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Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo.Data were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported.We analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%).Non-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks.ClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.Tofacitinib is a medicine that can be taken by patients to treat rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Serious side effects that might occur in patients taking tofacitinib are more frequently discussed than the mild, non-serious side effects that patients might consider to be more of a ‘nuisance’, which often occur shortly (3 months) after starting treatment. Here we looked at patients with RA or PsA who were taking tofacitinib or placebo (no medicine) during clinical trials, to find out how often they had certain non-serious side effects, how long they lasted, and whether they caused the patients to stop taking their medication. A similar number of patients with RA or PsA taking tofacitinib or placebo had non-serious side effects. The most common non-serious side effects in patients taking tofacitinib were a headache and diarrhea. The most common non-serious side effects in patients taking placebo (no medicine) were indigestion, a feeling of sickness, and/or headache. Most non-serious side effects were mild or moderate and stopped within about 4 weeks. Fewer than one in every 100 patients with RA, and no patients with PsA, stopped taking their medication because of non-serious side effects. Most patients who stopped taking their medication did so due to a feeling of gastrointestinal (stomach) discomfort.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal. Methods: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5–20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov ( NCT01976364) and is complete. Findings: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI –0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [–0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy). Interpretation: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety.

Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). We report the interim safety, tolerability, and efficacy of tofacitinib in PsA patients in OPAL Balance, a 3-year, open-label, long-term extension study (data cut-off: August 2017; database not locked, data may change). Methods Eligible patients from two phase (P) 3 (P3) tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered OPAL Balance ≤ 3 months after completing the P3 study or discontinuing for reasons other than study-drug-related adverse events (AEs). Patients received open-label tofacitinib 5 mg twice daily (BID), with adjustments to 10 mg BID permitted post-month (M) 1. Certain concomitant conventional synthetic disease-modifying antirheumatic drugs were allowed. Primary endpoints were incidence/severity of AEs and laboratory abnormalities, and changes from baseline in laboratory parameters (reported up to M36 and M30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30. Results A total of 686 patients were treated; at data cut-off, 68.2% remained in the study. Mean (range) treatment duration was 641 (1–1032) days; total treatment duration was 1153.2 patient-years. By M36, 79.6, 13.8, and 8.6% of patients reported AEs, serious AEs, and discontinuations due to AEs, respectively. Five deaths occurred; one within the risk period (incidence rate [IR; patients with events/100 patient-years] 0.1). IRs for AEs of special interest were: all (non-serious and serious) herpes zoster, 1.7; serious infections, 0.9; opportunistic infections, 0.3 (all disseminated/multi-dermatomal herpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0; major adverse cardiovascular events, 0.3; pulmonary embolisms, 0.1; and arterial thromboembolisms, 0.4. No patients had deep vein thrombosis. Alanine aminotransferase and aspartate aminotransferase levels were elevated ≥ 3-fold the upper limit of normal in 4.0 and 2.2% of patients, respectively. Changes in laboratory parameters were generally stable over time, although lymphocyte counts decreased slightly. Efficacy was maintained through M30. Conclusions In this interim analysis of OPAL Balance, tofacitinib safety and efficacy in patients with PsA appeared to be consistent with those of the P3 studies. Efficacy was maintained over time. Trial Registration ClinicalTrials.gov identifier: NCT01976364. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00209-4) contains supplementary material, which is available to authorized users., Plain Language Summary In many countries, tofacitinib is an approved medicine that can be used to treat psoriatic arthritis (PsA). In the study reported here (OPAL Balance), adult patients with PsA took tofacitinib for up to 3 years. We report a planned interim analysis, i.e., an analysis of information collected before the study finished. This early information suggests that the safety of tofacitinib, and how well it improved symptoms and quality of life (efficacy), was similar in this long study as in shorter studies. Information from the finished study will be reported later. OPAL Balance started on 17 February 2014. This interim analysis includes information collected by 31 August 2017. Before joining, patients had finished a 6-month or 12-month tofacitinib study (OPAL Broaden or OPAL Beyond). Patients in OPAL Balance took a 5 mg tofacitinib pill twice a day, but if PsA symptoms did not improve after 1 month, they could take a 10 mg pill twice a day. They could also take other medicines (including methotrexate or corticosteroids). Of the 686 patients who took tofacitinib, 546 (80%) experienced side effects over 3 years. These were considered serious for 95 patients (14%) and caused 59 patients (9%) to leave the study. Five patients died from causes not related to tofacitinib. Known tofacitinib side effects, including shingles (herpes zoster), serious infections (needing hospitalization), infections in patients with weakened immune systems, cancer, heart (cardiovascular) problems, and vein blockages (embolisms), were each reported by fewer than 20 patients. Most blood test results and tofacitinib efficacy were stable over 2.5 years. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00209-4) contains supplementary material, which is available to authorized users.

