubitz, M.
(2008). Rituximab as rescue therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: single centre experience with 15 patients. Nephrol Dial Transplant
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(2008). IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl. Acad. Sci. USA
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(2008). Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation. NEJM
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(2008). Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc. Natl. Acad. Sci. USA
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Oren, S, Mandelboim, M, Braun-Moscovici, Y, Paran, D, Ablin, J, Litinsky, I, Comaneshter, D, Levartovsky, D, Mendelson, E, Azar, R, Wigler, I, Balbir-Gurman, A, Caspi, D, Elkayam, O
(2008). Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response. Ann Rheum Dis
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Soriano, E. R., Galarza-Maldonado, C., Cardiel, M. H., Pons-Estel, B. A., Massardo, L., Caballero-Uribe, C. V., Achurra-Castillo, A. F., Barile-Fabris, L. A., Chavez-Corrales, J., Diaz-Coto, J. F., Esteva-Spinetti, M. H., Guibert-Toledano, M., Palazuelos, F. I., Keiserman, M. W., Lomonte, A. V., Mota, L. M. H., Pineda Villasenor, C., Alarcon, G. S., on behalf of GLADAR (Grupo Latino Americano de Est,
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Walshe, C. A., Beers, S. A., French, R. R., Chan, C. H. T., Johnson, P. W., Packham, G. K., Glennie, M. J., Cragg, M. S.
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(2008). Idiopathic Membranous Nephropathy: Diagnosis and Treatment. CJASN
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10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). 
0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P
therapy during the trial was prohibited. 
ski, Szechi
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