Improvements in Patient-Reported Outcomes Through Six Months of Guselkumab Treatment in Patients With Active Psoriatic Arthritis: Real-World Data From the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

OBJECTIVE: Evaluate patient-reported outcomes after 6 months of on-label guselkumab use in patients with rheumatologist-diagnosed active psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry. METHODS: This analysis includes registry participants who initiated and persisted with on-label guselkumab (after US Food and Drug Administration approval for PsA; 100 mg at weeks 0, 4, and every 8 weeks) at their 6-month follow-up visit (On-Label Persisters). Among patients not meeting response criteria at baseline, responses at 6 months were determined for patient-reported outcomes, including patient-reported pain (0-100 mm visual analog scale), patient global assessment of arthritis + psoriasis (PtGA; 0-100 visual analog scale), and Health Assessment Questionnaire-Disability Index (HAQ-DI; 0-3). Unadjusted, nominal P values were calculated via single-proportion, one-sided test (H0 = 0%; α = 0.05). RESULTS: Of 90 On-Label Persisters, most had treatment-resistant PsA (92.2% and 73.3% previously received ≥1 and ≥2 biologic/targeted synthetic disease-modifying antirheumatic drugs, respectively), with mean (SD) baseline patient-reported pain, PtGA, and HAQ-DI scores of 57.0 (24.6), 50.3 (24.4), and 0.9 (0.6), respectively. Among those with patient-reported pain and PtGA scores of at least 15 at baseline, 40.2% (33/82) and 46.8% (36/77), respectively, achieved at least 15-mm reductions at 6 months; among those with HAQ-DI scores of at least 0.35 and more than 0.5 at baseline, respectively, 30.4% (21/69) achieved improvements of at least 0.35 and 10.3% (6/58) achieved scores of 0.5 or lower at 6 months (all nominal P < 0.001). CONCLUSION: Pain and physical function are important contributors to health-related quality of life. In this real-world population of patients with treatment-resistant PsA and 6 months of persistent guselkumab treatment, clinically meaningful improvements in pain and physical function were achieved by approximately 40% and 30% of patients, respectively.

The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.

Continuous improvement through differential trajectories of individual minimal disease activity criteria with guselkumab in active psoriatic arthritis: post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study.

BACKGROUND: To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. METHODS: The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. RESULTS: Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p < 0.0001), with SJC ≤ 1 (20 weeks), PASI ≤ 1 (16 weeks), and ≤ 1 tender entheses (16 weeks) being faster than patient-reported criteria (pain ≤ 15 mm, patient global assessment of arthritis and psoriasis ≤ 20 mm, Health Assessment Questionnaire-Disability Index ≤ 0.5) and tender joint count ≤ 1. Higher baseline domain scores, older age, worse fatigue, and increased body mass index were significant predictors of longer time to achieve minimal levels of disease activity assessed via patient-reported criteria. CONCLUSIONS: Substantial proportions of guselkumab-treated patients achieved individual MDA criteria, each showing continuous improvement through week 100, although with distinct trajectories. Median times to achieve physician-assessed MDA criteria were significantly faster compared with patient-driven criteria. Identification of modifiable factors affecting the time to achieve patient-reported criteria has the potential to optimize the achievement and sustainability of MDA in the clinic via a multidisciplinary approach to managing PsA, involving both medical and lifestyle interventions. TRIAL REGISTRATION NUMBER: NCT03158285. TRIAL REGISTRATION DATE: May 16, 2017.

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

OBJECTIVE: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

A clinical review of structural damage in psoriatic arthritis for dermatologists: From pathogenesis to ongoing controversies.

