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Objective: To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR)., Methods: ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores., Results: Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points., Conclusion: Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning., Trial Registration Number: NCT02187055., Competing Interests: Competing interests: VS has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Genentech/Roche, GSK, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi and UCB. EM has received research grants, consulting fees or other remuneration from, and is a member of the speakers’ bureau for, AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, MedImmune, Pfizer Inc and Roche. RJM has received research grants and consulting fees from, or is a member of the speakers’ bureau for, AbbVie, AKL Pharma, Biogen, Bristol-Myers Squibb, Chugai, Eli Lilly, Novartis, Pfizer Inc, Roche, Sandoz, Sanofi and UCB. DG, KS and NI are employees and shareholders of Pfizer Inc. GVW and RD were employees and shareholders of Pfizer Inc at the time of the analysis. JSS has received consulting fees, speaking fees and honoraria from AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi and UCB Pharma; and has received institutional grants from AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc and Roche. RF has received research grants or consulting fees from AbbVie, ACEA, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Samsung, Sanofi-Aventis, Tahio and UCB., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Rheumatoid arthritis (RA) is a chronic, debilitating disease affecting an estimated 1.5 million patients in the US. The condition is associated with a substantial health and economic burden. An economic model was developed to evaluate the cost-effectiveness of tofacitinib (a novel oral Janus kinase inhibitor) versus biologic therapies commonly prescribed in the US for the treatment of RA., Methods: A cost-utility model was developed whereby sequences of treatments were evaluated. Response to treatment was modeled by HAQ change, and informed by a network meta-analysis. Mortality, resource use and quality of life were captured in the model using published regression analyses based on HAQ score. Treatment discontinuation was linked to response to treatment and to adverse events. Patients were modeled as having had an inadequate response to methotrexate (MTX-IR), or to a first biologic therapy (TNFi-IR)., Results: The tofacitinib strategy was associated with cost savings compared with alternative treatment sequences across all modeled scenarios (i.e. in both the MTX-IR and TNFi-IR scenarios), with lifetime cost savings per patient ranging from $65,205 to $93,959 (2015 costs). Cost savings arose due to improved functioning and the resulting savings in healthcare expenditure, and lower drug and administration costs. The tofacitinib strategies all resulted in an increase in quality-adjusted life years (QALYs), with additional QALYs per patient ranging from 0.01 to 0.22., Conclusions: Tofacitinib as a second-line therapy following methotrexate failure and as a third-line therapy following a biologic failure produces lower costs and improved quality of life compared with the current pathway of care.

