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Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation. Methods Two noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM® MarketScan® Commercial and Medicare Supplemental US insurance claims databases (March 2016–October 2018). Second, using data collected in the Corrona US RA Registry (February 2016–August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions. Results In each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses. Conclusion These results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA. Trial Registration Claims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020. Electronic supplementary material The online version of this article (10.1007/s12325-020-01501-z) contains supplementary material, which is available to authorized users.

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). To better understand tofacitinib treatment responses, we used group-based trajectory modeling to investigate distinct disease activity trajectories and associated baseline variables in patients with active RA. Methods: This post hoc analysis used data from a phase III study of methotrexate-naive patients receiving tofacitinib 5 mg twice daily. Changes in the 4-variable Disease Activity Score in 28 joints, using the erythrocyte sedimentation rate (DAS28-ESR) from baseline to month 24 were used in group-based trajectory modeling to identify distinct disease activity trajectories. Patient and disease characteristics, changes in radiographic progression and patient-reported outcomes, and safety up to month 24 were compared among trajectory groups. Results: From 346 methotrexate-naive patients, 5 disease trajectory groups, defined by DAS28-ESR scores, were identified, which progressed from high disease activity (HDA) to remission (group 1, n = 28), to low disease activity (LDA) rapidly (group 2, n = 107), to moderate disease activity (group 3, n = 98), to LDA gradually (group 4, n = 46), or remained in HDA (group 5, n = 67), at month 24. At baseline, groups 1 and 2 generally had lower disease activity and more favorable patient-reported outcomes, compared with other groups. Improvements in radiographic progression and patient-reported outcomes over 24 months were generally consistent with DAS28-ESR–predicted disease activity trajectories. Adverse event rates were generally comparable across groups. Conclusion: Distinct phenotypic subgroups identified heterogeneity in patients with RA normally analyzed as a single population. Trajectory modeling may enable separation of clinically meaningful subsets of patients with RA, and may help optimize treatment outcomes.

Introduction No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. Methods This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. Results Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. Conclusions In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. Funding Pfizer Inc Electronic supplementary material The online version of this article (10.1007/s40744-019-00177-4) contains supplementary material, which is available to authorized users.

Background Fatigue, a common symptom of rheumatoid arthritis (RA), is detrimental to health-related quality of life (HRQoL). We evaluated the impact of tofacitinib on fatigue, sleep, and HRQoL and explored associations between fatigue, related patient-reported outcomes (PROs), and disease activity in RA patients. Methods This post hoc analysis pooled data from three Phase 3 studies of tofacitinib (ORAL Scan; ORAL Standard; ORAL Sync) in RA patients. Patients received tofacitinib 5 or 10 mg twice daily, placebo, or adalimumab (active control; ORAL Standard only, not powered for superiority) with conventional synthetic disease-modifying antirheumatic drugs. Assessed through Month (M)12 were changes from baseline in disease activity, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Medical Outcomes Study Sleep scale (MOS-SS), and Short Form-36 Health Survey (SF-36) composite/domain scores, and proportions of patients reporting improvements from baseline in FACIT-F total and SF-36 domain scores ≥ minimum clinically important differences (MCIDs) or ≥ population normative values. Pearson correlations examined associations among PROs at M6. Treatment comparisons were exploratory, with p < 0.05 considered nominally significant. Results Generally, active treatment led to significant improvements from baseline in FACIT-F total, and MOS-SS and SF-36 composite/domain scores vs placebo, observed by M1 and maintained through M6 (last placebo-controlled time point). Through M6, more patients achieved improvements from baseline ≥ MCID and achieved scores ≥ population normative values in FACIT-F total and SF-36 domain scores with tofacitinib vs placebo. Through M12, some nominally significant improvements with tofacitinib vs adalimumab were observed. With active treatment at M6, FACIT-F scores were moderately (0.40–0.59) to highly (≥ 0.60) correlated with SF-36 composite/domain scores (particularly vitality), moderately correlated with most MOS-SS domain scores, and highly correlated with MOS-SS Sleep Problems Index I scores. Disease activity correlations were moderate with FACIT-F scores and low (0.20–0.39) to moderate with SF-36 general health domain/composite scores. Conclusion Tofacitinib and adalimumab generally conferred significant, clinically meaningful improvements in fatigue, sleep, and HRQoL (including vitality) vs placebo through M6, with improvements maintained to M12. M6 correlations between FACIT-F, PROs of sleep, HRQoL, and disease activity underscore the interrelatedness of multiple PROs and disease activity in RA. Trial registration ClinicalTrials.govNCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009).

Background:Differences in efficacy outcomes favouring males vs females with rheumatoid arthritis (RA) have been reported with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and tumour necrosis factor inhibitors; results with Janus kinase inhibitors are less clear.Objectives:To assess the impact of sex on efficacy, safety and persistence in tofacitinib RA clinical trials.Methods:Efficacy and safety analyses included data pooled from Phase (P)3 randomised controlled trials (RCTs) of patients (pts) with RA and an inadequate response (IR) to methotrexate (NCT00847613; NCT00853385) or ≥1 DMARD (NCT00856544) who received tofacitinib 5 or 10 mg twice daily (BID), adalimumab (ADA) 40 mg Q2W or placebo (PBO), with background csDMARDs. Persistence analyses of pts receiving tofacitinib 5 or 10 mg BID ± csDMARDs used data pooled from two long-term extension trials (NCT00661661; NCT00413699). Efficacy outcomes to Month (M)12 included: ACR20/50/70 responses, changes from baseline (Δ; BL) in DAS28-4(ESR), CDAI, HAQ-DI and FACIT-F, and DAS28-4(ESR) remission (Results:2265 pts were included from P3 RCTs. Demographics and BL characteristics were comparable across sexes and treatments. Tofacitinib or ADA vs PBO generally led to significantly higher ACR20/50/70 responses in both sexes through M6. To M12, ACR20/50/70 responses were broadly comparable across active treatments and between sexes, with significant differences favouring males at some time points, including M3 (Figure 1). Statistically significant differences favouring males vs females were observed in DAS28-4(ESR) remission rates at most time points, including M3 (Figure 1); a similar trend was observed for ΔDAS28-4(ESR). ΔCDAI, ΔHAQ-DI and ΔFACIT-F significantly favoured males vs females receiving tofacitinib 5 mg BID at most time points, while ΔHAQ-DI and ΔFACIT-F tended to favour females receiving tofacitinib 10 mg BID. Rates of adverse events (AEs), serious AEs (SAEs), severe AEs and discontinuations due to AEs were slightly higher in females vs males with tofacitinib 5 mg BID; this was generally reversed with tofacitinib 10 mg BID and ADA (Table 1). AEs of special interest (AESI) were comparable between sexes with tofacitinib and ADA, although low event numbers limit interpretation (Table 1). Time to all-cause discontinuation and discontinuation due to AEs/lack of efficacy with tofacitinib 5 mg BID was similar between sexes. Numerical differences favouring females vs males were observed for time to all-cause discontinuation and discontinuation due to AEs with tofacitinib 10 mg BID.Table 1.Safety summary to M24 in pooled DMARD-IR P3 RCTsTofacitinib5 mg BIDTofacitinib10 mg BIDADAPts with events,n (%)Females(N=707)Males(N=133)Females(N=698)Males(N=137)Females(N=162)Males(N=42)AEs562 (79.5)85 (63.9)529 (75.8)107 (78.1)119 (73.5)30 (71.4)SAEs107 (15.1)17 (12.8)71 (10.2)24 (17.5)13 (8.0)6 (14.3)Severe AEs86 (12.2)12 (9.0)55 (7.9)22 (16.1)14 (8.6)5 (11.9)Discontinuations due to AEs87 (12.3)10 (7.5)88 (12.6)10 (7.3)17 (10.5)5 (11.9)Death6 (0.8)4 (3.0)03 (2.2)1 (0.6)2 (4.8)AESISerious infections28 (4.0)6 (4.5)27 (3.9)6 (4.4)2 (1.2)1 (2.4)All HZ (non-serious/serious)35 (5.0)7 (5.3)43 (6.2)5 (3.6)2 (1.2)3 (7.1)MACE5 (0.7)02 (0.3)3 (2.2)03 (7.1)Malignancies (excl. NMSC)7 (1.0)1 (0.8)9 (1.3)1 (0.7)01(2.4)NMSC2 (0.3)5 (3.8)4 (0.6)2 (1.5)1 (0.6)1 (2.4)Venous thromboembolism3 (0.4)03 (0.4)1 (0.7)00HZ, herpes zoster; MACE, major adverse cardiovascular events; NMSC, non-melanoma skin cancerConclusion:Efficacy outcomes with tofacitinib and ADA were generally higher in males and comparable in females vs previously reported mixed population response rates for advanced therapies. Safety findings did not reveal a consistent pattern between sexes. Tofacitinib persistence was similar between sexes.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:H Niall Jones Consultant of: Pfizer Inc, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Ichnos, Inmedix, Janssen, Kiniksa, Merck, Myriad Genetics, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi, Scipher, SetPoint Medical, UCB, Hendrik Schulze-Koops Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead Sciences, Hexal Sandoz, Hospira, Janssen-Cilag, MSD, Novartis, Pfizer Inc, Roche, UCB, Grant/research support from: Novartis, Pfizer Inc, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche, Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc, Roche, Cassandra Kinch Shareholder of: Pfizer Canada ULC, Employee of: Pfizer Canada ULC, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rebecca Germino Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lihi Eder Speakers bureau: AbbVie, UCB, Consultant of: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer Inc, UCB, Grant/research support from: AbbVie, Eli Lilly, Pfizer Inc, UCB

