EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Upadacitinib in Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs: Efficacy and Safety Through 5 Years (SELECT-NEXT).

OBJECTIVE: To report 5-year efficacy and safety of upadacitinib (UPA) in rheumatoid arthritis (RA) from the phase III long-term extension (LTE) of SELECT-NEXT. METHODS: Patients on stable conventional synthetic disease-modifying antirheumatic drugs were randomized to UPA 15 mg once daily (QD), UPA 30 mg QD, or placebo for 12 weeks. Following this, placebo-randomized patients were switched to UPA 15 mg QD or UPA 30 mg QD in the LTE; UPA-randomized patients continued their original dose. Blinding remained until dose switching from UPA 30 mg QD to UPA 15 mg QD because of approval of UPA 15 mg QD; the earliest switch occurred at week 168. Efficacy (as observed) and treatment-emergent adverse events (TEAEs) are reported through 5 years. RESULTS: Overall, 611 (92%) randomized patients entered the LTE; 271 (44%) discontinued the study drug by 5 years, primarily because of adverse events (16%). Clinical outcomes improved or were maintained at 5 years; 51% and 43% of patients achieved Clinical Disease Activity Index remission and 75% and 66% achieved Disease Activity Score in 28 joints based on C-reactive protein < 2.6 among those initially randomized to UPA 15 mg QD and UPA 30 mg QD, respectively. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria responses increased from week 60 through 5 years. Results were similar regardless of initial randomization to UPA or placebo. TEAEs, including TEAEs of special interest, were consistent with earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were reported infrequently. No new safety signals were observed. CONCLUSION: The 5-year benefit-risk profile for UPA in RA remains favorable. (SELECT-NEXT; ClinicalTrials.gov: NCT02675426).

Maximal Exercise Tolerance, Objective Trunk Strength, and Mobility Measurements in Axial Spondyloarthritis.

OBJECTIVE: Although exercise therapy is safe, effective, and recommended as a nonpharmacological treatment for axial spondyloarthritis (axSpA), there is a lack of guidelines regarding type and dosage. Insufficient knowledge about physical and physiological variables makes designing effective exercise programs challenging. Therefore, the goal of this study was to simultaneously assess trunk strength, spinal mobility, and the cardiorespiratory fitness of patients with axSpA. METHODS: In a cross-sectional study, 58 patients with axSpA (mean age 40.8 yrs, 50% male, mean symptom duration 10.3 yrs) performed maximal cervical and trunk mobility and isometric strength tests in all planes (using David Back Concept devices) and a maximal cardiopulmonary bicycle exercise test (n = 25). Mobility and strength data were compared to healthy reference data. Cut-off values for clinical cardiopulmonary exercise testing interpretation were used to judge normality. Patients were compared based on radiographic involvement and symptom duration. RESULTS: Both strength (P ≤ 0.02) and mobility (P ≤ 0.001) were significantly lower for the patients with axSpA compared to the reference. Strength deficits were comparable between the radiographic and nonradiographic groups (P > 0.05, except trunk extension [P = 0.03]), whereas mobility showed higher deficits in the radiographic group (cervical extension [P = 0.02] and rotation [P = 0.01], and trunk extension [P = 0.03] and rotation [P = 0.03]), regardless of symptom duration. Similarly, symptom duration positively affected oxygen pulse (P = 0.03), relative anaerobic threshold (P = 0.02), and aerobic capacity (P = 0.02). CONCLUSION: In patients with axSpA, strength is more affected than mobility when compared to healthy controls. Likewise, mainly the metabolic component of aerobic capacity is impaired, affecting cardiopulmonary fitness. These findings indicate that future personalized exercise programs in patients with axSpA should incorporate exercises for cardiopulmonary fitness next to strength and mobility training.

When Usual Care Is Not So Usual: Protocol Violations and Generalizability in a Treat-to-Target Strategy Trial in Patients With Axial Spondyloarthritis.