Objectives: RA causes high disability levels and reduces health-related quality of life, triggering increased costs and risk of unemployment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. These post hoc analyses of phase 3 data aimed to assess monthly medical expenditure (MME) and risk of job loss for tofacitinib treatment vs placebo., Methods: Data analysed were from two randomized phase 3 studies of RA patients (n = 1115) with inadequate response to MTX or TNF inhibitors (TNFi) receiving tofacitinib 5 or 10 mg twice daily, adalimumab (one study only) or placebo, in combination with MTX. Short Form 36 version 2 Health Survey physical and mental component summary scores were translated into predicted MME via an algorithm and concurrent inability to work and job loss risks at 6, 12 and 24 months, using Medical Outcomes Study data., Results: MME reduction by month 3 was $100 greater for tofacitinib- than placebo-treated TNFi inadequate responders (P < 0.001); >20 and 6% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾16%, and risk of future job loss decreased ∼20% (P < 0.001 vs placebo). MME reduction by month 3 was $70 greater for tofacitinib- than placebo-treated MTX inadequate responders (P < 0.001); ⩾23 and 13% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾31% and risk of future job loss decreased ⩾25% (P < 0.001 vs placebo)., Conclusion: Tofacitinib treatment had a positive impact on estimated medical expenditure and risk of job loss for RA patients with inadequate response to MTX or TNFi., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs)., Methods: In a 12-month, phase III randomized controlled trial (ORAL Sync), patients (n = 795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included patient global assessment of arthritis (PtGA), patient assessment of arthritis pain (Pain), physical function (Health Assessment Questionnaire disability index [HAQ DI]), health-related quality of life (Short Form 36 health survey [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep])., Results: At month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ DI, all 8 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ DI, 7 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 5 mg BID. Improvements were sustained to month 12. Significantly more tofacitinib-treated patients reported improvements of greater than or equal to the minimum clinically important differences at month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for tofacitinib 10 mg BID)., Conclusion: Patients with active RA treated with tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo., (© 2016, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis compared the efficacy and safety of tofacitinib with biologic disease-modifying antirheumatic drugs in patients with RA and a prior inadequate response (IR) to tumor necrosis factor inhibitors (TNFi)., Methods: A systematic literature review identified 5 randomized placebo-controlled trials that evaluated tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) against placebo in patient populations with RA with a prior IR to TNFi. The definition of TNFi-IR varied across studies, and included patients with an IR or who had failed treatment with TNFi for any reason. A network meta-analysis was conducted comparing study data with regard to American College of Rheumatology response rates and Health Assessment Questionnaire-Disability Index improvement at weeks 12 and 24, rates of treatment withdrawal due to all causes; adverse events (AEs) and lack of efficacy; and rates of AEs, serious AEs, and serious infections., Findings: The 5 trials included a total of 2136 patients. Tofacitinib 5 mg twice daily combined with methotrexate was found to have relative risk estimates of American College of Rheumatology responses and change from baseline in Health Assessment Questionnaire-Disability Index score comparable with abatacept, golimumab, rituximab, and tocilizumab combined with conventional synthetic disease-modifying antirheumatic drugs. Withdrawal rates from trials due to all causes and AEs were comparable between treatments, and tofacitinib had a lower rate of withdrawals due to lack of efficacy. Rates of AEs and HAQ-DI were comparable between tofacitinib, other active treatments, and placebo. No serious infections were reported with tofacitinib during the placebo-controlled period (up to week 12) in this study population; rates of serious infection with other active treatments were generally low and similar to placebo., Implications: During a 24-week period, tofacitinib had efficacy and rates of AEs comparable with currently available bDMARDs in the treatment of patients with RA who had a prior IR to TNFi. ClinicalTrials.gov identifiers: ORAL Step, NCT00960440; ATTAIN, NCT00124982; GO-AFTER, NCT00299546; RADIATE, NCT00106522; REFLEX, NCT00462345., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint structural deterioration. Driven by recent expectations that patients in clinical trials randomized to placebo should be 'rescued' with active therapy within 6 months of starting treatment, the relative benefit of arresting joint damage with biologic agents beyond this period is unclear. With longer-term evidence of the rate of joint deterioration with minimal treatment, the efficacy of biologic agents and novel treatments might be projected beyond the placebo-controlled phase observed in clinical trials. The aim of this study was to estimate radiographic structural deterioration over time in patients with moderate-to-severe RA minimally treated with DMARDs., Methods: A literature review identified evidence of joint structural deterioration in patients with (DMARD-IR population) and without (non-DMARD-IR population) a history of inadequate response to DMARDs. Patients were minimally treated with one non-biologic DMARD or palliative care (non-DMARD-IR population only). Outcomes of interest were the (modified) Total Sharp Score (TSS) and subscales (Erosion Subscore [ES] and Joint Space Narrowing [JSN] Subscore), and Larsen score. Pooled joint-deterioration curves over time were obtained with meta-analysis models., Results: Mean change from baseline in TSS increased in the DMARD-IR population from 1.14 (95 % credible interval [CrI] 0.66, 1.67) to 9.84 (5.68, 14.46) at Weeks 12 and 104, respectively, and a non-linear increase of 1.56 (0.79, 2.34) and 5.13 (-1.35, 11.67) in the non-DMARD-IR population. At the same time points, mean changes (95 % CrI) were 0.51 (0.27, 0.83) and 4.43 (2.38, 7.21) for ES and 0.36 (0.09, 0.67) and 3.14 (0.80, 5.78) for JSN in the DMARD-IR population, whereas corresponding changes in the non-DMARD-IR population were 0.69 (0.31, 1.12) and 2.93 (0.92, 5.02), and 0.29 (0.17, 0.44) and 2.55 (1.45, 3.80), respectively. Larsen scores were only available for the non-DMARD-IR population, with mean changes (95 % CrI) of 0.08 (0.04, 0.11) and 0.65 (0.36, 0.96) at Weeks 12 and 104, respectively., Conclusion: Minimal treatment of RA with one non-biologic DMARD results in deterioration of joint structure in patients with or without a history of inadequate response to non-biologic DMARDs.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA., Methods: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36., Results: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24., Conclusions: In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