ObjectiveTo describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials.MethodsData were collected from patients in seven tofacitinib studies: six phase III (four RA, two PsA) and one phase II study (AS), and grouped into five analysis populations based on rheumatic disease diagnosis and category of prior inadequate response (IR) to treatment: conventional synthetic disease-modifying antirheumatic drugs-IR (RA and PsA), tumour necrosis factor inhibitors-IR (RA and PsA), or non-steroidal anti-inflammatory drugs-IR (AS). Only patients who received tofacitinib 5 or 10 mg twice daily or placebo were included. Pain assessments included: Patient’s Assessment of Arthritis Pain, Short-Form Health Survey 36v2 Question (Q)7 and Bodily Pain domain, Ankylosing Spondylitis Quality of Life Q9 and Q14, EuroQol Five Dimensions Pain/Discomfort dimension and Bath Ankylosing Spondylitis Disease Activity Index Q2 and Q3. Data were reported to month 6 (placebo to month 3) in the RA and PsA populations, and week 12 (tofacitinib and placebo) in the AS population.ResultsOverall, 3330 patients were included in this analysis. In the RA and PsA populations, pain improvements in tofacitinib-treated patients compared with placebo were observed at the earliest time point assessed and at month 3 (maintained to month 6). In the AS population, pain improvements compared with placebo were observed at week 12.ConclusionTofacitinib was associated with rapid and sustained improvements across multiple pain measures in patients with inflammatory rheumatic musculoskeletal diseases.

ObjectiveTo 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).MethodsORAL 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.ResultsSubstantial 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.ConclusionTreatment 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 numberNCT02187055.

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 3, 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 [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 eight SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ-DI, seven 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 ≥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. (NCT00856544) This article is protected by copyright. All rights reserved.

Background:Depression/anxiety are common in RA pts. SF-36 MCS ≤38 can identify probable major depressive disorder and/or probable generalised anxiety disorder (pMDD/pGAD) in RA pts. Tofacitinib is an oral JAK inhibitor for the treatment of RA.Objectives:To assess pMDD/pGAD prevalence in the tofacitinib RA program and efficacy by baseline (BL) pMDD/pGAD status.Methods:Data from pts receiving tofacitinib, ADA, or PBO were pooled from 5 Phase (P)3 and 1 P3b/4 trials. Demographics/BL characteristics were reported by BL pMDD/pGAD (SF-36 MCS ≤38, presence; >38, absence). Month (M)3/6/9/12 SF-36 MCS change from BL (Δ) was estimated, and % with pMDD/pGAD reported. M3/6/12 efficacy outcomes compared tofacitinib-treated pts by BL pMDD/pGAD.Results:BL pMDD/pGAD was seen in 44.5% (tofacitinib 5 mg BID), 39.8% (tofacitinib 10 mg BID), 45.4% (ADA 40 mg Q2W) and 39.1% (PBO) of pts. pMDD/pGAD pts had higher BL CRP and worse disability, fatigue, pain and sleep vs pts without. SF-36 MCS increases were greater for tofacitinib vs PBO/ADA (Fig 1a). The % of pts with BL pMDD/pGAD who continued to have pMDD/pGAD reduced over time, and was generally lower for tofacitinib vs PBO/ADA (Fig 1b). Regardless of BL pMDD/pGAD, efficacy was generally similar for tofacitinib 5 mg BID (Table) and 10 mg BID.Conclusion:~40% of RA pts had BL pMDD/pGAD. SF-36 MCS improvements were greater for tofacitinib vs PBO/ADA. With tofacitinib, % of pts with SF-36 MCS ≤38 reduced by ~60% at M12. Tofacitinib efficacy was similar in pts with/without BL pMDD/pGAD. Limitations include using SF-36 MCS to identify probable rather than confirmed MDD or GAD. Future research using gold standard psychiatric interviews to validate use of SF-36 MCS ≤38 is needed.Table.M3/6/12 efficacy with tofacitinib 5 mg BID, by BL pMDD/pGADaSF-36 MCS ≤38SF-36 MCS >38OR (95% CI)P valueACR20 (%)b,cM355.157.90.89 (0.74, 1.08)0.2330M661.762.80.96 (0.79, 1.16)0.6511M1258.458.60.99 (0.80, 1.22)0.9279ACR50 (%)b,cM325.929.20.85 (0.70, 1.03)0.1022M636.038.00.92 (0.76, 1.11)0.3724M1233.834.30.98 (0.80, 1.20)0.8366ACR70 (%)b,cM310.111.00.91 (0.69, 1.18)0.4704M616.516.51.00 (0.79, 1.26)0.9901M1218.317.51.06 (0.83, 1.34)0.6560DAS28-4(ESR))b,cM35.47.40.72 (0.49, 1.05)0.0872M65.98.50.68 (0.49, 0.94)0.0199*M128.011.90.64 (0.47, 0.89)0.0073**ΔHAQ-DI, LS meanc,dSF-36 MCS ≤38SF-36 MCS >38Difference (95% CI)P valueM3-0.41-0.430.01 (-0.04, 0.06)0.6008M6-0.49-0.48-0.01 (-0.06, 0.04)0.6617M12-0.52-0.52-0.01 (-0.06, 0.05)0.8475*paBL pMDD/pGAD = SF-36 MCS ≤38;bLogistic regression fit;cFor PBO pts advancing to tofacitinib post-M3, only PBO data were included;dMixed-effects linear model fitΔ, change from baseline; ACR, American College of Rheumatology; BID, twice daily; BL, baseline; CI, confidence interval; DAS28-4(ESR), Disease Activity Score in 28 joints, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; M, month; MCS, Mental Component Summary score; OR, odds ratio; P, Phase; pGAD, probable generalised anxiety disorder; PBO, placebo; pMDD, probable major depressive disorder; pt, patient; RA, rheumatoid arthritis; SF-36, Short Form-36 health surveyAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Rakesh Jain Grant/research support from: Allergan, Eli Lilly, Lundbeck, Otsuka, Pfizer Inc, Shire and Takeda, Consultant of: Acadia, Alfasigma, Allergan, Eisai, Eli Lilly, Evidera, Impel, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Supernus, Takeda and Teva, Speakers bureau: Alkermes, Allergan, Eli Lilly, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Takeda, Teva and Tris Pharmaceuticals, Fedra Irazoque-Palazuelos Consultant of: Bristol-Myers Squibb, Janssen, Pfizer Inc, Roche and UCB, Renato Guzman: None declared, Hugo Madariaga: None declared, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Karina Santana Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Abbas Ebrahim Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dario Ponce de Leon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Real-world data comparing tofacitinib with biologic disease-modifying antirheumatic drugs (bDMARDs) are limited.To compare characteristics, treatment patterns, and costs of patients with rheumatoid arthritis (RA) receiving tofacitinib versus the most common bDMARDs (adalimumab [ADA], etanercept [ETN], and abatacept [ABA]) following a single bDMARD in a U.S. administrative claims database.This study was a retrospective cohort analysis of patients aged ≥ 18 years with an RA diagnosis (ICD-9-CM codes 714.0x-714.4x; 714.81) and 1 previous bDMARD filling ≥ 1 tofacitinib or bDMARD claim in the Truven MarketScan Commercial and Medicare Supplemental claims databases (November 1, 2012-October 31, 2014). Monotherapy was defined as absence of conventional synthetic DMARDs within 90 days post-index. Persistence was evaluated using a 60-day gap. Adherence was assessed using proportion of days covered (PDC). RA-related total, pharmacy, and medical costs were evaluated in the 12-month pre- and post-index periods. Treatment patterns and costs were adjusted using linear models including a common set of clinically relevant variables of interest (e.g., previous RA treatments), which were assessed separately using t-tests and chi-squared tests.Overall, 392 patients initiated tofacitinib; 178 patients initiated ADA; 118 patients initiated ETN; and 191 patients initiated ABA. Tofacitinib patients were older versus ADA patients (P = 0.0153) and had a lower proportion of Medicare supplemental patients versus ABA patients (P = 0.0095). Twelve-month pre-index bDMARD use was greater in tofacitinib patients (77.6%) versus bDMARD cohorts (47.6%-59.6%). Tofacitinib patients had greater 12-month pre-index RA-related total costs versus bDMARD cohorts (all P0.0001) and greatest index use of monotherapy (P = 0.0080 vs. ABA). A similar (all P0.10) proportion of patients were persistent with tofacitinib (42.6%) versus ADA (37.6%), ETN (42.4%), and ABA (43.5%). Mean PDC was 0.55 for tofacitinib versus 0.57 (ADA), 0.59 (ETN), and 0.44 (ABA; P = 0.0003). Adjusted analyses generated similar findings to the unadjusted treatment patterns. Tofacitinib had lower adjusted 12-month post-index mean RA-related total costs ($23,568) versus ADA ($29,278; P0.0001), ETN ($26,885; P = 0.0248), and ABA ($30,477; P0.0001).In this study, tofacitinib was more commonly used as monotherapy and yielded at least comparable persistence and adherence with lower adjusted mean RA-related total costs versus ADA, ETN, and ABA. Further analysis is warranted given the greater 12-month pre-index bDMARD use and RA-related costs for tofacitinib versus bDMARDs.This study was sponsored by Pfizer. Harnett, Gerber, Gruben, Koenig, and Chen are employees and shareholders of Pfizer. Some data reported in this manuscript have been previously presented at the Academy of Managed Care Nexus 2015; Orlando, Florida; October 26-29, 2015, and was submitted in abstract form to the European League Against Rheumatism Congress; London, United Kingdom; June 8-11, 2016. All authors were involved in the conception and design of this study. Harnett and Gruben were involved in data collection and analysis. All authors interpreted the data, critically reviewed and revised the manuscript, and read and approved the final manuscript.

