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.

Safety of Guselkumab With and Without Prior Tumor Necrosis Factor Inhibitor Treatment: Pooled Results Across 4 Studies in Patients With Psoriatic Arthritis.

OBJECTIVE: Assess pooled safety results through the end of the phase II/III studies of guselkumab (GUS; ≤ 2 years) in tumor necrosis factor inhibitor (TNFi)-naïve and -experienced patients with psoriatic arthritis (PsA). METHODS: Data were pooled from the Phase 2 and DISCOVER-1 (both TNFi-naïve and -experienced), DISCOVER-2 (TNFi-naïve), and COSMOS (TNFi-experienced) studies. Patients with active PsA were randomized to GUS 100 mg every 4 or 8 weeks (Q4W + Q8W = Combined GUS) or placebo (PBO) with crossover to GUS Q4W or Q8W at week 24. Time-adjusted adverse event (AE) rates (events/100 patient-years [PY]) and clinical laboratory findings were assessed during the PBO-controlled period and through end of study (≤ 2 years). RESULTS: Of 1554 randomized patients (n = 373 [GUS Q4W], 664 [GUS Q8W], and 517 [PBO]), 1138 (73.23%) were TNFi-naïve and 416 (26.77%) were TNFi-experienced. Respective AE rates through week 24 were 220.8/100 PY (TNFi-naïve) and 251.6/100 PY (TNFi-experienced) in the Combined GUS group and 196.1/100 PY (TNFi-naïve) and 303.0/100 PY (TNFi-experienced) in the PBO group. Among all GUS-treated patients (including those who crossed over from PBO), low AE rates were maintained during long-term evaluation in both TNFi-naïve (139.7/100 PY) and TNFi-experienced (174.0/100 PY) patients. Rates/100 PY of AEs leading to treatment discontinuation, serious AEs, and other AEs of interest, as well as occurrence of elevated hepatic transaminase levels and decreased neutrophil counts were consistent between PBO and GUS-treated patients through week 24 regardless of prior TNFi use and remained low through the end of the studies. CONCLUSION: The safety profile of GUS in TNFi-experienced patients was consistent with that in TNFi-naïve patients, which remained favorable for up to 2 years. [ClinicalTrials.gov: Phase 2 (NCT02319759), DISCOVER-1 (NCT03162796), DISCOVER-2 (NCT03158285), and COSMOS (NCT03796858)].

Efficacy and safety of guselkumab in biologic-naïve patients with active axial psoriatic arthritis: study protocol for STAR, a phase 4, randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Axial involvement constitutes a specific domain of psoriatic arthritis (PsA). Interleukin (IL)-23 inhibitors have demonstrated improvement in axial PsA (axPsA) symptoms, but have not shown efficacy in treating ankylosing spondylitis (AS), suggesting differences in axPsA processes and treatments. In a post hoc, pooled analysis of patients with investigator- and imaging-confirmed sacroiliitis in two phase 3, randomized, placebo-controlled studies (DISCOVER-1 and DISCOVER-2), patients treated with guselkumab, an IL-23p19 inhibitor, had greater axial symptom improvements compared with placebo. Confirmatory imaging at baseline was restricted to the sacroiliac (SI) joints, occurred prior to/at screening, and was locally read. METHODS: The STAR study will prospectively assess efficacy outcomes in PsA patients with magnetic resonance imaging (MRI)-confirmed axial inflammation. Eligible, biologic-naïve patients with PsA (N =  405) for ≥ 6 months and active disease (≥ 3 swollen and ≥ 3 tender joints, C-reactive protein [CRP] ≥ 0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs will be randomized (1:1:1) to guselkumab every 4 weeks (Q4W); guselkumab at week (W) 0, W4, then every 8 weeks (Q8W); or placebo with crossover to guselkumab at W24, W28, then Q8W. Patients will have Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4, spinal pain component score (0-10 visual analog scale) ≥ 4, and screening MRI-confirmed axial involvement (positive spine and/or SI joints according to centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥ 3 in ≥ 1 region). The primary endpoint is mean change from baseline in BASDAI at W24; multiplicity controlled secondary endpoints at W24 include AS Disease Activity Score employing CRP (ASDAS), Disease Activity Index for PsA (DAPSA), Health Assessment Questionnaire - Disability Index (HAQ-DI), Investigator's Global Assessment of skin disease (IGA), and mean changes from baseline in MRI SI joint SPARCC scores. Centrally read MRIs of spine and SI joints (scored using SPARCC) will be obtained at W0, W24, and W52, with readers blinded to treatment group and timepoint. Treatment group comparisons will be performed using a Cochran-Mantel-Haenszel or chi-square test for binary endpoints and analysis of covariance, mixed model for repeated measures, or constrained longitudinal data analysis for continuous endpoints. DISCUSSION: This study will evaluate the ability of guselkumab to reduce both axial symptoms and inflammation in patients with active PsA. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, NCT04929210 , on 18 June 2021. PROTOCOL VERSION: Version 1.0 dated 14 April 2021.

