Background Guselkumab was efficacious in reducing signs and symptoms of psoriatic arthritis in the phase 3 DISCOVER-1 and DISCOVER-2 studies. We aimed to evaluate the efficacy of guselkumab in post... Show moreBackground Guselkumab was efficacious in reducing signs and symptoms of psoriatic arthritis in the phase 3 DISCOVER-1 and DISCOVER-2 studies. We aimed to evaluate the efficacy of guselkumab in post-hoc analyses of patients with psoriatic arthritis with imaging-confirmed sacroiliitis consistent with axial involvement. Methods In DISCOVER-1, 381 patients with active psoriatic arthritis (defined as 03 swollen joints, 03 tender joints, and C-reactive protein [CRP] 00middot3 mg/dL) and in DISCOVER-2, 739 patients with active psoriatic arthritis (defined as 05 swollen joints, 05 tender joints, and CRP 00middot6 mg/dL) were randomly allocated to receive guselkumab 100 mg every 4 weeks, guselkumab 100 mg every 8 weeks (week 0, week 4, then every 8 weeks), or placebo. These pooled, post-hoc analyses included patients with axial disease documented by previous imaging or pelvic radiography at screening consistent with sacroiliitis (confirmed by investigator). Efficacy assessments included least squares mean changes, with 95% CIs, in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, modified BASDAI (mBASDAI; excluding peripheral joint pain), spinal pain, and Ankylosing Spondylitis Disease Activity Score (ASDAS), and proportions of patients achieving at least a 50% improvement in BASDAI score (BASDAI50) and achieving ASDAS responses of inactive disease (score <1middot3), major improvement (change of 02middot0), and clinically important improvement (change of 01middot1). Findings Of the 1120 patients in the two DISCOVER studies, 312 (28%) were included in this analysis, of whom 118 were in the placebo group, 103 were in the guselkumab every 4 weeks group, and 91 were in the guselkumab every 8 weeks group. 191 (61%) were male, and 121 (39%) were female, and the mean age was 45middot1 (SD 11middot2). HLA-B27 status was assessed in 190 patients; 57 (30%) were HLA-B27-positive and 133 (70%) were HLA-B27-negative. At week 24, least squares mean changes from baseline in BASDAI were -2middot7 (95% CI -3middot2 to -2middot2) in both guselkumab groups versus -1middot3 (-1middot8 to -0middot9) in the placebo group; similar results were observed for mBASDAI and spinal pain. Least squares mean changes in ASDAS scores at week 24 were -1middot4 (95% CI -1middot7 to -1middot2) in both guselkumab groups and -0middot7 (-0middot9 to -0middot5) for placebo. At week 24, 36 (38%) patients in the guselkumab every 4 weeks group and 34 (40%) of those in the guselkumab every 8 weeks group achieved BASDAI50 versus 21 (19%) of placebo patients; greater proportions of guselkumab-treated patients achieved ASDAS responses versus placebo. Across outcomes, separation from placebo was observed at week 8. Improvements with guselkumab were seen at week 24 independent of HLA-B27 status. These improvements were maintained at week 52 in the guselkumab groups. Interpretation Patients with active psoriatic arthritis and imaging-confirmed sacroiliitis who were treated with guselkumab every 4 weeks or every 8 weeks had greater mean improvements in BASDAI and ASDAS (as early as week 8) than did placebo-treated participants, with sustained improvements at week 52. Funding Janssen Research & Development LLC. Copyright (c) 2021 Elsevier Ltd. All rights reserved. Show less
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic... Show moreBiallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome. Show less
Deodhar, A.; Gensler, L.S.; Sieper, J.; Clark, M.; Calderon, C.; Wang, Y.H.; ... ; Heijde, D. van der 2019
Objective To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with... Show moreObjective To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA. Methods In all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3. Results For study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies. Conclusion In these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications. Show less