BackgroundAnkylosing spondylitis (AS) impacts quality of life. We assessed patient-reported outcomes (PROs), pain, fatigue, health-related quality of life (HRQoL) and work productivity in a phase III trial of tofacitinib.MethodsAdults with AS and with inadequate response/intolerance to ≥2 non-steroidal anti-inflammatory drugs received tofacitinib 5 mg twice daily or placebo for 16 weeks. Afterwards, all received open-label tofacitinib until week 48. Change from baseline to week 48 was determined for PROs: total back pain; nocturnal spinal pain; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) overall spinal pain (Q2); Functional Assessment of Chronic Illness Therapy-Fatigue; BASDAI fatigue (Q1); AS Quality of Life (ASQoL); Short Form-36 Health Survey Version 2 (SF-36v2); EuroQoL-Five Dimension-Three Level health profile and Visual Analogue Scale; and the Work Productivity and Activity Impairment (WPAI) questionnaire. Improvements from baseline ≥minimum clinically important difference, and scores ≥normative values at week 16 were evaluated.ResultsIn 269 randomised and treated patients, at week 16, there were greater least squares mean improvements from baseline with tofacitinib 5 mg twice daily versus placebo in BASDAI overall spinal pain (–2.85 vs –1.34), BASDAI fatigue (–2.36 vs –1.08), ASQoL (–4.03 vs –2.01) and WPAI overall work impairment (–21.49 vs –7.64) (all pConclusionsIn patients with AS, treatment with tofacitinib 5 mg twice daily resulted in clinically meaningful improvements in pain, fatigue, HRQoL and work productivity versus placebo to week 16, which were sustained to week 48.Trial registration numberNCT03502616.

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis. Methods For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete. Findings Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794·6 days [SD 329·2] in long-term extension study, 879·0 days [396·6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48·8 years (SD 11·8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0·1 patients with events [95% CI 0·0–0·3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1·7 (1·2–2·5) for herpes zoster (non-serious and serious); 1·0 (0·6–1·6) for serious infections; 0·4 (0·1–0·8) for opportunistic infections; 0·7 (0·4–1·2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0·9 (0·5–1·5) for NMSC; 0·2 (0·1–0·6) for major adverse cardiovascular events; 0·1 (0·0–0·3) for pulmonary embolism; and 0·4 (0·1–0·8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36. Interpretation This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies.

ObjectiveTo assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).MethodsThis phase III, randomised, double-blind, placebo-controlled study enrolled patients aged ≥18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to ≥2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society ≥20% improvement (ASAS20) and ≥40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout.Results269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (pConclusionsIn adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified.Trial registration numberNCT03502616

Objectives Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses. Methods Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placebo. MIC in SPARCC SI joint and spine scores were assessed for patients with available MRI data (N = 164; 79%). Clinical endpoints at week 12, including Assessment of SpondyloArthritis international Society 20% improvement (ASAS20), were compared between patients achieving/not achieving MIC. Results A greater proportion of patients achieved MIC with tofacitinib 2, 5 and 10 mg BID vs placebo for SI joint (28.6, 38.6, 29.6 vs 11.8%) and spine scores (29.3, 36.4, 40.9 vs 11.8%). Generally, a greater proportion of patients treated with tofacitinib 2, 5 and 10 mg BID or placebo, respectively, who achieved MIC for SI joint and spine scores achieved ASAS20 (SI joint: 75.0, 88.2, 69.2, 75.0%; spine: 91.7, 85.7, 72.2, 75.0%) vs patients who did not achieve MIC (SI joint: 51.7, 84.0, 58.1, 48.3%; spine: 46.4, 85.7, 53.8, 48.3%). Numerically greater responses were seen in those patients achieving vs not achieving MIC across a range of other efficacy assessments. Conclusion Approximately one-third of tofacitinib-treated AS patients experienced clinically meaningful reductions in spinal MRI inflammation at week 12. Patients achieving MIC for MRI inflammation had greater clinical response.

