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ObjectiveTo identify factors associated with work-related issues in Canadian patients with axial spondyloarthritis.MethodsData from 542 Canadian patients who participated in the International Map of Axial Spondyloarthritis online survey were analyzed. Participants who were employed, unemployed, or on short-term disability were included in this analysis. Regression analysis was used to study the association between work-related issues, disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and psychological distress (12-item General Health Questionnaire [GHQ-12]).ResultsThe mean age of surveyed participants was 44.3 (SD 13.9) years, 81% were university educated, and 52.6% employed. A substantial proportion had high disease activity (BASDAI ≥ 4, 72.1%) and psychological distress (GHQ-12 ≥ 3, 53.1%); 81% had work-related issues. This study analyzed responses from a subset of participants who were either employed, unemployed, or on short-term disability (n = 339). Ninety percent of this subset reported at least 1 work-related issue in the year before questionnaire completion, with the most frequent being absenteeism (49.3%) and missing work for healthcare provider visits (42.5%). Factoring in disability benefits eliminated the association between work-related issues and disease activity for all variables except fatigue (r= 0.217;P= 0.03) and discomfort (r= 0.196;P= 0.047). Difficulty fulfilling working hours (β 2.342, 95% CI 1.413-3.272) and effect on professional advancement (β 1.426, 95% CI 0.355-2.497) were associated with psychological distress. In the presence of disability benefits, only the effect on professional advancement remained (β 2.304, 95% CI 0.082-4.527).ConclusionWork-related issues are associated with worse patient-reported outcomes, both physical and psychological.

Background/Aims Ixekizumab (IXE) is a high-affinity, monoclonal antibody targeting IL-17A and is approved for the treatment of psoriasis (PsO), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. We report long-term, end-of-study-program, safety outcomes in adult patients with PsO, PsA and axSpA who received at least one dose of IXE over 5 years (PsO) or 3 years (PsA and axSpA). Methods An integrated safety analysis consisting of data from 25 randomised clinical trials (RCTs; 17 PsO, 4 PsA, 4 axSpA) was used to examine long-term safety of IXE. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for all pooled studies by years of therapy and overall through March 2022, and reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at successive year intervals. Additional safety outcomes included selected safety topics of interest (among others). Results A total of 6892 patients with PsO, 1401 patients with PsA, and 932 patients with axSpA, with a cumulative IXE exposure of 18025.7 PY for PsO, 2247.7 PY for PsA, and 2097.7 PY for axSpA were included in this analysis. The IRs per 100 PY for any TEAE were as follows: patients with PsO=32.5; PsA=50.3; axSpA=38.0. The most commonly reported TEAEs were nasopharyngitis (PsO, IR = 8.8; PsA, IR = 9.0; axSpA IR = 8.4) and upper respiratory tract infection (PsO, IR = 6.2; PsA, IR = 8.3; axSpA IR = 5.8). Serious AEs were reported by 969 patients with PsO (IR = 5.4), 134 patients with PsA (IR = 6), and 101 patients with axSpA (IR = 4.8). Forty-five deaths were reported (PsO=36 [IR = 0.2]; PsA=6 [IR = 0.3]; axSpA=3 [IR = 0.1]). The IRs per 100 PY of discontinuation from the study drug due to AE were as follows: PsO, 2.9; PsA, 5.1; axSpA, 3.1. IRs of injection site reactions were: PsO, 5.9; PsA, 11.6; axSpA, 7.4. IRs of allergic reactions were: PsO, 5.6; PsA, 4.5; axSpA, 4.2. IRs of serious infections were low (PsO, IR = 1.3; PsA, IR = 1.2; axSpA, IR = 1.1). IRs of Candida were low across all indications (PsO, 1.9; PsA, 2.0; axSpA, 1.2), as were IRs of opportunistic infections (PsO, 1.8; PsA, 1.8; axSpA, 1.3). IRs were also low across all indications for depression, major adverse cerebro-cardiovascular events and malignancies (all IRs ≤1.6). Cases of inflammatory bowel disease (IBD) were uncommon (IRs ≤0.8 across indications). Conclusion In this updated analysis with 18025.7 PY for PsO, 2247.7 PY for PsA, and 