This is a 12-month study investigating the effectiveness and safety of tofactinib in treating the signs and symptoms of active psoriatic arthritis and improving physical function and preserving bone structure in patients with an inadequate response to a traditional, nonbiologic disease-modifying antirheumatic drug. Adalimumab is used as a comparator.
Background: Tofacitinib is an oral Janus kinase inhibitor under investigation for psoriatic arthritis (PsA). We evaluated tofacitinib efficacy and safety vs placebo (PBO) in patients (pts) with active PsA and an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drug (csDMARD). Methods: This was a randomized, PBO-controlled, double-blind, multicenter, Phase 3 study (NCT01877668). Eligible pts had a diagnosis of PsA for ≥6 months, meeting ClASsification criteria for Psoriatic ARthritis (CASPAR), active arthritis (≥3 tender/- painful and ≥3 swollen joints) and plaque psoriasis, IR to ≥1 csDMARD, and were tumor necrosis factor-inhibitor-naïve. Pts were randomized 2:2:2:1:1 to tofacitinib 5 mg twice daily (BID) (n = 107), tofacitinib 10 mg BID (n = 104), adalimumab (ADA) 40 mg SC injection once every 2 weeks (n = 106), PBO/tofacitinib 5 mg BID (n = 52), or PBO/tofacitinib 10 mg BID (n = 53). Pts who initially received PBO advanced to tofacitinib at Month (M) 3. Ongoing treatment with a stable dose of 1 csDMARD was required. Pts were followed through M12. M3 primary endpoints were American College of Rheumatology 20% improvement (ACR20) and change from baseline in Health Assessment Questionnaire Disability Index (DHAQ-DI). Secondary endpoints included 75% improvement from baseline Psoriasis Area and Severity Index (PASI75). Results: Of 422 randomized pts, 373 (88.4%) completed the study. Across treatment groups at baseline, mean age was 46.9-49.4 years, 47.2-59.6% were female, mean duration of PsA was 5.3-7.3 years, mean HAQ-DI was 1.1-1.2, and mean PASI was 8.3-10.1 (among pts with ≥3% BSA). Both tofacitinib 5 and 10 mg BID significantly improved ACR20 response rates vs PBO at M3 (50.5% [P ≤ .05] and 60.6% [P < .0001] vs 33.3%) and DHAQ-DI (-0.35 [P ≤ .05] and -0.40 [P <.001] vs -0.18); responses were maintained to M12. Greater efficacy was also observed for ADA vs PBO. Both tofacitinib doses significantly improved PASI75 response rates vs PBO at M3 (tofacitinib 5 mg BID 42.7%; tofacitinib 10 mg BID 44.3%; PBO 14.6%; both P< .0001). Over 12 months, the most common adverse events (AEs) were upper respiratory tract infection (7.5-10.6% of pts across groups), nasopharyngitis (7.5-11.5%), and headache (3.8-10.6%); serious AEs were reported by 3.8-8.5% of pts; 2.9-5.6% of pts discontinued due to AEs. Conclusion: Tofacitinib was superior to PBO in ACR20 response rate and DHAQ-DI at M3, which was maintained to M12. No new safety signals were identified.
<b>BACKGROUND: </b>Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs).<b>METHODS: </b>In this 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3.<b>RESULTS: </b>ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group (P=0.006 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial.<b>CONCLUSIONS: </b>The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668 .).