Psoriatic arthritis (PsA) is a chronic inflammatory disease that often goes unrecognized in patients with psoriasis. As a result, patients may develop significant structural damage before diagnosis and initiation of adequate treatment. Dermatologists are in an unique position to identify early signs and symptoms of PsA. Here, we briefly review the pathogenesis of PsA, differences in PsA presentation within real-world dermatology practice versus rheumatology clinical trials, and imaging modalities that can be used to assess structural damage. We then discuss several ongoing controversies related to prediction, assessment, and treatment of PsA-related structural damage. Debated questions include the following: (1) Does subclinical enthesitis predict progression from psoriasis to PsA?, (2) Does methotrexate inhibit progression of structural damage?, (3) Does structural damage correlate with clinical disease activity?, and (4) Can progression from psoriasis to PsA be prevented? Evidence presented herein suggests that dermatologists, together with rheumatologists, can play important roles in the early diagnosis and treatment of PsA, thereby potentially preventing irreversible structural damage.

Long-Term Safety of Guselkumab in Patients with Psoriatic Disease: An Integrated Analysis of Eleven Phase II/III Clinical Studies in Psoriasis and Psoriatic Arthritis.

INTRODUCTION: The benefit/risk profiles of biologics can be affected by comorbidities, certain demographic characteristics, and concomitant medications; therefore, it is important to evaluate the long-term safety profiles of biologics across broad patient populations. Guselkumab was well tolerated and efficacious across individual pivotal clinical studies in adults with moderate-to-severe psoriasis and/or active psoriatic arthritis (PsA). OBJECTIVES: The objective of the current analysis was to evaluate guselkumab safety in a large population of patients with psoriatic disease by pooling adverse event (AE) data from 11 phase II/III studies (seven in psoriasis; four in PsA). METHODS: Guselkumab was generally administered as 100 mg subcutaneous injections at Week 0, Week 4, then every 8 weeks (Q8W) in psoriasis studies and at Week 0, Week 4, then every 4 weeks (Q4W) or Q8W in PsA studies. Safety data were summarized for the placebo-controlled period (Weeks 0-16 in psoriasis; Weeks 0-24 in PsA) and through the end of the reporting period (up to 5 years in psoriasis; up to 2 years in PsA). Using the integrated data, incidence rates of key AEs were determined post hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PYs). AE rates were also determined in subgroups of patients defined by sex, age, body mass index (BMI), and prior biologic use. RESULTS: During the placebo-controlled period, 1061 patients received placebo (395 PYs) and 2257 received guselkumab (856 PYs). Through the end of the reporting period, 4399 guselkumab-treated patients contributed 10,787 PYs of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of AEs were 281 versus 272/100 PYs, and infections were 76.0 versus 72.2/100 PYs. Rates of serious AEs (5.6 vs. 7.8/100 PYs), AEs leading to discontinuation (4.9 vs. 6.6/100 PYs), serious infections (1.0 vs. 2.3/100 PYs), malignancy (0.59 vs. 0.25 patients/100 PYs), and major adverse cardiovascular events (MACE; 0.35 vs. 0.25/100 PYs) were low and comparable between guselkumab and placebo. Among guselkumab-treated patients, safety event rates through the end of the reporting period were numerically lower than or comparable with rates observed during the placebo-controlled period: AEs, 164/100 PYs; infections, 61.2/100 PYs; serious AEs, 5.4/100 PYs; AEs leading to discontinuation, 1.8/100 PYs; serious infections, 1.0/100 PYs; malignancy, 0.6/100 PYs; and MACE, 0.3/100 PYs. No AEs of Crohn's disease, ulcerative colitis, or active tuberculosis were reported among guselkumab-treated patients. In the psoriasis studies, no opportunistic infections were reported among guselkumab-treated patients. Three AEs of opportunistic infections were reported in guselkumab-treated patients with PsA (0.14/100 PYs; all after Week 52 in DISCOVER-2). AE rates were largely consistent across subgroups of guselkumab-treated patients defined by sex, age, BMI, and prior biologic use. CONCLUSIONS: In this analysis of 4399 guselkumab-treated patients with psoriatic disease followed for 10,787 PYs, guselkumab had a favorable AE profile. AE rates were similar between guselkumab- and placebo-treated patients and were consistent throughout long-term guselkumab treatment and across broad subgroups of patients with psoriatic disease. CLINICAL TRIALS REGISTRATIONS: Clinicaltrials.gov identifiers: NCT01483599, NCT02207231, NCT02207244, NCT02203032, NCT02905331, NCT03090100, NCT02325219, NCT02319759, NCT03162796, NCT03158285, and NCT03796858.

