Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
18250114 Gene expression profiling in rheumatoid arthritis: current concepts and future directions. 2008 Dec Over the last years microarray technologies have generated new perspectives for the high-throughput analysis of biological systems. Nowadays, it is possible to monitor thousands of genes in a single experiment. This molecular profiling technology combined with standardised and validated clinical measurements can allow a more precise characterisation of a patient's phenotype, and may lead to the design of therapeutic protocols and procedures better tailored to an individual patient's needs. In this report we provide an overview of expression profiling studies in rheumatoid arthritis (RA). RA is a chronic inflammatory disease in which both genetic and environmental factors are involved. The precise molecular mechanisms underlying RA are not fully understood. A systematic literature search revealed nine array-based expression profiling studies in patients with RA. Findings from these studies were compared with those of linkage and genome-wide association (GWA) studies. Although we observed many differences in study design, analysis and interpretation of results between the different studies, we extracted two sets of genes: (1) those differentially expressed in more than one study, and (2) genes differentially expressed in at least one of the reviewed studies and present in RA linkage or GWA loci. We suggest that both sets of genes include interesting candidate genes for further study in RA.
19104082 Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune 2009 Feb 26 T-helper (Th) cells activated by cytokines in the absence of T-cell receptor ligation are suspected to participate in inflammatory processes by production of interferon-gamma (IFN-gamma). Still, the relevance of such a mechanism has not been addressed in humans. Here we demonstrate that a subset of human effector-memory Th cells expressing functional interleukin-12R (IL-12R), IL-18Ralpha, and CCR5 ex vivo can be induced to secrete IFN-gamma by cytokines signaling via the IL-2R common gamma-chain in combination with IL-12 and IL-18. Cytokine-driven IFN-gamma production depends on JAK3- and p38 mitogen-activated kinase signals and is sensitive to suppression by CD25(++) regulatory T cells. Contrary to IFN-gamma(+) Th cells induced upon antigen-specific stimulation, their cytokine-activated counterparts characteristically lack expression of costimulator 4-1BB (CD137). Strikingly, the majority of Th cells infiltrating inflamed joints of rheumatoid arthritis patients is equipped with receptors prerequisite for cytokine-induced IFN-gamma secretion. Among these cells, we detected a substantial fraction that secretes IFN-gamma directly ex vivo but lacks 4-1BB expression, indicating that cytokine-induced IFN-gamma(+) Th cells operate in autoimmune inflammation. Our data provide a rationale for how human effector-memory Thcells can participate in perpetuating inflammatory processes in autoimmunity even in the absence of T-cell receptor ligation.
17785286 SLAM-associated protein solves a mystery of autoimmunity. 2007 Aug SLAM-associated protein (SAP) is essential for viral protection, lifelong immune memory (vaccination), and lifelong autoantibody production. We discuss how SAP is a key player in the development of autoimmune disease.
18328143 Resource utilization and the cost of rheumatoid arthritis in Brazil. 2008 Jan OBJECTIVE: To describe and analyze resource utilization in patients with rheumatoid arthritis (RA) treated at a tertiary public health facility over a one-year period. Costs for the patient and for society associated with the treatment of RA were also investigated. METHODS: One hundred consecutively selected RA patients were included. Resource utilization was evaluated retrospectively for one year. Systematic interviews were used in all patients and demographic, socioeconomic and clinical variables were recorded. RESULTS: One hundred patients were included. Most of the patients were women (92%) and had mean age and disease duration of 51 and 11 years, respectively. The majority of the patients were Steinbroker functional class I (48%). Mean HAQ score for the sample was 0.95 and mean Short-Form-36 scores were between 49.64 (bodily pain) and 70.00 (social functioning). The average monthly household income for the group was US$ 359. The patients had on average 4 outpatient visits and 21 laboratory exams per year. Drugs accounted for 59% of the total cost associated with RA. The average total cost for society was US$ 424.14 per patient per year, of which 95% were direct and 5% indirect costs. CONCLUSION: The management of RA patients is an important financial burden in Brazil. The effort to couple resource utilization with the best available evidence, associated with the limited funds available in the healthcare system (particularly in a developing country), emphasizes the importance of studies that critically evaluate resource utilization and cost in these chronic patients. The systematic use of such studies may prove helpful to optimize the health system.
