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Background: To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor inhibitors (TNFi), separately in induction treatment and maintenance treatment studies, and to identify predictors of successful discontinuation., Methods: We performed a systematic literature review of studies published from 2005 to May 2022 that reported outcomes after TNFi discontinuation among patients in remission/LDA. We computed prevalences of successful discontinuation by induction or maintenance treatment, remission criterion, and follow-up time. We performed a scoping review of predictors of successful discontinuation., Results: Twenty-two induction-withdrawal studies were identified. In pooled analyses, 58% (95% confidence interval (CI) 45, 70) had DAS28 < 3.2 (9 studies), 52% (95% CI 35, 69) had DAS28 < 2.6 (9 studies), and 40% (95% CI 18, 64) had SDAI ≤ 3.3 (4 studies) at 37-52 weeks after discontinuation. Among patients who continued TNFi, 62 to 85% maintained remission. Twenty-two studies of maintenance treatment discontinuation were also identified. At 37-52 weeks after TNFi discontinuation, 48% (95% CI 38, 59) had DAS28 < 3.2 (10 studies), and 47% (95% CI 33, 62) had DAS28 < 2.6 (6 studies). Heterogeneity among studies was high. Data on predictors in induction-withdrawal studies were limited. In both treatment scenarios, longer duration of RA was most consistently associated with less successful discontinuation., Conclusions: Approximately one-half of patients with RA remain in remission/LDA for up to 1 year after TNFi discontinuation, with slightly higher proportions in induction-withdrawal settings than with maintenance treatment discontinuation., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Individuals with ankylosing spondylitis (AS) have a greater cardiovascular (CV) risk than those in the general population. The effect of tumor necrosis factor inhibitors (TNFis) on CV risk, including on the development of hypertension (HTN), remains unclear, with some data suggesting higher risk. We assessed the association of TNFi use with incident HTN in a longitudinal AS cohort., Methods: Adults with AS enrolled in a prospective cohort in 2002-2018 were examined every 4-6 months. TNFi use during the preceding 6 months was ascertained at each study visit. We defined HTN by patient-reported HTN, antihypertensive medication use, or, on 2 consecutive visits, systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. We evaluated the association between TNFi use and the development of HTN with marginal structural models, estimated by inverse probability-of-treatment weighting, to account for time-dependent confounders and informative censoring. Potential confounders included age, sex, race, site, nonsteroidal antiinflammatory drug use, and disease activity., Results: We included 630 patients without baseline HTN and with at least 1 year of follow-up. Of these, 72% were male, mean age was 39 ± 13 years, and 43% used TNFi at baseline. On follow-up (median 5 yrs), 129 developed incident HTN and 163 started on TNFi during follow-up. TNFi use was not associated with incident HTN (adjusted HR 1.10, 95% CI 0.83-1.37)., Conclusion: In our prospective AS cohort, TNFi use was not significantly associated with incident HTN., (Copyright © 2022 by the Journal of Rheumatology.)

