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BIOLOGICS

Rituximab Pharmacokinetics in Patients With Rheumatoid Arthritis: B-Cell Levels Do Not Correlate With Clinical Response

Ferdinand Breedveld, Sunil Agarwal, Ming Yin, Song Ren, Nicole F. Li, Tim M. Shaw and Brian E. Davies

From Leiden University Medical Center, Leiden, the Netherlands (Dr Breedveld); Genentech Inc, South San Francisco, California (Dr Agarwal, Dr Yin, Dr Ren, Dr Li); Roche Products Ltd, Welwyn Garden City, United Kingdom (Dr Shaw); and Hoffmann-La Roche Inc, Nutley, New Jersey (Dr Davies).

Address for correspondence: Ferdinand Breedveld, Leiden University Medical Center, Rheumatology, PO Box 9600, Leiden, 2300 RC, the Netherlands.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX I
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received rituximab compared with those who received methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (methotrexate alone), 33% (rituximab alone), 41% (rituximab plus cyclophosphamide), and 43% (rituximab plus methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to rituximab. The mean terminal half-life of rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether rituximab was administered alone or with methotrexate or cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with rheumatoid arthritis, the timing of rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.

Key Words: Rituximab • pharmacokinetics • pharmacodynamics

Rituximab is a monoclonal antibody that selectively depletes B cells expressing the cell surface antigen, CD20, and is currently approved for the treatment of relapsed or refractory, low-grade or follicular, CD20+ B-cell non-Hodgkin lymphoma (NHL). CD20 is expressed on pre-B cells and mature B cells but not on stem cells, pro-B cells, or plasma cells.1,2 Because CD20 is not expressed on stem cells or plasma cells, depletion of CD20+ B cells does not appear to compromise either B-cell recovery (from stem cells) or immunoglobulin production (by plasma cells).3

The binding of rituximab to CD20+ B cells results in B-cell depletion through 3 putative mechanisms of action: antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and promotion of CD20+ B-cell apoptosis.4-6

Studies in patients with NHL have shown that treatment with rituximab results in a sustained but reversible depletion of peripheral CD20+ B cells for up to 6 months following completion of treatment. Median peripheral CD20+ B-cell levels return to normal by 12 months after completion of treatment.7

The pathogenesis and etiology of rheumatoid arthritis (RA) remain unknown, but it is thought that multiple exogenous or endogenous antigenic triggers (acting in the presence of a background genetic pre-disposition) initiate a self-perpetuating series of autoimmune responses within the synovial compartment of affected joints.8,9 Although B cells are among the cell populations that participate in the ongoing inflammatory process, their precise contribution to the immunopathogenesis of RA has not been fully characterized. Several possible mechanisms of action have been proposed: First, B cells may function as antigen-presenting cells and provide co-stimulatory signals required for CD4+ T-cell clonal functions. Second, the presence of B cells is critical in the activation of T cells, which is considered to be a key component in the pathogenesis of RA. Third, B cells in RA synovial membrane may secrete proinflammatory cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-6, and chemokines. Fourth, the RA synovial membrane contains B cells that produce the rheumatoid factor (RF) antibody,10 which is associated with a more aggressive disease course11 and may be a self-perpetuating stimulus for B cells. Because B cells are likely to play multiple roles in RA, their depletion therefore offers a rational mode of action for novel therapies in RA.

In RA, early open-label pilot studies showed that depletion of peripheral CD20+ B cells with a single course of rituximab was associated with substantial and sustained clinical improvements in patients with active RA that had previously been inadequately controlled by multiple disease-modifying antirheumatic drugs (DMARDs).12-14 Later open-label studies reproduced these findings.15,16

The role of B cells in RA was also investigated in a randomized, double-blind study of rituximab in 161 patients who had active RA despite ongoing treatment with methotrexate. The efficacy, tolerability, and safety results from this study showed that rituximab, given as a single course of 2 infusions 2 weeks apart both as monotherapy and in combination with either cyclophosphamide or continued methotrexate, provides significant improvements in disease symptoms at weeks 24, 48, and 104 compared with continuing methotrexate alone.3,17