Background Treatment satisfaction and adherence remain issues affecting outcomes for patients (pts) with rheumatoid arthritis (RA). A better understanding of the reasons for non-adherence, and differences between pt, caregiver and healthcare professional (HCP) views on adherence, may improve decision-making and outcomes. Objectives To survey pts, caregivers and HCPs, in order to investigate pt behaviours and attitudes, and communications between pts, caregivers and HCPs regarding adherence to RA therapy. Methods Surveys were conducted online by Harris Poll between Oct and Nov 2018, among pts/caregivers and HCPs from Australia, Brazil, Canada, Germany, Japan, Spain, Taiwan, UK and US. The pt survey included pts aged ≥18 years with a diagnosis of RA who had taken conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) with biological (b)DMARDs in the past 3 years. The caregiver survey included adults aged ≥18 years who lived with/provided care to a spouse/family member with RA and were involved in ≥2 care activities for a pt with RA who had taken csDMARDs with bDMARDs in the past 3 years. The HCP survey included responses from licensed rheumatologists (orthopaedists in Japan) who saw ≥10 pts with moderate/severe RA per month, ≥10% of whom had been prescribed a bDMARD. A post-weight was applied to raw data to adjust for the relative adult population size of each country vs the total for all 9 countries surveyed. Results In total, 900 pts, 714 caregivers and 840 HCPs responded to the surveys. Overall, 50% of both pts and caregivers reported that pts always took their current RA prescription medications exactly as directed. However, 67% of pts reported that they had not always adhered to dosing regimens (most common deviations: skipping doses [45%]; extending time between doses [44%]; taking other medications without HCP direction [38%]; taking less than the prescribed dose [34%]; dose splitting [31%]; and stopping medications altogether [28%]). Among HCP respondents, 98% reported asking pts about adherence to RA medication, even though 61% felt there was no way of knowing if pts were taking medications as prescribed and, overall, HCPs responded that 64% of pts did not always take RA medication as prescribed. While 87% of HCPs agreed that bDMARDs were most effective when taken in combination with csDMARDs and 92% reiterated this to pts, 62% were concerned that pts take bDMARDs without csDMARDs. Pts and caregivers reported that pts often stopped taking csDMARDs; however, HCPs underestimated the number of non-adherent pts (Figure A). The most common reason given by pts and caregivers for non–adherence to RA medication was difficulty in remembering to take medication; however, concerns about feeling ill and potential side effects were also common (Figure B). Despite this, 47% of pts and 51% of caregivers responded that pts often don’t share all side effects caused by their RA medication with HCPs, while 38% of HCPs believed that pts did not inform them of all side effects. Conclusion This study from a large, multinational cohort of pts with RA, caregivers and HCPs describes medication adherence patterns. Pts on bDMARDs often did not take their background csDMARDs; however, the extent of pt non-adherence was underestimated by HCPs. These results highlight gaps in communication and understanding of non-adherence between pts, caregivers and HCPs. Acknowledgement Study sponsored by Pfizer Inc. Medical writing support was provided by Anthony G McCluskey, PhD, of CMC Connect and funded by Pfizer Inc. Disclosure of Interests James Galloway Consultant for: Pfizer Inc, Ara Dikranian Consultant for: AbbVie, Pfizer Inc, Speakers bureau: AbbVie, Pfizer Inc, Cheryl L Koehn Shareholder of: Arthritis Consumer Experts, Grant/research support from: Canadian Institutes of Health Research, Arthritis Research Canada, St. Paul’s Hospital, Employee of: Arthritis Consumer Experts, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sander Strengholt Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Objectives To describe characteristics, treatment patterns and persistence in patients with RA treated with tofacitinib, an oral Janus kinase inhibitor, in Canadian clinical practice between 1 June 2014 and 31 May 2017. Methods Data were obtained from the tofacitinib eXel support programme. Baseline demographics and medication history were collected via patient report/special authorization forms; reasons for discontinuation were captured by patient report. Treatment persistence was estimated using Kaplan–Meier methods, with data censored at last follow-up. Cox regression was applied to analyse baseline characteristics associated with treatment discontinuation. Results The number of patients with RA enrolled from 2014 to 2017 was 4276; tofacitinib utilization increased during that period, as did the proportion of biologic (b) DMARD-naïve patients prescribed tofacitinib. Of patients who initiated tofacitinib, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and adverse events (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively. Prior bDMARD experience predicted increased tofacitinib discontinuation (vs bDMARD-naïve, P < 0.001). Increased retention was associated with older age (56–65 years and >65 years vs ⩽45 years; P < 0.05), and time since diagnosis of 15 to 730, 613, 667 and 592 days, respectively. Conclusion Since 2014, tofacitinib use in Canadian patients with RA increased, especially among bDMARD-naïve/post-1 bDMARD patients. Median drug survival was ∼2 years. Likelihood of persistence increased for bDMARD-naïve (vs bDMARD-experienced) patients and those aged ⩾56 (vs ⩽45) years.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1–30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose‐dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient‐reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

