Instrument selection for the ASAS core outcome set for axial spondyloarthritis.

OBJECTIVES: To define the instruments for the Assessment of SpondyloArthritis international Society-Outcomes Measures in Rheumatology (ASAS-OMERACT) core domain set for axial spondyloarthritis (axSpA). METHODS: An international working group representing key stakeholders selected the core outcome instruments following a predefined process: (1) identifying candidate instruments using a systematic literature review; (2) reducing the list of candidate instruments by the working group, (3) assessing the instruments' psychometric properties following OMERACT filter 2.2, (4) selection of the core instruments by the working group and (5) voting and endorsement by ASAS. RESULTS: The updated core set for axSpA includes seven instruments for the domains that are mandatory for all trials: Ankylosing Spondylitis Disease Activity Score and Numerical Rate Scale (NRS) patient global assessment of disease activity, NRS total back pain, average NRS of duration and severity of morning stiffness, NRS fatigue, Bath Ankylosing Spondylitis Function Index and ASAS Health Index. There are 9 additional instruments considered mandatory for disease-modifying antirheumatic drugs (DMARDs) trials: MRI activity Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joints and SPARCC spine, uveitis, inflammatory bowel disease and psoriasis assessed as recommended by ASAS, 44 swollen joint count, Maastricht Ankylosing Spondylitis Enthesitis Score, dactylitis count and modified Stoke Ankylosing Spondylitis Spinal Score. The imaging outcomes are considered mandatory to be included in at least one trial for a drug tested for properties of DMARD. Furthermore, 11 additional instruments were also endorsed by ASAS, which can be used in axSpA trials on top of the core instruments. CONCLUSIONS: The selection of the instruments for the ASAS-OMERACT core domain set completes the update of the core outcome set for axSpA, which should be used in all trials.

Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS). METHODS: This 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. RESULTS: 269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (p<0.0001) greater with tofacitinib (56.4%, 75 of 133) versus placebo (29.4%, 40 of 136), and the ASAS40 response rate was significantly (p<0.0001) greater with tofacitinib (40.6%, 54 of 133) versus placebo (12.5%, 17 of 136). Up to week 16, with tofacitinib and placebo, respectively, 73 of 133 (54.9%) and 70 of 136 (51.5%) patients had adverse events; 2 of 133 (1.5%) and 1 of 136 (0.7%) had serious adverse events. Up to week 48, with tofacitinib, 3 of 133 (2.3%) patients had adjudicated hepatic events, 3 of 133 (2.3%) had non-serious herpes zoster, and 1 of 133 (0.8%) had a serious infection; with placebo→tofacitinib, 2 (1.5%) patients had non-serious herpes zoster. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events or opportunistic infections. CONCLUSIONS: In adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified. TRIAL REGISTRATION NUMBER: NCT03502616.

Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data.

OBJECTIVES: Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within. METHODS: This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed. RESULTS: 12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts' average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database. CONCLUSIONS: DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).

Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years.

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 <20 years (vs <5 years; P < 0.01). In bDMARD-naïve, post-1 bDMARD, post-2 bDMARD and post-⩾3 bDMARD patients, median survival was >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.

Treatment patterns, unmet need, and impact on patient-reported outcomes of psoriatic arthritis in the United States and Europe.

Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The effects of PsA real-world treatment patterns on patient-reported outcomes in the US and 5 European countries (EU5; France, Germany, Italy, Spain, UK) were evaluated. Respondents from the 2016 National Health and Wellness Survey received advanced therapies (e.g., biologic disease-modifying antirheumatic drugs [DMARDs]), other therapies, (e.g., conventional synthetic DMARDs), or no treatment. Assessments included demographics, disease severity (patient-reported), comorbidities (Charlson Comorbidity Index), health status (Short Form-36 Health Survey), depression (Patient Health Questionnaire-9), work productivity (Work Productivity and Activity Index), and treatment adherence (Morisky Medication Adherence Scale-8). Overall, 1037 respondents from the US and 947 respondents from the EU5 were included. Of these, 21.7% US and 7.3% EU5 respondents received advanced therapies; 16.6% and 28.5%, other therapies; and 61.7% and 64.2%, no treatment, respectively. During treatment with advanced or other therapies, 40.8-54.7% US and 57.7-58.9% EU5 respondents self-reported moderate or severe PsA. Respondents receiving advanced therapies had the highest Charlson Comorbidity Index score (US, 1.25; EU5, 1.42); the lowest scores were with no treatment (0.52 and 0.49, respectively). Employment was lowest with other therapies (US, 47.7%; EU5, 41.1%). Overall work impairment was reported by 57.9% US and 62.6% EU5 respondents receiving advanced therapies. Medication adherence was generally low in the US and medium in the EU5 (Morisky Medication Adherence Scale-8: low, US 40.1-46.7%, EU5, 29.0-35.2%; medium, US 29.3-36.1%, EU5 37.8-49.3%; high, US 23.8-24.0%; EU5, 21.7-27.0%). Advanced and other therapies reduced PsA severity; however, > 40% of respondents reported moderate or severe PsA during treatment. Better management and adherence may reduce unmet need and disease burden. Further work is required to improve PsA diagnosis and time to treatment initiation.

Exposure-Response Analysis of Tofacitinib in Active Psoriatic Arthritis: Results from Two Phase 3 Studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure-response (E-R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four-category ordered categorical exposure-response model (ACR20 non-responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (Emax) model (using average concentrations of tofacitinib at steady state [Cavg]) adequately described the exposure-ACR response rate relationship. Model-predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E-R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration-time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of >2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA.

Effectiveness of Tofacitinib in Patients Initiating Therapy for Psoriatic Arthritis: Results from the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

INTRODUCTION: Randomized controlled trials have demonstrated tofacitinib efficacy for psoriatic arthritis (PsA); however, real-world effectiveness data are limited. This real-world analysis assessed baseline demographics/disease characteristics and tofacitinib effectiveness in patients with PsA in the CorEvitas PsA/Spondyloarthritis Registry. METHODS: This study (NCT05195814) included patients with PsA initiating tofacitinib from December 2017-December 2021, as monotherapy or with oral small molecules (methotrexate/leflunomide/sulfasalazine/apremilast), pre-existing use, or initiated concurrently. OUTCOMES: mean change from baseline in disease activity/patient-reported outcomes, proportion of patients achieving low disease activity (LDA)/remission at 6 ± 3 months, and discontinuation rates. RESULTS: Of 222 patients with PsA who initiated tofacitinib (60.8% as monotherapy), 123 patients had 6 ± 3 months of follow-up. At initiation, 59.7% were female, 92.3% were White, mean age was 56.3 years, PsA duration since diagnosis was 8.2 years, and 25.7% were biologic disease-modifying antirheumatic drug (bDMARD)-naïve. Improvements to 6 ± 3 months were observed with tofacitinib for Clinical Disease Activity Index for PsA (cDAPSA), DAPSA, PsA Disease Activity Score (PASDAS), Clinical Disease Activity Index, body surface area (BSA), tender/swollen joint count, patient fatigue, pain, Patient Global Skin Assessment, and Health Assessment Questionnaire-Disability Index. At 6 ± 3 months, 25.0%/7.8% of patients treated with tofacitinib achieved cDAPSA-defined LDA/remission, 18.2% achieved minimal disease activity, 30.8% had PASDAS ≤ 3.2, 42.9%/29.4% had resolved enthesitis/dactylitis, and 22.5% achieved BSA = 0%. Tofacitinib discontinuation occurred in 51.2% of patients (51.6% of monotherapy initiators) at/prior to 6 ± 3 months (27.6%/23.6%), 57.1% of whom switched to tumor necrosis factor/interleukin-17 inhibitors. Reasons for discontinuation were not reported in 85.3%/79.3% of patients who discontinued at/prior to 6 ± 3 months. CONCLUSIONS: This real-world US cohort analysis described patients with PsA newly initiating tofacitinib; most were bDMARD-experienced or receiving monotherapy treatment. In patients who remained on therapy (48.8%), tofacitinib was effective across multiple PsA domains at 6 ± 3 months. Limitations included small patient numbers at follow-up and potential selection bias. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05195814.