Pharmacokinetic and pharmacodynamic data accrued from this randomized, double-blind, phase IIa study facilitate an investigation of the relationships between rituximab pharmacokinetics, peripheral B-cell levels, and clinical response. These results are reported in this article.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX I
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients
Adult patients of either gender who had RA, defined by the revised 1987 American Rheumatism Association criteria,18 that was inadequately responsive to between 1 and 5 previous DMARDs other than methotrexate and was active despite ongoing treatment with at least 10 mg/wk of methotrexate for the preceding 6 months or longer were recruited into this double-blind trial. Eligible patients were seropositive for RF, defined as a plasma RF level of ≥20 IU/mL, and had at least 8 swollen joints and 8 tender joints in addition to at least 2 of the following: a serum C-reactive protein (CRP) level of ≥15 mg/L, an erythrocyte sedimentation rate (ESR) of ≥28 mm/h, and morning stiffness lasting >45 minutes.

Patients were permitted to receive nonsteroidal anti-inflammatory drugs at stable doses or glucocorticoids at doses that did not exceed 12.5 mg/d of prednisolone (or equivalent). Concurrent treatment with any DMARD, other than continuing methotrexate, or any biologic response modifier (eg, anti-TNF-{alpha} agents) was prohibited during the study.

The study was approved by the institutional review board or ethics committee at each study site. A list of study sites is provided in Appendix I. All patients gave written informed consent.

Treatments and Assessments
Patients were randomized to receive 1 of 4 treatments: continuing oral methotrexate alone (≥10-25 mg/wk) (control group; n = 40); rituximab monotherapy (1000 mg by intravenous infusion on days 1 and 15; n = 40); rituximab (1000 mg by intravenous infusion on days 1 and 15) plus cyclophosphamide (intravenous infusion of 750 mg on days 3 and 17; n = 41); or rituximab (1000 mg by intravenous infusion on days 1 and 15) plus methotrexate (≥10-25 mg/wk; n = 40). Placebo infusions and tablets were given to maintain the blinding of all treatment arms, and all 4 groups received a 17-day course of treatment with glucocorticoids. No further study treatment was given apart from continuing methotrexate in the 2 methotrexate-containing groups.

Clinical assessments (swollen joint count [SJC], tender joint count [TJC], 28-joint Disease Activity Score [DAS28], and Health Assessment Questionnaire Disability Index [HAQ-DI]) and laboratory assessments of disease activity (ESR, CRP, and RF titer) were performed at baseline and at weeks 12, 16, 20, 24, 32, and 48. The primary endpoint of the study was the proportion of patients at week 24 with an American College of Rheumatology (ACR) 50 response, defined as an improvement from baseline of at least 50% in SJC and TJC as well as in 3 of the 5 disease-activity measures of the ACR core set (patient-assessed pain, patient global assessment, physician global assessment, patient self-assessed disability, and acute-phase reactant [ESR or CRP]19). The study was unblinded at week 24 to facilitate the primary analysis, although investigators and patients remained blinded to treatment assignments during the post-week-24 follow-up period. The primary analysis was based on the intent-to-treat principle, and a last-observation-carried-forward method of imputation was applied for patients who withdrew before week 24.

Serum samples for pharmacokinetic analysis were collected from patients on days 1 (predose, during the infusion, and at the end of the infusion), 3, 15 (predose, during the infusion, and at the end of the infusion), and 17 and then at weeks 4, 8, 16, and 24. The concentration of rituximab in each serum sample was determined using a direct-antigen enzyme-linked immunosorbent assay. Rituximab concentrations were determined using a 4-parameter logistic fit of the standard curve (range, 2.5-160 ng/mL). Assay performance was checked using 3 quality control samples assayed in 2 replicates on each plate. Assays were acceptable if at least 4 of 6 single measurements for the 3 quality controls were within 20% of the respective historical mean values and no 2 replicates of the same control were outside the acceptable range. The mean recovery of quality control samples ranged from 97% to 108%; assay precision (percentage coefficient of variation) ranged from 10% to 22%. Pharmacokinetic parameters were calculated from the rituximab serum concentration-time data using noncompartmental pharmacokinetic methods and the computer program WinNonlin Pro version 4.0 (Pharsight Corporation, Mountain View, Calif). All pharmacokinetic parameters were analyzed descriptively.