2097.7 PY for axSpA, IXE maintained a long-term safety profile up to 5 years, consistent with previous reports. Disclosure A. Deodhar: Grants/research support; A.D. received direct payments from Eli Lilly and Company as a scientific consultant/speaker, and payments (investigator) made to Oregon Medical Research Center. A. Blauvelt: Consultancies; A.B. received consulting fee from AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, Anaptysbio, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, Janssen, Landos, Leo, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor. Member of speakers’ bureau; A.B. discloses direct payment for speaker bureaus from AbbVie, UCB. S. Schwartzman: Consultancies; S.S. is a consultant with AbbVie, Janssen, Lilly, Myriad, Novartis, Regeneron, Sanofi, UCB, Stelexis, Jubilant, and Teijin. Grants/research support; S.S. reports grants/contracts from Eli Lilly and Company, is a board member on the National Psoriasis Foundation Medical Board and part of the Scientific Advisory Board at Myriad. C. Salvarani: None. M. Feely: Shareholder/stock ownership; M.F. is an employee and shareholder at Eli Lilly and Company. Other; M.F. participated on a Data Safety Monitoring or Advisory Board at Eli Lilly and Company, is a Clinical Instructor in Dermatology at Mount Sinai and discloses previous employment with MC Medical Group, reimbursement of fees from Eli Lilly and Company and from Advisory Boards at the DREAM USA South Beach Symposium, is a current member of the AAD Investment Committee, Prevention Medical Review Board and ASDS Social Media Ambassador, and former member of the WDS Practice Advisory Committee, WDS Finance and Investment Committee, WDS Fundraising and Philanthropic Activities Committee, and former AAD Media Expert Team member and NPF Social Ambassador. A. Kronbergs: Shareholder/stock ownership; A.K. is an employee and shareholder at Eli Lilly and Company. N. Eberhart: Shareholder/stock ownership; N.E. is an employee and shareholder at Eli Lilly and Company. D. Zhu: Shareholder/stock ownership; D.Z. is an employee and shareholder at Eli Lilly and Company. E. Mevel: Shareholder/stock ownership; E.M. is an employee and shareholder at Eli Lilly and Company. T. Holzkaemper: Shareholder/stock ownership; T.H. is an employee and shareholder at Eli Lilly and Company. E. Krishnan: Shareholder/stock ownership; E.K. is an employee and shareholder at Eli Lilly and Company. M. Lebwohl: Consultancies; M.L. also reports consulting fees from AnaptysBio, Arcutis, Inc., Arena Pharmaceuticals, Aristea Therapeutics, Avotres Therapeutics, BioMX, Boehringer-Ingelheim, Brickell Biotech, Castle Biosciences,, Corevitas, Dermavant Sciences, Evommune, Inc., Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Hexima Ltd., Meiji Seika Pharma, Mindera, National Society of Cutaneous Medicine, New York College of Podiatric Medicine, Pfizer, Seanergy, SUN Pharma, Verrica, and Vial. Grants/research support; M.L. reports grants/contracts from Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Cara Therapeutics, Dermavant Sciences, Eli Lilly, Incyte, Inozyme, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc. P. Rahman: Consultancies; P.R. received consulting fees from AbbVie, Janssen, Novartis, Eli Lilly and Company and Pfizer. Grants/research support; P.R. discloses grants or contracts received from Janssen and Novartis. H. Marzo-Ortega: Consultancies; H.M-O. also discloses consulting fees from Abbvie, Eli Lilly and Company, Janssen, Moonlake, Novartis, Pfizer, and UCB. Honoraria; H.M-O. discloses payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Biogen, Eli-Lilly, Janssen, Novartis, Pfizer, and UCB. Grants/research support; H.M-O. discloses grants or contracts received from Janssen, Novartis and UCB. Other; H. M-O. additionally discloses support for attending meetings and/or travel from UCB, participation on a Data Safety Monitoring Board or Advisory Board at Pfizer, leadership or fiduciary role in other board, society (paid or unpaid) in the Executive Committee ASAS, the Medical Advisory Board of NASS and as Chair of the British Society for Spondyloarthritis. C. Bullock: Shareholder/stock ownership; C. Bullock is an employee and minor shareholder in Lilly.