Objective: To assess patient-reported outcomes (PROs) for tofacitinib, an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), in a 6-month, phase III, randomized controlled trial., Methods: Patients ages ≥18 years with active RA with an inadequate response to ≥1 tumor necrosis factor inhibitor (TNFi) and receiving stable background methotrexate were randomized 2:2:1:1 to tofacitinib 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib 5 mg or 10 mg twice daily at month 3. PROs measured at month 3 included patient global assessment of disease activity (PtGA), pain, Health Assessment Questionnaire (HAQ) disability index (DI), Medical Outcomes Study (MOS) Short Form 36 Health Survey version 2 (SF-36v2; acute), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and MOS Sleep Scale., Results: Patients received tofacitinib 5 mg (n = 133) or 10 mg (n = 134) or placebo advanced to tofacitinib 5 mg (n = 66) or 10 mg (n = 66). HAQ DI (reported previously), PtGA (P < 0.0001), and SF-36v2 physical and mental component summary (P < 0.05) scores were improved for both tofacitinib doses versus placebo. Furthermore, improvements greater than or equal to the minimum clinically important difference were more frequently reported by tofacitinib-treated patients versus placebo for PtGA (P < 0.05), pain (P < 0.0001), HAQ DI (P < 0.05), SF-36v2 physical and mental component summary scores (P < 0.05), and FACIT-F (P < 0.001 for 5 mg twice daily). No statistical differences were observed in the MOS Sleep Scale., Conclusion: Tofacitinib treatment resulted in significant, clinically meaningful improvements in multiple PROs versus placebo over 3 months of treatment in patients with active RA and a previous inadequate response to TNFi., (Copyright © 2015 by the American College of Rheumatology.)

Objective: Health measurements used to evaluate the effectiveness of rheumatoid arthritis (RA) therapies often fail to reflect patients' priorities, despite recommendations towards more patient-centered assessments. The goals of the current review are: (1) to present guidelines, tools, and required steps for successful implementation of patient-reported outcome (PRO) measurement in RA clinical trials; and (2) to identify gaps between recommendations and current practices., Methods: The first objective was addressed by reviewing existing frameworks for assessment of health-related quality of life among patients with RA and guidelines on the evaluation of PRO instruments, with a focus on evidence required to demonstrate the adequacy of PRO-based labeling claims. The second goal was addressed by conducting an empirical investigation of the overlap between patients' perspectives and current practices regarding PROs in RA studies, elaborated from systematic literature searches. The first search identified qualitative studies that reported direct input from patients with RA, while the second identified the main health outcomes measured in RA trials, with a focus on biologic therapy., Results: Our review revealed a set of outcomes that have thus far not been widely used to assess treatment benefit in RA, despite evidence of their importance to patients. The psychometric properties of PRO instruments used to evaluate commonly assessed domains are presented, as are recommendations for PRO tools that assess domains less often measured in RA studies., Conclusions: Although the validity of some PRO tools among patients with RA is well established, further work needs to be done in several health domains which have traditionally received insufficient attention.

Background: Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate., Methods: We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician)., Results: Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels., Conclusions: In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).

Background: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis., Methods: In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity)., Results: At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts., Conclusions: In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).

Background: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis., Methods: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity)., Results: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts., Conclusions: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).

Introduction: The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors., Methods: A systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-α inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-α inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria., Results: The literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-α inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-α inhibitors increased for six of the seven response criteria examined., Conclusions: For patients with prior exposure to TNF-α inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-α inhibitors.