Tofacitinib is an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis (RA). Tofacitinib can be administered as a monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs). This study describes RA patients' characteristics, treatment patterns, and costs for those initiating tofacitinib treatment as monotherapy or combination therapy, using US claims data from clinical practice.A retrospective cohort analysis of patients aged ≥18 years with RA (International Classification of Diseases, Ninth Revision code 714.xx) and with ≥1 tofacitinib claim in the Truven Marketscan (TM) or the Optum Clinformatics (OC) database. Index was defined as the first tofacitinib fill date (November 2012-June 2014). Patients were continuously enrolled for ≥12 months before and after index. Adherence was assessed using the proportion of days covered (PDC) and medication possession ratio (MPR). Persistence was evaluated using a 1.5× days' supply gap or switch. All-cause and RA-related costs in the 12-month pre- and post-index periods were evaluated. Unadjusted and adjusted analyses were conducted on data on treatment patterns and costs stratified by monotherapy status.A total of 337 (TM) and 118 (OC) tofacitinib patients met the selection criteria; 52.2% (TM) and 50.8% (OC) received monotherapy and 83.7% (TM) and 76.3% (OC) had pre-index biologic DMARD experience. Twelve-month mean PDC values were 0.56 (TM) and 0.53 (OC), and 12-month mean MPR was 0.84 (TM) and 0.80 (OC), with persistence of 140.0 (TM) and 124.6 (OC) days. Between 12-month pre- and post-index periods, mean (SD) 12-month RA-related medical costs decreased by $5784 ($31,832) in TM and $6103 ($25,897) in OC (both, P0.05), whereas total costs increased by $3996 ($30,397) in TM (P0.05) and $1390 ($26,603) in OC. There were no significant differences in adherence, persistence, or all-cause/RA-related costs between monotherapy and combination therapy in unadjusted/adjusted analyses.This analysis adds to the existing tofacitinib knowledge base and will enable informed clinical and policy decision making based on valuable datasets independent of randomized controlled trials.

Adherence to biologic disease-modifying antirheumatic drugs (bDMARDs) among patients with rheumatoid arthritis (RA) is often suboptimal in routine clinical practice. Low or nonadherence can reduce the effectiveness of bDMARD therapies.To evaluate filling of newly prescribed initial bDMARDs for the treatment of RA and evaluate potential for characterizing treatment decisions and patient outcomes.In this retrospective cohort analysis, patients aged ≥ 18 years with an RA diagnosis (ICD-9-CM code 714.xx) were selected from a de-identified database of clinical information from the Electronic Health Record (EHR; Humedica) database linked to health care claims (Optum) from commercial and Medicare Advantage health plans (2007-2013). The first biologic prescription date in EHR was the index date. Patients were categorized as filling the prescription within 30 days (early fillers), 31-180 days (late fillers), or not at all within 180 days (nonfillers) of index date.Of 373 patients meeting inclusion criteria, 170 (45.6%), 59 (15.8%), and 144 (38.6%) were categorized as early fillers, late fillers, and nonfillers, respectively. Most prescriptions were written or ordered for tumor necrosis factor inhibitors (88.7%). Compared with late and nonfillers, early fillers were younger and more likely to be female, with higher pain scores (among those reporting pain scores) and RA severity scores pre-index, and filled more prescriptions for any reason pre-index. More nonfillers (66.0%) were Medicare patients than early (17.7%) and late (35.6%) fillers. During days 0-30 post-index, conventional synthetic DMARD use was greatest for early fillers (45.9%) and lowest among nonfillers (24.3%); however, during days 31-180 post-index, the proportion was highest for late fillers (61.0%) and lowest for nonfillers (35.4%). Of early fillers, 12.9% did not fill/receive a bDMARD after 30 days. Only 23 patients had pre/post-index pain scores, and 47 patients had a rationale for stopping or not filling a bDMARD. In patients with pharmacy and medical coverage for 180 days post-index, early fillers had greater RA-related pharmacy and medical resource use and costs than late and nonfillers combined.These findings confirm a high rate of primary nonadherence to bDMARDs among patients with RA.

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.

Background: Persistence of active disease in patients (pts) with rheumatoid arthritis (RA) is highly variable following treatment initiation. One possible explanation is the existence of distinct disease activity/response trajectories influenced by baseline variables, such as sociodemographics, disease characteristics and health status.1 Objectives: To identify distinct disease activity trajectories over 12 months and distinguishing baseline factors using pooled data from 3 randomised, controlled Phase 3 (P3) studies of tofacitinib 5 mg twice daily (BID) in pts with active RA who were inadequate responders (IR) to conventional synthetic (cs)DMARDs, with or without prior biologic (b)DMARDs (NCT00847613, NCT00856544 and NCT00853385). Methods: Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28–4[ESR]) data from 3 P3 studies were pooled. A group-based trajectory modelling strategy was applied to find unique longitudinal groups of pts with similar disease activity over time.2 Trajectories were latent models, fit as polynomials. The number of groups and polynomial degree of each group were specified and fit for all combinations of up to 6 groups and up to a 4th degree polynomial; a best-fit model was chosen using Bayesian information criteria. Results: csDMARD-IR/bDMARD-naive pts (n=677) were separated into 5 unique disease activity trajectories (figure 1); csDMARD-IR pts who received prior bDMARDs (n=149) were separated into 4 trajectories (not shown). In the bDMARD-naive pts, Group 5 (3.8%) had the highest predicted baseline DAS (7.3) with minimal improvement (6.4) at Month 12; Group 4 (26.7%) had baseline DAS 7.0, improving to DAS 5.0 at Month 12; Groups 2 (30.4%) and 3 (36.6%) had baseline DAS 5.9 and 6.2, respectively, leading to low DAS (2.9) and moderate DAS (3.9), respectively, at Month 12; Group 1 (2.4%) had the lowest baseline DAS of 4.3, improving to remission (DAS 2.1) at Month 12 (figure 1). The 4 trajectories in csDMARD-IR pts who received prior bDMARDs were similar to Groups 2–5 in bDMARD-naive pts. While baseline demographics were generally similar between bDMARD-naive groups, there were statistically significant differences in baseline disease activity measures and pt-relevant outcomes between groups. Conclusions: It was possible to identify heterogeneous phenotypic subgroups as distinct disease activity trajectories in csDMARD-IR pts treated with tofacitinib. The groups were characterised by differences in disease activity and pt-relevant outcomes, including baseline pain and physical function. Very high disease activity may limit pts’ ability to achieve low disease activity. The identification of distinct trajectory groups could be used to develop personalised treatment optimisation algorithms incorporating clinical and molecular phenotypes. References [1]Barnabe C, et al. PLoS One2015;10:e0135327. [2]Nagin DS. In: Handbook of Quantitative Criminology. New York, NY. Springer 2010:53–67. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by R Knight of CMC and funded by Pfizer Inc. Disclosure of Interest: V. Bykerk Grant/research support from: Amgen, BMS, Genentech, UCB, Consultant for: AbbVie, Amgen, BMS, Gilead, Pfizer Inc, Sanofi-Regeneron, UCB, R. van Vollenhoven Grant/research support from: AbbVie, Amgen, BMS, GSK, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, AstraZeneca, Biotest, BMS, Celgene, Crescendo, Eli Lilly, GSK, Janssen, Merck, Novartis, Pfizer Inc, Roche, UCB, Vertex, C. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Keystone Grant/research support from: AbbVie, Amgen, BMS, Eli Lilly, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, BMS, Eli Lilly, Pfizer Inc, Roche