Efficacy and Safety of Tofacitinib in Patients with Psoriatic Arthritis or Ankylosing Spondylitis by Cigarette Smoking Status.

INTRODUCTION: Routine care studies of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) demonstrated attenuated responses to tumor necrosis factor inhibitors in current/past versus never smokers. This post hoc analysis assessed tofacitinib efficacy and safety in patients with PsA or AS by cigarette smoking status at trial screening. METHODS: Pooled data from phase 3 and long-term extension (safety only) PsA trials and phase 2 and 3 AS trials were assessed by current/past versus never smoker status. Analysis included efficacy and safety data for tofacitinib 5 (PsA/AS) and 10 (PsA only) mg twice daily (BID) or placebo, and safety data in AS for tofacitinib 2 and 10 mg BID. Efficacy outcomes included American College of Rheumatology ≥ 50% responses (ACR50) and minimal disease activity (MDA) responses to month (M)6/M3 (tofacitinib/placebo) in PsA; and ≥ 40% improvement in Assessment of SpondyloArthritis international Society responses (ASAS40) and AS Disease Activity Score (ASDAS) < 2.1 responses to week (W)16 in AS. Safety was assessed to M48/W48 (PsA/AS), adjusted for treatment/smoking status/median body mass index (BMI) status/sex/trial/treatment-smoking status interaction. RESULTS: PsA/AS cohorts included 342/178 current/past and 572/194 never smokers. Tofacitinib efficacy was generally greater versus placebo to M3/W6 (PsA/AS), and comparable in current/past and never smokers to M6/W16 (PsA/AS). In patients receiving ≥ 1 tofacitinib dose, adjusted treatment-emergent adverse event (TEAE)/serious AE (SAE)/discontinuation due to AE incidence rates (IRs) to M48 in PsA were higher in current/past versus never smokers; adjusted IRs to W48 in AS were higher in current/past versus never smokers for TEAEs, but similar for SAEs/discontinuation due to AEs. CONCLUSIONS: In both patients with PsA and AS, tofacitinib efficacy was greater versus placebo, and comparable across smoking categories. Adjusted IRs were higher in current/past versus never smokers for TEAEs, SAEs, discontinuation due to AEs in PsA, and for TEAEs in AS, complementing reports of associations between smoking and comorbidities in spondyloarthritis. Findings support increased surveillance/caution for patients with PsA or AS with smoking history. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01877668/NCT01882439/NCT03486457/NCT01976364/NCT01786668/NCT03502616.

Risk Stratification of Patients with Psoriatic Arthritis and Ankylosing Spondylitis for Treatment with Tofacitinib: A Review of Current Clinical Data.

In this commentary, we review clinical data which helps inform individualized benefit-risk assessment for tofacitinib in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). ORAL Surveillance, a safety trial of patients ≥ 50 years of age with rheumatoid arthritis (RA) and cardiovascular risk factors, found increased rates of safety outcomes (including major adverse cardiovascular events [MACE], malignancies excluding non-melanoma skin cancer, and venous thromboembolism) with tofacitinib versus tumor necrosis factor inhibitors (TNFi). Post hoc analyses of ORAL Surveillance have identified subpopulations with different relative risk versus TNFi; higher risk with tofacitinib was confined to patients ≥ 65 years of age and/or long-time current/past smokers, and specifically for MACE, patients with a history of atherosclerotic cardiovascular disease (ASCVD). In patients without these risk factors, risk differences between tofacitinib and TNFi could not be detected. Given differences in demographics, pathophysiology, and comorbidities, we sought to examine whether the risk stratification observed in RA is also appropriate for PsA and AS. Data from the PsA tofacitinib development program show low absolute risk of safety outcomes in patients < 65 years of age and never smokers, and low MACE risk in patients with no history of ASCVD, consistent with results from ORAL Surveillance. No MACE, malignancies, or venous thromboembolism were reported in the tofacitinib AS development program. The mechanism of the ORAL Surveillance safety findings is unknown, and there are no similar prospective studies of sufficient size and duration. Accordingly, it is appropriate to use a precautionary approach and extrapolate differentiating risk factors identified from ORAL Surveillance (age ≥ 65 years, long-time current/past smoking, and history of ASCVD) to PsA and AS. We recommend an individualized approach to treatment decisions based on these readily identifiable risk factors, in line with updated labeling for Janus kinase inhibitors and international guidelines for the treatment of PsA and AS.Trial Registration: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364, NCT00678210, NCT01710046, NCT01241591, NCT01186744, NCT01276639, NCT01309737, NCT01163253, NCT01786668, NCT03502616.