Background: Tofacitinib is an oral Janus kinase inhibitor under investigation for treatment of psoriatic arthritis (PsA). The safety and efficacy of tofacitinib for the treatment of PsA has been investigated in two Phase 3 randomised controlled trials (RCTs: OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]). Objectives: To evaluate patient-reported outcomes (PROs) in patients (pts) with active PsA enrolled in OPAL Broaden (N=422) and OPAL Beyond (N=394). OPAL Broaden pts had an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug and were naïve to tumour necrosis factor inhibitors (TNFi) whilst OPAL Beyond pts had an IR to ≥1 TNFi. Methods: Pts were randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo (PBO)→ tofacitinib 5 mg BID, PBO→ tofacitinib 10 mg BID and, in OPAL Broaden, also to adalimumab 40 mg subcutaneously every two weeks (active comparator). Pts receiving PBO advanced to either tofacitinib 5 mg BID or 10 mg BID at month 3 (M3) in both RCTs. Least squares mean changes from baseline in: Patient's Global Assessment of Arthritis (PtGA; Visual Analogue Scale [VAS]); Arthritis Pain (Pain; VAS); Short Form-36 Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); Dermatology Life Quality Index (DLQI) and Ankylosing Spondylitis Quality of Life (ASQOL) questionnaires are reported. Nominal p values are reported without adjustments for multiple comparisons. Results: Patients with active PsA in OPAL Broaden and OPAL Beyond RCTs receiving tofacitinib 5 mg and 10 mg BID reported improved PROs compared with PBO (Table 1). Greater improvements in PtGA and Arthritis Pain were observed as early as Week 2 through M3 with both tofacitinib doses compared with PBO in both studies (p≤0.05). Greater improvements were also reported in SF-36 Physical Component Summary, DLQI and ASQOL scores at M1 and M3 with both tofacitinib doses compared with PBO (p≤0.05). There were greater improvements in SF-36 physical functioning, bodily pain and vitality domains with both tofacitinib doses compared with PBO in both studies (p≤0.05) at M3. SF-36 social functioning domain showed greater improvement with tofacitinib 5 mg BID in OPAL Broaden and both tofacitinib doses in OPAL Beyond compared with PBO at M3 (p≤0.05). SF-36 role-physical domain showed greater improvement with tofacitinib 10 mg BID in OPAL Beyond at M3 compared with PBO (p≤0.05). FACIT-F showed a greater improvement in both studies at M3 with both tofacitinib doses compared with PBO (p≤0.05). In OPAL Broaden, improvements in PROs were similar between tofacitinib and adalimumab. Conclusions: Pts with active PsA receiving tofacitinib reported greater improve ments in PROs compared with PBO at M3 that were maintained throughout both RCTs.
BACKGROUND: The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints.
METHODS: Oral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders.
RESULTS: Overall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, -2.0 (0.14; 1.73), -2.4 (0.14; 2.4); DAPSA, -20.2 (1.72; 0.9), -24.4 (1.73; 1.23); and CPDAI, -2.9 (0.34; 1.03), -4.2 (0.36; 1.53); OPAL Beyond: PASDAS, -1.9 (0.14; 1.53), -2.1 (0.14; 1.84); DAPSA, -22.5 (1.67; 0.81), -21.0 (1.70; 0.84); and CPDAI, -3.3 (0.31; 1.41), -3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments.
CONCLUSIONS: This analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA.
TRIAL REGISTRATION: OPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668 , first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439 , first posted June 20, 2013.
Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). PsA is a heterogeneous disease and composite endpoints allow assessment of multiple clinical outcomes in one instrument. Objectives: To examine the effects of tofacitinib treatment on several composite endpoints in patients (pts) with PsA. Methods: In 2 placebo (PBO)-controlled, double-blind, multicentre, global Phase 3 studies, pts had active PsA and either had an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) and were tumour necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden [n=422; 12 months; NCT01877668]), or had an IR to ≥1 TNFi (OPAL Beyond [n=394; 6 months; NCT01882439]). Pts were randomised to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or PBO (advancing to tofacitinib 5 or 10 mg BID at Month 3, OPAL Broaden and OPAL Beyond), in addition to continuing on a single, stable csDMARD. Composite endpoints assessed: Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Score using 28 joints with C-reactive protein, Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAREA/DAPSA) and Composite Psoriatic Disease Activity Index (CPDAI). Results: Demographics and baseline disease characteristics were generally similar between treatment groups within the 2 studies, except for duration of PsA disease (longer in OPAL Beyond) and geographic distribution (OPAL Broaden having more Eastern EU pts). Baseline values for composite endpoints were generally similar across treatment groups and studies (table 1). Both doses of tofacitinib showed improvements in composite endpoints vs PBO at Month 3 in both studies (table 1). In OPAL Broaden, the effects of adalimumab were similar to both doses of tofacitinib across composite endpoints. Effect size for the composite endpoints (using a subpopulation of pts who had all available data for all endpoints) was highest for PASDAS and typically lowest for DAREA/DAPSA; this rank order of effect size was similar across treatment arms and studies. At Month 3, effect sizes in pts receiving active treatment ranged from 0.90 (DAREA/DAPSA for tofacitinib 5 mg BID) to 2.40 (PASDAS for tofacitinib 10 mg BID) in OPAL Broaden, and 0.81 (DAREA/DAPSA for tofacitinib 5 mg BID) to 1.84 (PASDAS for tofacitinib 10 mg BID) in OPAL Beyond (table 1). Standardised response means generally followed the same pattern as effect size across studies with both doses of tofacitinib (table 1). Conclusions: In 2 Phase 3 studies, tofacitinib 5 mg and 10 mg BID improved composite endpoint scores vs PBO over 3 months in pts with PsA. The largest effect size and standardised response means were observed for PASDAS. Effect sizes and standardised response means varied across endpoints but were consistent across studies.
