Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion

OBJECTIVE: New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients. METHODS: RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients. RESULTS: Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy. CONCLUSION: Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti-TNF treatment in patients with RA.     

Long‐term amelioration of established collagen‐induced arthritis achieved with short‐term therapy combining anti‐CD3 and anti–tumor necrosis factor treatments

Objective

The goal of rheumatoid arthritis (RA) treatment is to achieve clinical remission in order to limit structural damage and physical disability. To this end, recent emphasis has been placed on aggressive treatment early in the course of disease with drugs such as anti–tumor necrosis factor (anti‐TNF) agents. As T cells are also thought to play an important role in the initiation of RA, we hypothesized that targeting both TNF and T cells would result in better outcomes. The aim of this study was to examine the efficacy of combined therapy with anti‐CD3 and anti‐TNF in experimental RA.

Methods

Two anti‐mouse antibodies were developed as surrogate reagents for anti‐TNF and anti‐CD3 therapies. Collagen‐induced arthritis (CIA) was induced in DBA/1 mice, and antibodies were injected intraperitoneally, either alone on in combination, at predetermined subtherapeutic doses. The frequency and number of pathogenic and regulatory CD4+ T cell subsets in the draining lymph nodes were determined in order to investigate the mechanisms of action.

Results

Strikingly, the combination of the two antibodies demonstrated a potent synergy in established CIA, with long‐term inhibition of disease progression and protection from joint destruction. The results did not demonstrate any enhancement of CD25+FoxP3+ regulatory T cells, but a profound depletion of pathogenic T cells from the draining lymph nodes was associated with reduced numbers of T cells in the joints.

Conclusion

A short course of combination therapy with anti‐CD3 and anti‐TNF efficiently depletes pathogenic T cells from the draining lymph nodes, reducing the numbers of T cells in the joints and affording long‐lasting inhibition of established CIA.

     

Anti–interleukin‐6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled study

Objective

Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti‐TNF therapy. This study investigated the influence on steroidogenesis of an interleukin‐6 (IL‐6)–neutralizing strategy using IL‐6 receptor monoclonal antibodies (referred to as MRA).

Methods

In a placebo‐controlled, double‐blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17‐hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17β‐estradiol, as well as their respective molar ratios, were determined.

Results

MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA‐treated patients (minimum P < 0.004). Serum levels of estrone and 17β‐estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001).

Conclusion

Neutralization of IL‐6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.

     

Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti–tumor necrosis factor therapy in 18,572 patients

Objective

The risk of lymphoma is increased in patients with rheumatoid arthritis (RA), and spontaneous reporting suggests that methotrexate (MTX) and anti–tumor necrosis factor (anti‐TNF) therapy might be associated independently with an increased risk of lymphoma. However, data from clinical trials and clinical practice do not provide sufficient evidence concerning these issues because of small sample sizes and selected study populations. The objective of this study was to determine the rate of and standardized incidence ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, we sought to determine predictors of lymphoma in RA.

Methods

We prospectively studied 18,572 patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma cases received detailed followup. The SEER (Survey, Epidemiology, and End Results) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort.

Results

The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3–2.7). The SIR for biologic use was 2.9 (95% CI 1.7–4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4–4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI 1.9–7.5). The SIR for MTX was 1.7 (95% CI 0.9–3.2), and was 1.0 (95% CI 0.4–2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education.

Conclusion

Lymphomas are increased in RA. Although the SIR is greatest for anti‐TNF therapies, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with anti‐TNF therapy may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive anti‐TNF therapy. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma.

     

Genotoxicity of anti–tumor necrosis factor therapy in patients with juvenile idiopathic arthritis

Objective

To assess the possible effects of both inflammation and the anti–tumor necrosis factor agents (anti‐TNF) on DNA damage with a specific assay, and their effects on the repair capacity of DNA.

Methods

From a group of 20 children with juvenile idiopathic arthritis (JIA), 16 patients who completed the study and 16 control subjects were evaluated. DNA damage and repair capacity were analyzed by the comet assay at the level of peripheral lymphocytes before anti‐TNF (etanercept) injections and on the 15th, 90th, and 180th days after the first injection.