The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability.

Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin self-ubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wild-type ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.

A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling.

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)-Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

Tofacitinib Efficacy and Safety in Patients With Ankylosing Spondylitis by Prior Biologic Disease-Modifying Antirheumatic Drug Use: A Post Hoc Analysis.

OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in patients with ankylosing spondylitis (AS) by prior biologic disease-modifying antirheumatic drug (bDMARD) use. METHODS: Data from a placebo-controlled, double-blind study of patients with active AS were analyzed. Patients received tofacitinib 5 mg twice daily (BID) or placebo to week 16; all received open-label tofacitinib 5 mg BID to week 48 and were stratified by prior treatment (bDMARD-naive or tumor necrosis factor inhibitor [TNFi]-inadequate responder [IR], including bDMARD-experienced [non-IR]). Disease activity/safety were assessed throughout. RESULTS: Of 269 patients, 207 (77%) were bDMARD-naive; 62 (23%) were in the TNFi-IR subgroup. TNFi-IR patients had higher baseline BMI (28.0 vs. 26.1 kg/m2 ), longer symptom duration (14.4 vs. 13.2 years), and lower concomitant conventional synthetic DMARD use (14.5% vs. 30.9%) than bDMARD-naive patients. At week 16, for most outcomes, tofacitinib efficacy exceeded placebo for both subgroups and was sustained to week 48. At week 16, tofacitinib versus placebo differences were similar between bDMARD-naive and TNFi-IR patients (Assessment in Spondyloarthritis international Society 40 treatment difference [95% confidence interval]: 30.8% [19.1%-42.6%] vs. 19.4% [1.7%-37.0%]). Adverse event (AE) proportions were similar between tofacitinib-treated bDMARD-naive/TNFi-IR patients (77.5%/77.4%) at week 48 with no deaths. A numerically higher proportion of tofacitinib-treated TNFi-IR versus bDMARD-naive patients discontinued study drug (12.9% vs. 3.9%) or dose reduced/temporarily discontinued due to AEs (19.4% vs. 11.8%). CONCLUSION: Tofacitinib efficacy exceeded placebo at week 16 for bDMARD-naive/TNFi-IR patients and was sustained to week 48. The absolute magnitude of responses was generally greater in bDMARD-naive patients versus TNFi-IR patients. More TNFi-IR versus bDMARD-naive patients discontinued or dose reduced/temporarily discontinued tofacitinib due to AEs. Small sample size and sample size differences between subgroups limited the interpretation.

Tofacitinib Reduces Spinal Inflammation in Vertebral Bodies and Posterolateral Elements in Ankylosing Spondylitis: Results from a Phase 2 Trial.

