This post hoc analysis assessed tofacitinib and adalimumab efficacy and safety, stratified by baseline methotrexate (MTX) dose, in patients with rheumatoid arthritis (RA) in the Oral Rheumatoid Arthritis triaL (ORAL) Strategy study. ORAL Strategy (NCT02187055) was a global, 1-year, phase 3b/4 study. Patients with RA and an inadequate response to MTX were randomized to tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or adalimumab 40 mg once every 2 weeks plus MTX, with MTX dosed per the last weekly dose pre-randomization. This post hoc analysis stratified patients by MTX dose in tertiles normalized by body mass index (BMI) and weight at baseline. Efficacy was assessed using American College of Rheumatology (ACR) 50 response rates at month 6 (primary endpoint); safety was assessed throughout. Efficacy and safety were analyzed descriptively. Of 1146 patients, 97 received MTX < 15 mg/week at baseline, 712 received 15–17.5 mg/week, and 337 received > 17.5 mg/week. In the tofacitinib and adalimumab combination therapy groups, similar ACR50 response rates at month 6 were observed across the baseline BMI-normalized MTX dose tertiles. This trend was also observed in the tofacitinib monotherapy group; however, the ACR50 response rates at month 6 were numerically higher with combination versus tofacitinib monotherapy, regardless of baseline BMI-normalized MTX dose tertile. Generally similar results were observed for the baseline weight-normalized MTX data. No clear trends across baseline BMI-normalized MTX dose tertiles were observed for safety outcomes. In ORAL Strategy, tofacitinib efficacy was generally similar, and there were no clear safety trends regardless of baseline BMI-normalized MTX dose. ClinicalTrials.gov identifier, NCT02187055.

OBJECTIVE:Predictive biomarkers for patients with early rheumatoid arthritis (RA) are needed. This exploratory post hoc analysis investigated inflammatory biomarkers associated with baseline disease activity and biomarkers predictive of treatment response in patients who were seropositive with early RA from a phase 3 study. METHODS:The AVERT-2 study (NCT02504268) included patients who were disease-modifying antirheumatic drug naive and anti-citrullinated protein antibody positive randomized to abatacept and methotrexate (MTX) or placebo and MTX for 56 weeks. Correlations were assessed among biomarkers and disease activity, pharmacodynamic (PD) changes on disease-associated biomarkers in response to treatment, and baseline biomarkers to predict treatment response at week 52. RESULTS:In the analysis, 446 patients received abatacept and MTX and 300 received placebo and MTX. Of 103 biomarkers, 47 demonstrated a significant reduction in PD changes with abatacept and MTX versus placebo and MTX, with 18 out of 47 biomarkers showing correlations with baseline disease activity. High baseline interleukin-10 (IL-10) levels were associated with greater probability of achieving efficacy measures by week 52 in patients receiving abatacept and MTX versus placebo and MTX, consistent with a significant reduction in disease activity with abatacept and MTX (P < 0.03 to P < 0.0007). Higher baseline IL-10 levels were associated with lower bone erosive development with abatacept and MTX compared with placebo and MTX. CONCLUSION:Treatment with abatacept and MTX resulted in significantly greater reduction of biomarkers relevant to RA, and high baseline IL-10 levels predicted better treatment response with abatacept and MTX versus placebo and MTX across clinical outcomes. Findings suggest a well-suited mechanism of action for abatacept and MTX in patients with early RA and high baseline IL-10 levels.

OBJECTIVES:After the first tumour necrosis factor inhibitor (TNFi) failure, patients with rheumatoid arthritis (RA) often cycle to a second; however, switching mechanisms of action has been postulated to improve outcomes. The ongoing SELECT-SWITCH trial compared upadacitinib with adalimumab for active RA after first TNFi failure at 12 weeks. METHODS:Patients with inadequate response or intolerance to 1 nonadalimumab TNFi receiving stable methotrexate were randomised (1:1) to 15 mg once daily upadacitinib or 40 mg every-other-weekly adalimumab. The primary endpoint was achieving superiority in Disease Activity Score 28 (DAS28)-C-reactive protein (CRP) ≤3.2 at week 12. Ranked secondary endpoints (week 12, superiority) were (1) achieving ≥50% improvement in American College of Rheumatology response criteria (ACR50); (2) achieving DAS28-CRP <2.6; change from baseline in (3) DAS28-CRP; (4) pain; (5) Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS:Overall, 492 patients were randomised. Baseline characteristics were balanced between groups. Week 12 DAS28-CRP ≤3.2 response was superior with upadacitinib (43.3%) vs adalimumab (22.4%; difference, 21.0% [95% CI: 12.9-29.1]; P < .0001) as were ACR50 (38.2% vs 26.8% [P = .0068]), DAS28-CRP <2.6 (28.4% vs 14.5%; P = .0002), mean changes in DAS28-CRP (-2.432 vs -1.840; P < .0001) and pain (-3.165 vs -2.373; P = .0005), but not in HAQ-DI (-0.523 vs -0.496; P = .5849). Safety was comparable between treatments. CONCLUSIONS:The primary endpoint of the SELECT-SWITCH trial was met, with a higher percentage of patients with active RA who switched to upadacitinib after first TNFi failure achieving DAS28-CRP ≤3.2 at 12 weeks than those cycling to a second TNFi, adalimumab, with generally similar safety profiles. CLINICALTRIAL: GOV IDENTIFIER:NCT05814627.