Background:Ankylosing spondylitis (AS) can significantly impact quality of life. Tofacitinib is an oral Janus kinase inhibitor under investigation for the treatment of adult patients (pts) with AS. The safety/efficacy (including pt-reported outcomes [PROs]) of tofacitinib in pts with AS was assessed in a Phase 3 trial (NCT03502616).1Objectives:To evaluate the effect of tofacitinib on pt-reported pain, fatigue, overall health and work productivity in pts with active AS enrolled in the Phase 3 trial.Methods:Pts with an inadequate clinical response or intolerance to ≥2 oral NSAIDs were randomised in a double-blind fashion to tofacitinib 5 mg twice daily (BID) or placebo (PBO) for 16 weeks. At Week (W)16, all pts received open-label tofacitinib 5 mg BID up to W48. Least squares (LS) mean changes from baseline (Δ) up to W48 are reported for the following outcomes: pt assessment of nocturnal spinal pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Short Form-36 Health Survey version 2 (SF-36v2; W16 and W48 only), and Work Productivity and Activity Impairment Questionnaire (WPAI; W16 and W48 only).Results:At W16, there were greater improvements from baseline in pain (total back pain [previously published1] and nocturnal spinal pain) and fatigue (FACIT-F total score; experience and impact domain scores) with tofacitinib vs PBO (p≤0.05; Table 1); improvements were observed as early as W2. Also, improvements in SF-36v2 physical component summary (PCS) (Table 1), and physical functioning, role-physical, bodily pain, general health and social functioning domains (Figure 1) were greater with tofacitinib vs PBO at W16 (p≤0.05). Similarly, improvements in WPAI scores at W16 were greater with tofacitinib vs PBO (p≤0.05), except for % work time missed (Table 1). Improvements with tofacitinib continued up to W48 (Table 1/Figure 1). Generally, pts receiving PBO who advanced to tofacitinib at W16 reported similar improvements after switching to tofacitinib (Table 1/Figure 1).Table 1.PROs at baseline and Δ at W16 and W48Baseline,mean (SD) [N1]Δ, W16,LS mean (SE)Δ, W48,LS mean (SE)Tofacitinib5 mg BID (N=133)PBO(N=136)Tofacitinib5 mg BIDPBOp valueTofacitinib5 mg BIDPBO→tofacitinib5 mg BIDNocturnalspinal paina6.8 (1.9)6.8 (1.9)-2.67 (0.20)-0.84 (0.20)-3.52 (0.23)-3.01 (0.23)FACIT-Ftotal scorea,b27.2 (10.7)27.4 (9.3)6.54 (0.80)3.12 (0.79)0.00089.54 (0.90)7.35 (0.89)FACIT-F experience domaina8.9 (4.3)8.7 (4.0)2.85 (0.36)1.29 (0.36)0.00074.22 (0.40)3.40 (0.40)FACIT-Fimpactdomaina18.3 (6.9)18.8 (5.9)3.68 (0.49)1.81 (0.49)0.00285.32 (0.54)3.95 (0.54)SF-36v2 PCSb,c33.5 (7.3)33.1 (7.0) [135]6.69 (0.59)3.14 (0.59)8.81 (0.720)7.39 (0.71)SF-36v2 MCSc39.4 (11.1)39.8 (12.7) [135]3.45 (0.91)2.13 (0.92)0.25297.07 (0.93)6.35 (0.92)WPAIc% activity impairment56.5 (23.4)56.0 (21.4)-19.03 (1.97)-5.63 (1.97)-27.37 (2.34)-19.77 (2.31)% work time missed9.9 (22.4) [81]11.5 (24.6) [88]-3.65 (2.66)0.88 (2.62)0.1784-8.10 (2.14)-5.79 (2.05)% impairment while working48.4 (26.3) [79]49.6 (22.2) [85]-19.83 (2.27)-6.94 (2.30)-25.35 (2.77)-23.00 (2.66)% overall work impairment50.8 (27.4) [79]53.5 (23.1) [85]-21.49 (2.51)-7.64 (2.56)-27.63 (3.01)-23.22 (2.90)aMMRMbGlobal type I error-controlled endpointcAnalysis of covariance model for W16 and MMRM for W48MCS, mental component summary; MMRM, Mixed Model for Repeated Measures; N, number of pts in full analysis set; N1, number of pts included in the analysis (if different from N); SD, standard deviation; SE, standard errorConclusion:In pts with active AS, improvements in spinal pain, fatigue, overall health and work productivity were greater with tofacitinib vs PBO at W16; improvements continued up to W48. These PRO findings support the primary efficacy results of this Phase 3 trial,1 and add to the overall understanding of the benefit/risk profile of tofacitinib in patients with AS.References:[1]Deodhar et al. Arthritis Rheumatol 2020; 72 (S10): Abs L11.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Emma Mitchell, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:Victoria Navarro-Compán Speakers bureau: AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer Inc, UCB, Grant/research support from: AbbVie, Novartis, James Cheng-Chung Wei Speakers bureau: Eli Lilly, Janssen, Novartis, Pfizer Inc, Consultant of: Eli Lilly, Novartis, Pfizer Inc, Grant/research support from: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, UCB, Filip van den Bosch Shareholder of: AbbVie, Celgene, Eli Lilly, Galapagos, Gilead, Merck, Novartis, Pfizer Inc, UCB, Marina Magrey: None declared, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dona Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Oluwaseyi Dina Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee 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, GSK, Ichnos, Inmedix, Janssen, Kiniksa, Merck, Myriad Genetics, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi, Scipher, SetPoint Medical, UCB