Importance: Tumor necrosis factor inhibitors (TNFis) have revolutionized the management of ankylosing spondylitis (AS); however, the lack of notable clinical responses in approximately one-half of patients suggests important heterogeneity in treatment response. Identifying patients likely to respond or not respond to TNFis could provide opportunities to personalize treatment strategies., Objective: To develop models of the probability of short-term response to TNFi treatment in individual patients with active AS., Design, Setting, and Participants: This is a retrospective cohort study using data of the TNFi group (ie, treatment group) from 10 randomized clinical trials (RCTs) of TNFi treatment among patients with active AS, conducted from 2002 to 2016. Participants were adult patients with active AS who failed nonsteroidal anti-inflammatory drugs. Included RCTs were phase 3 and 4 studies that assessed the efficacy of an originator TNFi at week 12 and/or week 24, either compared with placebo or an antirheumatic drug. The cohort was divided into a training and a testing set. Data analysis was conducted from July 1, 2019, to November 30, 2020., Exposures: All included patients received an originator TNFi for at least 12 weeks., Main Outcomes and Measures: Outcomes included major response and no response based on the change of AS Disease Activity Score at 12 weeks. Machine learning algorithms were applied to estimate the probability of having major response and no response for individual patients., Results: The study included 1899 participants from 10 trials. The training set included 1207 individuals (mean [SD] age, 39 [12] years; 908 [75.2%] men), of whom 407 (33.7%) had major response and 414 (34.3%) had no response. In the reduced logistic regression models, accuracy was 0.74 for major response and 0.75 for no response. The probability of major response increased with higher C-reactive protein (CRP) level, patient global assessment (PGA), and Bath AS Disease Activity Index (BASDAI) question 2 score and decreased with higher body mass index (BMI) and Bath AS Functional Index (BASFI) score. The probability of no response increased with age and BASFI score, and decreased with higher CRP level, BASDAI question 2 score, and PGA. In the testing set (692 participants; mean [SD] age, 38 [11] years; 533 [77.0%] men), models demonstrated moderate to high accuracy., Conclusions and Relevance: In this cohort study, the probability of initial response to TNFi was predicted from baseline variables, which may facilitate personalized treatment decision-making.

Objectives: Withholding TNF inhibitors (TNFI) before surgery has been recommended due to concern for post-operative infection. We examined the risks of post-operative infections and mortality in patients with RA in relation to the pre-operative timing of infliximab infusion., Methods: In this population-based retrospective cohort study, we used US Medicare claims data from 2007 to 2015 to identify patients with RA who underwent coronary artery bypass grafting (CABG), aortic or vascular surgery, or bowel resection, and who were treated with infliximab in the 90 days prior to surgery. We examined associations between the timing of infusion and infections and mortality in the 30 days after surgery. We adjusted for the predicted probability of post-operative infection or death, demographic characteristics, use of MTX, post-operative blood transfusion and hospital volume., Results: We studied 712 patients with CABG, 244 patients with vascular surgery and 862 patients with bowel resections. Post-operative pneumonia occurred in 7.4-11.9%, urinary tract infection in 9.0-15.2%, surgical site infection in 3.2-18.9%, sepsis in 4.2-9.6% and death in 3.5-7.0% among surgery cohorts. There was no association between the time from last infliximab dose to surgery and the risk of post-operative infection or mortality in any surgical cohort. No subgroups were identified that had an increased risk of infection with more proximate use of infliximab., Conclusion: Among elderly patients with RA, risks of infection and mortality after major surgery were not related to the pre-operative timing of infliximab infusion., (© Published by Oxford University Press on behalf of the British Society for Rheumatology 2020. This work is written by a US Government employee and is in the public domain in the US.)

Nonsteroidal antiinflammatory drugs (NSAIDs) are the first-line pharmacotherapy for patients with axial spondyloarthritis (SpA). In recent years, treatment options have expanded with the availability of biologic agents, including tumor necrosis factor inhibitors and interleukin-17 inhibitors. However, a treatment strategy that clearly prevents syndesmophyte formation has not been established. Observational studies of patients with ankylosing spondylitis indicated potential disease-modifying effects of NSAIDs, but two randomized trials came to different conclusions. More broadly, whether any of the currently available medications for axial SpA have an effect on spine radiographic progression, beyond symptom control, remains inconclusive. In this article, we will review clinical studies of the disease modification effects of NSAIDs and biologics in axial SpA; examine genetic, animal, and clinical evidence of the effects of NSAIDs on bone formation; and discuss how future studies may investigate the question of disease modification in axial SpA., (© 2019, American College of Rheumatology.)

