Health Assessment Questionnaire at One Year Predicts All-Cause Mortality in Patients With Early Rheumatoid Arthritis.

OBJECTIVE: Higher self-reported disability (high Health Assessment Questionnaire [HAQ] score) has been associated with hospitalizations and mortality in established rheumatoid arthritis (RA), but associations in early RA are unknown. METHODS: Patients with early RA (symptom duration <1 year) enrolled in the Canadian Early Arthritis Cohort who initiated disease-modifying antirheumatic drugs and had completed HAQ data at baseline and 1 year were included in the study. Discrete-time proportional hazards models were used to estimate crude and multi-adjusted associations of baseline HAQ and HAQ at 1 year with all-cause mortality in each year of follow-up. RESULTS: A total of 1,724 patients with early RA were included. The mean age was 55 years, and 72% were women. Over 10 years, 62 deaths (3.6%) were recorded. Deceased patients had higher HAQ scores at baseline (mean ± SD 1.2 ± 0.7) and at 1 year (0.9 ± 0.7) than living patients (1.0 ± 0.7 and 0.5 ± 0.6, respectively; P < 0.001). Disease Activity Score in 28 joints (DAS28) was higher in deceased versus living patients at baseline (mean ± SD 5.4 ± 1.3 versus 4.9 ± 1.4) and at 1 year (mean ± SD 3.6 ± 1.4 versus 2.8 ± 1.4) (P < 0.001). Older age, male sex, lower education level, smoking, more comorbidities, higher baseline DAS28, and glucocorticoid use were associated with mortality. Contrary to HAQ score at baseline, the association between all-cause mortality and HAQ score at 1 year remained significant even after adjustment for confounders. For baseline HAQ score, the unadjusted hazard ratio (HR) was 1.46 (95% confidence interval [95% CI] 1.02-2.09), and the adjusted HR was 1.25 (95% CI 0.81-1.94). For HAQ score at 1 year, the unadjusted HR was 2.58 (95% CI 1.78-3.72), and the adjusted HR was 1.75 (95% CI 1.10-2.77). CONCLUSION: Our findings indicate that higher HAQ score and DAS28 at 1 year are significantly associated with all-cause mortality in a large early RA cohort.

Impact of immunogenicity on efficacy and tolerability of tumour necrosis factor inhibitors: pooled analysis of biosimilar studies in rheumatoid arthritis.

Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).

Palindromic Rheumatism Frequently Precedes Early Rheumatoid Arthritis: Results From an Incident Cohort.

BACKGROUND: This multicenter incident cohort aimed to characterize how often early rheumatoid arthritis (ERA) patients self-report episodic joint inflammation (palindromic rheumatism) preceding ERA diagnosis and which characteristics differentiate these patients from those without prior episodic symptoms. METHODS: Data were from patients with early confirmed or suspected RA (more than 6 weeks and less than 12 months) enrolled in the Canadian Early ArThritis CoHort (CATCH) between April 2017 to March 2018 who completed study case report forms assessing joint pain and swelling prior to ERA diagnosis. Chi-square and t tests were used to compare characteristics of patients with and without self-reported episodic joint inflammation prior to ERA diagnosis. Multivariable logistic regression was used to identify sociodemographic and clinical measures associated with past episodic joint inflammation around the time of ERA diagnosis. RESULTS: A total of 154 ERA patients were included; 66% were female, and mean (SD) age and RA symptom duration were 54 (15) years and 141 (118) days. Sixty-five (42%) ERA patients reported a history of episodic joint pain and swelling, half of whom reported that these symptoms preceded ERA diagnosis by over 6 months. ERA patients with past episodic joint inflammation were more often female, had higher income, were seropositive, had more comorbidities, fewer swollen joints, and lower Clinical Disease Activity Index (CDAI) around the time of ERA diagnosis (P < 0.05). These associations remained significant in multivariable regression adjusting for other sociodemographic and RA clinical measures. CONCLUSION: Almost half of ERA patients experienced episodic joint inflammation prior to ERA diagnosis. These patients were more often female, had higher income, and presented with milder disease activity at ERA diagnosis.

Prevalence and Characteristics of Metabolic Syndrome Differ in Men and Women with Early Rheumatoid Arthritis.