Background:Dactylitis, a hallmark of psoriatic arthritis (PsA), is a uniformly diffuse and sometimes painful swelling of the fingers and/or toes.1 Up to 50% of patients (pts) with PsA may experience dactylitis;1,2 as such, dactylitis is an accepted domain of PsA that should be considered in treatment decisions.3 In PsA, dactylitis typically involves feet more than hands; dactylitic joints more frequently have erosive damage, compared with non-dactylitic joints.2 There remains a need for effective therapies to treat dactylitis in pts with PsA. Improvements in dactylitis have been associated with tofacitinib, an oral Janus kinase inhibitor for the treatment of PsA.4,5Objectives:To assess the effect of tofacitinib on dactylitis by location (hands/feet) and individual digit involvement in pts with PsA.Methods:These post hoc analyses used data pooled from two Phase 3 studies (12-month OPAL Broaden [NCT01877668];5 6-month OPAL Beyond [NCT01882439]4) in pts with active PsA treated with tofacitinib 5 mg twice daily (BID; approved dose; to Month [M] 6), tofacitinib 10 mg BID (to M6) or placebo (PBO; to M3); pts were treated continuously with a single conventional synthetic disease-modifying antirheumatic drug. Pts were categorised by the presence of dactylitis at baseline (BL) in the hands and/or feet. Endpoints included change from BL in Dactylitis Severity Score (DSS),6 the number of dactylitic digits and the proportion of pts with dactylitis in individual digits at M1, M3 and M6. Descriptive statistics were generated by visit and treatment arm.Results:Data were pooled from 373 pts with DSS >0 at BL. BL characteristics, including gender, age, race, body mass index, PsA duration, BL DSS and dactylitic digits count were similar across dactylitis groups and treatment groups, except for pts with dactylitis in both the hands and feet, who had higher DSS compared to those with dactylitis in the hands or feet only, likely due to having more dactylitic digits (data not shown). Regardless of location, pts treated with tofacitinib had cumulative improvements from BL to M6 in DSS (Figure 1a) and in the number of dactylitic digits (Figure 1b); improvements in DSS were greater at M1 and M3, compared with PBO. Pts treated with tofacitinib 10 mg BID typically had numerically greater improvements in DSS, compared with pts treated with tofacitinib 5 mg BID (Figure 1a). Most pts treated with tofacitinib experienced improvement of dactylitis across all fingers and toes (Figure 1c–f); mean dactylitis presence was ≤15% at M6 in pts treated with tofacitinib for all digits. Generally, at M1 and M3, fewer pts treated with tofacitinib had dactylitis in any digit, compared with PBO (Figure 1c–f).Conclusion:Among pts with pre-existing dactylitis, treatment with tofacitinib resulted in improvements in dactylitis in hands, feet, or both, and in all digits as early as M1, and up to M6.References:[1]Kaeley et al. Semin Arthritis Rheum 2018; 48: 263-273.[2]Brockbank et al. Ann Rheum Dis 2005; 64: 188-190.[3]Coates et al. Arthritis Rheumatol 2016; 68: 1060-1071.[4]Gladman et al. N Engl J Med 2017; 377: 1525-1536.[5]Mease et al. N Engl J Med 2017; 377: 1537-1550.[6]Helliwell et al. J Rheumatol 2005; 32: 1745-1750.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Eric Comeau, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:Ana-Maria Orbai Consultant of: Eli Lilly, Novartis, Pfizer Inc, Grant/research support from: AbbVie, Eli Lilly, Horizon, Janssen, Novartis, Philip J Mease Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer Inc, Sun, UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer Inc, Sun, UCB, Philip Helliwell Paid instructor for: Janssen, Novartis, Pfizer Inc, Consultant of: Eli Lilly, Oliver FitzGerald Speakers bureau: AbbVie, Janssen, Pfizer Inc, Consultant of: Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Pfizer Inc, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Novartis and Pfizer Inc, Mohammed Bdewi Speakers bureau: AbbVie, Pfizer Inc, Dona Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rajiv Mundayat Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Pamela Young Shareholder of: Pfizer Inc, Employee of: Pfizer Inc.