Meaningful Improvement in General Health Outcomes with Guselkumab Treatment for Psoriatic Arthritis: Patient-Reported Outcomes Measurement Information System-29 Results from a Phase 3 Study.

OBJECTIVE: The Phase 3 DISCOVER-1 study of guselkumab is the first randomized controlled trial to use Patient-Reported Outcomes Measurement Information System (PROMIS) measures to assess the effects of treatment on general health outcomes in patients with psoriatic arthritis (PsA). METHODS: Patients (N = 381) with active PsA were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week 0, Week 4, then every 8 weeks (Q8W); or placebo with Week 24 crossover to guselkumab Q4W. The PROMIS-29 Profile contains four items for each of seven domains (anxiety, depression, fatigue, pain interference, physical function, sleep disturbance, and social participation) and one pain-intensity item. Raw domain scores are converted to standardized T-scores, with norms based on a US general population mean of 50 (1 standard deviation (SD) = 10). T-score changes of ≥ 5 are considered clinically meaningful. Least-squares mean PROMIS-29 T-score changes from baseline to Week 24 and Week 52 were summarized for the guselkumab and placebo groups; nominal p-values comparing results between guselkumab and placebo were calculated at Week 24 using a mixed model for repeated measures. The proportions of patients who achieved clinically meaningful improvement in PROMIS-29 T-scores were also summarized at Week 24 and Week 52; nominal p-values comparing results between guselkumab and placebo were calculated at Week 24 using the Cochran-Mantel-Haenszel test. RESULTS: In the DISCOVER-1 patient population, mean PROMIS-29 T-scores at baseline were ~ 1 SD worse for physical function and pain interference and were numerically worse for social participation, fatigue, and sleep disturbance compared with the US general population. At Week 24, mean PROMIS-29 T-scores improved in guselkumab-treated patients, approaching US population norms; T-scores continued to improve through Week 52. Significantly higher proportions of patients in both guselkumab treatment arms (31-52% across domains) had clinically meaningful improvements in pain interference, fatigue, physical function, sleep, and social participation at Week 24 versus placebo (all nominal p ≤ 0.05). CONCLUSION: In patients with active PsA, guselkumab treatment provided clinically meaningful reductions in fatigue and pain and improvement in physical function and social participation, as measured by the PROMIS-29 Profile. These improvements were maintained through 1 year. CLINICALTRIALS: GOV: Registration number, NCT03162796; Submission date 19 May 2017.

Ethnographic Observational Study of the Biologic Initiation Conversation Between Rheumatologists and Biologic-Naive Rheumatoid Arthritis Patients.