Objective: Metabolic syndrome (MetS) prevalence in early rheumatoid arthritis (ERA) is conflicting. The impact of sex, including menopause, has not been described. We estimated the prevalence and factors associated with MetS in men and women with ERA. Methods: A cross-sectional study of the Canadian Early Arthritis Cohort (CATCH) was performed. Participants with baseline data to estimate key MetS components were included. Sex-stratified logistic regression identified baseline variables associated with MetS. Results: The sample included 1543 participants; 71% were female and the mean age was 54 (SD 15) years. MetS prevalence was higher in men 188 (42%) than women 288 (26%, P < 0.0001) and increased with age. Frequent MetS components in men were hypertension (62%), impaired glucose tolerance (IGT, 40%), obesity (36%), and low high-density lipoprotein cholesterol (36%). Postmenopausal women had greater frequency of hypertension (65%), IGT (32%), and high triglycerides (21%) compared with premenopausal women (P < 0.001). In multivariate analysis, MetS was negatively associated with seropositivity and pulmonary disease in men. Increasing age was associated with MetS in women. In postmenopausal women, corticosteroid use was associated with MetS. Psychiatric comorbidity was associated with MetS in premenopausal women. MetS status was not explained by disease activity or core RA measures. Conclusion: The characteristics and associations of MetS differed in men and women with ERA. Sex differences, including postmenopausal status, should be considered in comorbidity screening. With this knowledge, the interplay of MetS, sex, and RA therapeutic response on cardiovascular outcomes should be investigated.

The influence of age at disease onset on disease activity and disability: results from the Ontario Best Practices Research Initiative.

This study aims to compare characteristics between late-onset rheumatoid arthritis (RA) and young-onset RA and determine the association between age at disease onset and disease severity. We cross-sectionally studied 971 patients at the time of entry into the Ontario Best Practices Research Initiative, a registry of RA patients followed up in routine care. We restricted patients to ≤5 years of disease duration. Late-onset RA was defined as an onset ≥60 years of age and young-onset RA <60 years. Group differences were compared, and multivariate linear regression models were used to test the influence of age at onset on Disease Activity Score in 28 Joints with erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire (HAQ) scores. The swollen joint count (6.2 vs. 5.3), acute phase reactants (C-reactive protein (CRP) 17.4 vs. 11.8 mg/L, ESR 30.6 vs. 21.5 mm/h), and comorbidity burden were higher in late-onset RA compared to young-onset RA (p < 0.01). Mean DAS28-ESR (4.6 vs. 4.3) and HAQ (1.2 vs. 1.1) scores were higher in late-onset RA patients (p < 0.05). Late-onset RA patients received more initial disease-modifying antirheumatic drug (DMARD) monotherapy and corticosteroids in comparison to greater DMARD/biologic combination therapy in young-onset RA patients (p < 0.05). Adjusted multivariate analyses showed that late-onset RA was independently associated with higher mean DAS28-ESR and HAQ scores, but not CDAI. Late-onset RA patients have greater disease activity that may contribute to disability early in the disease course. Despite this, initial treatment consists of less combination DMARD and biologic use in late-onset RA patients. This may have implications for future response to therapy and development of joint damage, disability, and comorbidities in this group.

Biosimilars in immune-mediated inflammatory diseases: initial lessons from the first approved biosimilar anti-tumour necrosis factor monoclonal antibody.

The introduction of targeted biological therapies has revolutionised the management of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel disease. Following treatment with these therapies, many patients experience significant improvements in different aspects of their disease, including symptoms, work productivity and other outcomes relevant for individuals and society. However, due to the complexity of biological drug development and manufacturing processes, the costs of these therapies are relatively high. Indeed, the financial burden on healthcare systems due to biological therapies is considerable and lack of patient access to effective treatment remains a concern in many parts of the world. As many reference biological therapies have now reached or are near to patent expiry, a number of 'biosimilar' drugs have been developed for use in various clinical settings, and some of these drugs are already in use in several countries. While the potential pharmacoeconomic benefits of cost-effective biosimilars seem clear, several issues have been raised regarding, for example, the definition of biosimilarity and the validity of indication extrapolation, as well as the 'switchability' and relative immunogenicity of biosimilars and their reference drugs. In this review, these issues will be discussed with reference to CT-P13, a biosimilar of the anti-tumour necrosis factor monoclonal antibody infliximab, which is approved in Europe and elsewhere for the treatment of various IMIDs. Other important issues, including those related to data collection during nonclinical and clinical development of biosimilars, are also discussed.

Determining the Minimally Important Difference in the Clinical Disease Activity Index for Improvement and Worsening in Early Rheumatoid Arthritis Patients.