Objectives To assess the safety and efficacy of upadacitinib versus adalimumab through 7 years in the ongoing SELECT-COMPARE study.Methods Patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) were randomised to placebo, upadacitinib 15 mg once daily or adalimumab 40 mg every other week (on background MTX). Inadequate responders were rescued to the alternate therapy, with placebo recipients switching to upadacitinib by week 26. Patients completing 48 weeks were eligible to enter the 10-year extension. Safety was assessed as treatment-emergent adverse events (TEAEs); efficacy was analysed by randomised group (non-responder imputation [NRI]) or treatment sequence (as observed [AO]).Results Upadacitinib was generally well tolerated, displaying TEAE rates comparable to adalimumab, but numerically higher rates of herpes zoster, creatine phosphokinase elevation, non-melanoma skin cancer, lymphopenia and hepatic disorders. Responses with continuous upadacitinib or adalimumab were maintained through 372 weeks; week 372 Clinical Disease Activity Index remission (≤2.8) and 28-joint Disease Activity Score based on C-reactive protein<2.6 were achieved by 145/230 (63.0%) and 178/204 (83.2%) (AO)/142/651 (21.8%) and 172/651 (26.4%) (NRI) of patients with upadacitinib versus 46/86 (53.5%) and 59/81 (72.8%) (AO)/43/327 (13.1%) and 55/327 (16.8%) (NRI) with adalimumab. Initial non-responders/incomplete responders benefited from switching, with improvements in efficacy endpoints maintained through week 336 post switch, without additional safety concerns.Conclusion The safety profile of upadacitinib remained consistent with previous analyses, with no new safety concerns through 7 years. Upadacitinib and adalimumab (continuous or rescue treatment) maintained disease activity targets throughout the 7-year treatment period. Upadacitinib exhibited an acceptable benefit–risk profile for long-term RA treatment.Trial registration number NCT02629159.

OBJECTIVES:This systematic literature review (SLR) on safety outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi). METHODS:An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For safety, randomised, placebo-controlled or active-controlled trials on all JAKi investigated in IMIDs, long-term extension (LTE) studies, pooled trial data analyses, and cohort and claims studies were included. RESULTS:We screened 13,905 records, of which 209 were finally included. Three safety trials and 13 post hoc analyses, 83 efficacy randomised controlled trials (RCTs) with adequate safety reporting, 56 integrated safety analyses and LTE of RCTs, 20 additional conference abstracts on RCT data, as well as 37 real-world cohort studies were presented to the task force. Safety profiles of JAKi were overall consistent across compounds and indications, but impacts of patient profiles, treatment dosing, and other cofactors like background medications on drug safety could be observed. Furthermore, differential effects of variously selective JAKi on distinct adverse events of special interest (AESI) and laboratory outcomes were discerned. CONCLUSION:A substantial amount of literature was published on JAKi safety since 2019. A comprehensive overview of these data supports the optimal use of JAKi in patients with IMIDs, by consideration and balance of their benefits as well as risks in every patient.

In light of the introduction of new Janus kinase inhibitors (JAKi), new indications for JAKi and recent safety considerations that have arisen since the preceding consensus statement on JAKi therapy, a multidisciplinary taskforce was assembled, encompassing patients, health care professionals, and clinicians with expertise in JAKi therapy across specialties. This taskforce, informed by two comprehensive systematic literature reviews, undertook the objective to update the previous expert consensus for using JAKi developed in 2019. The taskforce deliberated on overarching principles, indications, dosage and comedication strategies, warnings and contraindications, screening protocols, monitoring recommendations, and adverse effect profiles. The methodology was based on the European Alliance of Associations for Rheumatology standard operating procedures, with voting on these important elements. Furthermore, an updated research agenda was proposed. The task force did not address when a JAKi should be prescribed but rather considerations once this decision has been made. This update aimed to equip clinicians with the necessary knowledge and guidance for the efficient and safe administration of this expanding and significant class of drugs.