Background/Aims Guselkumab is a monoclonal antibody approved to treat moderate-to-severe plaque psoriasis and active psoriatic arthritis (PsA). In this analysis, safety data from 11 Phase 2/3 studies of guselkumab were pooled to evaluate guselkumab safety in a large population of patients with psoriatic disease. Methods Guselkumab was generally administered as 100-mg injections at Week (W)0, W4, then Q8W in 7 psoriasis studies and at W0, W4, then Q4W or Q8W in 4 PsA studies. Patients randomized to placebo crossed over to guselkumab Q8W at W16 in 5 PsO studies and to guselkumab Q4W or Q8W at W24 in all PsA studies. Safety data were summarized for the placebo-controlled period (W0-W16 in PsO; W0-W24 in PsA) and through the end of the reporting period (up to 5 years in PsO; up to 2 years in PsA). Incidence rates of key safety events were integrated post-hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PY). Results During the placebo-controlled periods, 1061 patients received placebo (395 PY) and 2257 received guselkumab (856 PY). Through the long-term reporting periods, 4399 guselkumab-treated patients (PsO: 2891; PsA: 1508) contributed 10787 PY of follow-up (PsO: 8662 PY; PsA: 2125 PY). In PsO and PsA studies, pooled incidence rates of overall adverse events (AEs) were similar between guselkumab- and placebo-treated patients. Rates of serious AEs, AEs leading to discontinuation, serious infections, malignancy, and major adverse cardiovascular events were low and generally similar between guselkumab- and placebo-treated patients. Rates of safety events remained consistent through the long-term reporting period for guselkumab-treated patients (Table). No cases of Crohn’s disease or ulcerative colitis were reported in guselkumab-treated patients. No serum sickness-like or anaphylactic reactions related to guselkumab were reported. No opportunistic infections were reported in any guselkumab-treated PsO patient. Three cases of opportunistic infection were reported in pooled PsA studies (0.14/100 PY; all post-W52 in DISCOVER-2). No cases of active tuberculosis were reported across all studies. Conclusion In the most comprehensive analysis of guselkumab safety to date, AE rates in guselkumab-treated patients were similar to those observed with placebo and were stable throughout long-term follow-up. Disclosure B. Strober: Grants/research support; AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Eli Lilly, Meiji Seika Pharma, Novartis, Pfizer, UCB Pharma, Sun Pharma, Regeneron, Dermira, Leo Pharma, Inc, Arcutis, Are. L. Coates: Grants/research support; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB; grant/research support from AbbVie, Amgen, Celgene, Eli Lilly, Jan. J. Yu: Shareholder/stock ownership; Janssen Research & Development, LLC, Johnson & Johnson. K. Rowland: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. E. Leibowitz: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. M. Miller: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. A. Kollmeier: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. S. Li: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. Y. Wang: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson & Johnson. D. Chan: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson. S. Chakravarty: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson & Johnson; Y. Yang, Janssen Pharmaceutical Companies, Johnson & Johnson. Y. Yang: Shareholder/stock ownership; Janssen Pharmaceutical Companies, Johnson & Johnson. M. Shawi: Shareholder/stock ownership; Janssen Pharmaceutical Companies of Johnson and Johnson. M. Lebwohl: Grants/research support; Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Verrica, AbbVie, Amgen, Eli Lilly, Janssen, Ortho Dermatologics, Pfizer, UCB Pharma, Avotres Therapeutics, AnaptysBio, Aristea Therapeutics, BioMX, Cara Therapeutics, Castle Biosciences, Dermavant, Evommune, Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Hexima, Meiji Seika Pharma, Mindera Health, Regeneron, Seanergy, Incyte, Arrive Technologies, Dr Reddy's Laboratories, Evelo Biosciences, Helsinn Therapeutics, LEO Pharma, Mount Sinai, CorEvitas (formerly Cor. P. Rahman: Shareholder/stock ownership; Janssen, Novartis, AbbVie, Eli Lilly and Company, Pfizer.