OBJECTIVE: Simplified measures to quantify rheumatoid arthritis (RA) disease activity are increasingly used. The minimum clinically important differences (MCID) for some measures, such as the Clinical Disease Activity Index (CDAI), have not been well-defined in real-world clinic settings, especially for early RA patients with low/moderate disease activity. METHODS: Data from Canadian Early Arthritis Cohort patients were used to examine absolute change in CDAI in the first year after enrollment, stratified by disease activity. MCID cut points were derived to optimize the sum of sensitivity and specificity versus the gold standard of patient self-reported improvement or worsening. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated against patient self-reported improvement (gold standard) and for change in pain, Health Assessment Questionnaire (HAQ), and Disease Activity Score in 28 joints (DAS28) improvement. Discrimination was examined using the area under receiver operator curves. Similar methods were used to evaluate MCIDs for worsening for patients who achieved low disease activity. RESULTS: A total of 578 patients (mean ± SD age 54.1 ± 15.3 years, 75% women, median [interquartile range] disease duration 5.3 [3.3, 8.0] months) contributed 1,169 visit pairs to the improvement analysis. The MCID cut points for improvement were 12 (patients starting in high disease activity: CDAI >22), 6 (moderate: CDAI 10-22), and 1 (low disease activity: CDAI <10). Performance characteristics were acceptable using these cut points for pain, HAQ, and DAS28. The MCID for CDAI worsening among patients who achieved low disease activity was 2 units. CONCLUSION: These minimum important absolute differences in CDAI can be used to evaluate improvement and worsening and increase the utility of CDAI in clinical practice.

The Relationship Between Function and Disease Activity as Measured by the HAQ and DAS28 Varies Over Time and by Rheumatoid Factor Status in Early Inflammatory Arthritis (EIA). Results from the CATCH Cohort.

OBJECTIVE: To investigate the relationship between function and disease activity in early inflammatory arthritis (EIA). METHODS: Canadian Early Arthritis Cohort (CATCH) (n=1143) is a multi-site EIA cohort. Correlations between the Health Assessment Questionnaire Disability Index (HAQ) and DAS28 were done at every 3 months for the first year and then at 18 and 24 months. We also investigated the relationship between HAQ and DAS28 by age (<65 versus ≥65) and RF (positive vs negative). RESULTS: Mean HAQ and DAS28 scores were highest at the initial visit with HAQ decreasing over 24 months from a baseline of 0.94 to 0.40 and DAS28 scores decreasing from 4.54 to 2.29. All correlations between HAQ and DAS28 were significant at all time points (p<0.01). The correlations between HAQ and DAS28 were variable over time. The strongest correlation between HAQ and DAS28 occurred at initial visit (most DMARD naive) (n=1,143) and 18 months (r=0.57, n=321) and 24 months (r=0.59, n=214). The baseline correlation between HAQ and DAS28 was significantly different than correlations obtained at 3, 6, and 12 months (p=0.02, 0.01, and 0.01, respectively). Age did not change the association between HAQ and DAS28 {<65 years old (r=0.50, n=868) versus ≥65 (r=0.48, n=254), p=0.49}. The correlation between HAQ and DAS28 was stronger with RF+ patients (r=0.63, n=636) vs RF negative (r=0.47, n=477), p=0.0043. CONCLUSION: Over 2 years in EIA, HAQ and DAS both improved; correlations at time points were different over 2 years and RF status affected the correlations.

Determining best practices in early rheumatoid arthritis by comparing differences in treatment at sites in the Canadian Early Arthritis Cohort.

OBJECTIVE: To determine site variation by comparing outcomes across sites in an early rheumatoid arthritis cohort. METHODS: Sites from the Canadian Early Arthritis Cohort database with at least 40 patients were studied. Comparisons were made among sites in change in 28-joint Disease Activity Score (DAS28), proportion of patients in DAS28 remission, and treatment strategies. RESULTS: The study included 1138 baseline patients at 8 sites, with baseline (SD) age 52 years (16.9); 72% women; 23% erosions; 54% ever smokers; 51% rheumatoid factor-positive; 37% anticitrullinated protein antibody-positive; disease duration 187 (203) days; DAS28 4.5 (1.4). Site had an effect on outcomes when adjusting for confounders. At 6 and 12 months, sites B and H, the 2 largest sites, had the best changes in DAS28 (-1.82 and -2.09, respectively, at 6 mos, and -2.27 for both at 12 mos; p < 0.001). Site H had the most patients in DAS28 remission at 6 months [64.5% compared to other sites that had from 34.1% to 51.7% (p < 0.001)], and at the last followup, sites B and H had the most in remission. Subcutaneous methotrexate was used more overall and earlier at sites B and H. Those sites used less steroid therapy, and site B had the second-highest use of triple disease-modifying antirheumatic drugs at any visit. Medications were increased more in 2 of the 3 smallest sites. Biologics were used by 9 months most in the smallest (50.0%) and then largest (19.6%) sites. CONCLUSION: Sites in an early inflammatory arthritis cohort yielded different outcomes. Better outcomes up to 12 months may result from initial treatment with early combination therapy and/or subcutaneous methotrexate.