Blood samples were drawn for evaluation of lymphocyte subtypes on day 1 (60 minutes before and after the rituximab infusion), day 3, and day 15 (60 minutes before and after the rituximab infusion); at weeks 16, 20, and 24; and at 8-week intervals thereafter. Because circulating rituximab binds to CD20+ B cells—a property that interferes with the flow cytometric measurement of CD20—the B-cell surface antigen CD19 is used as a marker for CD20 because both have a similar expression profile on B cells.1 Levels of circulating CD19+ B cells were measured by fluorescence-activated cell sorting (FACS). The lower limit of normal (LLN) number of circulating CD19+ B cells was defined as 80 x 103 cells/µL, with B-cell depletion defined as a level of B cells ≤20% LLN (cutoff value = 16 x 103 cells/µL).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX I
 ACKNOWLEDGEMENTS
 REFERENCES
 
Baseline Patient Characteristics
A total of 161 patients were randomized and received at least 1 dose of study treatment—40 patients in each of the methotrexate-alone, rituximab monotherapy, and rituximab plus methotrexate groups and 41 in the rituximab plus cyclophosphamide group.

Patients were comparable across treatment groups at baseline for gender, age, duration of RA, previous DMARD treatment, disease activity (measured by SJC, TJC, ESR, CRP, and DAS28), HAQ-DI scores, and methotrexate dose at study entry (Table I).


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  		Table I Demographic and Baseline Characteristics of Patients

 

The disposition of patients in each treatment group at week 24 (the primary endpoint) and week 48 is shown in Table II. The attrition rate between baseline and week 24 was low in all groups and was lowest in the rituximab plus methotrexate group. Between weeks 24 and 48, there were fewer dropouts in the rituximab-treated groups than in the methotrexate-alone group, and, again, the dropout rate was lowest in the rituximab plus methotrexate group (Table II).


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  		Table II Disposition of Patients by Week 48

 

Clinical Efficacy, Tolerability, and Safety
Results of clinical efficacy, tolerability, and safety have been reported previously.3 In brief, the proportion of patients who achieved an ACR 50 score at week 24—the primary outcome measure in this study—was 13% in the methotrexate-alone group, 33% in the rituximab monotherapy group (P = .059 vs methotrexate alone), and 41% (P = .005) and 43% (P = .005) in the rituximab plus cyclophosphamide and rituximab plus methotrexate groups, respectively. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal in the rituximab-treated groups compared with the methotrexate-alone group.

Pharmacokinetics of Rituximab
Of the 121 patients who received rituximab, 10 were excluded from the pharmacokinetic data analysis because of missing data or split infusions. Pharmacokinetic parameters were similar whether rituximab was administered alone or in combination with methotrexate or cyclophosphamide (Table III, Figure 1).


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  		Table III Summary of Pharmacokinetic Parameters for Rituximaba Administered Either Alone or With Cyclophosphamide or Methotrexate

 

Figure 1
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  		Figure 1. Mean rituximab serum concentration versus time in patients with rheumatoid arthritis is not influenced by coadministration of cyclophosphamide or methotrexate.

 

The mean areas under the plasma concentrationtime curves for rituximab were similar across treatment groups. Rituximab had a mean terminal half-life of 19 to 22 days after the second infusion. Systemic clearance of rituximab was slow at 242, 226, and 221 mL/d with rituximab monotherapy, rituximab plus cyclophosphamide, and rituximab plus methotrexate, respectively. The volume of distribution of rituximab at steady state was low at 4.28 to 4.74 L and similar to normal plasma volume in all treatment arms.