Background:Tofacitinib is an oral JAK inhibitor for the treatment of psoriatic arthritis (PsA).Objectives:To assess tofacitinib 5 mg BID as monotherapy after methotrexate (MTX) withdrawal vs with continued background MTX in patients (pts) with PsA.Methods:OPAL Balance (NCT01976364) was an open-label (OL) long-term extension (LTE) study of tofacitinib in pts with PsA who participated in Phase (P)3 studies (OPAL Broaden,NCT01877668; OPAL Beyond,NCT01882439). Pts who completed ≥24 months’ tofacitinib treatment in the LTE (stable 5 mg BID for ≥3 months) and were receiving oral MTX (7.5–20 mg/week; stable for ≥4 weeks) entered the multicentre, 12-month, double-blind, MTX withdrawal substudy. Pts remained on OL tofacitinib 5 mg BID and were randomised 1:1 to receive placebo (tofacitinib monotherapy, ie, blinded MTX withdrawal) or MTX (tofacitinib + MTX; same stable doses). Primary endpoints were changes from substudy baseline (Δ) in PASDAS and HAQ-DI at Month (M)6. Secondary efficacy endpoints were assessed at all time points. Safety was assessed throughout the substudy.Results:Of 180 pts randomised, 179 were treated (tofacitinib monotherapy n=90; tofacitinib + MTX n=89). Pt characteristics were similar between treatment arms. At M6, least squares mean (LSM) (standard error [SE]) ΔPASDAS was 0.229 (0.079) for tofacitinib monotherapy and 0.138 (0.081) for tofacitinib + MTX, and LSM (SE) ΔHAQ-DI was 0.043 (0.027) and 0.017 (0.028), respectively (Figure 1); no clinically meaningful differences were observed. Efficacy and pt-reported outcomes were generally similar between treatment arms at M6 and M12 (data not shown). Rates of pts achieving minimal disease activity, and maintaining an absence of enthesitis and dactylitis, were sustained to M12 in both treatment arms (Figure 2). Adverse event rates (Table) and laboratory parameters were comparable between treatment arms, but liver enzyme elevations were more common with tofacitinib + MTX.Conclusion:No clinically meaningful differences in efficacy and safety were observed in PsA pts who received OL tofacitinib 5 mg BID as monotherapy after MTX withdrawal vs with continued MTX. Safety was consistent with previous P3 studies. The substudy was an estimation study and not powered for hypothesis testing.Table.Safety outcomes to Month 12Pts with events, n (%) AEs of special interestTofacitinib monotherapy N=90Tofacitinib + MTXN=89AE43 (47.8)41 (46.1)Serious AE4 (4.4)3 (3.4)Discontinuations due to AE3 (3.3)4 (4.5)Death00 Herpes zoster (serious/non-serious)1 (1.1)2 (2.2) Serious infection02 (2.2) Opportunistic infectiona01 (1.1) Malignancy (excl. NMSC)a1 (1.1)1 (1.1) NMSCa00 Major adverse cardiovascular eventa00 Venous thromboembolismc00 Arterial thromboembolismc1 (1.1)0 Gastrointestinal perforationa00 Interstitial lung diseaseb00Laboratory parametersdALT ≥3×ULN05 (5.6) ALT (IU/L), mean (SE)-2.7 (1.6)2.5 (1.3)AST ≥3×ULN03 (3.4) AST (IU/L), mean (SE)-1.5 (1.2)1.7 (0.8)Reviewed by independentaexternal/binternal adjudication committeecPer Standardised MedDRA Query termsdWithout regard to baseline abnormalityALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normalAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Laura C Coates: None declared, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, James Cheng-Chung Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB Pharma, Dona Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). Objectives To report the safety, tolerability and efficacy of tofacitinib in patients (pts) with active PsA from an ongoing, open-label, long-term extension (LTE) study (OPAL Balance, NCT01976364; November 2017 data-cut; database not locked). Methods Eligible pts from 2 Phase (P)3 tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered a 3 year LTE ≤3 months after completing the P3 study or discontinuing for reasons unrelated to study drug. Pts received tofacitinib 5 mg BID to Month (M)1, after which dose adjustments between 5 and 10 mg BID were permitted to improve efficacy, or for safety reasons. Pts receiving a csDMARD at P3 study entry continued the same csDMARD in the LTE. Primary endpoints were incidence and severity of adverse events (AEs) and changes from baseline (Δ) in laboratory values. Safety data are reported up to M36. Efficacy was evaluated up to M30 (when n>50) as a secondary endpoint. Results 686 pts were treated in OPAL Balance; 468 (68.2%) remained in the study at data cut-off. Mean (range) LTE tofacitinib exposure was 614 (1–1032) days. On Day 1, 675 pts (98.4%) received a csDMARD, which was discontinued in 86 pts (12.7%). To M36, 2189 AEs were reported in 546 pts (79.6%), 95 pts (13.8%) had serious AEs and 59 pts (8.6%) discontinued due to AEs. Serious infections occurred in 12 pts (1.7%), herpes zoster (HZ) in 20 pts (2.9%; 1 serious event), major adverse cardiovascular events in 5 pts (0.7%), malignancies in 24 pts (3.5%; including 