18651199 Clinical results of bone ingrowth TKA in patients with rheumatoid arthritis. 2008 Dec Patients with rheumatoid arthritis (RA) often are not considered for TKA with bone ingrowth fixation because of poor bone quality, but we asked whether implants with sintered metal bead surfaces could be used to durably fix implants in this group of patients. We prospectively evaluated a consecutive series of 47 patients (64 knees) between January 1, 1994, and December 30, 2001, in two separate medical centers using one TKA system. Standard primary implants were used in all knees except those with major bone defects, and in these patients we used long diaphyseal stems to stabilize the implants. Minimum followup was 61 months (mean +/- standard deviation, 83 +/- 6 months; range, 61-124 months). Survivorship was 98.4% at 10 years postoperatively. No components failed because of loosening. One femoral component was revised for fracture because of a massive intraosseous rheumatoid cyst. No knees had radiographic evidence of migration or widening radiolucent lines. Knee Society clinical, pain, and function scores improved after surgery and were maintained throughout followup. These data suggest bone ingrowth implants can provide durable fixation in patients with RA. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
16758372 Common carotid intima-media thickness and von Willebrand factor serum levels in rheumatoid 2007 Apr High atherosclerosis prevalence was found in rheumatoid arthritis (RA), and the von Willebrand factor (vWF) was shown to be a marker for endothelial damage. The aim of this study was to evaluate the association of intima-media thickness of the left common carotid artery with vWF serum levels in rheumatoid arthritis patients without cardiovascular risk factors. We included 55 RA female patients, each with at least 5 years of duration of the disease, and 20 healthy female subjects as members of the control group. The vWF, cholesterol, triglycerides, and the immune variables-rheumatoid factor and reactive C protein-were evaluated. The media thickness and intima-media thickness (IMT) in patients and in the control subjects were assessed by Doppler ultrasound of the left common carotid artery. Although the ages for RA patients and healthy female controls were not different, the IMT of the left common carotid artery (IMT CCA) in rheumatoid arthritis patients was increased in comparison with healthy control measurements, the mean being 0.67 mm (SD 0.18) vs 0.58 mm (SD 0.10) with a p value 0.01. The vWF serum levels showed differences in RA patients from those in control patients, 145.6 (SD 30.08) vs 121.8 (SD 37.17), respectively, with p=0.007. A correlation was also found between vWF with IMT CCA in the RA patients: r=0.390 and p<0.05. We concluded that the measurements of the left common carotid artery intima-media thickness together with the von Willebrand factor serum levels could give valuable information about the artery status and the atherosclerosis process in early stages in patients with rheumatoid arthritis without cardiovascular risk factors.
18240243 Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced ly 2008 Feb OBJECTIVE: To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. METHODS: Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. RESULTS: Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. CONCLUSION: Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.
18092129 Interleukin-17 gene expression in patients with rheumatoid arthritis. 2008 Interleukin-17 is a proinflammatory cytokine. Recent animal studies have shown that IL-17 plays a role in the initiation and progression of arthritis. However, whether IL-17 has a prominent role in human rheumatoid arthritis (RA) or not remains unclear. Here we investigated the role of IL-17 in patients with RA. cDNA was prepared from knee joint synovial tissues of RA (n = 11) and osteoarthritic (OA, n = 10) patients and PBMC of RA (n = 52) and healthy subjects (n = 34). IL-17 gene expression level was measured by real-time PCR, and was compared with various clinical parameters. IL-17 gene expression in synovial tissues of RA was similar to that in OA. IL-17 gene expression level in PBMC of RA patients was significantly higher than in the control. The response (changes in DAS) to two-week treatment with anti-TNF-alpha blockers (infliximab or etanercept) did not correlate with changes in IL-17 gene expression levels. The IL-17/TNF-alpha gene expression ratio at baseline (before treatment) tended to be lower in responders to the treatment. Expression of IL-17 gene in PBMC may be associated with the inflammatory process of RA. IL-17/TNF-alpha expression ratio is a potentially suitable marker of response to anti-TNF-alpha therapy.