These data indicate that the pharmacokinetic characteristics of rituximab are not discernibly altered when it is administered in combination with either cyclophosphamide or methotrexate. This observation is supportive of the contention that rituximab does not require dose adjustment when given with either cyclophosphamide or methotrexate.

Peripheral B-Cell Levels and Relationship With Rituximab Serum Concentrations
The normal range of circulating CD19+ B-cell levels in healthy volunteers, as defined by the central analytical laboratory for this study, is 80 to 616 x 103 cells/µL. In this study population with active RA on treatment with methotrexate prior to randomization, the baseline CD19+ B-cell count range was 42 to 707 x 103 cells/µL (n = 147 evaluable for this parameter). At baseline, and before any treatment, approximately 16% of patients in this study had a peripheral B-cell count that was below the LLN. In patients in the methotrexate-alone, rituximab monotherapy, methotrexate plus cyclophosphamide, and rituximab plus methotrexate groups, the baseline mean (±SD) peripheral CD19+ B-cell levels were similar across the groups: 187 ± 96 (n = 35), 209 ± 139 (n = 39), 196 ± 97 (n = 36), and 175 ± 106 (n = 37) x 103 cells/µL, respectively.

Peripheral B-cell depletion occurred in all patients treated with rituximab for whom B-cell-level data were available. Posttreatment samples on day 15 showed peripheral B-cell depletion (≤20% of the LLN) in the rituximab groups (overall mean ± SD, 12.9 ± 10.2; range, 0-15 x 103 cells/µL). In contrast, a transient increase in B-cell counts in the methotrexate-alone group, consequential of the 2-week glucocorticoid regimen, returned to the baseline level by week 16 and thereafter (Figure 2).


Figure 2
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  		Figure 2. Peripheral B-cell levels over 1 year in patients with rheumatoid arthritis treated with methotrexate (MTX) or rituximab (RTX). LLN, lower limit of normal.

 
At week 16, mean peripheral B-cell return—defined as an increase in CD19+ count above the nadir—began when serum rituximab concentrations fell to <10 µg/mL (Figure 3), although in a small sub-set of patients, peripheral B-cell levels remained depleted despite serum concentrations of rituximab of <10 µg/mL. Moreover, once started, the rate of peripheral B-cell return was highly variable. Based on observed-case analysis, the mean peripheral B-cell count had recovered to LLN in 10% of patients (n = 107) by 24 weeks and in 36% of patients (n = 101) by 48 weeks. By 104 weeks, there were 10 patients who had no signs of peripheral B-cell return.


Figure 3
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  		Figure 3. Rituximab serum concentration-time profile in relation to the mean B-cell time profile in patients treated with rituximab.

 
Ten of 121 patients who were followed for at least 2 years or until B-cell return after the first course of treatment with rituximab showed prolonged depletion (ie, B-cell counts ≤20% LLN at week 104). Three of these patients received rituximab 2 x 1000 mg alone, and 7 received rituximab 2 x 1000 mg plus methotrexate as their first course of treatment in the phase IIa study. The mean pharmacokinetic parameters for the patients with prolonged B-cell depletion were comparable to the combined data for all study patients; individual values of the pharmacokinetic parameters were within the range of values seen in the whole study, and none of the individual values represented the extreme of each range (Table IV).


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  		Table IV Mean Pharmacokinetic Parameters for Subjects With Prolonged B-Cell Depletion

 

Relationship Between Clinical Response, Rituximab Pharmacokinetics, and Peripheral B-Cell Levels
The time course of the ACR response over 48 weeks in rituximab-treated patients (Figure 4) suggests that clinical response is not predicted by the pharmacokinetics of rituximab (Figure 1).


Figure 4
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  		Figure 4. Time course of American College of Rheumatology (ACR) 20, 50, and 70 response rates over 48 weeks in relation to mean B-cell levels in patients treated with rituximab.

 
Although the serum concentrations of rituximab appear to be inversely related to recovery of peripheral B cells in some patients, the evidence for peripheral B-cell levels being related to clinical response is, at present, unclear. This is because although peripheral B cells were initially depleted in all rituximab-treated patients, not all patients had a clinical response at the ACR 20 level or higher at week 24 (Figure 4).