Background: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of psoriatic arthritis (PsA). Cytokines involved in lymphocyte development, function and homeostasis signal through JAKs, and reductions in mean lymphocyte count over time have been reported in tofacitinib‐treated patients (pts) with rheumatoid arthritis.1 Objectives: To characterise the effects of tofacitinib on absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs) in pts with PsA. Methods: Data were pooled from 2 placebo (PBO)‐controlled, double‐blind, Phase 3 studies (OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]). Pts had active PsA and inadequate response to ≥1 conventional synthetic DMARD (OPAL Broaden) or to ≥1 tumour necrosis factor inhibitor (OPAL Beyond). Pts were randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (active control; OPAL Broaden only) or PBO. PBO pts advanced in a blinded manner to tofacitinib 5 or 10 mg BID at Month (M)3. ALCs and LSCs were collected every 3 months as part of safety monitoring procedures in the Phase 3 studies (any abnormalities were confirmed upon retesting). Median ALCs and LSCs are reported up to M6. Incidence rates (pts with event/100 ptyears) for serious infections (SIs) were assessed by confirmed (two sequential measurements) ALC categories (≥2.0,<2.0‐1.5,<1.5‐1.0 and <1.0‐0.5 × 103/ mm3) up to M12. Results: The analysis included 816 pts: tofacitinib 5 mg BID, n=238; tofacitinib 10 mg BID, n=236; adalimumab, n=106; PBO, n=236. Up to M6, minimal decreases in median ALC were observed in pts who received tofacitinib 5 mg BID, tofacitinib 10 mg BID or PBO (up to M3 only) (Table). LSCs, including total T cells (CD3+), cytotoxic T cells (CD8+) and NK cells (CD16 +56+), showed a similar trend to ALC for both tofacitinib doses and PBO (Table), with minimal decreases over 6 months. B cells (CD19+) showed numerical increases across treatments. Percentage changes from baseline in LSCs at M6 showed a generally similar pattern to absolute values. In adalimumab‐treated pts, ALCs and all LSCs increased over 6 months. Up to M6, no pts receiving tofacitinib or adalimumab had confirmed ALC<0.5×103/mm3; 1 pt receiving PBO had a confirmed ALC<0.5×103/mm3 over 3 months, resulting in discontinuation from the study before advancing to active treatment. Up to M12, SIs were reported in 7 tofacitinib‐(including 2 pts who advanced from PBO) and 1 adalimumab‐treated pt; of these, 1 SI (PBO advanced to tofacitinib) occurred >6 months after treatment initiation. There was no trend that suggested an increased risk of SIs in any ALC category (data not shown). Conclusions: Up to M6 in tofacitinib‐treated pts with active PsA, minimal changes in ALCs and LSCs were observed. Although incidence of SIs did not appear to be related to ALC, conclusions are limited by the small number of events. (Table Presented) .
Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed the efficacy of tofacitinib using pooled data from two phase 3 studies of patients with active PsA. Methods: Data were pooled from OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439). Patients had active PsA and either an inadequate response (IR) to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) and were tumor necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden), or had IR to ≥ 1 TNFi (OPAL Beyond). Pooled data included tofacitinib 5 or 10 mg twice daily (BID; to month 6) and placebo (to month 3; patients then switched to tofacitinib 5 or 10 mg BID). Patients also received one background csDMARD. Endpoints included American College of Rheumatology (ACR)20 response and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at month 3 (primary endpoints), ACR50/70 response, HAQ-DI response (decrease from baseline ≥ 0.35) and improvements in painful and swollen joint counts, psoriasis, enthesitis and dactylitis to month 6. Results: A total of 710 patients were included (tofacitinib 5 mg BID: 238; tofacitinib 10 mg BID: 236; placebo: 236). Primary endpoints showed significant improvements at month 3 in patients receiving tofacitinib 5 or 10 mg BID vs. placebo. Significant improvements in HAQ-DI response, painful and swollen joints, psoriasis, enthesitis and dactylitis vs. placebo were observed for both tofacitinib doses at month 3. Efficacy was maintained to month 6 (final pooled time point). Conclusions: In a pooled analysis of csDMARD-IR/TNFi-naïve and TNFi-IR patients, tofacitinib was superior to placebo at month 3 across four PsA domains: peripheral arthritis, psoriasis, enthesitis and dactylitis. Trial Registration: OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439). Funding: Pfizer Inc.