18565255 Methotrexate selectively modulates TH1/TH2 balance in active rheumatoid arthritis patients 2008 Mar OBJECTIVE: The mechanism by which low dose methotrexate (MTX, the gold standard treatment for rheumatoid arthritis) exerts its anti-inflammatory effect in rheumatoid arthritis (RA) patients is still debated. Lately, the MTX immunosuppressive effect has been related to apoptosis, especially in active RA patients, with ROS involvement. METHODS: In the present research we investigated MTX oxidative effect and its ability to modulate immune balance in active versus non-active RA patients. RESULTS: Our results show that MTX induces IL-10 secretion (a TH2 cytokine) and significantly reduces TH1 profile in Peripheral Mononuclear Cells (PMNC) derived from active RA patients (n=28). Additionally, we found that MTX modulates the immune status towards TH2 dominance by decreasing the IL-12R and the CXCR3 receptors typical for the TH1 population. Moreover, MTX was found to inhibit the production of nitric oxide (NO) in these patients, a phenomenon that might contribute to MTX action toward cytokine homeostasis. A significant correlation was found between MTX IL-10 induction and NO inhibition in active RA patients. CONCLUSION: Our data suggest that, in active RA patients, apoptosis induction by MTX may be primarily due to IL-10 production via modulation of oxidative stress, which may restore the critically important immune balance. These findings may contribute to determining which group of RA patients may better respond to MTX therapy.
18205922 Key regulatory molecules of cartilage destruction in rheumatoid arthritis: an in vitro stu 2008 BACKGROUND: Rheumatoid arthritis (RA) is a chronic, inflammatory and systemic autoimmune disease that leads to progressive cartilage destruction. Advances in the treatment of RA-related destruction of cartilage require profound insights into the molecular mechanisms involved in cartilage degradation. Until now, comprehensive data about the molecular RA-related dysfunction of chondrocytes have been limited. Hence, the objective of this study was to establish a standardized in vitro model to profile the key regulatory molecules of RA-related destruction of cartilage that are expressed by human chondrocytes. METHODS: Human chondrocytes were cultured three-dimensionally for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatants from SV40 T-antigen immortalized human synovial fibroblasts (SF) derived from a normal donor (NDSF) and from a patient with RA (RASF), respectively. To identify RA-related factors released from SF, supernatants of RASF and NDSF were analyzed with antibody-based protein membrane arrays. Stimulated cartilage-like cultures were used for subsequent gene expression profiling with oligonucleotide microarrays. Affymetrix GeneChip Operating Software and Robust Multi-array Analysis (RMA) were used to identify differentially expressed genes. Expression of selected genes was verified by real-time RT-PCR. RESULTS: Antibody-based protein membrane arrays of synovial fibroblast supernatants identified RA-related soluble mediators (IL-6, CCL2, CXCL1-3, CXCL8) released from RASF. Genome-wide microarray analysis of RASF-stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation (adenosine A2A receptor, cyclooxygenase-2), the NF-kappaB signaling pathway (toll-like receptor 2, spermine synthase, receptor-interacting serine-threonine kinase 2), cytokines/chemokines and receptors (CXCL1-3, CXCL8, CCL20, CXCR4, IL-1beta, IL-6), cartilage degradation (matrix metalloproteinase (MMP)-10, MMP-12) and suppressed matrix synthesis (cartilage oligomeric matrix protein, chondroitin sulfate proteoglycan 2). CONCLUSION: Differential transcriptome profiling of stimulated human chondrocytes revealed a disturbed catabolic-anabolic homeostasis of chondrocyte function and disclosed relevant pharmacological target genes of cartilage destruction. This study provides comprehensive insight into molecular regulatory processes induced in human chondrocytes during RA-related destruction of cartilage. The established model may serve as a human in vitro disease model of RA-related destruction of cartilage and may help to elucidate the molecular effects of anti-rheumatic drugs on human chondrocyte gene expression.
16652417 Controlled trial of methotrexate versus CH-1504 in the treatment of rheumatoid arthritis. 2006 May OBJECTIVE: To investigate the clinical efficacy, safety, tolerability, and toxicity profile of a metabolically stable antifolate, CH-1504, compared to methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). METHODS: A 24-week open-label trial of MTX and CH-1504 was performed in 20 patients with RA. RESULTS: Improvements in clinical and laboratory indicators were observed in both study groups. Improvement in the CH-1504 group was greater than in the MTX group. Both treatments were generally well tolerated; however, the liver function test abnormalities and gastrointestinal related adverse events expected with this class of medication were not seen with CH-1504. CONCLUSION: CH-1504 appears to be clinically efficacious and may possess a superior safety and tolerance profile compared to MTX.