American College of Rheumatology hybrid analysis of certolizumab pegol plus methotrexate in patients with active rheumatoid arthritis: data from a 52-week phase III trial.

OBJECTIVE: The American College of Rheumatology (ACR) hybrid (a modified mean percent response to treatment) was officially recommended by the ACR as a revision to 20%, 50%, and 70% response criteria (ACR20/50/70) scores, but has not been tested in clinical trials. We performed a post hoc analysis of a phase III study of certolizumab pegol (Rheumatoid Arthritis Prevention of Structural Damage 1 [RAPID 1]) using the ACR hybrid. METHODS: Patients with active rheumatoid arthritis were randomized to certolizumab pegol (200 mg or 400 mg every other week) plus methotrexate or placebo plus methotrexate. ACR hybrid scores were compared with ACR20/50/70 outcomes. RESULTS: Differences between active treatment and placebo were significant throughout the study using the ACR20 and ACR hybrid outcomes. In the certolizumab pegol 200 mg group, the median ACR hybrid score at week 52 (last observation carried forward) was 49.99. A total of 258 (65.8%) of 392 and 172 (43.9%) of 392 patients had ACR20 and ACR50 responses, respectively. An additional 55 patients (14.0%) and 59 patients (15.1%) had mean improvements in ACR core measures of ≥ 20% and ≥ 50%, respectively, and therefore had positive ACR hybrid scores, despite lacking ACR20 and ACR50 responses, respectively. In the placebo group, median ACR hybrid scores were <10 at most time points; unlike other measures, the ACR hybrid measure indicated worsening scores for many patients. CONCLUSION: ACR hybrid analysis had greater sensitivity than traditional ACR20/50/70 criteria, demonstrating improvements in ACR20 nonresponders treated with certolizumab pegol. Negligible benefit was observed with placebo using ACR hybrid analysis.

Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission.

OBJECTIVE: The target outcome in early rheumatoid arthritis (ERA) is now remission. This meta-analysis compared the efficacy of initial methotrexate monotherapy versus combination therapy (methotrexate plus biological agent) for clinical remission and radiographic non-progression among ERA patients with minimal or no previous methotrexate exposure. METHODS: A systematic search was performed for randomised controlled trials of ERA using predefined criteria. A random effects model was used to pool the risk ratio (RR) for clinical and radiographic remission at 52-56 weeks of follow-up. RESULTS: Seven trials of combination therapy with infliximab, adalimumab, etanercept or abatacept were included. The majority of studies defined clinical remission as a 28-joint disease activity score (DAS28) of 2.6 or less. Radiographic non-progression was primarily defined as a modified total Sharp score change of less than 0.5 units. All trials demonstrated risk estimates in favour of combination therapy: the pooled RR for achieving clinical remission was 1.74 (95% CI 1.54 to 1.98) and for radiographic non-progression was 1.30 (95% CI 1.01 to 1.68). Significant heterogeneity among studies for the latter outcome was detected (p<0.001). CONCLUSIONS: The efficacy of combination therapy with a biological agent is superior to methotrexate monotherapy for remission. Combination therapy has a greater initial effect on clinical remission than radiographic non-progression. Uniform definitions of remission are needed and the proportion of subjects who achieve the combined endpoint of clinical and radiographic remission should be considered as a meaningful outcome in future studies of ERA.

Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients.

OBJECTIVE: To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab. METHODS: RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected. RESULTS: Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred. CONCLUSIONS: In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study.

OBJECTIVE: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. RESULTS: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. CONCLUSION: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies.

OBJECTIVE: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56. RESULTS: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001). CONCLUSIONS: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade.

OBJECTIVE: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. METHODS: Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. RESULTS: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. CONCLUSION: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.

Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study.

OBJECTIVE: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS: Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritus, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION: A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.