Background Little in-depth qualitative research has been conducted to investigate reasons for rheumatoid arthritis (RA) patient (pt) preferences for different modes of treatment administration. An understanding of pt preference can help physicians personalise therapy recommendations. Objectives To describe potential RA pt preferences for RA treatment modes and reasons for these preferences. Methods Pt demographic information was obtained at screening alongside qualitative interviews conducted using a semi-structured interview guide among adult RA pts in the US, UK, France, Germany, Italy, Spain, Switzerland and Brazil who were currently taking a DMARD (biologic or non-biologic). A 100-point allocation task was used to evaluate the strength of preference (0–100; 100=strong) across 4 treatment modes: oral (OR; once daily), self-injection (SI; weekly), clinic-injection (CI; weekly) and infusion (INF; monthly). Transcripts were developed in English; ATLAS.ti software (v7.5) was used for qualitative coding and analysis. Results 100 interviews (30 US; 10 in each of 7 other countries) were conducted (female: 75.0%; mean age: 53.9 years; mean time since diagnosis: 11.6 years). Current RA medication mode included OR (60.0%), injection (57.0%) and INF (14.0%); 79.0% and 37.0% of pts had experience with injection and INF medications, respectively; 31.0% of pts were taking a combination of biologic and non-biologic DMARDs. Among the 4 treatment modes, OR was allocated the highest mean (standard deviation [SD]) preference points (47.3 [33.1]) and the greatest percentage of pts with a 1st choice rank (57.0%); this was followed by SI (29.7 [27.7]; 29.0%), INF (15.4 [24.6]; 16.0%) and CI (7.5 [14.1]; 2.0%). Preferences by country suggested that the mean points allocated to OR were greater in the US vs other countries. Across all pts and treatment modes, 56.0% of pts had a ‘strong’ 1st choice preference (ie, a pt allocation ≥the mean pts across the 1st ranked choices [70]); of these pts, the majority chose OR (62.5%; SI: 23.2%; INF: 10.7%; CI: 3.6%). Speed of administration was among the most common reasons for choosing OR or SI as a 1st choice, together with ease of administration (OR) and frequency of dosing (SI; table 1). Difficulty remembering was the most common reason for not choosing OR and avoidance of pain was the most common reason for not choosing SI as a 1st choice. Conclusions More pts preferred OR as an RA treatment mode, followed by SI. Rationales for preference included ease of use, concerns about drug interactions, dosing frequency, feelings of control and avoidance of pain and needles. While 56.0% of pts felt strongly about their 1st choice preference, nearly half did not and may be receptive to and benefit from discussions with their healthcare professional and/or pt support groups about RA treatment mode options. Acknowledgements Study sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest P. Taylor Grant/research support from: Celgene, Eli Lilly, UCB Pharma, Consultant for: AbbVie, Biogen, Eli Lilly, Galapagos, Janssen, Merck, Pfizer Inc, Roche, Sandoz, Sanofi, UCB Pharma, N. Betteridge Consultant for: Eli Lilly, Grunenthal, Janssen, Pfizer Inc, Roche, Sanofi Genzyme, T. M. Brown Consultant for: Pfizer Inc, Employee of: RTI-HS, J. Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Kivitz Consultant for: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, Speakers bureau: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, C. Zerbini Grant/research support from: Amgen, Celltrion, Eli Lilly, GSK, Merck, Novartis, Pfizer Inc, Sanofi, Consultant for: Eli Lilly, Pfizer Inc, Sanofi, D. Whalley Consultant for: Pfizer Inc, Employee of: RTI-HS, O. Olayinka-Amao Consultant for: Pfizer Inc, Employee of: RTI-HS, C. Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Ponce de Leon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

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.

Objective. To compare the efficacy and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), as monotherapy and combined with disease-modifying antirheumatic drugs (DMARDs) versus biological DMARDs (bDMARDs) and other novel DMARDs for second-line moderate-to-severe rheumatoid arthritis (RA) patients by means of a systematic literature review (SLR) and network meta-analysis (NMA). Methods. MEDLINE®, EMBASE®, and Cochrane Central Register of Controlled Trials were searched to identify randomized clinical trials (RCTs) published between 1990 and March 2015. Efficacy data based on American College of Rheumatology (ACR) response criteria, improvements in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 6 months, and discontinuation rates due to adverse events were analyzed by means of Bayesian NMAs. Results. 45 RCTs were identified, the majority of which demonstrated a low risk of bias. Tofacitinib 5 mg twice daily (BID) and 10 mg BID monotherapy exhibited comparable efficacy and discontinuation rates due to adverse events versus other monotherapies. Tofacitinib 5 mg BID and 10 mg BID + DMARDs or methotrexate (MTX) were mostly comparable to other combination therapies in terms of efficacy and discontinuation due to adverse events. Conclusion. In most cases, tofacitinib had similar efficacy and discontinuation rates due to adverse events compared to biologic DMARDs.

Summary Background Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. Methods We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28 Findings At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06–28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45–34·92]; p Interpretation In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. Funding Pfizer.

Background The detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials. Methods Data were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn. Results The analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline. Conclusions A trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data. Trial registration Clinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009) Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1106-y) contains supplementary material, which is available to authorized users.

Objective Tofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)–based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies. Methods In all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment. Results A total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18–22% using the DAS28-4(CRP), 5–10% using the DAS28-4(ESR), 4–7% using the SDAI, 5–6% using the CDAI, and 2–7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP). Conclusion Although tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.

OBJECTIVE: To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX.METHODS: In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep).RESULTS: At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab.CONCLUSION: Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo.

To evaluate 12-month treatment patterns, healthcare resource use (HCRU), and costs for patients with rheumatoid arthritis (RA), following initiation of index TNF inhibitors (TNFi) and subsequent biologic DMARDs (bDMARDs).This was a retrospective cohort analysis of adults with RA newly initiating TNFi in the Truven Marketscan Commercial Claims and Encounters and Medicare Supplemental Databases during 2010-2013. A sub-group of patients who switched to a bDMARD within 12 months post-index and within 180 days of last index TNFi were subsequently evaluated over 12 months. TNFi/bDMARD treatment patterns were characterized as: continuers, no gap180 days in prescription/administration of index TNFi; discontinuers, gap180 days; switchers, initiated new bDMARD. Concomitant conventional synthetic DMARD use, co-morbid chronic illnesses, and RA severity were assessed. All-cause/RA-related HCRU and costs were evaluated 12 months post-index.Of 9567 identified patients, 67.2%, 17.3%, and 15.4% were continuers, discontinuers, and switchers, respectively. Switchers had the highest 12-month unadjusted mean all-cause costs of $34,585 vs $33,051 for continuers (p = 0.1158) and $24,915 for discontinuers (p 0.0001; discontinuers vs continuers, p 0.0001). RA-related costs comprised 82.8%, 31.4%, and 85.7% of total costs for continuers, discontinuers, and switchers, respectively. Of 764 switchers, 68.2% switched to alternative TNFi (cyclers), the rest to non-TNFi bDMARDs; 36.7% of patients who switched to TNFi switched again (to third-line bDMARD) vs 27.6% (p = 0.0313) of those who switched to non-TNFi bDMARDs. Switchers to non-TNFi bDMARDs had higher mean 12-month all-cause costs of $76,580 compared with $50,689 for switchers to alternative TNFi (p 0.0001); biologic-administration visits comprised 78.8% of the greater total RA-related costs of switchers to non-TNFi bDMARDs.Real-world TNFi discontinuation/switching rates correspond to randomized controlled trial non-response rates. TNFi cycling is common and associated with an increased likelihood of switching to third-line bDMARD. Switching to non-TNFi bDMARDs was associated with higher costs, mostly attributed to in-office administrations.