16622719 Twenty-four-week follow-up examination of a leukocytapheresis therapy in rheumatoid arthri 2006 Several clinical trials have demonstrated that leukocytapheresis (LCAP) is a safe and effective therapy for patients with refractory rheumatoid arthritis (RA). However, most of those reports were limited to short-term clinical observation. We have treated 11 RA patients with LCAP and observed them for 24 weeks after the final administration. The 11 cases included 3 diabetes patients, 2 patients with interstitial pneumonia, 1 patient with diffuse panbronchiolitis, and 1 patient with old pulmonary tuberculosis. Alternative therapies for all of these patients were considered difficult. Once-a-week LCAP administration was added for 5 weeks to the previous therapeutic regime in all patients, and the treatment efficacy was prospectively qualified. At 4 weeks after the final LCAP therapy, 8 of the 11 patients (73%) had achieved an American College of Rheumatology (ACR) 20% response, and 3 of the 11 (27%) had achieved both ACR 50% and ACR 70% responses. Although the efficacy decreased after the observation periods, an ACR 20% response was maintained in 5 patients (45%) at 24 weeks. Although only a limited number of patients were examined in this study, the results suggested that LCAP therapy will be beneficial to RA patients, including patients who cannot be treated with tumor necrosis factor inhibitors or conventional disease-modifying antirheumatic drugs.
16548360 [Clinical observation on treatment of rheumatoid arthritis with biqi capsule]. 2006 Feb OBJECTIVE: To study the indication and clinical efficacy of Biqi capsule (BC) in treating patients with rheumatoid arthritis (RA). METHODS: One hundred and forty-two RA patients were randomly divided into the BC treated group and the control group treated with nimesulide tablet (NT). There were 36 patients with dampness-heat blockage syndrome type and 35 patients with Qi deficiency and blood stasis syndrome type in each group. The treatment course lasted for 8 weeks. RESULTS: The total effective rate in the BC group was 66.2% (47 cases), while that in the control group was 60.6% (43 cases). The total effective rate in the patients with Qi deficiency and blood stasis syndrome type in the BC group was 91.4%, superior to that with dampness-heat blockage type (41.7%). Only one patient showed mild adverse reaction in the BC group. CONCLUSION: BC is a kind of safe and effective herble medicine for treatment of RA, especially for those of Qi deficiency and blood stasis syndrome type.
17599733 Association of a haplotype in the promoter region of the interferon regulatory factor 5 ge 2007 Jul OBJECTIVE: To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA). METHODS: Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP). RESULTS: Four of the 5 SNPs located in the 5' region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of approximately 0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort. CONCLUSION: Given the fact that anti-CCP-negative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.
16414976 Radiological hand involvement in systemic sclerosis. 2006 Aug BACKGROUND: The osteoarticular and soft tissue structures of the hand may be involved in systemic sclerosis (SSc), causing functional disability. OBJECTIVE: To assess radiological hand features in a cross sectional study of SSc patients and in controls. METHODS: Hand radiology was done systematically in patients with SSc seen over a two year period and in unselected controls with rheumatoid arthritis or digital trauma. Two independent investigators blind to the diagnosis carried out the radiological assessment. RESULTS: 120 consecutive SSc patients (median (range) age, 56.5 (20 to 90) years; disease duration, 6 (0 to 42) years) and 42 controls (22 with rheumatoid arthritis and 20 with digital trauma) were studied. Radiological abnormalities in SSc patients included erosion (21%), joint space narrowing (28%), arthritis (defined by concomitant erosion and joint space narrowing) (18%), radiological demineralisation (23%), acro-osteolysis (22%), flexion contracture (27%), and calcinosis (23%). In univariate and multivariate analysis, the resorption of distal phalanges was significantly associated with digital ulcers, extra-articular calcification, and pulmonary arterial hypertension; flexion contracture was associated with the diffuse cutaneous form and high HAQ (Health Assessment Questionnaire) disability score. Calcinosis was most often seen in patients with digital ulcers, but was similarly observed in patients with the diffuse or limited cutaneous subtypes. CONCLUSIONS: Flexion contracture was associated with disability and occurred in patients with the diffuse cutaneous subtype of SSc, consistent with the tendency towards fibrosis and functional impairment of this subtype. Calcinosis and acro-osteolysis were both associated with vascular complications, highlighting a potential role of vascular injury in such lesions.
17543163 B-cell: a logical target for treatment of rheumatoid arthritis. 2007 Mar The interest for B-cells in rheumatoid arthritis (RA) is currently being revived. They are involved in the development and activation of lymphoid architecture by regulating dentritic cell and T-cell function through cytokine production. Receptor editing an revising are also essential in B-cells and aid in preventing autoimmunity. Abnormalities in the subset distribution and a default in any task assigned to the B-cells may favor autoimmunity. Beneficied responses to B-cell depletion in RA by anti-CD20 monoclonal antibody rituximab illustrate the importance of B-lymphocytes in the pathogenesis of this disease. A new avenue has thus been opened, whereby B-lymphocytes return as a significant contributor to autoimmune disorders.
