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Objective: The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700)., Methods: Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies., Results: Of 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data., Conclusion: Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy., (© 2021 The Journal of Rheumatology.)

Objective: Adaptive trial design was developed initially for oncology to improve trial efficiency. If optimized for rheumatology, it may improve trial efficiency by reducing sample size and time., Methods: A systematic review assessed design of phase II clinical trials in rheumatoid arthritis., Results: Fifty-six trials were reviewed. Most trials had 4 groups (1 control and 3 intervention), with an average group size of 34 patients. American College of Rheumatology 20 measured at 16 weeks was the most commonly used primary endpoint., Conclusion: The next step is to undertake a systematic review of adaptive designs used in early-phase trials in nonrheumatic conditions.

Objective: The Outcome Measures in Rheumatology (OMERACT) Shared Decision Making (SDM) Working Group aims to determine the core outcome domain set for measuring the effectiveness of SDM interventions in rheumatology trials., Methods: A white paper was developed to clarify the draft core domain set. It was then used to prepare for interviews to investigate reasons for lack of consensus on it and to suggest further improvements., Results: OMERACT scientists/clinicians (n = 13) and patients (n = 10) suggested limiting the core domain set to outcome domains, removing process domains, and clarifying remaining domains., Conclusion: A revised core domain set will undergo further consensus-building.

Objective: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission., Methods: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates., Results: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83., Conclusion: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

Objective: To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA)., Methods: The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported., Results: Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96-8.58), infection 38.60 (36.24-41.12), serious infection 1.68 (1.35-2.07), malignancies 1.09 (0.84-1.42), and autoimmune disorders 1.33 (1.05-1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study., Conclusion: These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.

Objective: The objectives of the Outcome Measures in Rheumatology (OMERACT) Stiffness special interest group (SIG) are to characterize stiffness as an outcome in rheumatic disease and to identify and validate a stiffness patient-reported outcome (PRO) in rheumatology., Methods: At OMERACT 2016, international groups presented and discussed results of several concurrent research projects on stiffness: a literature review of rheumatoid arthritis (RA) stiffness PRO measures, a qualitative investigation into the RA and polymyalgia rheumatica patient perspective of stiffness, data-driven stiffness conceptual model development, development and testing of an RA stiffness PRO measure, and a quantitative work testing stiffness items in patients with RA and psoriatic arthritis., Results: The literature review identified 52 individual stiffness PRO measures assessing morning or early morning stiffness severity/intensity or duration. Items were heterogeneous, had little or inconsistent psychometric property evidence, and did not appear to have been developed according to the PRO development guidelines. A poor match between current stiffness PRO and the conceptual model identifying the RA patient experience of stiffness was identified, highlighting a major flaw in PRO selection according to the OMERACT filter 2.0., Conclusion: Discussions within the Stiffness SIG highlighted the importance of further research on stiffness and defined a research agenda.

Objective: The importance of contextual factors (CF) for appropriate patient-specific care is widely acknowledged. However, evidence in clinical trials on how CF influence outcomes remains sparse. The 2014 Outcome Measures in Rheumatology (OMERACT) Handbook introduced the role of CF in outcome assessment and defined them as "potential confounders and/or effect modifiers of outcomes in randomized controlled trials." Subsequently, the CF Methods Group (CFMG) was formed to develop guidance on how to address CF in clinical trials., Methods: First, the CFMG conducted an e-mail survey of OMERACT working groups (WG) to analyze how they had addressed CF in outcome measurement so far. The results facilitated an informed discussion at the OMERACT 2016 CFMG Special Interest Group (SIG) session, with the aim of gaining preliminary consensus regarding an operational definition of CF and to make a first selection of potentially relevant CF., Results: The survey revealed that the WG had mostly used the OMERACT Handbook and/or the International Classification of Functioning, Disability and Health (ICF) definition. However, significant heterogeneity was found in the methods used to identify, refine, and categorize CF candidates. The SIG participants agreed on using the ICF as a framework along with the OMERACT Handbook definition. A list with 28 variables was collected including person-related factors and physical and social environments. Recommendations from the SIG guided the CFMG to formulate 3 preliminary projects on how to identify and analyze CF., Conclusion: New methods are urgently needed to assist researchers to identify and characterize CF that significantly influence the interpretation of results in clinical trials. The CFMG defined first steps to develop further guidance.