Results

The amount of damage as detected by the aforementioned assay was higher in patients with JIA compared with controls. On the 15th day after the initial anti‐TNF injection, there was a decrease in the mean DNA tail length of JIA patients, however on the 90th day an increase was observed; thereafter, an upward trend was observed until the end of the study. JIA patients had a DNA repair capacity that was significantly less than that of controls.

Conclusion

The results of the comet technique suggests that JIA patients already have increased basal DNA damage before anti‐TNF therapy; they are more sensitive to the DNA damage produced by H₂O₂, and have a less efficient DNA repair system in comparison with control cells. After an initial improvement at 2 weeks, parameters of genotoxicity worsened, and DNA repair was further impaired 6 months after the addition of an anti‐TNF agent to treatment.     

Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled study

OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). METHODS: In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. RESULTS: MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). CONCLUSION: Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.     

Neutropenia in patients receiving anti–tumor necrosis factor therapy

Objective

To examine the rates of and risk factors for neutropenia together with the dynamics of neutrophil and other white cell subset counts in a cohort of patients treated with a tumor necrosis factor (TNF) inhibitor for inflammatory arthritis.

Methods

We performed a retrospective cohort study examining the association between baseline demographics, clinical features, medications used, and development of neutropenia, and behavior of neutrophil and other white cell subset counts during TNF inhibitor therapy.

Results

In 367 patients (298 [81.2%] with rheumatoid arthritis, 38 [10.4%] with ankylosing spondylitis, and 31 [8.4%] with psoriatic arthritis), 69 (18.8%) had at least one episode of neutropenia (<2.0 × 10⁹/liter) during TNF inhibitor therapy, and of these, 6% developed serious infections secondary to neutropenia. There was no significant difference in disease, demographic, or drug variables between patients with and without neutropenia. However, patients with neutropenia had significantly lower baseline neutrophil counts (4.2 × 10⁹/liter; 95% confidence interval [95% CI] 3.8, 4.6 versus 6.2 × 10⁹/liter; 95% CI 6.0, 6.5), and a previous history of neutropenia while receiving disease‐modifying antirheumatic drugs increased the risk while receiving TNF inhibitors (hazard ratio 2.97; 95% CI 1.69, 5.25). A significant drop in mean neutrophil count (1.12 × 10⁹/liter; 95% CI 0.92, 1.32) was observed after 2 weeks of TNF inhibitor therapy. Other white cell subsets tended to significantly increase.

Conclusion

TNF inhibitor therapy is associated with a significant reduction in peripheral blood neutrophil count, leading to 19% of patients becoming neutropenic. Risk of neutropenia is significantly higher in patients with a low baseline neutrophil count or previous history of neutropenia. We suggest that patients receiving TNF inhibitor therapy would benefit from regular complete blood cell count monitoring.     

Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long‐term treatment with anti–tumor necrosis factor α antibody

Objective

Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor α (TNFα). Anti‐TNFα antibody improved endothelial function in RA patients after a 12‐week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long‐term infliximab‐treated RA patients.

Methods

Seven RA patients (5 women; age range 25–73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial‐dependent and independent vasodilatation were measured by brachial ultrasonography.

Results

Following infliximab infusion, a rapid increase in the percentage of endothelial‐dependent vasodilatation was found in all patients (mean ± SD 9.4 ± 5.5% 2 days postinfusion compared with 2.8 ± 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial‐independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02).

Conclusion

Our study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long‐term use of drugs that block TNFα function to reduce the high incidence of cardiovascular complications in RA.

     

Dyslipidemia and changes in lipid profiles associated with rheumatoid arthritis and initiation of anti–tumor necrosis factor therapy

Objective

To investigate the frequency of lipid testing in clinical practice and to explore the relationship between rheumatoid arthritis (RA), dyslipidemia, and other cardiovascular (CV) risk factors with RA treatment.