INTRODUCTION: This post hoc analysis of phase 2 trial data assessed the efficacy of tofacitinib on magnetic resonance imaging (MRI) outcomes with the detailed anatomy-based Canada-Denmark (CANDEN) MRI scoring system and evaluated tofacitinib suppression of spinal inflammation in patients with active ankylosing spondylitis (AS). METHODS: Patients with active AS (per modified New York criteria) were randomized 1:1:1:1 to receive tofacitinib 2, 5, or 10 mg twice daily (BID), or placebo, in a 16-week, phase 2, double-blind clinical trial. Spine MRI assessments were performed at baseline and week 12. For post hoc analysis, MRI images from patients receiving tofacitinib 5 or 10 mg BID, or placebo, were re-evaluated by two readers blinded to time point/treatment and assessed by the CANDEN MRI scoring system. Least squares mean changes from baseline to week 12 were reported for CANDEN-specific MRI outcomes, with analysis of covariance used for comparisons of pooled tofacitinib and tofacitinib 5 or 10 mg BID versus placebo. p values without multiplicity adjustment were reported. RESULTS: MRI data from 137 patients were analyzed. At week 12, CANDEN spine inflammation score and vertebral body, posterior elements, corner, non-corner, facet joint, and posterolateral inflammation subscores were significantly reduced with pooled tofacitinib versus placebo (p < 0.0001; except non-corner subscore, p < 0.05). Total spine fat score was numerically increased with pooled tofacitinib versus placebo. CONCLUSIONS: In patients with AS, tofacitinib treatment was associated with significant reductions in MRI scores of spinal inflammation versus placebo, as assessed by the CANDEN MRI scoring system. Tofacitinib reduced inflammation in posterolateral elements of the spine and facet joints, which has not been described previously. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT01786668).

Post-Marketing Safety Surveillance of Tofacitinib over 9 Years in Patients with Psoriatic Arthritis and Rheumatoid Arthritis.

INTRODUCTION: The safety of tofacitinib in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in clinical studies of ≤ 4 and 9.5 years, respectively. Post-marketing surveillance (PMS) data for tofacitinib from spontaneous and voluntary adverse event (AE) reports have been published for RA, but not PsA. To inform the real-world safety profile of tofacitinib in PsA, we evaluated AE reports submitted to the Pfizer safety database (including RA data for context). METHODS: Endpoints included AEs, serious AEs (SAEs), AEs of special interest (AESIs; serious infections, herpes zoster, cardiovascular events, malignancies, venous thromboembolism), and fatal cases. Exposure was estimated using IQVIA global commercial sales data. Number, frequency, and reporting rates (RRs; number of events/100 patient-years' [PY] exposure) were summarized by indication and formulation (immediate release [IR] 5 or 10 mg twice daily], modified release [MR] 11 mg once daily, or all tofacitinib). The data-collection period differed by indication (PsA: 14 December 2017 [US approval, IR/MR] to 6 November 2021; RA: 6 November 2012 [US approval, IR] to 6 November 2021; MR approval, 24 February 2016). RESULTS: A total of 73,525 case reports were reviewed (PsA = 5394/RA = 68,131), with 20,706/439,370 PY (PsA/RA) of exposure. More AEs were reported for IR versus MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR versus IR. AE RRs (RA) in the first 4 years after IR approval were 95.9 (IR; 49,439 PY) and 147.0 (MR; 2000 PY). Frequency of SAEs, AESIs, and fatal cases was mostly similar across formulations and indications. The most frequently-reported AE Preferred Terms (PsA/RA) included drug ineffective (20.0%/17.8%), pain (9.7%/10.6%), condition aggravated (9.9%/10.5%), headache (8.8%/7.9%) and, for PsA, off-label use (10.5%/3.4%). CONCLUSIONS: Tofacitinib PMS safety data from submitted AE reports were consistent between PsA and RA, and aligned with its known safety profile. Exposure data (lower MR versus IR; estimation from commercial sales data), reporting bias, reporter identity, and regional differences in formulation use limit interpretation.

Association between baseline cardiovascular risk and incidence rates of major adverse cardiovascular events and malignancies in patients with psoriatic arthritis and psoriasis receiving tofacitinib.