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.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).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, P0.001 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; P0.001). 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.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.).

Objectives:To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor α inhibitor.Methods:Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks’ follow-up. The patient’s assessment of arthritis pain (pain), patient’s assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded.Results:At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (⩾0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components.Conclusions:CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Objective To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. Methods Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. Results By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550–treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04–0.06 mg/dl) were seen in all CP-690,550 treatment arms. Conclusion Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.

Objective.To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA).Methods.Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments.Results.Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66–3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs.Conclusion.Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.

BACKGROUND Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING 114 centers in 19 countries. PATIENTS 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE Pfizer.

Objectives To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. Methods In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). Results PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. Conclusions Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. Trial registration number NCT01039688.

Background Tofacitinib is an oral JAK inhibitor for the treatment of RA. Limited real-world data exist comparing tofacitinib with biologic DMARDs (bDMARDs) in biologic-experienced (BE) RA patients (pts). Objectives To compare pt characteristics, treatment patterns and costs in BE RA pts receiving tofacitinib vs ADA, ETN and ABA using US claims data. Methods This retrospective cohort study included pts aged ≥18 years with RA (ICD9: 714.0x–714.4x; 714.81) and ≥1 tofacitinib (identified first) or bDMARD claim in the Truven MarketScan® Commercial and Medicare Supplemental healthcare claims database (01/11/2012–31/10/2014). Pts were continuously enrolled for ≥12 months (mos) pre- /post-index and had 1 bDMARD pre-index (due to greater imbalance in number of tofacitinib/bDMARD pts with ≥2 prior bDMARDs). Monotherapy was defined as absence of select conventional synthetic DMARDs within 90 days post-index. Outcomes were treatment persistence (index refills without a 60-day gap after prescription/administration days9 supply expiration), adherence (proportion of days covered [PDC]), and 12-mo pre-/post-index RA-related costs. Adjusted analyses were performed using generalized linear models, which included demography, disease status/duration and pre-index therapy variables; 12-mo pre-index costs were included for cost-related dependent variables. Results 392 tofacitinib, 178 ADA, 118 ETN and 191 ABA pts met selection criteria. 12-mo pre-index bDMARD use was most common for tofacitinib (78%) vs ADA (60%), ETN (49%) and ABA (48%) pts (all p Conclusions More BE pts started tofacitinib vs ADA, ETN and ABA after recent (prior 12 mos) bDMARD use; BE tofacitinib pts had the highest proportion of monotherapy use. Persistence and adherence were at least similar for tofacitinib and bDMARD pts. Tofacitinib pts had lower adjusted RA-related total costs post-index vs bDMARD pts. Acknowledgement Study sponsored by Pfizer Inc. Editorial support provided by K Munn of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Harnett Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Gerber Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Koenig Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy.In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of2.6. The most common treatment-emergent adverse events occurring in10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed.In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.

Objective To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. Methods In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. Results Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). Conclusion Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

Background Biologic DMARDs (bDMARDs) are used to treat patients (pts) with moderate to severe rheumatoid arthritis (RA). Pts may experience clinical benefits from treatment with bDMARDs alone or with a conventional synthetic DMARD (csDMARD). Objectives To assess treatment patterns and healthcare resource use (HCRU) after prescription/administration of a bDMARD alone or with a csDMARD. Methods In this retrospective cohort analysis, pts aged ≥18 years (yrs) with an RA diagnosis (ICD9: 714.xx) who were prescribed/administered a DMARD (2007–2011) were selected from de-identified US electronic health records (EHR; Humedica). Index date was date of first prescription/administration for a bDMARD (adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, anakinra, tocilizumab). Pts did not receive bDMARDs for ≥6 months pre-index and were followed for ≥1 yr post-index. Pts were classified by index biologic monotherapy (Bmono) or combination therapy with bDMARD and csDMARD (B+CScombo; based on methotrexate, leflunomide, sulfasalazine, hydroxychloroquine at index). Regression analyses for switch (new bDMARD/csDMARD prescription/administration and no index drug for ≥120 days) and RA-related costs were assessed controlling for differences in pt demographics/characteristics. RA-related costs were derived from a pt subset with linked Optum claims data and applied to RA visits and pharmacy use in EHR. Results Of 2119 pts initiating a bDMARD, 70.6% received Bmono and 29.1% received B+CScombo; 0.2% had ≥2 biologics. Pt characteristics and treatment patterns are presented in Table 1. Mean age and percentage of females were similar for Bmono and B+CScombo pts. Compared with B+CScombo pts, Bmono pts were more likely to be treated by a rheumatologist, had a higher Deyo-Charlson Co-morbidity Index score and were more likely to have cardiovascular disease, hyperlipidaemia, hypertension and renal disease. Most Bmono and B+CScombo pts were prescribed a TNF inhibitor (TNFi). During 1-yr follow-up (FU), B+CScombo pts were less likely to switch index regimen vs Bmono pts (OR 0.37; 95% CI 0.27, 0.51; p Conclusions In this analysis of EHR data characterising bDMARD prescriptions/administrations in pts with RA, 70.6% received Bmono, and had a greater prevalence of co-morbidities and were more likely to be treated by a rheumatologist vs B+CScombo pts. B+CScombo pts were less likely to switch index regimen in 1-yr of FU and had lower RA-related medical HCRU but greater total costs vs Bmono pts. High prevalence of Bmono use may be due to a stricter concomitant csDMARD definition or the data source, which included specialties other than rheumatology. Acknowledgements This study was sponsored by Pfizer Inc. Editorial Support was provided by Karen Irving at Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Harnett Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Gerber Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Wiederkehr Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., E. Mahgoub Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., G. Wallenstein Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Koenig Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Background Tumour necrosis factor inhibitors (TNFi) have transformed the management of rheumatoid arthritis (RA). However, 28–41% of patients (pts) with RA receiving TNFi in clinical trials do not achieve an ACR20 response; 1 inferior outcomes are usually observed when used without conventional synthetic DMARDs (csDMARDs). 2 Objectives To evaluate 12-month (mo) treatment patterns, healthcare resource use (HCRU) and costs for pts with RA after initiation of index TNFi and switch from index TNFi to second-line biologic agent. Methods This was a retrospective cohort analysis of pts aged ≥18 years with ≥2 outpatient or 1 inpatient visits for RA (ICD-9 code: 714.xx) who initiated TNFi in a US claims database (Truven Marketscan® Commercial Claims and Encounters and Medicare Supplemental Databases; 2010–2013). Pts with another inflammatory disease diagnosis of interest or who had pre-index biologic agent or >1 biologic agent within 14 days (d) were excluded. Treatment patterns were characterised by start of non-index biologic agent (switchers), gap >180 d between index prescription/administration and no other biologic agent (discontinuers) or no gap >180 d and no other biologic agent (continuers). Treatment patterns and all-cause/RA-related HCRU and costs were assessed over 12 mos post-index and in a subset of switchers within 180 d of last index TNFi prescription/administration who had another 12 mos continuous enrolment post-switch. Results 9567 pts initiated TNFi, 44.6% without csDMARD. During follow-up (FU), 67.2% of pts were continuers, 17.3% discontinuers and 15.4% switchers (Figure). Switchers had greatest unadjusted 12-mo mean all-cause total costs ($34585) vs continuers ($33051) and discontinuers ($24915); 85.7%, 82.8% and 31.4%, respectively, of total costs were RA-related. Most of the 12-mo mean RA-related total cost ($24319) for all pts was due to prescriptions (74.4%) and outpatient visits (23.6%). Of 764 switchers with 12 mos continuous enrolment post-switch, 68.2% switched to alternative TNFi and 31.8% to non-TNFi biologic agent. Overall, 36.7% of pts who switched from index TNFi to second-line TNFi switched again during 12 mos of FU vs 27.6% of pts who switched from index TNFi to non-TNFi biologic agent (p=0.0134; Figure). Pts who switched to non-TNFi biologic agent had greater unadjusted 12-mo mean all-cause total costs ($76580) vs those who switched to an alternative TNFi ($50689). RA-related costs accounted for 58.4% and 54.3% of total costs for pts who switched to non-TNFi biologic agent and alternative TNFi, respectively. Biologic administration visits accounted for 78.8% ($14205) of the greater total RA-related costs of pts who switched to non-TNFi biologic agent vs alternative TNFi. Conclusions In a US claims database, a large proportion of pts initiated TNFi without csDMARD. Real-world TNFi discontinuation/switch rates were similar to previous non-response rates. 1 Pts who switched from TNFi to non-TNFi biologic agents were less likely to switch again but had greater costs overall, mostly due to biologic administration visits. References Agarwal SK et al. J Rheumatol 2008; 35: 1737-1744. Emery P et al. Ann Rheum Dis 2013; 72: 1897-1904. Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by Karen Irving at Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Harnett Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Wiederkehr Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Gerber Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Koenig Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bourret Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Background Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To compare the effects of twice daily (BID) tofacitinib 5 mg and 10 mg monotherapy versus methotrexate (MTX) on patient-reported outcomes (PROs) in the 24-month Phase 3, randomised, double-blind, parallel-group ORAL Start study (NCT01039688) in MTX-naive patients. Results from a 12-month interim analysis have been presented previously [1,2] here we present the final analysis at 24 months. Methods MTX-naive patients with moderate-to-severe active RA were randomised 2:2:1 to receive tofacitinib 5 mg (n=373) or 10 mg BID (n=397), or MTX (n=186) titrated from 10 mg per week to 20 mg per week by Week 8. Secondary PRO endpoints included the mean change from baseline in: Patient Global Assessment of arthritis (PtGA; Visual Analogue Scale [VAS]), pain (VAS), physical function (Health Assessment Questionnaire-Disability Index; HAQ-DI), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale; FACIT-F), and health-related quality of life (HR-QoL; Short Form 36 version 2, acute; SF-36). Analyses used a linear mixed-effect model with baseline values as covariates in the full analysis set (all randomised patients who received ≥1 dose of study drug and had ≥1 post-baseline measurement). Least squares (LS) mean changes from baseline (±standard error [SE]) and proportions of patients reporting improvements ≥minimum clinically important differences (MCID; no imputation for missing data) in PROs at Month 24 are presented. P-values presented here are with no correction for type I error inflation. Results A total of 658 patients completed the 24-month study (266, 286, and 106 in the tofacitinib 10 mg and 5 mg and MTX groups, respectively). Over 24 months, significantly (p Conclusions In this Phase 3 trial in MTX-naive patients with RA, tofacitinib 5 and 10 mg BID monotherapy significantly improved multiple PROs over 24 months compared with MTX. References Lee EB et al. Arthritis Rheum 2012; 64 (Suppl 10): S1049. Strand V et al. Ann Rheum Dis 2013; 72: 252-253. Acknowledgements Writing support was provided by Erin Bekes PhD, of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest R. Alten Grant/research support: Pfizer Inc, Speakers bureau: Pfizer Inc, V. Strand Consultant for: Pfizer Inc, R. Fleischmann Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, T. Koncz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Zwillich Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Wallenstein Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.3168