OBJECTIVE: The objective of this study was to evaluate the impact of protocol violations in the treat-to-target group in the Tight Control in Spondyloarthritis (TICOSPA) trial and to compare the proportion of patients optimally treated according to the Assessment of Spondyloarthritis International Society (ASAS)/EULAR 2016 recommendations for patients with axial spondyloarthritis (axSpA) between the treat-to-target versus usual care (UC) arms. METHODS: This study was a cluster-randomized, controlled 48-week trial including patients with axSpA who fulfilled the ASAS criteria, had an Axial Spondyloarthritis Disease Activity Score >2.1, and were biologic disease-modifying antirheumatic drug naive. Eighteen axSpA expert centers were randomly allocated to one treatment arm: (a) treat-to-target prespecified management strategy (four-week visits), and (b) UC treatment decisions at the rheumatologist's discretion (12-week visits). Protocol violations in the treat-to-target arm and the fulfillment of the 2016 ASAS/EULAR recommendations in both arms were evaluated at every visit. ASAS Health Index (ASAS-HI) and disease activity outcomes at 48 weeks were compared between treat-to-target violators versus nonviolators. Patients treated according to the ASAS/EULAR recommendations were compared between both arms. RESULTS: A total of 160 patients initiated the trial (80 patients with treat to target; 80 patients with UC). In the treat-to-target arm, 51.2% patients violated the protocol at least once (62.2% of violations resulting in maintenance/reduction of treatment against protocol). After 48 weeks, treat-to-target violators versus nonviolators showed similar ratios of ASAS-HI improvement. The proportion of patients managed according to the ASAS/EULAR recommendations after the first 12 weeks were 63.9% versus 61.8% for the treat-to-target and UC arms, respectively. CONCLUSION: Protocol violations in the treat-to-target arm in the TICOSPA trial were frequent, although they did not have an impact on the rate of the primary outcome. The groups with UC was optimally treated, partly explaining the nonachievement of the primary objective in the TICOSPA trial.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

INTRODUCTION: 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. METHODS: 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%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week 264. RESULTS: Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week 26. Clinically relevant improvements in all efficacy measures were observed through 228 weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. CONCLUSION: Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. TRIAL REGISTRATION: NCT02629159.

Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 100-Week Results from the KEEPsAKE 2 Randomized Clinical Trial.

INTRODUCTION: Long-term therapeutic options providing durable response and tolerability are needed for psoriatic arthritis (PsA). The ongoing KEEPsAKE 2 trial is evaluating risankizumab treatment in patients with active PsA who previously had inadequate response/intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and/or 1-2 biologic DMARDs (bDMARD-IR). Herein, we report results through 100 weeks of treatment. METHODS: KEEPsAKE 2 is a global phase 3 trial. Patients with active PsA were randomized 1:1 to double-blind subcutaneous risankizumab 150 mg or placebo (weeks 0, 4, and 16). At week 24, all patients received open-label risankizumab every 12 weeks until end of study. Efficacy endpoints included achieving ≥ 20% improvement in PsA symptoms using American College of Rheumatology criteria (ACR20), attaining minimal disease activity (MDA; meeting ≥ 5/7 criteria of low disease activity and extent), and improving in other measures. RESULTS: At the cutoff date, 345/443 (77.9%) patients were ongoing in the study. ACR20 was achieved in 57.1% and 52.5% of the continuous risankizumab and placebo/risankizumab cohorts, respectively, at week 100 and in 60.0% and 55.8%, respectively, at week 52. In week 52 responders, maintenance of ACR20 at week 100 was achieved in 74.8% (continuous risankizumab) and 78.7% (placebo/risankizumab) of patients. In the continuous risankizumab and placebo/risankizumab cohorts, respectively, MDA was achieved by 33.0% and 33.3% of patients at week 100 and by 27.2% and 33.8% at week 52. Among MDA responders at week 52, maintenance of MDA response was achieved by 83.6% and 73.0% of the continuous risankizumab and placebo/risankizumab cohorts, respectively. Risankizumab was well tolerated through week 100. CONCLUSIONS: Risankizumab demonstrated durable efficacy and tolerability through 100 weeks; most patients who achieved ACR20 and MDA responses at week 52 maintained this achievement through week 100. There were no new safety signals in patients who had csDMARD-IR and bDMARD-IR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03671148.

Risankizumab, a biologic disease-modifying antirheumatic drug, helps control the body's immune system to reduce symptoms of psoriatic arthritis (a disease that inflames the joints of people who have the skin condition psoriasis). The ongoing KEEPsAKE 2 study is evaluating how well risankizumab works and how safe it is for treating adult patients with active psoriatic arthritis who previously experienced inadequate response to one or more specific types of disease-modifying anti-arthritis drugs. Patients were randomly assigned to receive either risankizumab or an inactive drug; after 24 weeks, all patients received risankizumab. At study week 100, 57% of patients who were assigned to receive continuous risankizumab since the start of the study experienced a 20% or more improvement in a measure of psoriatic arthritis symptoms using criteria established by the American College of Rheumatology (ACR20); a similar proportion of patients achieved a 20% improvement at both weeks 24 and 52. Similarly, 56% and 53% of patients who switched from inactive drug to risankizumab achieved ACR20 at weeks 52 and 100 (more than before switching to risankizumab at week 24). Minimal disease activity (MDA) was evaluated by assessing joint and skin symptoms, affected body surface area, pain, and physical function. At week 100, 33% of patients achieved MDA (both groups), which was similar to week 52. Most patients who achieved ACR20 or MDA at week 52 maintained responses at week 100. Improvements with risankizumab were seen in several other measures of treatment outcomes through week 100. Risankizumab was generally safe through 100 weeks.

