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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.

ObjectiveEvaluation of the efficacy and safety of guselkumab, a human monoclonal antibody targeting the interleukin-23p19 subunit, in patients with psoriatic arthritis (PsA) through 1 year.MethodsAdults who met ClASsification criteria for Psoriatic ARthritis, with active disease (≥3 swollen and ≥3 tender joints; C reactive protein ≥0.3 mg/dL) despite standard treatment (31% previously received ≤2 tumour necrosis factor inhibitors (TNFi)), were randomised (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week0, Week4, then Q8W; or placebo with cross-over to guselkumab 100 mg Q4W at Week24 (PBO→Q4W) through Week48. Clinical efficacy through Week52 (employing non-responder imputation) and adverse events (AEs) through Week60 were evaluated.ResultsOf 381 treated patients, 90% completed the study. Numerical increases in the proportions of patients achieving ≥20% improvement in ACR criteria (ACR20) were observed post-Week24, reaching 73% (94/128) and 60% (76/127) for Q4W-randomised and Q8W-randomised patients, respectively, by Week52. Proportions of patients achieving ACR50/ACR70/skin responses and minimal/very low disease activity were maintained, as were improvements in physical function and health-related quality of life, through Week52 in guselkumab-randomised patients. Response to guselkumab was maintained in both TNFi-naïve and TNFi-experienced patients. Serious AEs and serious infections occurred in similar proportions of guselkumab Q4W-randomised (3% and 0%) and Q8W-randomised (6% and 2%) patients through Week60, with no new safety concerns versus observations through Week24. No guselkumab-treated patient and two patients receiving placebo died; no study participant developed opportunistic infection or inflammatory bowel disease.ConclusionGuselkumab provided sustained improvement across multiple clinical manifestations of PsA, maintaining a favourable benefit-risk profile, through 1 year regardless of prior TNFi exposure.

ObjectivesTo evaluate the efficacy through 52 weeks of guselkumab, an interleukin 23-p19 subunit inhibitor, in subgroups of pooled psoriatic arthritis (PsA) patients from the DISCOVER-1 and DISCOVER-2 trials defined by baseline patient characteristics.MethodsAdults with active PsA despite standard therapies were enrolled in DISCOVER-1 (≥3 swollen and ≥3 tender joints, C reactive protein (CRP) level ≥0.3 mg/dL) and DISCOVER-2 (≥5 swollen and ≥5 tender joints, CRP ≥0.6 mg/dL, biological-naïve). Randomised patients received 100 mg guselkumab at weeks 0, 4, and then every 4 or 8 weeks (Q4W/Q8W) or placebo. Guselkumab effects on joint (ACR20/50/70), skin (IGA 0/1, IGA 0), patient-reported outcome (Health Assessment Questionnaire Disability Index/Functional Assessment of Chronic Illness Therapy-Fatigue) and disease severity (minimal disease activity/PsA Disease Activity Score low disease activity) endpoints were evaluated by patient sex, body mass index, PsA duration, swollen/tender joint counts, CRP level, percent body surface area with psoriasis, Psoriasis Area and Severity Index score, and conventional synthetic disease-modifying antirheumatic drug use at baseline.ResultsBaseline patients characteristics in DISCOVER-1 (N=381) and DISCOVER-2 (N=739) were well balanced across randomised groups. At week 24, 62% (232/373) and 60% (225/375), respectively, of guselkumab Q4W-treated and Q8W-treated patients pooled across DISCOVER-1 and DISCOVER-2 achieved the primary endpoint of ACR20 response versus 29% (109/372) of placebo-treated patients. Guselkumab treatment effect at week 24 was observed across patient subgroups. Within each patient subgroup, response rates across all disease domains were sustained or increased at week 52 with both guselkumab regimens.ConclusionsGuselkumab Q4W and Q8W resulted in robust and sustained improvements in PsA signs and symptoms consistently in subgroups of patients defined by diverse baseline characteristics.Trial registration numbersNCT03162796, NCT03158285.

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.

The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis. This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57–70]) and every 8 weeks group (159 [64%] of 248 [58–70]) than in the placebo group (81 [33%] of 246 [27–39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22–39] for the every 4 weeks group and 31% [23–40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit–risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. Janssen Research and Development.

Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50–68]) and every 8 weeks group (66 [52%] of 127 [43–61]) than in the placebo group (28 [22%] of 126 [15–30]), with percentage differences versus placebo of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. Guselkumab demonstrated a favourable benefit–risk profile and might be an effective treatment option for patients with active psoriatic arthritis. Janssen Research and Development.

ObjectiveEvaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA).MethodsPost hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data.Results442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported.ConclusionIn biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets.

Objective To evaluate efficacy and safety of the interleukin‐23p19‐subunit inhibitor, guselkumab, in DISCOVER‐1 patients with active psoriatic arthritis (PsA) by prior use of tumor necrosis factor inhibitor (TNFi). Methods The phase 3, randomized, placebo‐controlled DISCOVER‐1 study enrolled patients with active PsA (swollen joint count ≥3, tender joint count ≥3, and C‐reactive protein level ≥ 0.3 mg/dl) despite standard therapies; approximately one‐third could have received two or fewer prior TNFi. Patients were randomized to 100 mg of guselkumab every 4 weeks (Q4W); 100 mg of guselkumab at week 0, at week 4, and every 8 weeks (Q8W); or placebo with crossover to guselkumab Q4W at week 24. Efficacy end points of ≥20% and ≥50% improvement in individual American College of Rheumatology (ACR) criteria and achieving the minimal disease activity (MDA) components were summarized by prior TNFi status. Results In DISCOVER‐1, 118 (31%) patients previously received one or two TNFi. As previously reported, rates for acheiving ≥20% improvement in the composite ACR response at week 24 and week 52 were similar in TNFi‐naive and TNFi‐experienced patients randomized to guselkumab Q4W (76% and 68%, respectively) and Q8W (61% and 58%, respectively). Similar trends were observed for response rates of ≥20% and ≥50% improvement in individual ACR criteria and for achieving individual MDA components at week 24; TNFi‐naive patients were more likely to achieve end points related to physical function and pain than TNFi‐experienced patients. Overall, response rates were maintained or increased through week 52 regardless of prior TNFi use. Through week 60 in guselkumab‐treated TNFi‐naive and TNFi‐experienced patients, 62% and 64%, respectively, reported one or more adverse events (AEs); 4% and 6% had serious AEs, respectively. Conclusion Through 1 year, 100 mg of guselkumab Q4W and Q8W provided sustained improvements across multiple domains in both TNFi‐naive and TNFi‐experienced patients with active PsA.

ObjectiveEvaluate 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.MethodsBiologic-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.Results664 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.ConclusionIn 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 numberNCT03158285.

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.