17158139 Sex: a major predictor of remission in early rheumatoid arthritis? 2007 Jan BACKGROUND: The treatment goal of early rheumatoid arthritis is remission. This study reports remission rates in clinical practice using a cohort of patients with early rheumatoid arthritis. METHODS: 698 patients with early rheumatoid arthritis were included. Mean age at inclusion was 58 years and mean disease duration was 6.4 months; 64% of the patients were women, 56% were positive for antibodies to cyclic citrullinated peptide and 60% were positive for rheumatoid factor. Remission was defined as a disease activity score <2.6, with or without ongoing treatment with drugs for rheumatoid arthritis. RESULTS: After 2 years, 261 of 689 patients were in remission (37.9%), and after 5 years, the remission rate was 38.5%. However, only 26.1% were in remission at both these time points. Multiple logistic regression analyses found sex to be a main predictor for remission. Thus, significantly fewer women were in remission after 2 years (32.1% v 48%, p = 0.001) after 5 years (30.8% v 52.4%, p = 0.001) and at both these time points (19.1% v 39.3%, p = 0.001). Although disease activity was not with certainty more pronounced in women at onset of disease, the disease course became markedly worse in women. The disparity in remission frequency between women and men could not be explained by differences in disease duration, age or treatment with disease modifying antirheumatic drugs or glucocorticoids. CONCLUSIONS: Early remission of rheumatoid arthritis by 28-joint Disease Activity Score<2.6 was as frequent or more frequent in this study than in most previous reports. Importantly, women had more severe disease with a considerably lower remission rate than men, although the disease activity before treatment seemed similar.
18378514 Cancer risk in hospitalized rheumatoid arthritis patients. 2008 May OBJECTIVES: Patients diagnosed with RA have been at an increased risk of many cancers and at a decreased risk of some cancers. We planned to revisit the theme by using a nation-wide population of RA patients. METHODS: An RA research database was constructed by identifying hospitalized RA patients from the Hospital Discharge Register and cancer patients from the Cancer Registry. Earlier studies from Sweden have shown that some 75% of RA patients have been hospitalized at some time point. Follow-up of 42,262 RA patients was carried out from year 1980 to 2004 including separate follow-ups for shorter intervals. Standardized incidence ratios (SIRs) were calculated for cancer in RA patients by comparing with subjects without RA. RESULTS: Many cancers were in excess in RA patients, especially Hodgkin disease, non-Hodgkin lymphoma and squamous cell skin cancer; a novel association was found for non-thyroid endocrine tumours. Colon, rectal and endometrial cancers were decreased in RA patients. When RA patients were first hospitalized after 1999, the SIRs for melanoma, squamous cell skin and upper aerodigestive tract cancers and for leukaemia were increased compared with previous periods. CONCLUSIONS: This study, the largest so far published, quantified the increased and decreased site-specific risks of cancer in RA patients. The recent increases in the risks of squamous cell skin and upper aerodigestive tract cancers, melanoma and leukaemia call for continuous vigilance and recording of changes in treatment.
19122375 [Various clinical symptoms in human parvovirus B19 infection]. 2008 Dec Human parvovirus B19 infection causes erythema infectiosum in child, aplastic crisis in patients with chronic hemolytic anemia, chronic pure red cell aplasia in immunocompromised patients and hydrops fetalis. Human parvovirus B19 causes arthritis and acute glomerulonephritis due to immunological mechanism. Other disorders, rheumatoid arthritis, vasculitis and thrombotic microangiopathy, are linked in human parvovirus B19 infection. Parvovirus B19 infection causes choronic rheumatoid-like arthropathy. Autoantibody and low complement were seen in acute human parvovirus infection, and parvovirus B19 infection present clinically lupus like tableau.
17642239 [Targeting CD20 in rheumatoid arthritis]. 2007 Jul Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovitis and bone destruction. Although anti-rheumatic drugs including methotrexate along with tumor necrosis factor (TNF) blocker markedly improved the disease activity, the treatment for the patients who failed to TNF blockers still has not been established. Recent clinical trials with CD20 antibody(rituximab and HuMax-CD20) provide sufficient evidence of excellent tolerability and high efficacy of therapy in refractory RA. A single course of rituximab, which is a genetically engineered chimeric murine variable regions/human IgG1 anti-CD20 monoclonal antibody, with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to one or more anti-TNF therapies.