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). Objectives: This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Design: Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Methods: Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). Results: For patients with PsA (N = 783) and PsO (N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. Conclusion: In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. Registration ClinicalTrialsgov: NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253. Plain Language Summary: People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease].• People who are more likely to have CV disease may also be more likely to have certain types of cancer.• Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO.• We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials.• In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day.• After the trials had ended, we measured people's risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment.• We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity.• We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib:• There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease.• There were more cases of heart-related problems in people who had had CV disease before.• More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib.• We should test for cancer in people with high risk of CV disease.

Early Real-World Experience of Tofacitinib for Psoriatic Arthritis: Data from a United States Healthcare Claims Database.

INTRODUCTION: This study characterized real-world demographic and baseline clinical characteristics, as well as treatment persistence and adherence, in patients with psoriatic arthritis (PsA) who had newly initiated tofacitinib treatment. METHODS: This retrospective cohort study included patients aged 18 years or older in the IBM MarketScan™ US database with at least one tofacitinib claim (first = index) between December 14, 2017 and April 30, 2019; PsA diagnoses on/within 12 months pre-index; and no diagnoses of rheumatoid arthritis any time pre-index. Patients were continuously enrolled for 12 months pre-index and 6 months post-index, with no pre-index claims for tofacitinib. Patient demographic and clinical characteristics on the day of index, and history of advanced treatments (including tofacitinib monotherapy or combination therapy), were recorded. Outcomes at 6 months post-index included tofacitinib persistence (less than 60-day gap without tofacitinib treatment) and adherence (proportion of days covered [PDC] and medication possession ratio 80% or higher). RESULTS: Of the 10,354 patients with tofacitinib claims within the study period, 318 patients with PsA met the inclusion criteria. More than 60% of patients received tofacitinib monotherapy post-index, with a mean duration of PsA of 760.5 days at index. For patients who received tofacitinib combination therapy post-index, methotrexate was the most common concomitant conventional synthetic disease-modifying antirheumatic drug. At 6 months post-index, persistence was similar in patients receiving tofacitinib monotherapy (69.8%) versus combination therapy (73.1%); adherence (as measured by PDC ≥ 0.8) was numerically lower in patients receiving tofacitinib monotherapy (56.8%) versus combination therapy (65.5%). CONCLUSIONS: This analysis of US-based claims data described patients who had newly initiated tofacitinib treatment an average of 2 years after PsA diagnosis, with approximately two-thirds of patients receiving tofacitinib monotherapy. Observed rates of tofacitinib persistence were similar across patients who received tofacitinib monotherapy and combination therapy 6 months after initiation; adherence rates were numerically lower in patients receiving monotherapy.

Tofacitinib is a drug approved to treat patients with psoriatic arthritis (PsA) that has been shown to improve PsA symptoms and quality of life in controlled clinical trials. However, there is not much information on everyday use of tofacitinib outside of clinical trials in the USA. This study is one of the first to describe the characteristics of patients with PsA in the USA who take tofacitinib, including their typical age, sex, where they live, how long they have had PsA, and how they use tofacitinib. Use of tofacitinib included how patients followed tofacitinib prescription timings and dose (adherence) and how long they took tofacitinib for after it was prescribed (persistence). We used data collected from a US health insurance claims database (IBM MarketScan™) for patients with PsA and at least one claim for tofacitinib. In total, 318 patients were included and over 60% of them received tofacitinib therapy only (monotherapy; no conventional synthetic disease-modifying antirheumatic drug [csDMARD] therapy). For patients treated with both tofacitinib and a csDMARD (combination therapy), methotrexate was the most common drug prescribed. Six months after their first prescription of tofacitinib, around 70% of patients were still taking tofacitinib (monotherapy or combination therapy). However, a slightly lower number of patients taking tofacitinib monotherapy were taking it as originally instructed (adherence 57%), compared with those taking tofacitinib combination therapy (adherence 66%). Our results provide valuable information on the use of tofacitinib in US real-life settings outside of clinical trials and could help to improve the quality of care for patients with PsA.

The effect of tofacitinib on residual pain in patients with rheumatoid arthritis and psoriatic arthritis.