12 pts with NMSC) and uveitis in 2 pts (0.3%). No AEs of gastrointestinal perforation or inflammatory bowel disease were reported. There were 5 deaths (not attributed to treatment, as assessed by the investigator) due to metastatic pancreatic carcinoma, acute cardiac failure/hypertensive heart disease, chronic obstructive pulmonary disease, pulmonary embolism and cardiovascular insufficiency. Four AEs of latent tuberculosis were reported in pts whose previously negative QuantiFERON response became positive. ALT was elevated ≥3 x ULN in 27 pts (4.0%), and AST≥3 x ULN in 15 pts (2.2%). Changes in laboratory values observed in P3 studies were generally stable in the LTE, except for a modest decrease in absolute lymphocyte count over time. Eight pts (1.2%) discontinued (protocol-mandated) due to laboratory value changes. ACR responses, ΔHAQ-DI, PASI75 response, ΔLeeds Enthesitis Index, ΔDactylitis Severity Score and ΔPain were maintained up to M30. Conclusions Over 36 months in the LTE, the safety profile of tofacitinib in active PsA pts was generally similar to that of the P3 studies. No new safety risks were identified. Efficacy across various PsA disease domains was maintained over time. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest P. Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, L. Coates Grant/research support from: AbbVie, Janssen, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer Inc, Sun Pharma, UCB, 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, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer Inc, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, J. Covarrubias-Cobos Grant/research support from: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is an oral Janus kinase inhibitor under investigation for psoriatic arthritis (PsA). Interim data (database not locked) from ≤24 months9 participation (3 years9 total treatment duration) for patients (pts) with active PsA in an ongoing, open-label, long-term extension study (LTE; NCT01976364 OPAL Balance) is reported. Objectives To evaluate the safety, tolerability and efficacy of tofacitinib in pts with active PsA. Methods Eligible pts from 2 pivotal Phase 3 tofacitinib PsA studies (NCT01877668 OPAL Broaden, NCT01882439 OPAL Beyond) could enter a 3-year LTE ≤3 months after completing the qualifying study or discontinuing for non study-drug-related reasons. Pts were to receive tofacitinib 5 mg twice daily (BID) for 1 month, after which an increase to 10 mg BID or reduction back to 5 mg BID was permitted at any time for efficacy or safety reasons. Concomitant treatment with a single conventional synthetic disease-modifying antirheumatic drug (csDMARD) was allowed but not required. Primary endpoints were incidence and severity of adverse events (AEs) and change from baseline in laboratory values. Efficacy was a secondary endpoint. Results 680/685 enrolled pts were treated. 608 (89.4%) remained at data cut-off. Mean (range) duration of tofacitinib exposure in this LTE was 206 (3–741) days. 661 (97.2%) pts took a csDMARD on Day 1, and 73 (11.0%) later discontinued csDMARD. To Month 24, 860 AEs were reported in 367 (54.0%) pts, 41 (6.0%) pts had serious AEs and 24 (3.5%) pts discontinued due to AEs. Special interest AEs included 6 serious infections (0.9%), 10 herpes zoster events (1.5%) including 1 serious event, 2 major adverse cardiovascular events (0.3%) and 2 malignancies (0.3%). There were 3 deaths (not attributed to treatment, as assessed by the investigator) due to metastatic pancreatic carcinoma, acute cardiac failure and pulmonary embolism. No GI perforation, inflammatory bowel disease or uveitis cases were reported. One AE of latent TB was reported. One pt met discontinuation criteria for laboratory values due to increased serum creatinine >50% and >0.5 mg/dL over the average of screening and baseline creatinine. Small mean decreases in absolute lymphocyte and neutrophil counts, and small mean increases in serum lipid markers, were observed; 18 (2.6%) pts started new lipid-lowering medication during the LTE (80 [11.8%] pts were on lipid-lowering drug at baseline). Efficacy was maintained in the LTE (Table 1). Conclusions Over 24 months in the LTE, the safety profile of tofacitinib in pts with active PsA was generally similar to that of the pivotal Phase 3 studies. No new safety signals were identified. Efficacy was maintained over time. Acknowledgements To be presented at AAD 2017 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by S Morgan of CMC and was funded by Pfizer Inc. Disclosure of Interest P. Nash Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Merck, Novartis, Pfizer Inc, Sanofi, Roche, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, L. Coates Speakers bureau: Pfizer Inc, A. Kivitz Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Pfizer Inc, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Pfizer