Background: Pain is a core domain of psoriatic arthritis (PsA).1 Rapid, sustained pain reduction is a priority for patients (pts) and physicians when choosing treatment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Objectives: This post hoc analysis aimed to estimate time to clinically meaningful pain improvement with tofacitinib. Methods: Data were analysed from 2 Phase 3 studies of tofacitinib in pts with active PsA and an inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) (OPAL Broaden; NCT01877668; 12-month study), or to ≥1 tumour necrosis factor inhibitor (OPAL Beyond; NCT01882439; 6-month study). Pts treated with tofacitinib 5 mg twice daily (BID) and placebo (PBO) advanced to tofacitinib 5 mg BID at Month 3 (PBO-tofacitinib), in combination with csDMARDs, were included in this analysis. Current arthritis pain severity was reported by pts using a 100 mm visual analogue scale, where higher scores indicated greater severity of pain. Pain improvement was defined as the first post-baseline improvement of ≥30% (meaningful change), ≥50% (substantial change) or ≥70% relative to baseline.2 Time-to-event analyses were performed using a Kaplan-Meier (KM) method on pooled data. Descriptive analyses of the rate of improvements by study were performed. Results: Overall, 354 pts were available for analysis. Rates of pain improvement over time with tofacitinib 5 mg BID were approximately the same in both studies (Figure). By Month 1, ≥40% of pts experienced ≥30% pain improvement, and by Month 2, approximately 55% of pts experienced ≥30% pain improvement (Figure). KM analyses showed that pts receiving tofacitinib 5 mg BID achieved improvements in pain severity of 30-70% significantly faster compared with pts in the PBO-tofacitinib group (Table). The median time to ≥30% pain improvement was 55 days in the tofacitinib 5 mg BID group and 106 days in the PBO-tofacitinib group (pts switched to tofacitinib 5 mg BID at Month 3; p=0.0132). Similar trends between treatment groups were observed across other pain improvement thresholds. Conclusion: In pts with active PsA, faster, clinically meaningful pain improvements were reported in pts receiving tofacitinib 5 mg BID vs pts receiving PBO who switched to tofacitinib 5 mg BID at Month 3. After switch from PBO to active treatment, pain improvement was observed in line with pts receiving active treatment from Day 0. To achieve pain improvement at greater thresholds, longer duration of active treatment was required.
<b>OBJECTIVE: </b>To evaluate the effect of baseline risk factors on radiographic progression in patients with active psoriatic arthritis (PsA) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and were treated with tofacitinib or adalimumab (ADA).<b>METHODS: </b>Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. OPAL Broaden was a 12-month, double-blind phase III trial. Patients received tofacitinib 5 mg twice daily (BID; n = 107), tofacitinib 10 mg BID (n = 104), or ADA 40 mg once every 2 weeks (n = 106), all with 1 background csDMARD. Radiographs (baseline and Month 12) were scored using the van der Heijde-modified total Sharp score (mTSS) for PsA. Radiographic nonprogression was defined as an increase from baseline in mTSS ≤ 0.5, ≤ 0, or ≤ 0.66. Changes from baseline in mTSS and nonprogression (≤ 0.5 increase from baseline in mTSS) were analyzed by baseline C-reactive protein (CRP) > 2.87 or ≤ 2.87 mg/l. Baseline predictors of radiographic progression were analyzed.<b>RESULTS: </b>At Month 12, > 90% of patients receiving tofacitinib or ADA met all radiographic nonprogression criteria. Mean changes from baseline through Month 12 in mTSS, erosion, and joint space narrowing scores were close to 0. Changes in radiographic outcomes were minimal, irrespective of baseline CRP levels > 2.87 or ≤ 2.87 mg/l, with a small numerical difference observed for tofacitinib 5 mg BID. A significant relationship was observed between baseline CRP level and increases from baseline in mTSS > 0.5 at Month 12.<b>CONCLUSION: </b>Elevated CRP levels at baseline were associated with greater structural progression. Changes in radiographic outcomes were minimal regardless of CRP levels. [Clinical trial registration number (www.ClinicalTrials.gov): NCT01877668].