Methods

Patients in this retrospective database study were ages ≥18 years and had ≥2 physician diagnoses for RA or osteoarthritis (OA; comparator group) between March 2004 and March 2008. Outcomes of interest included the percentage of RA and OA patients receiving lipid tests, lipid profiles (total cholesterol, low‐density lipoprotein [LDL] cholesterol, and high‐density lipoprotein [HDL] cholesterol) of RA versus OA patients, and lipid profiles of RA patients before and after initiation with a tumor necrosis factor (TNF) inhibitor. We used multivariable regression to control potential confounders between the cohorts.

Results

Over a median ≥2‐year followup, fewer RA patients than OA patients had ≥1 lipid test (62.0% [95% confidence interval (95% CI) 61.5–62.5] versus 69.8% [95% CI 69.5–70.1]). Mean total cholesterol and LDL cholesterol were each 4 mg/dl lower in the RA cohort (P < 0.0001); HDL cholesterol was similar between the cohorts. Across the RA cohort, 25.2% of patients had suboptimal LDL cholesterol levels (≥130 mg/dl). Among RA patients not receiving lipid‐lowering therapy who initiated TNF inhibitor therapy (n = 96), mean total cholesterol and LDL cholesterol increased by 5.4 and 4.0 mg/dl, respectively.

Conclusion

Patients with RA were less likely to be tested for hyperlipidemia and had more favorable lipid profiles than patients with OA. TNF inhibitor therapy modestly increased all lipid parameters. Additional studies are needed to determine the effect of traditional CV risk factors and inflammation and the impact of biologic agents on CV outcomes in RA patients.     

Improvement in patient‐reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti–tumor necrosis factor therapy

Objective

To assess the effects of treatment with rituximab plus methotrexate on patient‐reported outcomes in patients with active rheumatoid arthritis (RA) who experienced inadequate response to anti–tumor necrosis factor therapy.

Methods

Patients with active RA were randomly assigned to rituximab (1,000 mg on days 1 and 15) or placebo. The primary end point was the proportion of patients with an American College of Rheumatology 20% response at week 24. Additional goals were to assess treatment effects on pain, fatigue, functional disability, health‐related quality of life, and disease activity by comparing mean changes between groups. The analysis was conducted in the intent‐to‐treat population. The proportion of patients who achieved the minimum clinically important difference on the Health Assessment Questionnaire (HAQ) disability index (DI), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F), and Short Form 36 (SF‐36) was determined.

Results

Rituximab patients had statistically significantly greater pain relief. The FACIT‐F showed significantly greater improvement in rituximab patients than placebo patients from weeks 12 through 24. Mean improvement from baseline in functional disability (measured by the HAQ DI) was significantly greater in rituximab patients from weeks 8 to 24. The mean ± SD change from baseline for the SF‐36 Physical Component Score was 6.64 ± 8.74 for rituximab patients and 1.48 ± 7.32 for placebo patients (P < 0.0001). The mean change from baseline for the SF‐36 Mental Component Score was 5.32 ± 12.41 for rituximab patients and 2.25 ± 12.23 for placebo patients (P = 0.0269).

Conclusion

Rituximab produced rapid, clinically meaningful, and statistically significant improvements in patient‐reported pain, fatigue, functional disability, health‐related quality of life, and disease activity. These effects were sustained throughout the study.     

Deactivation of vascular endothelium by monoclonal anti–tumor necrosis factor α antibody in rheumatoid arthritis

Objective. To assess whether monoclonal antibody to tumor necrosis factor α (TNFα) reduces endothelial activation in rheumatoid arthritis (RA). Methods. Levels of serum E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), and circulating leukocytes (differential counts) were measured in RA patients before and up to 4 weeks after infusion of either placebo or chimeric anti-TNFα antibody cA2 (1 or 10 mg/kg). Results. Treatment with anti-TNFα decreased serum E-selectin and ICAM-1 levels, with the earliest detectable changes observed on days 1–3 after anti-TNFα infusion. No effect on VCAM-1 levels was detected. In parallel, there was a rapid and sustained increase in circulating lymphocytes. The extent of the decrease in serum E-selectin and ICAM-1 levels and the increase in lymphocyte counts was significantly higher (P ≤ 0.05) in patients in whom a clinical benefit of anti-TNFα was observed (≥20% response, by Paulus criteria, at week 4) compared with that in patients who failed to respond to anti-TNFα at this time point. Conclusion. We propose that decreased serum levels of adhesion molecules may reflect diminished activation of endothelial cells in the synovial microvasculature, leading to reduced migration of leukocytes into synovial joints, and thus prolonging the therapeutic effect of anti-TNFα in RA.     