Earlier clinical response predicts low rates of radiographic progression in biologic-naïve patients with active psoriatic arthritis receiving guselkumab treatment.

OBJECTIVE: Assess relationship between earlier clinical improvement and radiographic progression (RP) over 2 years in guselkumab-treated patients with active psoriatic arthritis (PsA). METHOD: Post hoc analyses combined data from DISCOVER-2 biologic-naïve adults with active PsA randomized to either guselkumab 100 mg every 4 weeks (Q4W) or guselkumab at W0, W4, then Q8W. Correlations (Spearman's coefficient) between baseline disease parameters and total PsA-modified van der Heijde-Sharp (vdH-S) score were examined. Repeated-measures mixed models, adjusted for known RP risk factors, assessed the relationship between Disease Activity Index in PsA (DAPSA) improvement, DAPSA improvement exceeding the median or the minimal clinically important difference (MCID), or DAPSA low disease activity (LDA) at W8 and RP rate, assessed by change from baseline in vdH-S score through W100. RESULTS: Baseline age, PsA duration, CRP level, and swollen joint count, but not psoriasis duration/severity, weakly correlated with baseline vdH-S score. Elevated baseline CRP (parameter estimate [ß] = 0.17-0.18, p < 0.03) and vdH-S score (ß = 0.02, p < 0.0001) significantly associated with greater RP through W100. Greater improvement in DAPSA (ß = -0.03, p = 0.0096), achievement of DAPSA improvement > median (least squares mean [LSM] difference: -0.66, p = 0.0405) or > MCID (-0.67, p = 0.0610), or DAPSA LDA (-1.44, p = 0.0151) by W8 with guselkumab significantly associated with less RP through W100. The effect of W8 DAPSA LDA on future RP was strengthened over time among achievers vs. non-achievers (LSM difference enhanced from -1.05 [p = 0.0267] at W52 to -1.84 [p = 0.0154] at W100). CONCLUSIONS: In guselkumab-treated patients with active PsA, earlier improvement in joint symptoms significantly associated with lower RP rates through 2 years, indicating blockade of the IL-23 pathway may modify long-term disease course and prevent further joint damage. Key Points • Greater improvement in DAPSA at Week 8 of guselkumab treatment was significantly associated with less progression of structural joint damage at 2 years in patients with active psoriatic arthritis (PsA). • Early control of peripheral joint disease activity with blockade of the IL-23 pathway may modify long-term PsA trajectory and prevent further joint damage.

Efficacy of Guselkumab on Axial-Related Symptoms Through up to 2 Years in Adults with Active Psoriatic Arthritis in the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Study.