Background: Pain is a priority for patients (pts) with psoriatic arthritis (PsA) and physicians. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. As pain is a multidimensional phenomenon, there is growing interest in understanding mechanisms of pain relief during treatment. Objectives: To examine the potential role of inflammation in the effect OF tofacitinib on pain in pts with PsA, using mediation modelling. Methods: Data were from the Phase 3 OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439) studies of pts with active PsA treated with tofacitinib 5 mg twice daily (BID) or placebo; pts were tumour necrosis factor inhibitor (TNFi)-naïve or had previous inadequate response (IR) to >1 TNFi. All pts continued on a stable dose of a single conventional synthetic DMARD. Analyses used pooled and individual trial data (mean scores from Months 1, 2 and 3). Mediation modelling seeks to explain mechanisms underlying an observed relationship between independent and dependent variables via other explanatory variables (mediators). In this model, pain (100 mm visual analogue scale) was the designated dependent variable, treatment (tofacitinib 5 mg BID vs placebo) the independent variable and inflammation, measured by swollen joint count (SJC) and C-reactive protein (CRP), was a mediator. The primary model designated treatment effect on pain mediated via CRP/SJC as an indirect effect and treatment effect not attributable to CRP/SJC as a direct effect. Models were re-specified based on initial results; model invariance by population (TNFi-naïve vs TNFi-IR pts) was assessed. Results: In the pooled analysis (N=469), 25.9% (p<0.01) of the tofacitinib treatment effect on pain was mediated by CRP/SJC (indirect effect), of which changes via CRP and SJC were 17.8% (p<0.01) and 8.1% (p>0.05), respectively. The treatment effect on pain not attributable to CRP/SJC (direct effect) was 74.1% (p<0.0001). In TNFi-naïve and TNFi-IR pts, indirect effects via SJC were not statistically significant. In the re-specifed model with CRP as sole mediator, the indirect effect was 21.3% for pooled data (p<0.01; Figure A) and 36.1% (p<0.05) and 16.7% (p<0.05) for TNFi-naïve and TNFi-IR pts, respectively (Figures B, C); the 19.4% difference between TNFi-naïve vs TNFi-IR pts was not statistically significant. Conclusion: While inflammation, as assessed by CRP/SJC, was a significant mediator of the overall treatment effect on pain in tofacitinib-treated pts with PsA, the majority of the treatment effect was not attributable to CRP/SJC changes. When mediators were assessed individually, only CRP was a significant mediator in the pooled analysis. In the re-specified model, CRP-mediated effects differed in TNFi-naïve vs TNFi-IR pts, but this was not statistically significant. These results suggest that CRP/SJC-associated inflammation only partially explains pain in PsA; other potential mediators need to be identified to better understand the treatment effect of tofacitinib on pain.
Objectives Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). We evaluated patient-reported outcomes (PROs) in patients with PsA refractory to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and tumour necrosis factor inhibitor-naïve in a 12-month, phase III randomised controlled trial (OPAL Broaden [NCT01877668]). Methods Patients (N=422) received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every 2 weeks or placebo advancing to tofacitinib 5 mg or 10 mg twice daily at month 3. Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences (MCID); and scores ≥normative values in: Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level questionnaire (EQ-5D-3L) and Ankylosing Spondylitis Quality of Life (ASQoL) were determined. Nominal p values were cited without multiple comparison adjustments. Results At month 3, PtGA, Pain, PGJS, FACIT-Fatigue, EQ-5D-3L, ASQoL and SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP) and vitality domain scores exceeded placebo with both tofacitinib doses (p≤0.05); SF-36v2 social functioning with 5 mg twice daily (p≤0.05). Percentages reporting improvements ≥MCID in PtGA, Pain, PGJS, FACIT-Fatigue, ASQoL and SF-36v2 PCS, PF, BP and general health scores exceeded placebo with both tofacitinib doses (p≤0.05) and were similar with adalimumab. Conclusion csDMARD-IR patients with active PsA reported statistically and clinically meaningful improvements in PROs with tofacitinib compared with placebo at Month 3.