Objective: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA)., Methods: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel., Results: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended., Conclusion: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA., (© 2019, American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To estimate minimal clinically important improvement (MCII) of RAPID-3 (Routine Assessment of Patient Index Data 3) in rheumatoid arthritis (RA)., Methods: RAPID-3 was computed before and after treatment escalation in a prospective study of adults with active RA. Patient judgment of improvement was used as the standard for a receiver-operating characteristic curve, from which MCII was estimated., Results: Mean RAPID-3 improved from 16.3 to 11.1 between visits. MCII was -3.8 based on simultaneously optimized sensitivity and specificity, -3.5 using the 0.80 specificity criterion, and -4.1 using the Youden index., Conclusion: RAPID-3 improvement of 3.8/30 units appears clinically meaningful.

Objective: We examined agreement between the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) response criteria in rheumatoid arthritis (RA) and tested whether discordant responses were associated with patients' baseline characteristics or changes in RA activity encapsulated by the different criteria., Methods: In a prospective longitudinal study, we examined responses of 243 patients with active RA to escalation of antirheumatic treatment. We computed agreement between pairs of response criteria using κ coefficients and identified patient characteristics associated with unique responses to individual criteria., Results: We found that 110 patients (45.3%) had an ACR 20% improvement (ACR20) response, 135 (55.5%) had a EULAR moderate/good response, and 83 (34.1%) had an SDAI50 response. Agreement was moderate to good (ACR20/EULAR κ 0.57; ACR20/SDAI50 κ 0.64; EULAR/SDAI50 κ 0.59). All who had SDAI50 response also had a EULAR response. Patient characteristics at baseline generally did not distinguish those who responded to both, 1, or neither criterion. Discordance was most often because of improvements in the erythrocyte sedimentation rate or C-reactive protein level among EULAR and SDAI50 responders, which were not as common among ACR20 responders. Based on receiver-operating characteristic curves, SDAI35 response had a better balance of sensitivity and specificity relative to ACR20 and EULAR moderate/good responses than SDAI50., Conclusion: Discordant responses to RA improvement criteria are most often because of differences in responses of acute-phase reactants. SDAI35 response had higher sensitivity for improvement, as reflected by other response criteria, than SDAI50 response.

Objective: To compare the efficacy of 6 tumor necrosis factor-α inhibitors (TNFi) in treatment of ankylosing spondylitis (AS) at 12 weeks and 24 weeks., Methods: We performed a systematic literature review of randomized controlled trials of TNFi in patients with active AS. We included trials that reported efficacy at 10 to 14 weeks (12-week analysis) and at 24 to 30 weeks (24-week analysis). We used Bayesian network metaanalysis (NMA) to compare their relative efficacy to improve the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and C-reactive protein (CRP) level., Results: We included 20 trials of 6 TNFi, with 43 treatment arms and 3220 participants. All TNFi were significantly better than placebo in reducing BASDAI and BASFI at 12 weeks and 24 weeks; all but certolizumab pegol (CZP) were statistically better than placebo in reducing CRP at 12 weeks; all but CZP and infliximab-dyyb (IFX biosimilar) were significantly better than placebo in reducing CRP at 24 weeks. IFX was superior to the other TNFi in decreasing BASDAI at 12 weeks, but not at 24 weeks. Excluding 1 open-label trial, there were no differences among TNFi., Conclusion: Based on this NMA of clinical trials, IFX was superior to other TNFi in reducing BASDAI at 12 weeks, but sensitive to inclusion of an open-label trial, and its efficacy was diminished at 24 weeks. The analysis was limited by few direct comparison trials. Further study of relative safety and longterm effectiveness will help inform the choice of TNFi in treating active AS.