INTRODUCTION: Guselkumab previously showed greater improvements versus placebo in axial symptoms in patients with psoriatic arthritis (PsA) (assessed by Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]), in post hoc analyses of the phase 3, placebo-controlled, randomized DISCOVER-1 and DISCOVER-2 studies. We now evaluate durability of response in axial-related outcomes through 2 years of DISCOVER-2. METHODS: DISCOVER-2 biologic-naive adults with active PsA (≥ 5 tender/ ≥ 5 swollen joints, C-reactive protein ≥ 0.6 mg/dl) were randomized to guselkumab 100 mg every 4 weeks (Q4W) or at week 0, week 4, then Q8W, or placebo → guselkumab Q4W at week 24. Among patients with imaging-confirmed sacroiliitis (investigator-identified), axial symptoms were assessed through 2 years utilizing BASDAI, BASDAI Question #2 (spinal pain), modified BASDAI (mBASDAI; excludes Question #3 [peripheral joint pain]), and ASDAS. Mean changes in scores and proportions of patients achieving ≥ 50% improvement in BASDAI (BASDAI 50) and ASDAS responses, including major improvement (decrease ≥ 2.0), were determined through week 100. Treatment failure rules (through week 24) and nonresponder imputation of missing data (post-week 24) were utilized. Mean BASDAI component scores were assessed through week 100 (observed data). Exploratory analyses evaluated efficacy by sex and HLA-B*27 status. RESULTS: Among 246 patients with PsA and imaging-confirmed sacroiliitis, guselkumab-treated patients had greater mean improvements in BASDAI, mBASDAI, spinal pain, and ASDAS scores, lower mean BASDAI component scores, and greater response rates in achieving BASDAI 50 and ASDAS major improvement vs. placebo at week 24. Differences from placebo were observed for guselkumab-treated patients in selected endpoints regardless of sex or HLA-B*27 status. At week 100, mean improvements were ~ 3 points for all BASDAI scores and 1.6-1.7 for ASDAS; 49-54% achieved BASDAI 50 and 39% achieved ASDAS major improvement at week 100. CONCLUSIONS: Guselkumab treatment provided durable and meaningful improvements in axial symptoms and disease activity in substantial proportions of patients with active PsA and imaging-confirmed sacroiliitis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03158285.

Efficacy of Guselkumab in Treating Nails, Scalp, Hands, and Feet in Patients with Psoriasis and Self-reported Psoriatic Arthritis.

INTRODUCTION: The aim of this study was to evaluate guselkumab efficacy on regional psoriasis in a subset of psoriasis patients with a self-reported psoriatic arthritis (PsA) diagnosis. METHODS: In the phase 3 VOYAGE-1 and -2 studies, at week (W)0, patients with moderate-to-severe psoriasis were randomized to guselkumab 100 mg, placebo → guselkumab 100 mg at W16 through W44, or adalimumab 80 mg then 40 mg at W1 through W48 (VOYAGE-1) or W24 (VOYAGE-2). Pooled efficacy outcomes, including scalp-specific Investigator's Global Assessment (ss-IGA), hands and/or feet Physician's Global Assessment (hf-PGA), fingernail PGA (f-PGA), Nail Psoriasis Area and Severity Index (NAPSI), and Dermatology Life Quality Index (DLQI), were compared (nominal p-values) through W24 in patients with self-reported PsA diagnosis. Response rates/percentage improvement from baseline were determined, employing treatment failure rules and non-response/no improvement data imputation. RESULTS: A total of 76, 153, and 106 psoriasis patients with self-reported PsA were randomized to the placebo, guselkumab, or adalimumab groups, respectively; the baseline characteristics of patients in all three arms were comparable. At W16, a greater proportion of guselkumab- versus placebo-treated patients achieved ss-IGA 0/1 (80.6% vs. 22.7%, p < 0.001), hf-PGA 0/1 (68.9% vs. 14.8%, p < 0.001), f-PGA 0/1 (47.6% vs. 17.0%, p < 0.001), and DLQI 0/1 (45.6% vs. 2.7%, p < 0.001) responses; mean percentage NAPSI improvement was also greater with guselkumab (39.5% vs. 6.5%, p < 0.001). At W24, patients receiving guselkumab had higher ss-IGA 0/1 (77.5% vs. 58.5%, p = 0.003) and DLQI 0/1 (47.7% vs. 34.3%, p = 0.024) response rates versus those receiving adalimumab. Response rates/mean percentage improvements at W48 (VOYAGE-1) were numerically greater with guselkumab than adalimumab (e.g., NAPSI improvement: 75.6% vs. 60.9%). CONCLUSIONS: Guselkumab-treated patients with psoriasis and self-reported PsA showed meaningful improvements in nail, scalp, and palmoplantar psoriasis. TRIAL REGISTRATION: VOYAGE-1 (ClinicalTrials.gov Identifier: NCT02207231) and VOYAGE-2 (ClinicalTrials.gov Identifier: NCT02207244).

Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study.