Objective: The aim of this Outcome Measures in Rheumatology (OMERACT) Working Group was to determine the core set of outcome domains and subdomains for measuring the effectiveness of shared decision-making (SDM) interventions in rheumatology clinical trials., Methods: Following the OMERACT Filter 2.0, and based on a previous literature review of SDM outcome domains and a nominal group process at OMERACT 2014, (1) an online Delphi survey was conducted to gather feedback on the draft core set and refine its domains and subdomains, and (2) a workshop was held at the OMERACT 2016 meeting to gain consensus on the draft core set., Results: A total of 170 participants completed Round 1 of the Delphi survey, and 116 completed Round 2. Respondents came from 29 countries, with 49% being patients/caregivers. Results showed that 14 out of the 17 subdomains within the 7 domains exceeded the 70% criterion (endorsement ranged from 83% to 100% of respondents). At OMERACT 2016, only 8% of the 96 attendees were patients/caregivers. Despite initial votes of support in breakout groups, there was insufficient comfort about the conceptualization of these 7 domains and 17 subdomains for these to be endorsed at OMERACT 2016 (endorsement ranged from 17% to 68% of participants)., Conclusion: Differences between the Delphi survey and consensus meeting may be explained by the manner in which the outcomes were presented, variations in participant characteristics, and the context of voting. Further efforts are needed to address the limited understanding of SDM and its outcomes among OMERACT participants.

Objective: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016., Methods: Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores., Results: People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0-50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 "Eyeball Test" for instrument selection., Conclusion: The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials.

Objective: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop an approach to identify and measure RA flares. An overview of our OMERACT 2014 plenary is provided., Methods: Feasibility and validity of flare domains endorsed at OMERACT 11 (2012) were described based on initial data from 3 international studies collected using a common set of questions specific to RA flare. Mean flare frequency, severity, and duration data were presented, and domain scores were compared by flare status to examine known-groups validity. Breakout groups provided input for stiffness, self-management, contextual factors, and measurement considerations., Results: Flare data from 501 patients in an observational study indicated 39% were in flare, with mean (SD) severity of 6.0 (2.6) and 55% lasting > 14 days. Pain, physical function, fatigue, participation, and stiffness scores averaged ≥ 2 times higher (2 of 11 points) in flaring individuals. Correlations between flare domains and corresponding legacy instruments were obtained: r = 0.46 to 0.93. A combined definition (patient report of flare and 28-joint Disease Activity Score increase) was evaluated in 2 other trials, with similar results. Breakout groups debated specific measurement issues., Conclusion: These data contribute initial evidence of feasibility and content validation of the OMERACT RA Flare Core Domain Set. Our research agenda for OMERACT 2016 includes establishing duration/intensity criteria and developing criteria to identify RA flares using existing disease activity measures. Ongoing work will also address discordance between patient and physician ratings, facilitate application of flare criteria to clinical care, elucidate the role of self-management, and finalize recommendations for RA flare measurement.

Objective: In patients with early active axial spondyloarthritis (axSpA) with a disease duration of < 5 years, the longterm efficacy of 3 years of continuous etanercept (ETN) treatment was assessed., Methods: In a previously reported ESTHER trial, patients with axSpA were randomized to treatment with ETN (n = 40) versus sulfasalazine (SSZ; n = 36) in the first year. We analyzed the clinical, laboratory, and magnetic resonance imaging (MRI) response in the pooled dataset of patients (study population; n = 61), including patients with ankylosing spondylitis (AS, n = 31) and nonradiographic axSpA (nr-axSpA, n = 30) who were continuously treated with ETN for 3 consecutive years. Data were analyzed using the last observation carried forward and completer analysis., Results: In the entire group of patients in the study population (n = 61), the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.7 (± 1.3) at baseline to 2.6 (± 2.4) at Year 3. The Ankylosing Spondylitis Disease Activity Score (ASDAS) decreased from 3.4 (± 0.8) to 1.5 (± 1.0). Also, mean values for MRI spine and sacroiliac joint scores showed a significant decrease. Response rates in the nr-axSpA group were similar and at least as good compared to the AS group for all outcome measures. When comparing remission stages, we found that ASDAS inactive disease correlated better with C-reactive protein and MRI remission than with Assessment of SpondyloArthritis international Society partial remission., Conclusion: There was a consistent and sustained clinical response in patients with early axSpA treated with ETN over 3 years. ClinicalTrials.gov registration number NCT00844142.