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator in rheumatoid arthritis. Objectives To assess efficacy of tofacitinib 5 and 10 mg twice-daily (BID) using disease activity scores (DAS) across a wide range of baseline (BL) values. Methods Demographic and BL disease characteristics of patients (pts) in five Phase 3 studies (monotherapy: NCT00814307; background DMARD: NCT00960440, NCT00847613, NCT00856544, NCT00853385) were similar. Data were pooled, and BL DAS values based on 28-joint counts using C-reactive protein (DAS28-3(CRP)) were divided into four groups (≤25th, >25th-50th, >50th-75th, >75th percentiles); for each, mean change from BL, proportion of pts improving by ≥1.2 from BL, and proportions of pts with values ≤3.2 and Results 3072 pts (PBO, 673; 5 mg, 1200; 10 mg, 1199) were divided into groups using BL DAS28-3(CRP) quartiles: ≤4.71 (Q1); >4.71-5.34 (Q2); >5.34-6.01 (Q3); >6.01 (Q4). In each group, both tofacitinib doses demonstrated clinically significant improvements in DAS28-3(CRP)-based analyses compared with PBO. Pts with higher BL values had greater mean reductions in DAS, with correspondingly larger differences from PBO. All BL groups showed numerical benefit of 10 mg BID over 5 mg BID across all DAS28-3(CRP)-based analyses and the proportions of pts achieving various DAS thresholds were 2-13 percentage points greater with 10 mg BID vs 5 mg BID. Data for Q1 and Q4 are shown in Table 1. Conclusions Across a range of BL disease activities, tofacitinib was consistently efficacious at both doses in reducing DAS28-3 (CRP) vs PBO. All groups showed numerical benefit in efficacy of 10 mg BID over 5 mg BID across all measures of DAS28-3 (CRP); the magnitude of benefit of 10 mg BID over 5 mg BID appeared to be independent of BL status. As expected, pts in the lowest quartile were more likely to achieve DAS28-3(CRP) ≤3.2 and Disclosure of Interest R. Fleischmann Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Zwillich Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mebus Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA). Objectives To evaluate the cardiovascular (CV) event rates and changes in blood pressure (BP) in the tofacitinib Phase 3 (P3) and long-term open-label extension (LTE) studies. Methods Five P3 studies in patients (pts) with inadequate response to nonbiologic/biologic disease-modifying anti-rheumatic drugs (DMARDs) and 2 LTE studies were included. Tofacitinib was administered as monotherapy or with background nonbiologic DMARDs, predominantly methotrexate. One P3 study included adalimumab (ADA) as active control. An independent CV Safety Endpoint Adjudication Committee performed blinded adjudication of deaths, potential major adverse CV events (MACE), and events of congestive heart failure (CHF). MACE was defined as CV death and non-fatal CV events. Results: MACE IRs (per 100 pt-y) in placebo (PBO) and tofacitinib groups in P3 were low. IR in the LTE studies in the tofacitinib All Dose group (0.19) was lower than in P3 (0.57). IRs of CHF in tofacitinib were low. In P3, mean changes from baseline at Month 3 for systolic and diastolic BP, respectively, were -0.1 mmHg and -0.8 mmHg for PBO and -0.2 and 0.3 mmHg for tofacitinib. Mean BP changes at Months 6 and 12 and in the LTE studies remained stable. Conclusions Incidence rates of MACE were similar across groups in P3 with lower rates in LTE, suggesting no increased risk over 3 years of follow up. Tofacitinib was not associated with clinically meaningful increases in BP. Although the number of events have been fewand longer observation periods are warranted, CV risk does not appear to be increased with tofacitinib treatment and rates of CV events are consistent with those observed among patients with RA of similar disease severity.1-3 References Solomon DH et al. Circulation 2003; 107: 1303-1307; Solomon DH et al. Ann Rheum Dis 2006; 65: 1608-1612; 3. Nicola PJ et al. Arthritis Rheum 2006; 54: 60-67. Disclosure of Interest C. Charles-Schoeman Grant/Research support from: Pfizer Inc., Consultant for: Pfizer Inc., P. Wicker Consultant for: Pfizer Inc., U. Sechtem Consultant for: Pfizer Inc., M. Gonzalez-Gay Consultant for: Pfizer Inc., S. Wood Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., M. Boy Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Geier Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Soma Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Background Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To assess the efficacy of tofacitinib monotherapy in patients (pts) with early RA (eRA), as defined by disease duration (i.e., time since diagnosis) 1 Methods Pts were randomised 2:2:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or MTX. Post-hoc subgroup analyses from the planned 12-Mo interim analyses of signs and symptoms (rates of ACR20, 50 and 70; DAS28-4[ESR] [DAS]-defined remission and low disease activity [LDA] [DAS Results 409 of 952 pts receiving treatment had a disease duration Image/graph Conclusions Tofacitinib monotherapy significantly inhibited progression of structural damage and improved RA signs and symptoms and physical functioning vs MTX, in MTX-naive pts with early as well as established disease. References Lee EB et al Arthritis Rheum 20;64(10[supplement]):S1049. Disclosure of Interest T. J. Huizinga Grant/research support from: Dutch Arthritis Foundation, The Dutch NIH en the EU, Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boeringher, Takeda, Eli Lilly, Employee of: LUMC, Paid instructor for: Roche, Pfizer, Speakers bureau: Roche, Pfizer, R. Fleischmann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Wilkinson Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Koncz Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Benda Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Background Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To compare the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily (BID) relative to biologic disease-modifying antirheumatic drugs (DMARDs) in the treatment of RA patients with a prior inadequate response to tumour necrosis factor inhibitors (TNFi-IR). Methods Five randomised controlled trials (RCTs) evaluating tofacitinib combined with methotrexate (MTX) and various biologic DMARDs combined with non-biologic DMARDs, were identified through a systematic literature search. 1-9 Individual study efficacy data, based on American College of Rheumatology (ACR) responses and change from baseline in Health Assessment Questionnaire (HAQ) at Week 12, were combined with network meta-analyses. Comparisons of safety were based on rates of treatment withdrawal due to adverse events (AEs). Results The RCT arms of interest included 1946 patients: mean ages 52.2–55.4 years; mean disease duration 9.6–12.6 years; mean swollen and tender joint counts 14–23.4 and 26–33.9, respectively. Tofacitinib 5 mg and 10 mg BID combined with MTX showed relative risk estimates of ACR responses comparable to abatacept, golimumab, rituximab and tocilizumab combined with nonbiologic DMARDs at Week 12 (Table). Based on HAQ scores, tofacitinib was more efficacious than golimumab, and comparable with rituximab. Withdrawal rates from trials due to AEs were comparable. Image/graph Conclusions Analyses of available RCTs revealed that tofacitinib has similar efficacy in improving signs and symptoms as biologic DMARDs for TNFi-IR patients. Further analyses are needed to explore factors that may impact the magnitude of the placebo response and factors that could confound comparative treatment effects in RA management (e.g. starting DMARD dose, duration and number of prior TNFi). Also, safety comparisons over a longer time period would be more informative. References Westhovens R et al. Rheumatology 2006; 45: 1238–46; Genovese MC et al. N Engl J Med 2005; 353: 1114–23; Smolen JS et al. Lancet 2009; 374: 210–21; Emery P et al. Ann Rheum Dis 2008; 67: 1516–23; Keystone E et al. Arthritis Rheum 2008; 59: 785–93; Keystone E et al. Ann Rheum Dis 2009; 68: 216–21; Cohen SB et al. Arthritis Rheum 2006; 54: 2793–806; Cohen SB et al. Ann Rheum Dis 2010; 69: 1158–61; Burmester GR et al. Lancet 2013; Jan 4 [Epub ahead of print] Disclosure of Interest M. Vieira Consultant for: Pfizer Inc., G. Wallenstein Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Koncz Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Jansen Consultant for: Pfizer Inc.