OBJECTIVE: Post hoc analysis of pooled data from nine randomised controlled trials to assess the effect of tofacitinib (oral Janus kinase inhibitor for treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) on residual pain in patients with RA or PsA with abrogated inflammation. METHODS: Patients who received ≥1 dose of tofacitinib 5 mg twice daily, adalimumab or placebo with/without background conventional synthetic disease-modifying antirheumatic drugs and had abrogated inflammation (swollen joint count (SJC)=0 and C reactive protein (CRP)<6 mg/L) after 3 months' therapy were included. Assessments included Patient's Assessment of Arthritis Pain at month 3 (Visual Analogue Scale [VAS] 0-100 mm). Scores were summarised descriptively; treatment comparisons assessed by Bayesian network meta-analyses (BNMA). RESULTS: From the total population with RA/PsA, 14.9% (382 of 2568), 17.1% (118 of 691) and 5.5% (50 of 909) of patients receiving tofacitinib, adalimumab and placebo, respectively, had abrogated inflammation after 3 months' therapy. Patients with RA/PsA with abrogated inflammation receiving tofacitinib/adalimumab had higher baseline CRP versus placebo; patients with RA receiving tofacitinib/adalimumab had lower SJC and longer disease duration versus placebo. Median residual pain (VAS) at month 3 was 17.0, 19.0 and 33.5 in patients with RA treated with tofacitinib, adalimumab or placebo, and 24.0, 21.0 and 27.0 in patients with PsA, respectively. Residual pain reductions with tofacitinib/adalimumab versus placebo were less prominent in patients with PsA versus patients with RA, with no significant differences between tofacitinib/adalimumab, per BNMA. CONCLUSION: Patients with RA/PsA with abrogated inflammation receiving tofacitinib/adalimumab had greater residual pain reduction versus placebo at month 3. Results were similar between tofacitinib and adalimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registry (NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT01877668; NCT01882439).

Identification of Distinct Disease Activity Trajectories in Methotrexate-Naive Patients With Rheumatoid Arthritis Receiving Tofacitinib Over Twenty-Four Months.

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.

Time to response for clinical and patient-reported outcomes in patients with psoriatic arthritis treated with tofacitinib, adalimumab, or placebo.

BACKGROUND: This study examined the time to clinically meaningful response in patients with active psoriatic arthritis treated with tofacitinib, adalimumab, or placebo switching to tofacitinib. METHODS: Data were from two phase 3 studies, OPAL Broaden (12 months) and OPAL Beyond (6 months). Patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks (OPAL Broaden only), or placebo switching to tofacitinib 5 or 10 mg BID at month 3. Baseline to initial response time was according to pre-defined clinically meaningful criteria on Health Assessment Questionnaire-Disability Index (HAQ-DI; ≥ 0.35-point improvement), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; ≥ 4-point improvement), Psoriatic Arthritis Disease Activity Score (PASDAS; post-baseline score ≤ 3.2 and > 1.6-point improvement from baseline), and minimal disease activity (MDA; meeting at least 5 of 7 criteria) composite. RESULTS: In OPAL Broaden, median time to initial HAQ-DI score response was 29, 53, and 30 days in patients treated with tofacitinib 5 mg BID, tofacitinib 10 mg BID, or adalimumab, compared with 162 and 112 days in patients treated with placebo switching to tofacitinib 5 or 10 mg BID at month 3, respectively. Across studies, median time to initial FACIT-F total score response was shorter in patients receiving tofacitinib 5 mg BID (31 days) vs other groups (84-92 days). Median time to initial response was approximately 11 (MDA)/6-9 months (PASDAS) in tofacitinib/adalimumab groups in OPAL Broaden. CONCLUSION: This analysis demonstrates tofacitinib's efficacy on most patient-reported and clinical endpoints over time and shows a shorter time to initial, clinically meaningful response in patients receiving tofacitinib vs patients switching from placebo to tofacitinib. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01877668. Registered June 12, 2013. ClinicalTrials.gov , NCT01882439. Registered June 18, 2013.