BACKGROUND: Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). METHODS: Adults with active PsA (≥ 3 swollen joints, ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon É£ (IFNÉ£), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. RESULTS: Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNÉ£ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNÉ£ levels versus nonresponders. CONCLUSIONS: Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03796858.

Six-Month Persistence and Multi-domain Effectiveness of Guselkumab in Adults with Psoriatic Arthritis: Real-World Data from the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

INTRODUCTION: The aim of this work is to evaluate treatment persistence and clinical outcomes after 6 months of on-label guselkumab use in patients with rheumatologist-diagnosed active psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry. METHODS: Participants with PsA who initiated and persisted with on-label guselkumab use post-Food and Drug Administration (FDA) approval for active PsA (7/13/2020; subcutaneous 100 mg at weeks 0, 4, and every 8 weeks) at their 6-month follow-up visit (occurring through 3/31/2023) comprised the primary analysis population (On-Label Persisters). Hierarchical, multiplicity-controlled primary and secondary outcomes were mean (95% confidence interval) changes from baseline at 6 months in clinical Disease Activity Index for PsA (cDAPSA; primary), Physician Global Assessment (PGA) of arthritis and psoriasis (visual analog scale [VAS] 0-100), patient-reported pain (VAS 0-100), and percent body surface area with psoriasis (%BSA). Paired t tests determined changes that were statistically significantly different from 0 (α = 0.05). RESULTS: Among 114 patients who initiated on-label guselkumab and had eligible baseline and 6-month visits, 90 (78.9%) had persistent use. Among these On-Label Persisters at baseline, mean duration of PsA symptoms = 13.6 years; mean cDAPSA, PGA, and patient-reported pain = 22.0, 42.3, and 57.0, respectively; 94.4% had a history of psoriasis (mean BSA 7.6%); and 18.9% and 73.3%, respectively, previously received 1 or ≥ 2 biologic/targeted synthetic disease-modifying antirheumatic drugs. The mean change (improvement) in cDAPSA was - 5.4 (- 8.5, - 2.3; p < 0.001) at 6 months. Significant mean improvements in PGA (- 19.0 [- 24.2, - 13.8]), patient-reported pain (- 9.1 [- 14.4, - 3.8]), and %BSA (- 5.1 [- 7.6, - 2.7]) were also observed (all p < 0.001). CONCLUSIONS: In this real-world PsA population, generally characterized by longstanding, treatment-resistant, active disease at baseline, persistent guselkumab use in nearly 80% of patients with on-label use was accompanied by significant improvements in joint and skin symptoms and patient-reported pain at 6 months. These registry data support results from randomized clinical trials demonstrating the efficacy of guselkumab in improving PsA signs and symptoms. TRIAL REGISTRATION: clinicaltrials.gov: NCT02530268.

Response to treatment in psoriatic arthritis, the effect of age: analysis of patients receiving ustekinumab in the PsABio real-world study.

BACKGROUND: This post-hoc analysis of PsABio (NCT02627768) evaluated safety, effectiveness and treatment persistence in patients < 60 and ≥ 60 years of age receiving ustekinumab over 3 years. METHODS: Measures included adverse events (AE), clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) low disease activity (LDA) including remission, Psoriatic Arthritis Impact of Disease-12 (PsAID-12), Minimal Disease Activity, dactylitis, nail/skin involvement and time to treatment stop. Data were analysed descriptively. RESULTS: Overall, 336 patients < 60 and 103 ≥ 60 years received ustekinumab, with a similar gender balance. A numerically lower proportion of younger patients reported at least one AE: 124/379 (32.7%) vs 47/115 (40.9%) for patients < 60 and ≥ 60 years, respectively. Serious AEs were low (< 10%) in both groups. At 6 months, the proportion of patients with cDAPSA LDA was 138/267 (51.7%) and 35/80 (43.8%) for patients < 60 and ≥ 60 years, respectively, with the effectiveness being maintained through 36 months. PsAID-12 mean scores reduced for both groups from a baseline mean of 5.73 and 5.61 for patients < 60 and ≥ 60 years, respectively, to 3.81 and 3.88, respectively, at 6 months, and 2.02 and 3.24, respectively, at 36 months. Regarding treatment persistence, 173/336 (51.5%) vs 47/103 (45.6%) patients < 60 and ≥ 60 years, respectively, stopped or switched treatment. CONCLUSION: Fewer AEs were observed over 3 years for younger versus older patients with PsA. There were no clinically meaningful treatment response differences. Persistence was numerically higher in the older age group.