Background/Aims Ixekizumab (IXE) has demonstrated efficacy at week (wk) 16 which was maintained through 2 years (yrs) and was associated with a consistent safety profile in patients (pts) with r- and nr-axSpA, who are bDMARD-naïve and TNFi-experienced. We aimed to report safety and efficacy from the COAST programme at 3 yrs: 1 yr of the originating studies (COAST-V/W/X) and 2 yrs of COAST-Y. Methods COAST-Y (NCT03129100) is the phase 3, long-term extension study of the 3 originating studies COAST-V/W/X. Pts continued with the dose received at the end of the originating trial at week (wk) 52, either with 80 mg IXE every 4 wks (Q4W) or every 2 wks (Q2W). Pts assigned to adalimumab (ADA) or placebo (PBO) were re-randomised to IXE Q4W or Q2W at wk 16 in COAST-V and -W. Pts who received PBO for 52 wks in COAST-X were switched to IXE Q4W to continue in COAST-Y. Starting at wk 116 (wk 64 of COAST-Y), pts receiving IXE Q4W could have their dose escalated to Q2W based on investigator's opinion. This analysis focused on pts receiving ≥1 dose of IXE Q4W, observed data while on IXE Q2W dose escalation are excluded. Continuous data are summarised as observed. Safety data while on IXE were analysed for pts who received ≥1 dose of IXE; observed data while on PBO or ADA are excluded. Results A total of 932 pts received ≥1 dose of IXE, 414 received ≥1 dose of IXE Q4W, and 562/932 (60%) pts completed 3 yrs of follow-up (PBO→IXE Q4W, 63/119 (53%); ADA→IXE Q4W, 29/44 (66%); and IXE Q4W→IXE Q4W, 114/251(45%)). Through 3 yrs, the most frequently reported treatment-emergent adverse events were infections [incidence rate (IR) 25.7/100 patient years (PY)] and injection site reactions [IR 7.4/100 PY], the majority of which were mild/moderate in severity. Serious adverse events were reported at an IR of 4.8/100 PY, of which osteoarthritis was the most frequent at 0.4/100 PY. A total of 3 deaths were reported among all pts who received ≥1 dose of IXE [IR 0.1/100 PY]. For all patients, baseline disease activity (Ankylosing Spondylitis Disease Activity Score; ASDAS) was high. A similar improvement in disease activity through 3 yrs was confirmed across additional efficacy endpoints. Conclusion This analysis in COAST-Y demonstrated that the safety profile is consistent with the established safety profile, with no new safety signals observed. Patients on IXE Q4W had sustained improvement through 3 years. Disclosure A. Deodhar: Consultancies; A. Deodhar has served as a speaker and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos NV, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB Pharma. D. Poddubnyy: Shareholder/stock ownership; D. Poddubnyy has served as a speaker and/or consultant for: AbbVie, BIOCAD, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis, and UCB Pharma. Grants/research support; D.P. has received grant and/or research support from: AbbVie, Eli Lilly and Company, Merck Sharp & Dohme, Novartis, and Pfizer. P. Rahman: Consultancies; P. Rahman has served as a speaker for: Abbott, AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; P.R. has received grant and/or research support from: Janssen and Novartis. R. Bolce: Shareholder/stock ownership; R. Bolce is an employee and shareholder of: Eli Lilly and Company. S. Liu Leage: Shareholder/stock ownership; S. Liu-Leage is an employee and shareholder of: Eli Lilly and Company. A. Kronbergs: Shareholder/stock ownership; A. Kronbergs is an employee and shareholder of: Eli Lilly and Company. C. Johnson: Shareholder/stock ownership; C. Johnson is an employee and shareholder of: Eli Lilly and Company. A. Leung: Corporate appointments; A. Leung is an employee of: Syneos Health; and a contractor for: Eli Lilly and Company. D. van der Heijde: Consultancies; D. van der Heijde has served as a consultant for: AbbVie, Bayer Pharmaceuticals, Bristol Myers Squibb, Cyxone, Eisai, Eli Lilly and Company, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB Pharma. Other; D. van der Heijde is the director of: Imaging Rheumatology BV. A. Kiprianos (Non-author Presenter): Shareholder/stock ownership; A. Kiprianos is an employee and shareholder in Lilly.