Objective: The aim was to determine whether the time trade-off (TTO) and standard gamble utilities can detect treatment-related improvement in overall quality of life in patients with active RA., Methods: We measured TTO and standard gamble utilities in 192 patients before and after escalation of anti-rheumatic treatment in a prospective longitudinal study. We also examined associations between changes in utilities and patient-reported improvement during the study, and with EULAR responses., Results: Mean TTO at baseline was 0.68 (median 0.82) and mean standard gamble 0.80 (median 0.93). Both utilities improved significantly with treatment. Standardized response means, a measure of responsiveness, were 0.37 for the TTO and 0.20 for the standard gamble, and comparable to those of two mental health measures and the CRP, but lower than other RA activity measures. Changes in utilities were not significantly associated with patient-reported improvement. The standard gamble, but not the TTO, had a graded association with EULAR responses., Conclusion: Utilities by the TTO and standard gamble were able to detect improvement in overall quality of life with anti-rheumatic treatment in patients with active RA, suggesting applicability in clinical trials. The standard gamble was associated with reference measures of improvement, although not as strongly as measures of RA activity, as expected with its generic orientation., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.)

Objective: Medications for rheumatoid arthritis (RA) may affect survival. However, studies often include limited followup and do not account for selection bias in treatment allocation. Using a large longitudinal database, we examined the association between prednisone use and mortality in RA, and whether this risk was modified with concomitant disease-modifying antirheumatic drug (DMARD) use, after controlling for propensity for treatment with prednisone and individual DMARDs., Methods: In a prospective study of 5,626 patients with RA followed for up to 25 years, we determined the risk of death associated with prednisone use alone and combined treatment of prednisone with methotrexate (MTX) or sulfasalazine. We used the random forests method to generate propensity scores for prednisone use and each DMARD at study entry and during followup. Mortality risks were estimated using multivariate Cox models that included propensity scores., Results: During followup (median 4.97 years), 666 patients (11.8%) died. In a multivariate, propensity-adjusted model, prednisone use was associated with an increased risk of death (hazard ratio [HR] 2.83 [95% confidence interval (95% CI) 1.03-7.76]). However, there was a significant interaction between prednisone use and MTX use (P = 0.03), so that risk was attenuated when patients were treated with both medications (HR 0.99 [95% CI 0.18-5.36]). However, combination treatment also weakened the protective association of MTX with mortality. Results were similar for sulfasalazine., Conclusion: Prednisone use was associated with a significantly increased risk of mortality in patients with RA. This association was mitigated by concomitant DMARD use, but combined treatment also negated the previously reported beneficial association of MTX with survival in RA., (© 2016, American College of Rheumatology.)

Objective: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA)., Methods: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework., Results: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS., Conclusion: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas., (© 2015, American College of Rheumatology.)