Genetic and Molecular Distinctions Between Axial Psoriatic Arthritis and Radiographic Axial Spondyloarthritis: Post Hoc Analyses from Four Phase 3 Clinical Trials.

INTRODUCTION: Emerging evidence suggests psoriatic arthritis (PsA) with axial involvement (axPsA) and radiographic axial spondyloarthritis (r-axSpA) may possibly represent distinct disorders, with some differing clinical manifestations, genetic associations, and radiographic findings. Moreover, axPsA and r-axSpA may respond differently to therapies: guselkumab (interleukin [IL]-23p19 subunit inhibitor [i]) and ustekinumab (IL-12/23p40i) demonstrated improvements in axial symptoms in patients with PsA; however, neither risankizumab (IL-23p19i) nor ustekinumab demonstrated efficacy versus placebo in patients with r-axSpA. Current analyses aim to further understand potential molecular distinctions between axPsA and r-axSpA and examine the pharmacodynamic effects of guselkumab in patients with axPsA and those with PsA without axial involvement (non-axPsA). METHODS: Post hoc analyses utilized biomarker data from blood and serum samples collected from a subset of participants in phase 3 studies of ustekinumab in r-axSpA and guselkumab in PsA (DISCOVER-1 and DISCOVER-2). Participants with axPsA were identified by investigator-verified sacroiliitis (imaging-confirmed) and axial symptoms. HLA mapping, serum cytokine analysis, and whole-blood RNA sequencing were conducted. RESULTS: Relative to r-axSpA, patients with axPsA had a lower prevalence of HLA-B27, HLA-C01, and HLA-C02 alleles and a higher prevalence of HLA-B13, HLA-B38, HLA-B57, HLA-C06, and HLA-C12 alleles. Compared with r-axSpA, patients with axPsA had elevated baseline levels of serum IL-17A and IL-17F cytokines, enrichment of IL-17 and IL-10 pathway-associated genes, and neutrophil gene markers. Across axPsA and non-axPsA cohorts, reductions in cytokine levels and normalization of pathway-associated gene expression with guselkumab treatment were comparable. CONCLUSION: The differences in HLA genetic associations, serum cytokines, and enrichment scores support the concept that axPsA and r-axSpA may be distinct disorders. The comparable pharmacodynamic effects of guselkumab on cytokine levels and pathway-associated genes observed in patients with axPsA and non-axPsA are consistent with demonstrated clinical improvements across PsA cohorts. These findings contribute to the understanding of potential genetic and molecular distinctions between axPsA and r-axSpA. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03162796, NCT0315828, NCT02437162, and NCT02438787.

Guselkumab, a Selective Interleukin-23 p19 Subunit Inhibitor, Resolves Dactylitis in Patients With Active Psoriatic Arthritis: Pooled Results Through Week 52 From Two Phase 3 Studies.

OBJECTIVE: Previous analyses of pooled DISCOVER-1 and DISCOVER-2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. METHODS: Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0-3/digit; total = 0-60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER-2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. RESULTS: Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab-randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new-onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab-randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER-2). CONCLUSION: Through 1 year, approximately 75% of guselkumab-randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long-term patient outcomes.

Low rates of radiographic progression associated with clinical efficacy following up to 2 years of treatment with guselkumab: results from a phase 3, randomised, double-blind, placebo-controlled study of biologic-naïve patients with active psoriatic arthritis.