Correlations between peripheral B-cell return and the return of symptoms were also unclear. Differences in the patterns of peripheral B-cell return were not discernible between patients who were ACR responders at week 24 and those who were not (Figures 5A and 5B). Neither were differences in the patterns of peripheral B-cell return discernible between patients who were ACR responders at week 24 and subsequently maintained or lost their response at week 48 (Figures 5C and 5D).


Figure 5
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  		Figure 5. B-cell levels relative to clinical response in rheumatoid arthritis. (A) American College of Rheumatology (ACR) 20 response at week 24: responders versus nonresponders; (B) ACR 50 response at week 24: responders versus nonresponders; (C) ACR 20 response maintained versus response lost at week 48 among 24-week responders; (D) ACR 50 response maintained versus response lost at week 48 among 24-week responders.

 
From these results, it appears that peripheral B-cell depletion does not correlate with achievement of an ACR response at week 24. Thus, peripheral B-cell depletion has little value for predicting clinical response. Furthermore, repletion of peripheral B cells does not correlate with the durability of ACR response at week 48.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX I
 ACKNOWLEDGEMENTS
 REFERENCES
 
The depletion of peripheral B cells occurred immediately following the administration of 2 infusions of rituximab 14 days apart. B-cell recovery began as early as week 16, coincident with a rituximab serum concentration below 10 µg/mL, but both the onset and rate of B-cell recovery were highly variable. This observation gives rise to the need to consider the distribution and repletion patterns of B-cell populations in other (nonperipheral) compartments, notably lymphoid and synovial tissue. B cells residing in such tissues may be more resistant to depletion based on complex circulatory dynamics and survival factors from the microenvironment.20

Although all patients receiving rituximab in this study experienced complete depletion of peripheral B cells, and symptomatic response was seen in the majority, not all patients were responders at the ACR 20 level. Moreover, different levels of response (ACR 20, ACR 50, or ACR 70) were seen in responders. It is not possible, therefore, to predict response on the basis of initial peripheral B-cell depletion. The reasons for the lack of correlation between the degree of B-cell depletion and clinical response are unclear. One potential explanation may be the presence of residual B cells in nonperipheral compartments in some patients following rituximab therapy, as noted above. Alternatively, because the level of B cells measured in peripheral blood is a function of the sensitivity of the FACS analysis, a more sensitive FACS analysis with higher levels of gating may reveal the presence of low levels of B cells (even in the periphery), which could contribute to continuing disease.

Patients with RA who were responders to rituximab in this study showed patterns of peripheral B-cell recovery similar to those of nonresponders. Furthermore, the pattern of peripheral B-cell recovery was not distinguishable between responders who maintained their response versus responders whose response waned over time.

Prolonged depletion of peripheral B cells following rituximab administration raises a theoretical concern regarding the susceptibility of these patients to infection. However, in this study, the overall incidence of infections up to 48 weeks did not distinguish rituximab-treated patients from those receiving methotrexate alone. Furthermore, it was observed that 10 patients in this trial had peripheral B-cell depletion at 104 weeks or beyond and did not have return of signs or symptoms of RA at this point (data on file). There was no evidence of serious or prolonged infections in any of these 10 patients, and, because of the functional integrity of the existing memory B cells, these patients maintained immunoglobulin levels and tetanus vaccine titers. Other than showing low peripheral B-cell levels, the safety profiles of these patients remain unremarkable, with no significant safety signals in the 10 patients despite prolonged B-cell depletion following rituximab treatment. Observation of these patients is continuing.

The pharmacokinetics of rituximab were unaffected by the coadministration of either cyclophosphamide or methotrexate, indicating that dosage adjustments of rituximab are not a prerequisite for the concomitant use of these DMARDs with rituximab in patients with RA. This was not a dose-ranging study; therefore, it was not possible to determine whether peripheral B-cell depletion or clinical response was a function of rituximab dose. The lack of a correlation between the rituximab pharmacokinetics and clinical efficacy may have been attributable to the high doses of rituximab used in this study and the likely consequence that both pharmacokinetics and efficacy were at the plateau of their respective dose-response curves.