Objective: Thresholds of minimal clinically important improvement (MCII) are needed to plan and interpret clinical trials. We estimated MCIIs for the rheumatoid arthritis (RA) activity measures of patient global assessment, pain score, Health Assessment Questionnaire Disability Index (HAQ), Disease Activity Score-28 (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI)., Methods: In this prospective longitudinal study, we studied 250 patients who had active RA. Disease activity measures were collected before and either 1 month (for patients treated with prednisone) or 4 months (for patients treated with disease modifying medications or biologics) after treatment escalation. Patient judgments of improvement in arthritis status were related to prospectively assessed changes in the measures. MCIIs were changes that had a specificity of 0.80 for improvement based on receiver operating characteristic curve analysis. We used bootstrapping to provide estimates with predictive validity., Results: At baseline, the mean (±SD) DAS28-ESR (erythrocyte sedimentation rate) was 6.16±1.2 and mean SDAI was 38.6±14.8. Improvement in overall arthritis status was reported by 167 patients (66.8%). Patients were consistent in their ratings of improvement versus no change or worsening, with receiver operating characteristic curve areas ≥0.74. MCIIs with a specificity for improvement of 0.80 were: patient global assessment -18, pain score -20, HAQ -0.375, DAS28-ESR -1.2, DAS28-CRP (C-reactive protein) -1.0, SDAI -13, and CDAI -12., Conclusions: MCIIs for individual core set measures were larger than previous estimates. Reporting the proportion of patients who meet these MCII thresholds can improve the interpretation of clinical trials in RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: The patient global assessment (PGA) is intended to provide an integrated summary of all symptoms of arthritis, but it is not clear which disease features most impact patients' assessments of changes in their overall status. We investigated what aspects of rheumatoid arthritis (RA) activity correlated best with prospectively measured changes in the PGA and with patients' retrospective judgments of improvement., Methods: We studied 250 patients with active RA in a prospective longitudinal study. Disease activity measures were collected before and after treatment escalation. Prospectively measured changes in PGA and patients' judgments of improvement or worsening at the followup visit were tested for correlations with changes in patient-reported measures of symptoms and functioning, joint counts, and laboratory tests., Results: Patients improved during the study, with the mean ± SD PGA decreasing from 55.6 ± 25.2 to 37.6 ± 24.0. At the followup visit, 167 patients (66.8%) reported improvement in overall arthritis status. Changes in pain severity, stiffness severity, and fatigue were the only significant correlates of changes in PGA. In contrast, changes in the Health Assessment Questionnaire, tender joint count or Disease Activity Score in 28 joints (DAS28), and stiffness severity were associated with retrospective judgments of improvement., Conclusion: Prospectively measured changes in PGA in RA were related solely to other patient-reported measures, but patients' retrospective judgments of improvement were related to functional limitations, tender joint count, and DAS28. Patients' subjective judgments of improvement reflect aspects of RA different from the PGA and may be a simple complementary measure of treatment efficacy., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Despite wide use of the Short-Form 36 (SF-36) health survey in clinical trials of rheumatoid arthritis (RA), estimates of minimum clinically important improvement (MCII) for its scales are not well-established. We estimated MCIIs for SF-36 scales in patients with active RA., Methods: In this prospective longitudinal study, we studied 243 patients who had active RA and who completed the SF-36 before and after treatment escalation. We first assessed responsiveness with standardized response means (SRMs). For scales with adequate responsiveness (SRM ≥0.50), we used patient judgments of improvement in arthritis status as anchors for estimating MCIIs. We used receiver operating characteristic curve analysis to identify the MCIIs as the change associated with a specificity of 0.80 for improvement., Results: Patients had substantial improvement in RA activity with treatment. However, among SF-36 scales, only the physical functioning and bodily pain scales and the physical component summary had adequate responsiveness. Using 0.80 specificity for improvement as the criterion, the MCIIs were 7.1 for the physical functioning scale, 4.9 for the bodily pain scale, and 7.2 for the physical component summary., Conclusion: Low responsiveness precluded estimation of valid MCIIs for many SF-36 scales in patients with RA, particularly the scales assessing mental health. Although the SF-36 has been included in many clinical trials to broaden the assessment of health status, low responsiveness limits the interpretation of changes in its mental health-related scales., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To examine the association of the American College of Rheumatology (ACR) response criteria (20% improvement [ACR20], ACR50, and ACR70) and the European League Against Rheumatism (EULAR) response criteria with patient-reported improvement in rheumatoid arthritis (RA) activity., Methods: Two hundred fifty patients with active RA were studied prospectively, before and after escalation of antirheumatic treatment. Patients were asked to report if they subjectively judged that they had experienced important improvement with treatment, and the proportion of patients who reported improvement was compared with the proportion who met the ACR20, ACR50, ACR70, and EULAR response criteria., Results: Improvement in overall arthritis status was reported by 167 patients (66.8%), while 107 patients (42.8%) had an ACR20 response, 52 (20.8%) had an ACR50 response, 24 (9.6%) had an ACR70 response, and 136 (54.4%) had a EULAR moderate/good response. ACR20 response had a sensitivity of 0.57 and a specificity of 0.85 for clinically important improvement as judged by patients. Sensitivities of the ACR50, ACR70, and EULAR moderate/good responses were 0.30, 0.14, and 0.68, respectively, while their specificities were 0.97, 0.99, and 0.73, respectively. The ACR hybrid score with the highest sensitivity and specificity for important improvement was 19.99., Conclusion: Among patients with active RA, ACR20 responses are highly specific measures of improvement as judged by patients, but exclude a substantial proportion of patients who consider themselves improved. Response criteria are associated with, but not equivalent to, patient-perceived improvement., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS)., Methods: All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model., Results: TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching., Conclusion: Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup., (Copyright © 2013 by the American College of Rheumatology.)