OBJECTIVE: Evaluate relationship between radiographic progression and clinical outcomes in post hoc analyses of patients with psoriatic arthritis (PsA) receiving up to 2 years of guselkumab therapy in the phase 3, placebo-controlled, randomised trial, DISCOVER-2. METHODS: Biologic-naïve adults with active PsA (≥5 swollen joints /≥5 tender joints ; C reactive protein ≥0.6 mg/dL) were randomised to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then every 8 weeks (Q8W); or placebo→guselkumab 100 mg Q4W (week 24). Radiographs (hands/feet) at week 0, week 24, week 52 and week 100 were scored via PsA-modified van der Heijde-Sharp (vdH-S) methodology. In these post hoc analyses, mean changes in vdH-S scores were summarised according to achievement of American College of Rheumatology 20/50/70 response; low disease activity (LDA) defined by Disease Activity in Psoriatic Arthritis (DAPSA) ≤14 or Psoriatic ArthritiS Disease Activity Score (PASDAS) ≤3.2, or minimal/very low disease activity (MDA/VLDA); and normalised physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI) ≤0.5). Response rates for achieving MDA/VLDA and each component were determined among patients with and without radiographic progression (change in total vdH-S score >0.5). No formal hypothesis testing was performed. RESULTS: 664 of 739 treated patients in DISCOVER-2 continued study treatment at week 52 and were included in these analyses. Mean changes in vdH-S scores from weeks 0 to 100 among all patients in the Q4W and Q8W groups were 1.7 and 1.5, respectively. Among all guselkumab-randomised patients, those who achieved ACR20/50/70, DAPSA LDA, PASDAS LDA, MDA, VLDA and HAQ-DI ≤0.5 (normalised physical function) had smaller mean changes in vdH-S scores than did non-responders at week 52 (0.2-1.2 vs 1.7-4.1) and week 100 (0.3-1.2 vs 2.0-4.6). Relative to patients with radiographic progression, those without progression were more likely to achieve the MDA criteria related to swollen and tender joint counts, patient-reported pain and global assessment, and normalised physical function through week 100. CONCLUSION: In these post hoc analyses, the achievement of low levels of disease activity, including MDA, was associated with diminished rates of radiographic progression observed in patients receiving up to 2 years of guselkumab. Radiographic non-progressors were more likely to achieve patient-reported MDA criteria of minimal pain and normalised physical function compared with radiographic non-responders. TRIAL REGISTRATION NUMBER: NCT03158285.

Impact of key manifestations of psoriatic arthritis on patient quality of life, functional status, and work productivity: Findings from a real-world study in the United States and Europe.

OBJECTIVES: To determine the individual impact of key manifestations of psoriatic arthritis (PsA) on quality of life (QoL), physical function, and work disability. METHODS: Data from the Adelphi 2018 PsA Disease-Specific Programme, a multinational, cross-sectional study of PsA patients, were used. PsA manifestations included peripheral arthritis (number of joints affected), psoriasis (body surface area [BSA]), axial involvement (inflammatory back pain [IBP] and sacroiliitis) enthesitis, and dactylitis. General, and disease-specific QoL, physical function, and work disability were measured with EQ-5D-5L, PsAID-12, HAQ-DI, and WPAI, respectively. Multivariate regression adjusting for potential confounders evaluated the independent effect of PsA manifestations on each outcome. RESULTS: Among the 2222 PsA patients analysed, 77.0% had active psoriasis and 64.4% had peripheral arthritis; 5.9%, 6.8%, 10.2%, and 3.6% had enthesitis, dactylitis, IBP, or sacroiliitis, respectively. Mean EQ VAS scores were significantly poorer in patients with vs. without enthesitis (59.9 vs. 75.6), dactylitis (63.6 vs. 75.4), and with greater peripheral joint involvement (none: 82.5; 1-2 affected joints: 74.1; 3-6 joints: 74.2; >6 joints: 65.0). Significantly worse mean PsAID-12 scores were associated with vs. without enthesitis (4.39 vs. 2.34) or dactylitis (4.30 vs. 2.32), and with greater peripheral joint involvement (none: 1.21; 1-2 joints: 2.36; 3-6 joints: 2.74; >6 joints: 3.92), and BSA (none: 1.49; >3-10%: 2.96; >10%: 3.43). Similar patterns were observed with HAQ-DI and WPAI scores. CONCLUSION: Most PsA manifestations were independently associated with worse general, and PsA-specific QoL, physical function, and work disability, highlighting the need for treatments targeting the full spectrum of PsA symptoms to lower the burden of disease.