Synovial fibroblast hyperplasia in rheumatoid arthritis: Clinicopathologic correlations and partial reversal by anti–tumor necrosis factor therapy

Objective

Synovial fibroblast (SF) hyperplasia contributes to the pathogenesis of rheumatoid arthritis (RA), but quantitative information on this process is scarce. This study was undertaken to evaluate the fibroblast‐specific marker Hsp47 as a quantitative marker for SFs and to analyze its clinicopathologic correlates and evolution after anti–tumor necrosis factor α (anti‐TNFα) therapy.

Methods

Synovial biopsy samples were obtained from 48 patients with RA and 20 controls who were healthy or had osteoarthritis (OA). Twenty‐five RA patients who had active disease at the time of biopsy underwent a second biopsy after anti‐TNFα therapy. Immunolabeling for Hsp47, inflammatory cells, and vascular cell markers was performed. Hsp47‐positive lining and sublining fractional areas were quantified, and their correlation with clinicopathologic variables was analyzed.

Results

In normal and diseased synovial tissue, Hsp47 was specifically and uniformly expressed by lining, sublining, and perivascular fibroblasts. Lining SF area was significantly increased in both RA and late OA tissue compared to normal tissue. Sublining SF area was increased in RA tissue but not in late OA tissue compared to normal tissue. Lining SF area was positively correlated with macrophage density, Disease Activity Score in 28 joints, and RA disease duration. In contrast, sublining SF area was negatively correlated with RA disease duration and activity. A significant reduction in lining SF area but not sublining SF area was observed after anti‐TNFα therapy.

Conclusion

Our findings indicate that Hsp47 is a reliable marker for quantifying SFs in human synovial tissue. Our data suggest that lining and sublining SFs undergo different dynamics during the course of the disease. Lining SF expansion parallels the activity and temporal progression of RA and can be partially reversed by anti‐TNFα therapy.

     

Anti–tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis

Objective

Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)–blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti‐TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF‐κB ligand (RANKL) in synovial tissue.

Methods

The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double‐blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one‐way analysis of variance, with Tukey's post hoc test.

Results

Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF‐primed osteoblasts and endothelial cells.

Conclusion

Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti‐TNF therapy.

     

B cell depletion may be more effective than switching to an alternative anti–tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti–tumor necrosis factor agents

Objective

Patients with rheumatoid arthritis (RA) in whom the response to anti–tumor necrosis factor (anti‐TNF) therapy is inadequate have several therapeutic options, such as switching to an alternative anti‐TNF agent or initiating B cell–depleting therapy with rituximab (RTX). Although both therapeutic options have been proven effective in trials, no head‐to‐head comparisons are available. The aim of this study was to compare the effectiveness of RTX with that of an alternative anti‐TNF agent in the management of patients with RA who had an inadequate response to anti‐TNF therapy.

Methods

This prospective cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti‐TNF agent and subsequently received either 1 cycle of RTX or an alternative anti‐TNF agent. The primary outcome was the evolution of RA disease activity (as measured on the Disease Activity Score in 28 joints [DAS28]), which was analyzed using multivariate regression models for longitudinal data.

Results

One hundred sixteen patients with RA were included; 50 patients received 1 cycle of RTX, and 66 patients were treated with a second or a third alternative anti‐TNF agent. At baseline, there were no significant differences between the 2 groups in age, sex, disease duration, and disease activity. Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti‐TNF agent (P = 0.01). At 6 months, the mean decrease in the DAS28 was −1.61 (95% confidence interval [95% CI] −1.97, −1.25) among patients receiving RTX and −0.98 (95% CI −1.33, −0.62) among those receiving subsequent anti‐TNF therapy.

Conclusion

The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti‐TNF agent in patients with RA in whom active disease persists despite anti‐TNF therapy.