Background Tofacitinib is a novel oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives Describe efficacy and safety for adalimumab (ADA) patients (pts) transitioning to tofacitinib open label extension (OLE) without washout. Methods In the Phase 3 randomised controlled trial (RCT, NCT00853385) ORAL Standard, pts on background MTX received tofacitinib 5 mg BID, tofacitinib 10 mg BID, ADA 40 mg sc injections (Q2 Wk), placebo (PBO) to tofacitinib 5 mg BID, or PBO to tofacitinib 10 mg BID (4:4:4:1:1). Primary results were reported. 1 Eligible pts from the RCT were permitted to enrol in an OLE receiving tofacitinib 10 mg BID without washout (last RCT ADA dose to first OLE tofacitinib dose ≤1 Wk). In this post-hoc analysis, results are described for ADA pts 4.5 months (Mo) before and at end of the RCT, and 4.5 Mo after transition to tofacitinib in OLE. Data for tofacitinib 10 mg BID during RCT and OLE are shown at the same time points. Results 145 of 204 pts randomised to ADA were eligible and enrolled in OLE; 125 started tofacitinib without washout. There were 8 (6.4%) discontinuations during the first 4.5 Mo of OLE (3 drug-related AE, 1 unrelated AE, 1 pregnancy, 1 death, 2 other reasons). 148 of 201 pts randomised to tofacitinib 10 mg BID were eligible and enrolled in OLE; 124 took their first dose of tofacitinib in the OLE ≤1 Wk after their last dose of tofacitinib in the RCT. There were 9 discontinuations in the first 4.5 Mo of OLE (1 drug-related AE, 2 unrelated AE, 6 other reasons). ACR20 response rate in ADA to tofacitinib pts (N= 124) was 74.2% at 4.5 Mo before end of RCT, 76.6% at end of RCT, and 90.5% at 4.5 Mo after transition to tofacitinib. ACR50 response rates (44.4%, 50.8%, 65.5%) and ACR70 response rates (16.1%, 21.0%, 36.2%) at the same time points showed a similar pattern. Mean change from baseline in HAQ-DI was -0.55, -0.60, and -0.70 at the same time points. Results in tofacitinib to tofacitinib pts were similar at the same time points and showed a similar pattern of increases from RCT to OLE. Image/graph Conclusions Changing directly from ADA in RCT to tofacitinib in OLE resulted in sustained clinical response, with numerical improvements in ACR 20, 50, and 70 response rates and mean change in HAQ-DI from baseline. Safety-related events appeared to increase post-transition from ADA to tofacitinib; however, similar increases were seen in pts treated with tofacitinib in the RCT after they transitioned to OLE tofacitinib. The increase in safety-related events in both groups suggests that the increase was not simply the result of overlapping immunomodulatory effects of ADA and tofacitinib. References R.F. van Vollenhoven et al. N Engl J Med 2012; 367: 508-519. Disclosure of Interest M. Genovese Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer Inc, Roche, UCB, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Zwillich Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, B. Benda Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Phase (P) 2 and 3 studies demonstrated tofacitinib is effective and has a manageable safety profile as both monotherapy and in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs). Objectives To assess whether there are relative differences in efficacy or safety between mono- and combination therapy in RA patients (pts) with an inadequate response (IR) to DMARDs. Methods Pooled tofacitinib data from three combination therapy P3 studies (≈2100 pts) (ORAL Sync, Standard and Scan) were compared to one monotherapy P3 study (≈600 pts) (ORAL Solo), all DMARD IR pts. The proportion of pts achieving ACR20, 50 and 70, DAS28-4(ESR) (DAS)-defined remission and low disease activity (LDA) (DAS Results Demographic and baseline (BL) disease characteristics of pts across the four studies were generally similar, except geographic region of enrolment; the highest level of mean BL values of joint counts, CRP, HAQ and DAS were seen in the monotherapy study (DAS 6.69 vs 6.29-6.46 with monotherapy vs combination therapy, respectively). In the efficacy and safety analyses (Figure), point estimates for the ORs ranged from 1.0–1.3 for rates of ACR20/50/70, LDA, HAQ and AEs, 1.9 for DAS-defined remission and 0.5 for d/c due to AEs and SAEs. Across all endpoints, the CIs included 1, indicating similar response and risk rates for tofacitinib mono- and combination therapy. Image/graph Conclusions In this meta-analysis, no statistically significant differences in efficacy or safety endpoints were observed with tofacitinib administered as monotherapy or in combination with DMARDs in DMARD IR pts. A randomised clinical trial directly comparing mono- and combination therapy is warranted to confirm these results. Disclosure of Interest E. Keystone: None Declared, R. Fleischmann: None Declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, J. Kremer: None Declared, D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., C. Mebus Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., G. Wallenstein Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Benda Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Krishnaswami: None Declared