Comparative effectiveness of guselkumab in psoriatic arthritis: updates to a systematic literature review and network meta-analysis.

OBJECTIVE: The IL-23 p19-subunit inhibitor guselkumab has been previously compared with other targeted therapies for PsA through network meta-analysis (NMA). The objective of this NMA update was to include new guselkumab COSMOS trial data, and two key comparators: the IL-23 inhibitor risankizumab and the Janus kinase (JAK) inhibitor upadacitinib. MATERIAL AND METHODS: A systematic literature review was conducted to identify randomized controlled trials up to February 2021. A hand-search identified newer agents up to July 2021. Bayesian NMAs were performed to compare treatments on ACR response, Psoriasis Area and Severity Index (PASI) response, modified van der Heijde-Sharp (vdH-S) score, and serious adverse events (SAEs). RESULTS: For ACR 20, guselkumab 100 mg every 8 weeks (Q8W) and every 4 weeks (Q4W) were comparable (i.e. overlap in credible intervals) to most other agents, including risankizumab, upadacitinib, subcutaneous TNF inhibitors and most IL-17A inhibitors. For PASI 90, guselkumab Q8W and Q4W were better than multiple agents, including subcutaneous TNF and JAK inhibitors. For vdH-S, guselkumab Q8W was similar to risankizumab, while guselkumab Q4W was better; both doses were comparable to most other agents. Most agents had comparable SAEs. CONCLUSIONS: Guselkumab demonstrates better skin efficacy than most other targeted PsA therapies, including upadacitinib. For vdH-S, both guselkumab doses are comparable to most treatments, with both doses ranking higher than most, including upadacitinib and risankizumab. Both guselkumab doses demonstrate comparable ACR responses to most other agents, including upadacitinib and risankizumab, and rank favourably in the network for SAEs.

Impact of Physician-Defined Flares on Quality of Life and Work Impairment: An International Survey of 2238 Patients With Psoriatic Arthritis.

OBJECTIVE: To describe psoriatic arthritis (PsA) flares and their effect on patient-reported outcomes (PROs). METHODS: Cross-sectional surveys of rheumatologists/dermatologists and their patients with PsA were conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States, capturing data on physician-reported patient flare status, demographics, PsA severity, and clinical outcomes. Patient-completed surveys captured data on PROs: 5-level EuroQol 5-dimension, Work Productivity and Activity Impairment questionnaire, Health Assessment Questionnaire-Disability Index, and 12-item Psoriatic Arthritis Impact of Disease questionnaire. Patients were compared by flare status using parametric and nonparametric tests. Multivariate regression was used to identify flare associations. Multivariate logistic regression adjusted for patient demographics and physician specialty assessed the effect of flare status. RESULTS: Among 2238 patients (586 from the US, 1652 from Europe) managed by 572 physicians, physician-reported flare was present for 168 patients (7.5%), and self-reported flare was present for 95 patients (10% of available data). Mean (SD) flare count over 12 months was 2.2 (4.9), lasting on average 16.4 (16.2) days. Flare status was linked to worse PROs. Patients who had not flared in the last 12 months or had never flared had a higher quality of life, lower overall work impairment, and a lower degree of disability compared with patients who were currently experiencing a flare (all; P < 0.01). CONCLUSION: Actively experiencing a flare adversely affected QOL, disability, and work productivity. PsA flares should be routinely assessed and managed in clinical care.