Objective: The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set to measure RA flare., Methods: Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare. At OMERACT 11, breakout groups discussed key domains and instruments to measure them, and proposed a research agenda. Patients were active research partners in all focus groups and domain identification activities. Processes for domain selection and patient partner involvement were case studies for OMERACT Filter 2.0 methodology., Results: A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (>70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue, participation, stiffness, and self-management). The RA FG developed preliminary flare questions (PFQ) to measure domains. In combined plenary voting sessions, OMERACT 11 attendees endorsed the proposed RA core set to measure flare with ≥78% consensus and the addition of 3 additional domains to the research agenda for OMERACT 12., Conclusion: At OMERACT 11, a core domain set to measure RA flare was ratified and endorsed by attendees. Domain validation aligning with Filter 2.0 is ongoing in new randomized controlled clinical trials and longitudinal observational studies using existing and new instruments including a set of PFQ.

Objective: Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA)., Methods: The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported., Results: Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA., Conclusion: These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

Objective: To determine the extent to which participants at the Outcome Measures in Rheumatology (OMERACT) 11 meeting agree that instruments used in clinical trials to measure OMERACT core outcome domains in acute gout fulfill OMERACT filter requirements of truth, discrimination, and feasibility; and where future research efforts need to be directed., Methods: Results of a systematic literature review and analysis of individual-level data from recent clinical studies of acute gout were presented to OMERACT participants. The information was discussed in breakout groups, and opinion was defined by subsequent voting in a plenary session. Endorsement was defined as at least 70% of participants voting in agreement with the proposition (where the denominator excluded those participants who did not vote or who voted "don't know")., Results: The following measures were endorsed for use in clinical trials of acute gout: (1) 5-point Likert scale and/or visual analog scale (0 to 100 mm) to measure pain; (2) 4-point Likert scale for joint swelling; (3) 4-point Likert scale for joint tenderness; and (4) 5-point Likert scale for patient global assessment of response to treatment. Measures for the activity limitations domain were not endorsed., Conclusion: Measures of pain, joint swelling, joint tenderness, and patient global assessment in acute gout were endorsed at OMERACT 11. These measures should now be used in clinical trials of acute gout.

Objective: To identify a comprehensive list of features that might discriminate between gout and other rheumatic musculoskeletal conditions, to be used subsequently for a case-control study to develop and test new classification criteria for gout., Methods: Two Delphi exercises were conducted using Web-based questionnaires: one with physicians from several countries who had an interest in gout and one with patients from New Zealand who had gout. Physicians rated a list of potentially discriminating features that were identified by literature review and expert opinion, and patients rated a list of features that they generated themselves. Agreement was defined by the RAND/UCLA disagreement index., Results: Forty-four experienced physicians and 9 patients responded to all iterations. For physicians, 71 items were identified by literature review and 15 more were suggested by physicians. The physician survey showed agreement for 26 discriminatory features and 15 as not discriminatory. The patients identified 46 features of gout, for which there was agreement on 25 items as being discriminatory and 7 items as not discriminatory., Conclusion: Patients and physicians agreed upon several key features of gout. Physicians emphasized objective findings, imaging, and patterns of symptoms, whereas patients emphasized severity, functional results, and idiographic perception of symptoms.

Objective: To investigate the effects of longterm low-dose chronotherapy with modified-release (MR) prednisone for rheumatoid arthritis (RA) on the hypothalamus-pituitary-adrenal (HPA) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study. This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone including patients previously treated with prednisone (ClinicalTrials.gov number NCT00146640)., Methods: Corticotropin-releasing hormone (CRH) tests were performed on 28 patients at 3 timepoints: at baseline on prestudy immediate-release (IR) prednisone, after the 3-month double-blind phase on either IR prednisone or MR prednisone, and after the 9-month open-label extension on MR prednisone. Changes of cortisol were assessed and compared to individual patients' efficacy and safety data., Results: The increase (mean, SD) of cortisol plasma concentrations after injection of corticorelin was 5.5 (4.37) μg/dl on IR prednisone at baseline (n = 21) and 5.3 (4.07) μg/dl on MR prednisone at 12 months (n = 22). Numbers of normal/suppressed/no response reactions did not differ among treatments. Switching from IR to MR prednisone did not influence responses, nor did longterm treatment of up to 12 months with MR prednisone. No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone., Conclusion: Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months. We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA.