OBJECTIVE Assess long-term efficacy and safety of guselkumab, an IL-23p19-subunit inhibitor, in patients with active psoriatic arthritis (PsA) from the Phase-3 DISCOVER-2 trial. METHODS In DISCOVER-2, patients with active PsA (≥5 swollen and ≥5 tender joints; CRP ≥0.6 mg/dL) despite prior nonbiologic therapy were randomized to: guselkumab 100mg every-4-weeks (Q4W); at Week0, Week4, and Q8W; or placebo➔guselkumab Q4W at Week24. Efficacy assessments included ≥20%/50%/70% improvement in ACR components (ACR20/50/70), Investigator's Global Assessment of psoriasis score=0 (IGA=0; indicating complete skin clearance), enthesitis (Leeds Enthesitis Index) and dactylitis (Dactylitis Severity Score) resolution, and changes in PsA-modified van der Heijde-Sharp (vdH-S) radiographic scores. Clinical data (imputed as no response/no change from baseline if missing) and observed radiographic data were summarized through Week100; safety assessments continued through Week112. RESULTS Of 739 randomized and treated patients, 652 (88%) completed treatment through Week100. Across groups of guselkumab-treated patients (including placebo➔Q4W) ACR20 (68%-76%), ACR50 (48%-56%), ACR70 (30%-36%), and IGA=0 (55%-67%) responses and enthesitis (62%-70%) and dactylitis (72%-83%) resolution rates at Week100 indicated amelioration of arthritis signs/symptoms and extra-articular manifestations was durable through 2years. Mean changes in PsA-modified vdH-S scores from Week52-100 (0.13-0.75) indicated the low rates of radiographic progression observed among guselkumab-treated patients at earlier timepoints extended through Week100. Through Week112, 8% (5.8/100 patient-years) and 3% (1.9/100 patient-years) of 731 guselkumab-treated patients had a serious adverse event or serious infection, respectively; one death occurred (road traffic accident). CONCLUSION In biologic-naive PsA patients, guselkumab provided durable improvements in multiple disease domains with no unexpected safety findings through 2years.

We describe public preferences for unexpected genomic findings and explore predictors of preferences using an online survey in an Eastern Canadian province. Items measuring attitudes toward features of unexpected findings and genomic sequencing concerns were entered in logistic regression models predicting interest in unexpected findings. Very high levels of interest were observed in unexpected findings for treatable disorders and carrier results, with lesser interest in unexpected findings for non-treatable disorders and unclassified variants. Respondents who endorsed items measuring features of patient control and choice over their genomic data and testing options were 3–5 times more likely to be very interested in receiving unexpected findings. Respondents with high genomic sequencing concerns were less interested in the return of any unexpected result. Self-reported history of a genetic condition was significantly related to interest in receiving most categories of unexpected genomic information, while prior use of direct-to-consumer testing was significantly related only to interest in the return of unexpected genomic findings for disorders not currently treatable. Findings highlight the need for specific elements of information and transparency regarding the return of unexpected findings and can inform the development of patient-centered materials and return of results policies.

As COVID-19 vaccines become available, different model-based approach have been developed to evaluate strategic priorities for vaccine allocation to reduce severe illness. One strategy is to directly prioritize groups that are likely to experience medical complications due to COVID-19, such as older adults. A second strategy is to limit community spread by reducing importations, for example by vaccinating members of the mobile labour force, such as rotational workers. This second strategy may be appropriate for regions with low disease prevalence, where importations are a substantial fraction of all cases and reducing the importation rate reduces the risk of community outbreaks, which can provide significant indirect protection for vulnerable individuals. Current studies have focused on comparing vaccination strategies in the absence of importations, and have not considered allocating vaccines to reduce the importation rate. Here, we provide an analytical criteria to compare the reduction in the risk of hospitalization and intensive care unit (ICU) admission over four months when either older adults or rotational workers are prioritized for vaccination. Vaccinating rotational workers (assumed to be 6,000 individuals and about 1% of the Newfoundland and Labrador (NL) population) could reduce the average risk of hospitalization and ICU admission by 42%, if no community spread is observed at the time of vaccination, because epidemic spread is reduced and vulnerable individuals are indirectly protected. In contrast, vaccinating all individuals aged 75 and older (about 43,300 individuals, or 8% of the NL population) would lead to a 24% reduction in the average risk of hospitalization, and to a 45% reduction in the average risk of ICU admission, because a large number of individuals at high risk from COVID-19 are now vaccinated. Therefore, reducing the risk of hospitalization and ICU admission of the susceptible population by reducing case importations would require a significantly lower number of vaccines. Benefits of vaccinating rotational workers decrease with increasing infection prevalence in the community. Prioritizing members of the mobile labour force should be considered as an efficient strategy to indirectly protect vulnerable groups from COVID-19 exposure in regions with low disease prevalence.