Upadacitinib in Active Non-radiographic Axial Spondyloarthritis: 1-Year Data From a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial.

OBJECTIVE: Upadacitinib improved the signs and symptoms of non-radiographic axial spondyloarthritis (nr-axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT-AXIS 2 nr-axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr-axSpA in SELECT-AXIS 2. METHODS: Patients aged at least 18 years diagnosed with nr-axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52-week double-blind period. Efficacy was assessed using non-responder imputation incorporating multiple imputation (NRI-MI) and as-observed analyses for binary endpoints, and mixed-effects model repeated measures for continuous endpoints. RESULTS: Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI-MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI-MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. CONCLUSION: Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit-risk profile of upadacitinib treatment for nr-axSpA.

Long-Term Safety of Risankizumab in Patients with Psoriatic Disease: A Comprehensive Analysis from Clinical Trials.

INTRODUCTION: Risankizumab has demonstrated a favourable safety profile in patients with psoriatic disease (moderate-to-severe psoriasis [PsO] and psoriatic arthritis [PsA]). We evaluated the long-term safety of risankizumab in psoriatic disease. METHODS: Long-term safety was evaluated by analysing data from 20 (phase 1-4) clinical trials for plaque PsO and four (phase 2-3) trials for PsA. Treatment-emergent adverse events (TEAEs) and AEs in areas of special interest were reported among patients receiving ≥ 1 dose of risankizumab. Exposure-adjusted event rates were presented as events (E) per 100 patient-years (PY). RESULTS: The long-term safety data analyses included 3658 patients with PsO (13,329.3 PY) and 1542 patients with PsA (3803.0 PY). The median (range) treatment duration for patients with PsO and PsA was 4.1 (0.2-8.8) years and 2.8 (0.2-4.0) years, respectively. In the PsO population, rates of TEAEs, serious AEs and AEs leading to discontinuation were 145.5 E/100 PY, 7.4 E/100 PY and 1.9 E/100 PY, respectively; in the PsA population, these rates were 142.6 E/100 PY, 8.6 E/100 PY, and 1.8 E/100 PY, respectively. The rates of serious infections (excluding COVID-19-related infections) in the PsO and PsA populations were 1.2 and 1.4 E/100 PY, respectively. The rates of opportunistic infections (excluding tuberculosis and herpes zoster) were low (< 0.1 E/100 PY) in both populations. The rates of both nonmelanoma skin cancer (NMSC) and malignant tumours excluding NMSC were 0.6 and 0.5 E/100 PY in PsO and PsA, respectively, which are within the benchmarks of prior epidemiological studies. Adjudicated major cardiovascular event rates were 0.5 E/100 PY in PsO and 0.3 E/100 PY in PsA, which are within the epidemiologic reference benchmarks for both indications. No additional safety concerns were identified with this long-term exposure. CONCLUSIONS: The results support the favourable safety profile of risankizumab for long-term treatment of psoriatic disease with no new safety concerns and similar safety profiles among both PsO and PsA populations.

Classification Criteria for Axial Disease in Youth with Juvenile Spondyloarthritis.

OBJECTIVES: To develop and validate classification criteria for axial disease in youth with juvenile spondyloarthritis (SpA; AxJSpA). METHODS: This international initiative consisted of four phases: 1) Item generation; 2) Item reduction; 3) Criteria development; and 4) Validation of the AxJSpA criteria by an independent team of experts in an internationally representative Validation cohort. RESULTS: These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians and collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included: imaging: active inflammation, imaging: structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% CI: 91.4-99.7), sensitivity of 64.3% (95% CI: 54.9-73.1) and Area Under the Receiver Operating Characteristic (AUROC) curve of 0.81 (95% CI: 0.76-0.86). CONCLUSIONS: The new AxJSpA classification criteria require an entry criterion, physician diagnosis of juvenile SpA, and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.