Objective: While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use., Methods: We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time-varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time-varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival., Results: During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09-1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use., Conclusion: MTX use was associated with a 70% reduction in mortality in RA., (Copyright © 2013 by the American College of Rheumatology.)

Ankylosing spondylitis (AS) is associated with both significant direct and indirect costs, which vary by country, and have generally increased dramatically since the introduction of anti-tumor necrosis factor therapy. The cost-effectiveness of biologic agents is controversial, although cost-effectiveness studies need to consider the potential impact of anti-tumor necrosis factor treatments on work ability. Alternatives to reduce costs associated with biologics have been examined, including on-demand dosing and lower dose alternatives. Other treatment measures, such as total hip arthroplasty and physical therapy, are also effective in reducing pain and improving function in patients with AS, although the optimal type or combination of physical therapy treatment modalities, the optimal frequency and duration of treatment and whether therapy is equally effective in stable disease and uncontrolled AS need to be determined. No studies have examined differences in patient outcomes based on subspecialty care. Establishing an evidence base for these questions would help inform policy decisions to design the most cost-effective measures to treat AS.

The inflammatory arthritides are a diverse group of conditions characterised by joint inflammation which can lead to pain, deformity and disability. Of these diseases, rheumatoid arthritis (RA) and spondyloarthritis are two of the most common. While the clinical and demographic features of these diseases differ, the central role of inflammation in their pathogenesis has allowed the development of highly effective treatment strategies with wide applicability. These strategies include the use of biological agents which target the cytokine tumour necrosis factor (TNF), a key mediator of inflammation. With the advent of effective agents, therapy has become more aggressive, reducing disease activity and allowing, at least in RA, remission in many patients. While the array of available effective treatments is extensive, the use of objective measures of disease activity can guide treatment decisions (treat to target) and lead to improved outcomes., (Copyright © 2012. Published by Elsevier Ltd.)

Objective: To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity., Methods: We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII., Results: On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80-1.83), 15.82 (95% CI 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment., Conclusion: The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start.

Background: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs)., Methods: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics", or "traditional" disease modifying antirheumatic drugs (DMARDs), and "placebo". We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models., Results: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration., Conclusion: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Context: Hydroxychloroquine, a commonly used antirheumatic medication, has hypoglycemic effects and may reduce the risk of diabetes mellitus., Objective: To determine the association between hydroxychloroquine use and the incidence of self-reported diabetes in a cohort of patients with rheumatoid arthritis., Design, Setting, and Patients: A prospective, multicenter observational study of 4905 adults with rheumatoid arthritis (1808 had taken hydroxychloroquine and 3097 had never taken hydroxychloroquine) and no diagnosis or treatment for diabetes in outpatient university-based and community-based rheumatology practices with 21.5 years of follow-up (January 1983 through July 2004)., Main Outcome Measures: Diabetes by self-report of diagnosis or hypoglycemic medication use., Results: During the observation period, incident diabetes was reported by 54 patients who had taken hydroxychloroquine and by 171 patients who had never taken hydroxychloroquine, with incidence rates of 5.2 per 1000 patient-years of observation compared with 8.9 per 1000 patient-years of observation, respectively (P < .001). In time-varying multivariable analysis with adjustments for possible confounding factors, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62 (95% confidence interval, 0.42-0.92) compared with those who had not taken hydroxychloroquine. In Poisson regression, the risk of incident diabetes was significantly reduced with increased duration of hydroxychloroquine use (P < .001 for trend); among those taking hydroxychloroquine for more than 4 years (n = 384), the adjusted relative risk of developing diabetes was 0.23 (95% confidence interval, 0.11-0.50; P < .001), compared with those who had not taken hydroxychloroquine., Conclusion: Among patients with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes.