Background: Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease; the onset of dermatologic symptoms often precedes rheumatic manifestations 1 Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. It has been shown that tofacitinib can improve dermatologic symptoms in patients (pts) with PsA.2,3 Objectives: To investigate the efficacy of tofacitinib in improving additional dermatologic endpoints in adult pts with active PsA. Methods: This analysis included data from 2 placebo (PBO)-controlled, double-blind, Phase 3 studies in pts with active PsA and an inadequate response (IR) to >1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) who were tumour necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden [12 months; NCT01877668]; N=422)2 or had an IR to >1 TNFi (OPAL Beyond [6 months; NCT01882439]; N=394).3 Pts must have had active plaque psoriasis at screening only and were required to receive a stable dose of 1 csDMARD. Pts were randomised to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or PBO (advanced to tofacitinib 5 or 10 mg BID at Month [M]3). Percentage (%) change from baseline (BL) (D) in Psoriasis Area and Severity Index (PASI) total score, % of pts achieving >75% PASI improvement from BL (PASI75) stratified by BL PASI severity (>0 to £10, or >10), and DPatient's Global Joint and Skin Assessment-Visual Analogue Scale Psoriasis question (PGJS-VAS Psoriasis) were measured at M1, 3, 6, and at M9 and 12 (OPAL Broaden only).% DPASI total score and PASI75 were measured only in pts with BL affected body surface area (BSA) >3% and PASI >0. Safety endpoints were also analysed. Results: BL demographics were similar between treatment groups and studies. BL median PASI scores (pts with BL BSA >3% and PASI >0) ranged from 5.6 to 7.8 (OPAL Broaden) and 7.1 to 8.8 (OPAL Beyond). BL mean PGJS-VAS Psoriasis ranged from 51.0 to 54.8 (OPAL Broaden) and 53.5 to 58.9 (OPAL Beyond). At M1 and 3, % DPASI total score, PASI75 response rates in pts with mild or moderate/severe dermatologic symptoms at BL, and DPGJS-VAS Psoriasis were improved vs PBO in tofacitinib-treated pts; these improvements were maintained to M12 in OPAL Broaden and M6 in OPAL Beyond (Table). Similar effects were observed in adalimumab-treated pts vs PBO in OPAL Broaden across these endpoints. Serious adverse events (AEs) and discontinuations due to AEs were similar across treatment groups up to M6 in OPAL Beyond and M12 in OPAL Broaden. Conclusion: In pts with PsA (TNFi-naïve or TNFi-IR), tofacitinib improved dermatologic endpoints, and responses were maintained to the end of each study. Tofacitinib may provide a treatment option for pts with active PsA, including the dermatologic symptoms of PsA.
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.
Background: Current treatments for PsA have proven effective in reducing patient (pt)-reported pain;1,2 however, residual pain often remains. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Objectives: This descriptive analysis evaluated the effect of tofacitinib, adalimumab and placebo on residual pain in pts with PsA whose inflammation was attenuated after 3 months of therapy. Methods: Data were included from OPAL Broaden (NCT01877668), a randomised, double-blind, placebo-controlled Phase 3 trial of 12 months' duration in pts with PsA.3 Pts were randomised to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks or placebo. This analysis assessed pts with 'residual pain' at Month (M)3. Residual pain was considered as pain in pts with complete attenuation of inflammation at M3, defined by a swollen joint count (SJC) of 0 and CRP levels <6 mg/L. Pain was measured by a visual analogue scale (VAS; 0 [“no pain”]-100 mm [“most severe pain”]). Changes in pain from baseline to M3 and residual pain (VAS pain reported at M3) were assessed. Results: Demographics and baseline disease characteristics have previously been reported in the primary study, and were generally similar between treatment groups.3 At M3, 100/422 (23.7%) pts with PsA had achieved SJC of 0 and CRP <6 mg/L. At M3, more tofacitinib-treated (tofacitinib 5 mg BID, n=23/107 [21.5%]; tofacitinib 10 mg BID, n=33/104 [31.7%]) and adalimumab-treated pts (n=31/106 [29.2%]) achieved SJC of 0 and CRP <6 mg/L vs placebo (PsA: n=13/105 [12.4%]). Baseline pain appeared numerically higher in tofacitinib-treated pts (tofacitinib 5 mg BID, 54.7 mm; tofacitinib 10 mg BID, 58.4 mm) vs adalimumab-treated pts (47.7 mm) and placebo (50.4 mm). In pts who achieved SJC of 0 and CRP <6 mg/L at M3, improvements in pain from baseline to M3 appeared numerically greater in pts receiving tofacitinib vs those receiving placebo (Figure 1a). When considering absolute (residual) pain at M3, mean residual pain was similar across treatment groups (ranging from 22.7-29.2 mm; Figure 1b), despite a higher baseline pain in tofacitinib treatment groups. Conclusion: Changes from baseline in pain and absolute pain at M3 suggest that in pts with PsA whose inflammation has been completely attenuated, tofacitinib might have an effect on residual pain not obviously attributable to inflammation. However, the sample population was small, and there were large standard deviations. To confirm these results and to understand the mechanisms by which tofacitinib may improve residual pain, a meta-analysis will be performed using individual participant data from pts with rheumatic disease who have participated in tofacitinib randomised controlled trials.