OBJECTIVE: This ethnographic market research study investigated the biologic initiation conversation between rheumatologists and biologic-naive patients with rheumatoid arthritis to assess how therapy options, particularly mode of administration, were discussed. METHODS: Consenting rheumatologists (n = 16) and patients (n = 48) were videotaped during medical visits and interviewed by a trained ethnographer. The content, structure, and timing of conversations regarding biologic initiation were analyzed. RESULTS: The mean duration of physician-patient visits was approximately 15 minutes; biologic therapies were discussed for a mean of 5.6 minutes. Subcutaneous (SC) and intravenous (IV) therapy options were mentioned in 45 and 35 visits, respectively, out of a total of 48 visits. All patients had some familiarity with SC administration, but nearly half of patients (22 of 48) were unfamiliar with IV therapy going into the visit. IV administration was not defined or described by rheumatologists in 77% of visits (27 of 35) mentioning IV therapy. Thus, 19 of 22 patients who were initially unfamiliar with IV therapy remained unfamiliar after the visit. Disparities in physician-patient perceptions were revealed, as all rheumatologists (16 of 16) believed IV therapy would be less convenient than SC therapy for patients, while 46% of patients (22 of 48) felt this way. In post-visit interviews, some patients seemed confused and overwhelmed, particularly when presented with many treatment choices in a visit. Some patients stated they would benefit from visual aids or summary sheets of key points. CONCLUSION: This study revealed significant educational opportunities to improve the biologic initiation conversation and indicated a disparity between patients' and rheumatologists' perception of IV therapy.

Use of a Flexible Intramedullary Rod and its Influence on Patient Satisfaction and Femoral Size in Total Knee Arthroplasty.

Improper femoral component size remains a source of multiple postoperative complications following total knee arthroplasty (TKA). However, the use of a flexible intramedullary (IM) rod may help optimize femoral component size and therefore improve outcomes. The purpose of this study was to assess (1) patient-reported functional outcomes, (2) overall quality of life, and (3) changes in implant sizing associated with total knee arthroplasties performed with a flexible IM rod compared to a conventional, rigid rod. We reviewed 277 patients who had surgery using the rigid rod and 364 using the flexible rod to determine the tendency of each rod for selecting particular component sizes. Additionally, 100 patients were prospectively randomized (1:1) to the flexible or the conventional rigid IM rod cohorts. Outcomes were assessed using Knee Society scores (KSSs), SF-36 physical scores, and SF-36 mental scores preoperatively and at 6 weeks, 3 months, 1 year, and 2 years postoperatively. The retrospective arm of the study showed that the flexible IM rod cohort tends to have smaller component sizes than their conventional counterparts. In the prospective phase of the study, the increase in clinical KSSs from preoperative levels was better in the flexible rod cohort (160% vs. 143% increases, respectively). The functional KSSs had slightly higher increases in the flexible rod cohort from their preoperative levels (68% vs. 62% increases, respectively). With both clinical and functional KSSs, the flexible rod cohort had a higher score than the rigid rod cohort at all follow-up points. There was better postoperative range of motion (ROM) in the flexible rod cohort (28% vs. 22% increases, respectively). The SF-36 physical scores were slightly different, with the flexible IM rod cohort having a more marked improvement in scores (64% vs. 46% increases, respectively). The SF-36 mental score had a slightly better improvement at latest follow-up in the flexible IM rod cohort (12% vs. 6% increases, respectively). Those patients who underwent TKA using a flexible IM rod had better improvements in their patient-reported outcomes and decreased risk of oversizing the femoral component. The use of such a rod is not detrimental to outcomes and may have a positive impact on outcomes. Future studies should focus on alignment and long-term outcomes associated with the use of a flexible rod.

Perioperative medical management of antiphospholipid syndrome: hospital for special surgery experience, review of literature, and recommendations.

UNLABELLED: Patients with antiphospholipid syndrome (APS), who are predisposed to vascular thrombotic events, are at additional risk for thrombosis when they undergo surgery. Serious perioperative complications (recurrent thrombosis, catastrophic exacerbation, or bleeding) occur despite prophylaxis. We describe our perioperative experience with APS patients who underwent a variety of surgeries, review the literature, and discuss strategies that may guide other physicians in their perioperative evaluation and management of patients with APS. RECOMMENDATIONS: perioperative strategies should be clearly identified before surgical procedure; pharmacological and physical antithrombosis interventions vigorously employed; periods without anticoagulation kept to a minimum; and any deviation from a normal course should be considered a potential disease related event.