Background: Functional capacity is an important outcome in rheumatoid arthritis and is generally measured using the Health Assessment Questionnaire disability index (HAQ). Functional limitation incorporates both activity and damage. Because irreversible damage increases over time, the HAQ may be less likely to show improvement in late than in early rheumatoid arthritis., Objective: To determine the relation between sensitivity to change of the HAQ and duration of rheumatoid arthritis in reports of clinical trials., Methods: Data were pooled from clinical trials that measured responses of HAQ scores at three or six months. The effect size of the HAQ was calculated and linear regression used to predict the effect size by duration of rheumatoid arthritis at group level. Treatment effect was adjusted for by including the effect sizes of pain scores and of tender joint counts as additional independent variables in separate models. Subgroup analysis employed contemporary regimens (methotrexate, leflunomide, combination therapies, and TNF inhibitors) only., Results: 36 studies with 64 active treatment arms and 7628 patients (disease duration 2.5 months to 12.2 years) were included. The effect sizes of the HAQ decreased by 0.02 for each additional year of mean disease duration using all trials, and by 0.04/year in the subgroup analysis (p

Objective: To determine the role of medication toxicity in the discontinuation of antirheumatic treatment among patients with ankylosing spondylitis (AS), and to compare the toxicity of different medications., Methods: In a prospective longitudinal study of 241 patients with AS, we examined the duration of treatment and discontinuations due to side effects of new courses of sulfasalazine, methotrexate, ibuprofen, naproxen, indomethacin, diclofenac, piroxicam, nabumetone, and celecoxib., Results: Of the 241 patients, 167 reported having a new treatment course of either sulfasalazine (n = 49), methotrexate (n = 19), ibuprofen (n = 105), naproxen (n = 57), indomethacin (n = 50), diclofenac (n = 38), piroxicam (n = 34), nabumetone (n = 27), or celecoxib (n = 25), for a total of 404 new treatment courses. Side effects were reported in 6.7% (ibuprofen) to 47.3% (methotrexate) of the courses. Between 2% (ibuprofen) and 23.5% (piroxicam) of courses were discontinued due to toxicity. For each medication, the duration of treatment was most often limited by factors other than toxicity. The time to drug discontinuation for any reason and the time to discontinuation due to toxicity did not differ between sulfasalazine and methotrexate. The time to drug discontinuation for any reason did not differ among nonsteroidal antiinflammatory drugs (NSAIDs), but discontinuations due to toxicity occurred earlier with piroxicam than with other NSAIDs., Conclusion: Although medication toxicity is common among patients with AS, it is an uncommon cause of discontinuation of antirheumatic treatment.

Objective: Current treatment of rheumatoid arthritis (RA) emphasizes the early and consistent use of disease modifying antirheumatic drugs (DMARD). We studied how often these medications were used to treat patients with RA, and whether use of these medications has increased over time., Methods: We used the National Ambulatory Medical Care Surveys to determine national probability estimates of the use of DMARD [hydroxychloroquine, intramuscular gold, auranofin, methotrexate (MTX), sulfasalazine, azathioprine, D-penicillamine, and cyclosporine] by patients with RA. The National Ambulatory Medical Care Surveys record information about treatments provided in outpatient settings by a nationally representative cross sectional sample of physicians. Estimates of the use of DMARD were based on the treatments reported on 502 visits by patients with RA in 1980-81, 339 visits by patients with RA in 1985, 386 visits by patients with RA in 1989-91, and 383 visits by patients with RA in 1993-95., Results: DMARD were used in 30.3% of visits in 1980-81, 36.3% of visits in 1985, 24.9% of visits in 1989-91, and 43.6% of visits in 1993-95 (p for trend < 0.0001). Increased use of MTX accounted for most of the increased prevalence of DMARD use; MTX was used in 27.3% of visits in 1993-95. Use of DMARD increased in 1993-95 in all age, sex, and racial subgroups, and among visits reported by rheumatologists, but did not increase over time among visits reported by physicians other than rheumatologists., Conclusion: Use of DMARD in RA has increased in the recent past, but DMARD are currently used by fewer than 44% of patients with RA. Use of DMARD has not increased over time among patients of physicians other than rheumatologists.