Inc, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo, Corrona, Dermira, Janssen, Eli Lilly, Merck, Novartis, Pfizer Inc, Sun, UCB, Zynerba, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo, Genetech, Janssen, Novartis, Pfizer Inc, UCB, D. Gladman Grant/research support from: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, Consultant for: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, Speakers bureau: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, J. Covarrubias-Cobos Grant/research support from: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is an oral Janus kinase inhibitor. The minimally important changes (MICs) for the SPondyloArthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joint (SIJ) and spine scores based on agreement with global change scores by readers are ≥2.5 and ≥5, respectively.1 Objectives To assess whether MIC in SIJ and spine can discriminate between tofacitinib and placebo (PBO) in patients (pts) with ankylosing spondylitis (AS) and if this is concordant with clinical responses. Methods In this 16-week (wk), Phase 2, double-blind, dose-ranging study (NCT01786668),2 207 adult pts meeting modified New York AS criteria were randomised 1:1:1:1 to PBO or tofacitinib 2, 5 or 10 mg twice daily (BID) for 12 wks. Clinical endpoints included in this post-hoc analysis were: Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) and ASAS 40% improvement (ASAS40) response rates, AS disease activity score major improvement (ASDAS MI; change ≥2.0 from baseline), ASDAS inactive disease (ASDAS ID; Results MRI data for 164 pts were evaluated. Baseline demographics were generally balanced between treatment groups and typical of AS populations.2 Tofacitinib 2, 5 and 10 mg BID improved mean (range) SPARCC scores vs PBO (SIJ: -2.2 [-22.0, 10.5], -3.5 [-34.5, 11.0], -3.6 [-29.0, 0.5] vs -0.7 [-9.5, 6.5]; spine: -3.2 [-34.5, 20.5], -5.5 [-36.5, 8.0], -6.7 [-32.5, 7.5] vs -0.8 [-8.0, 14.0]). Approximately 3 times more pts achieved MIC in SIJ or spine in the pooled tofacitinib group vs PBO (SIJ: 34.1% vs 11.8%, p Conclusions Pts who received tofacitinib who had AS experienced clinically meaningful reductions in axial MRI inflammation. Pts achieving MIC for MRI inflammation had increased clinical response rates. References Maksymowych WP et al. J Rheumatol 2012; 39: 1666–1674. van der Heijde D et al. Ann Rheum Dis 2016; In press. Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by A Pedder of CMC and funded by Pfizer Inc. Disclosure of Interest W. Maksymowych Grant/research support from: AbbVie, Pfizer Inc, Sanofi, UCB, Consultant for: AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer Inc, Roche, Sanofi-Aventis, UCB, Employee of: Imaging Rheumatology BV, X. Baraliakos Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer Inc, Roche, MSD, UCB, A. Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer Inc, UCB, M. Brown Grant/research support from: AbbVie, Janssen, Leo Pharma, UCB, Consultant for: AbbVie, Janssen, Novartis, Pfizer Inc, UCB, Speakers bureau: AbbVie, Janssen, Novartis, Pfizer Inc, UCB, S. Sherlock Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Aim To assess efficacy and safety of fosdagrocorat (PF-04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients. Methods This multicenter, double-blind, parallel-group, active- and placebo-controlled Phase 2 study (NCT00938587) randomized 86 patients (1 : 1 : 1 : 1) to receive fosdagrocorat 10 mg, fosdagrocorat 25 mg, prednisone 5 mg or placebo, all with stable background methotrexate therapy. The primary outcome was change from baseline in Disease Activity Score of 28 joints (DAS28-4[C-reactive protein (CRP)]) after 2 weeks of treatment. Secondary outcomes included American College of Rheumatology (ACR) response rates, change from baseline in ACR core components and Health Assessment Questionnaire Disability Index. Results At week 2, improvements from baseline in DAS28-4(CRP) with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo were −1.69, −2.22, −1.17 and −0.96, respectively, and were statistically significantly greater for both fosdagrocorat doses versus placebo (P < 0.05) and for fosdagrocorat 25 mg versus prednisone 5 mg (P < 0.001). The effects of fosdagrocorat on secondary outcomes were generally consistent with those observed for the primary outcome. Adverse events (AEs) were reported for eight (38%), three (14%), four (19%) and 12 (55%) patients treated with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo, respectively. Most AEs were mild in severity. Four patients discontinued treatment due to AEs (fosdagrocorat 10 mg, n = 2; placebo, n = 2). There were no serious AEs. Conclusion Fosdagrocorat 10 and 25 mg demonstrated efficacy in improving signs and symptoms in RA patients, with manageable AEs. Additional studies are needed to assess the longer-term safety and efficacy of fosdagrocorat.