Objective: Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. Methods: Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C-reactive protein, HAQ-DI, Patient’s/Physician’s Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. Results: Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. Conclusion: Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.
Background: An international task force has agreed that remission and low disease activity (LDA) are treatment targets for patients (pts) with PsA, and recommends the Disease Activity Index in Psoriatic Arthritis (DAPSA) and minimal disease activity (MDA) to assess disease activity states.1 Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Objectives: In this post hoc analysis, we compared DAPSA LDA with MDA, and DAPSA remission with very low disease activity (VLDA) and DAS28-3(CRP) remission, in pts with PsA receiving tofacitinib. Methods: Data were pooled from 2 Phase 3 studies (OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]) for pts receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo (PBO). DAPSA was determined by summing: swollen joint count (SJC66); tender/painful joint count (TJC68); Patient's Global Assessment of Arthritis (PtGA; visual analogue scale [VAS]); pain (VAS); and CRP. Pts were classified as achieving MDA or VLDA when meeting ≥5 (MDA) or 7 (VLDA) of the following criteria: TJC68 ≤1; SJC66 ≤1; Psoriasis Activity and Severity Index ≤1 or body surface area ≤3%; pain (VAS) ≤15; PtGA (VAS) ≤20; HAQ-DI ≤0.5; tender entheseal points (using Leeds Enthesitis Index [LEI]) ≤1. A logistic regression model was used to assess demographic and baseline characteristics as predictors of a trend in DAPSA scores at Month (M)3. DAPSA LDA (≤14), MDA, DAPSA remission (DAPSA ≤4), VLDA and DAS28-3(CRP) remission (DAS28-3[CRP]<2.6) rates were compared at M1, M3 and M6 for pts receiving tofacitinib 5 mg BID and at M6 for pts receiving tofacitinib 5 or 10 mg BID. Agreement between disease activity indices at M6 was evaluated using a kappa test. The percentage of tofacitinib-treated pts who achieved MDA, VLDA and non-response was reported at M6, stratified by achievement of DAPSA LDA, remission or non-response. Results: This analysis included 709 pts: tofacitinib 5 mg BID, n=237; tofacitinib 10 mg BID, n=236; PBO, n=236. At M3, older patients treated with tofacitinib, and tofacitinib-or PBO-treated pts with higher baseline SJC66, TJC68, PtGA VAS, HAQ-DI, LEI and Pain VAS, were significantly (p<0.05) more likely to have higher DAPSA. DAPSA LDA, MDA, remission (DAPSA and DAS28-3[CRP]) and VLDA rates generally increased from M1 to M6 for patients receiving tofacitinib 5 mg BID (Figure a). At M6, most tofacitinib-treated pts who achieved MDA, and all who achieved VLDA, were also in DAPSA remission or LDA (Figure b). At least moderate agreement (defined by kappa values 0.41-0.60) was observed between DAPSA LDA and MDA, and between DAPSA remission and VLDA, with both doses of tofacitinib at M6 (Figure c). Conclusion: Remission and LDA rates generally increased over time in pts with PsA receiving tofacitinib. DAPSA LDA showed moderate agreement with MDA, and DAPSA remission showed at least moderate agreement with VLDA, confirming that DAPSA and MDA are useful measurement tools to assess disease activity in pts with PsA treated with tofacitinib.
This is a 12-month study investigating the effectiveness and safety of tofactinib in treating the signs and symptoms of active psoriatic arthritis and improving physical function and preserving bone structure in patients with an inadequate response to a traditional, nonbiologic disease-modifying antirheumatic drug. Adalimumab is used as a comparator.