Objective: To describe changes in antirheumatic medication use by patients with rheumatoid arthritis (RA) over the 15 years 1981 to 1996., Methods: Medication use was ascertained every 6 months by mailed Health Assessment Questionnaire in a cohort of patients recruited from the local community (n = 305; mean duration of RA at study entry 14.2 yrs). Patients were treated by 53 rheumatologists and over 200 other physicians during the study. The proportions of patients treated with nonsteroidal antiinflammatory drugs (NSAID), disease modifying antirheumatic drugs (DMARD), prednisone, intraarticular corticosteroids, and analgesics were determined in serial cross sectional analyses, and trends in medication use over time were analyzed using linear regression., Results: From 1981 to 1996, the proportion of patients treated with DMARD increased from 32 to 47% (average increase 1.06% each year; p < 0.0001), while the proportion treated with NSAID decreased from 86 to 76% (average decrease 0.57% each year; p < 0.0001). The proportion of patients treated with prednisone remained between 30 and 40%, with a trend toward increasing use over time (average increase 0.2% each year; p = 0.05). In contrast, the proportion treated with intraarticular corticosteroids decreased from 14.4 to 6.7% (average decrease 0.46% each year; p < 0.0001). In 1996, the most prevalent patterns of medication use were the use of NSAID alone (24.4%), use of an NSAID and DMARD (16.3%), and use of an NSAID, DMARD, and prednisone (12.2%). Use of an NSAID as the only antirheumatic medication decreased over time, and the use of DMARD in combination with other medications increased., Conclusion: The proportion of patients with RA treated with DMARD increased substantially from 1981 to 1996. This change in practice occurred during the time in which the concept of inverting the traditional therapeutic pyramid became popular, and may reflect a translation among clinicians of the philosophy of "early DMARD use" to "consistent DMARD use," even among patients with RA of moderate or longstanding duration.

Observational studies and meta-analyses of controlled clinical trials have been used to identify which measures of rheumatoid arthritis activity are most sensitive to change. These analyses often pool studies of different drugs, although it is not known if arthritis activity measures are differentially responsive to different drugs. In meta-analyses, estimates of the relative sensitivity to change of different measures may also be confounded by differences in drug efficacy, if studies of different drugs contribute different measures to the meta-analysis. To determine if the type of treatment acts as an important effect modifier or confounder in studies of the relative sensitivity to change of arthritis activity measures, we computed effect sizes for four measures (weighted tender joint count, grip strength, duration of morning stiffness, and erythrocyte sedimentation rate) used in each of 16 trials of five different disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, cyclosporin A, intramuscular gold, and D-penicillamine) in rheumatoid arthritis. In a complete factorial analysis of variance, effect sizes differed significantly among drugs (p = 0.0006), but differed only marginally among measures (p = 0.08). No interaction was detectable between drugs and measures. These results suggested that effect modification by drugs was not present, but that pooled estimates of the sensitivity to change of different measures may be confounded in meta-analyses, if trials of more efficacious drugs contribute different measures than trials of less efficacious drugs. In a similar analysis of 26 trials of nine nonsteroidal anti-inflammatory drugs, we found significant differences in effect sizes among measures (p < 0.0001), but no differences among drugs (p = 0.96), and no interaction between drugs and measures. This study suggests that pooled analyses of the relative sensitivity to change of arthritis activity measures based on trials of different disease-modifying drugs may be confounded by drug effects, but confounding by drug effects is unlikely if these meta-analyses are based on trials of different nonsteroidal anti-inflammatory drugs. Although the power of these analyses to detect small interaction effects was limited, effect modification by drugs was not observed, indicating that the measures we examined were not strongly differentially responsive to different drugs.