Observations from this study have implications for clinicians in that empiric measurement of serum rituximab levels and monitoring of peripheral B-cell levels are not indicative of the time to repeat treatment with rituximab because neither appears to directly coincide with the return of disease activity. Further studies are required to clarify the relationship between peripheral and compartmental B-cell depletion and clinical response in RA. In the mean-time, the observations from this study suggest that retreatment decisions with rituximab should not be based on peripheral B-cell levels but instead should be based on clinical symptoms.


   APPENDIX I
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX I
ACKNOWLEDGEMENTS
 REFERENCES
 
List of Study Sites
St Vincent's Hospital Sydney Ltd, Darlinghurst, New South Wales, Australia. Centre Hospitalier, Universitaire Leige, Leige, Belgium. Universitair Ziekenhuis, Gent, Belgium. Instutut de Rheumatologie de Montreal, Montreal, Quebec, Canada. Research Institute of Rheumatic Diseases, Prague, Czech Republic. Zentrum für Therapistudien, Leipzig, Germany. Rheumaklinik Wiesbaden 2, Wiesbaden, Germany. Rambam Medical Center, Haifa, Israel. BNEI Zion Medical Center, Haifa, Israel. Universita di Siena, Azienda Ospedal, Siena, Italy. Spedali Civili di Brescia, Brescia, Italy. Azienda Ospedaliera Policlinico di Modena, Modena, Italy. Universita Degli Studi, Genova, Italy. Leiden University Medical Centre, Leiden, the Netherlands. Medical University of Lublin, Lublin, Poland. Medical University of Wroclaw, Wroclaw, Poland. Instutute of Rheumatology, Warsaw, Poland. Medical University of Poznan, Poznan, Poland. Hospital de Valme, Sevilla, Spain. Hospital de La Paz de Madrid, Madrid, Spain. Hospital Universitario de Canarias, La Laguna, Spain. Hospital Universitario Gregorio Maranon, Madrid, Spain. University College London Hospitals, London, United Kingdom. Cannock Chase Hospital, Cannock, United Kingdom. Leeds General Infirmary, Leeds, United Kingdom. Haywood Hospital, Stoke-on-Trent, United Kingdom.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX I
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: Dr Agarwal and Dr Ren are employed by and own stock in Genentech Inc.

DOI: 10.1177/0091270007305297


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX I
 ACKNOWLEDGEMENTS
 REFERENCES
 

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4. Anderson DR, Grillo-Lopez A, Varns C, Chambers KS, Hanna N. Targeted anti-cancer therapy using rituximab, a chimeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma. Biochem Soc Trans. 1997;25: 705-708.[Web of Science][Medline] [Order article via Infotrieve]

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7. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16: 2825-2833.[Abstract]

8. Panayi GS. The immunopathogenesis of rheumatoid arthritis. Br J Rheumatol. 1993;32(suppl 1): 4-14.[Abstract/Free Full Text]

9. Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999;97: 188-196.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Tighe H, Carson DA. Rheumatoid factors. In: Kelley WN, Ruddy S, Sledge CB, Harris ED, eds. Textbook of Rheumatology. Philadelphia, Pa: Saunders; 1997: 241-249.

11. Van Zeben D, Hazes JMW, Zwinderman AH, Cats A, van der Voort EA, Breedveld FC. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow-up study. Ann Rheum Dis. 1992;51: 1029-1035.[Abstract/Free Full Text]

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13. Leandro MJ, Edwards JCW, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis. 2002;62: 883-888.

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15. Kramm H, Hansen KE, Gowing HE, Bridges A. Successful therapy of rheumatoid arthritis with rituximab: renewed interest in the role of B cells in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol. 2004;10: 28-32.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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18. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31: 315-324.[Web of Science][Medline] [Order article via Infotrieve]

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20. Gong Q, Ou Q, Ye S, et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol. 2005;174: 817-826.[Abstract/Free Full Text]
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