The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF‐04171327 (fosdagrocorat) is a phosphate ester prodrug of PF‐00251802 (dagrocorat), a selective high‐affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF‐04015475. This study evaluated the cytochrome P450 (CYP)–mediated drug–drug interaction (DDI) potential of PF‐00251802 and PF‐04015475 in vitro and used model‐based prediction approaches to estimate clinical impact. PF‐00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF‐00251802 and PF‐04015475 are time‐dependent inhibitors and inducers of CYP3A in vitro; PF‐00251802 is also a time‐dependent inhibitor of CYP2D6. Model‐based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open‐label, multiple‐dose study evaluated the effect of PF‐04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF‐04171327 resulted in equivalent pharmacokinetic profiles (AUCinf, 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF‐04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF‐00251802 and PF‐04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).

ObjectivesTo compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis).MethodsIn this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored.ResultsEmax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; pConclusionsTofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications.Trial registration numberNCT01786668.

Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7–14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose–response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism. In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5–60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8. Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects. This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile. NCT02767089 (retrospectively registered: 21 April 2016).

Background. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly prevalent. Linezolid is effective and well-tolerated in the treatment of adults with MRSA infections. Objective. To evaluate the clinical efficacy and safety of iv/oral linezolid in children with MRSA infections. Methods. Data were obtained from two independent clinical trials. In an outpatient trial children (5 to 17 years of age) with uncomplicated skin and skin structure infections (SSSIs) were treated with linezolid or cefadroxil. In an inpatient trial hospitalized children (0 to 11 years of age) with pneumonia, bacteremia or complicated SSSI caused by resistant Gram-positive pathogens were administered iv linezolid with the option to switch to oral suspension (patients >90 days of age) or iv vancomycin. A subset of patients with MRSA infections from the two clinical trials is analyzed herein. Results. In the outpatient trial children with skin infections caused by MRSA were treated with linezolid (15 patients) and cefadroxil (10 patients). In the microbiologically evaluable population, the clinical cure rate was 92.3% in the linezolid group and 85.7% in the cefadroxil group (P = 0.64). The pathogen eradication rate for MRSA was 92.3 and 85.7% in the linezolid and cefadroxil groups, respectively (P = 0.64). There were very few adverse events or drug-related adverse events and no serious adverse events in the outpatient trial. In the inpatient trial 20 children treated with linezolid and 14 treated with vancomycin had infections caused by MRSA. In the microbiologically evaluable population, the clinical cure rate was 94.1% in the linezolid group and 90.0% in the vancomycin group (P = 0.69). Pathogen eradication rates were 88.2 and 90.0% for the linezolid and vancomycin groups, respectively (P = 0.89). Susceptibility patterns of the MRSA isolates showed distinct patterns between the outpatient and inpatient trials. In the inpatient trial fewer patients in the linezolid group had drug-related adverse events than did those in the vancomycin group (20%vs. 43%; P = 0.15). Conclusions. Intravenous/oral linezolid is effective and well-tolerated in children with MRSA infections.

Background. Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. Methods. This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days post-therapy. Results. Linezolid and cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study Conclusions. Linezolid is well-tolerated and as effective as cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components. Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%). Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX. ClinicalTrials.gov: NCT00427934