Objective: To evaluate the prognostic value of HLA-DRB1 antigens, rheumatoid factor (RF), and C-reactive protein (CRP) with the radiographic outcome of rheumatoid arthritis (RA)., Methods: In total, 139 patients with early RA (< 2 years) were followed up. At the end of 3 year treatment with disease modifying antirheumatic drugs (DMARD) HLA genotyping and external radiographic scoring were performed. The time up to the first development of erosive disease [Ratingen radiographic score (RS) > 0, > 5, > 10] was compared by methods of survival analysis., Results: At 4 years' disease duration, DRB1*04 or DRB1*01 positive patients had RS > 0 or > 10 (73% and 27%, respectively) significantly more frequently than DRB1*04 or DRB1*01 negative patients (37% and 7%, respectively). Nearly independently of the genetic predisposition, RF and elevated CRP at the start of DMARD treatment were predictive for erosive RA at 4 years. Elevated CRP (> or = 15 mg/l) increased the probability of erosive RA in DRB1*04 or DRB1*01 positive patients from 64.0% (in patients with CRP < 15 mg/l) to 83.9%, and in DRB1*04 and DRB1*01 negative patients from 18.8% to 70.1%. The corresponding figures for RF+ and RF- patients were 58.2% and 82.5% in HLA predisposed patients and 23.5% and 60.2% in those who were negative for DRB1*04 and DRB1*01. The probability of a RS > 10 was 40.9% for HLA predisposed patients with elevated CRP. In contrast, no case with RS > 10 was found in 43 patients who had neither of these 2 risk factors., Conclusion: Our findings support that HLA predisposition plays an important role with regard to radiographic progression. However, this effect is modified by RF serum concentration and disease activity.

Objective: To estimate the frequency of and to identify possible risk factors involved with terminating an initial disease modifying antirheumatic drug (DMARD) therapy. We hypothesized that treatment termination depends not only on side effects and inefficacy but also on the therapeutic setting and the health beliefs of the patient., Methods: We observed an inception cohort of 302 patients with early rheumatoid arthritis (< 2 years) and first prescription of DMARD for 3 years. Survival analysis was used to estimate treatment continuation under rheumatological care. The study group comprised 4 rheumatological outpatient clinics and 7 private practices in Berlin., Results: Of the initial cohort 80% continued the same drug or were in remission after one year, 70% after 2 years. Within the first 2 years, methotrexate therapy was terminated in 15% of the cases and sulfasalazine therapy in 40%, respectively. In both forms of therapy, the discontinuation rate was dependent on initial disease activity. However, the influence of the patient's psychological status at baseline was equally strong. DMARD treatment was terminated earlier and more frequently in patients with poor psychological well being. These findings hold true after controlling for disease activity or severity., Conclusion: Patient psychological well being and disease activity at start of initial DMARD therapy are important predictors of early drug discontinuation. By influencing psychological well being (e.g., by patient education programs), continuation of DMARD therapy might be further improved.

Objective: (1) To characterize potential changes in diclofenac pharmacokinetics and renal function in patients with rheumatoid arthritis (RA) treated with diclofenac and cyclosporine; (2) to prospectively collect longitudinal safety data during use of this drug combination., Methods: Twenty patients with severe, treatment refractory RA were sequentially treated with stable doses of diclofenac (100-200 mg/day) for one month followed by diclofenac combined with cyclosporine (3 mg/kg/day) for one month. Pharmacokinetic profiles of diclofenac were obtained at the end of each treatment period. Combined therapy was continued for an additional 5 months, during which doses of both drugs could be individually titrated and safety data collected., Results: During co-administration, diclofenac exposure doubled, as shown by an average 104% increase in the area-under-the-curve. Diclofenac half-life was not altered. Serum creatinine was significantly elevated from a baseline value of 0.8 +/- 0.1 mg/dl on diclofenac alone to 1.0 +/- 0.3 mg/dl after one month co-administration with cyclosporine. The magnitude of creatinine elevation was not correlated with that of change in diclofenac exposure, suggesting the pharmacokinetic interaction per se may not additionally contribute to the effect on renal function resulting from this drug combination. During longterm treatment with both medications, prospectively collected safety data indicated that renal function could be stabilized when drug doses were individually titrated in response to serial clinical and laboratory evaluations. The overall pattern of adverse events and laboratory abnormalities in the study population were similar to those reported in patients with RA treated with other nonsteroidal antiinflammatory agents and concomitant cyclosporine., Conclusion: Diclofenac can be safely combined with cyclosporine in the management of RA when appropriate clinical monitoring and dose titrations are performed. Due to the pharmacokinetic interaction that increases diclofenac systemic exposure, it would be prudent to start combination therapy with diclofenac doses at the lower end of the therapeutic dose range.