OBJECTIVE:To determine whether higher serum exposure during subcutaneous (SC) abatacept (ABA) treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA). METHODS:Data from Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT2; ClinicalTrials.gov: NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody-positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed. The association between steady-state ABA concentration exposures (ie, steady-state time-averaged serum concentration, steady-state trough serum concentration, steady-state maximum serum concentration) and first infection was evaluated using Kaplan-Meier plots of probability vs time receiving treatment and Cox proportional hazards models. RESULTS:The PK model of SC ABA was defined as a linear 2-compartment model with first-order absorption and elimination, and higher body weight was the only covariate with a clinically relevant effect in the final PPK model. Infections occurred in 330/693 patients treated with ABA + methotrexate (MTX; 47.6%; 11/693 [1.6%] with serious infections) and 134/301 of those treated with ABA placebo + MTX (44.5%; 4/301 [1.3%] with serious infections). Exposure-response analysis demonstrated no exposure relationship for an increased risk of first infection for patients with concomitant use of MTX and glucocorticoids (GCs) during the induction period, baseline GC use, or higher-than-median body weight (> 70 kg) at baseline. CONCLUSION:This exposure-response analysis of AVERT-2 showed no increase in the risk of first infection, regardless of ABA exposure level, in patients with RA treated with SC ABA. Similarly, no effect on the risk of first infection was found for concomitant MTX and GC use in patients with RA treated with SC ABA + MTX.

Objectives Evaluate the risks and benefits of upadacitinib 15 mg vs adalimumab in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate based on cardiovascular (CV) risk.Methods In SELECT-COMPARE, patients received upadacitinib 15 mg, placebo or adalimumab 40 mg every other week, with background methotrexate. This post hoc analysis assessed patients with lower (age <65 years; no CV risk factors) and higher CV risk (age ≥65 years and/or ≥1 CV risk factor). Safety and efficacy outcomes were compared between upadacitinib and adalimumab over the short term (~6 months) and long term (5 years) based on CV risk.Results The study included 211 lower-risk patients (upadacitinib, n=129; adalimumab, n=82) and 767 higher-risk patients (upadacitinib, n=522; adalimumab, n=245). Rates of malignancy excluding nonmelanoma skin cancer (NMSC), major adverse cardiovascular event and venous thromboembolism were comparable between upadacitinib and adalimumab in both risk groups but numerically higher in the higher-risk group. Upadacitinib showed higher rates of herpes zoster versus adalimumab in both risk groups and numerically higher rates of serious infection and NMSC in the higher-risk group. Upadacitinib demonstrated consistently better efficacy outcomes, including 28-joint Disease Activity Score (C reactive protein) <2.6, Clinical Disease Activity Index remission and Boolean remission at 6 months, which were generally maintained through 5 years.Conclusions Regardless of baseline CV risk, upadacitinib demonstrated comparable safety to adalimumab, except for higher rates of herpes zoster in both CV risk groups and NMSC and serious infections in the higher-risk group. Upadacitinib consistently showed better clinical and functional outcomes than adalimumab. The benefit–risk profile of upadacitinib in RA patients was favourable, independent of CV risk category, in both short and long term.

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.

OBJECTIVE:To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study. METHODS:Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission. RESULTS:A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE. CONCLUSION:The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228 weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase 3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15 mg once daily or adalimumab 40 mg every other week were switched to the alternate therapy by week 26. Efficacy was evaluated through 228 weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20

OBJECTIVE:The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS:Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS:Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION:Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Objectives To assess the safety and efficacy of upadacitinib versus adalimumab from SELECT-COMPARE over 5 years.Methods Patients with rheumatoid arthritis and inadequate response to methotrexate were randomised to receive upadacitinib 15 mg once daily, placebo or adalimumab 40 mg every other week, all with concomitant methotrexate. By week 26, patients with insufficient response to randomised treatment were rescued; patients remaining on placebo switched to upadacitinib. Patients completing the 48-week double-blind period could enter a long-term extension. Safety and efficacy were assessed through week 264, with radiographic progression analysed through week 192. Safety was assessed by treatment-emergent adverse events (TEAEs). Efficacy was analysed by randomised group (non-responder imputation (NRI)) or treatment sequence (as observed).Results Rates of TEAEs were generally similar with upadacitinib versus adalimumab, although numerically higher rates of herpes zoster, lymphopenia, creatine phosphokinase elevation, hepatic disorder and non-melanoma skin cancer were reported with upadacitinib. Numerically greater proportions of patients randomised to upadacitinib versus adalimumab achieved clinical responses (NRI); Clinical Disease Activity Index remission (≤2.8) and Disease Activity Score based on C reactive protein <2.6 were achieved by 24.6% vs 18.7% (nominal p=0.042) and 31.8% vs 23.2% (nominal p=0.006), respectively. Radiographic progression was numerically lower with continuous upadacitinib versus adalimumab at week 192.Conclusion The safety profile of upadacitinib through 5 years was consistent with the known safety profile of upadacitinib, with no new safety risks. Clinical responses were numerically higher with upadacitinib versus adalimumab at 5 years. Upadacitinib demonstrates a favourable benefit–risk profile for long-term rheumatoid arthritis treatment.Trial registration number NCT02629159.