ObjectivesTo evaluate the recapture of response with open-label (OL) ixekizumab (IXE) retreatment at week 104 in patients with axial spondyloarthritis who flared after withdrawal of IXE therapy.MethodsCOAST-Y (NCT03129100) is a phase III extension study that included a double-blind, placebo-controlled, randomised withdrawal-retreatment period (RWRP). Patients who achieved remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) ResultsOf the 155 patients who entered the RWRP (placebo, n=53; IXE Q4W, n=48; IXE Q2W, n=54), 138 (89%) completed week 104. Of the placebo-treated patients (n=53), 28 (53%) experienced a flare during weeks 24–104; of these, 4 (14%) recaptured ASDAS LDA before retreatment with OL IXE, and 23 (82%) recaptured ASDAS LDA and 19 (68%) met ASDAS ID after retreatment. Of the continuously treated IXE patients (n=102), 13 experienced flare; 7 of 13 (54%) recaptured ASDAS LDA before switching to OL IXE retreatment, while 5 of 13 (38%) recaptured ASDAS LDA and 4 of 13 (31%) met ID after switching.ConclusionsNinety-six per cent of patients withdrawn to placebo recaptured at least ASDAS LDA and 71% recaptured ASDAS ID with IXE retreatment at week 104. This may provide support to patients who may require a brief interruption in therapy.

To identify factors associated with work-related issues in Canadian patients with axial spondyloarthritis (axSpA).Data from 542 Canadian patients who participated in the International Map of Axial Spondyloarthritis (IMAS) online survey were analysed. Participants who were employed, unemployed, or on short-term disability were included in this analysis. Regression analysis was used to study the association between work-related issues, disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and psychological distress (12-item General Health Questionnaire [GHQ-12]).Mean ± SD age of surveyed participants was 44.3 ± 13.9 years, 81.0% were university educated, and 52.6% employed. A substantial proportion had high disease activity (BASDAI, 72.1%) and psychological distress (GHQ-12, 53.1%); 81.1% had workrelated issues. This study analysed responses from a subset of participants who were either employed, unemployed, or on short-term disability (n=339). Ninety percent of this subset reported at least one work-related issue in the year before questionnaire completion, with the most frequent being absenteeism (49.3%) and missing work for healthcare provider visits (42.5%). Factoring in disability benefits eliminated the association between work-related issues and disease activity, for all variables except fatigue (r=0.217; p=0.028) and discomfort (r=0.196; p=0.047). Difficulty fulfilling working hours (B=2.342; 95% CI, 1.413 to 3.272) and impact on professional advancement (B=1.426; 95% CI, 0.355 to 2.497) were associated with psychological distress. In the presence of disability benefits, only the impact on professional advancement remained (B=2.304; 95% CI, 0.082 to 4.527).Work-related issues are associated with worse patient-reported outcomes, both physical and psychological.

INTRODUCTION: The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA).METHODS: Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains.RESULTS: In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W -20.1%, Q8W -19.6%, placebo -10.5%), work productivity (Q4W -20.1%, Q8W -19.2%, placebo -10.6%), and nonwork activity (Q4W -20.5%, Q8W -21.2%, placebo -9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1-25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism.CONCLUSION: Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment.TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03158285.

Background Psoriasis is a chronic, immune-mediated inflammatory disease with an implied connection to psychiatric disorders. Objective This study aims to illustrate an association between psoriasis and psychiatric disorders using real world data gathered from the Newfoundland and Labrador population. Methods Data on 15,100 patients with psoriasis and 75,500 controls (1:5) was collected from the Newfoundland and Labrador Centre for Health Information’s Electronic Health Records. The cases and controls were matched for age, sex, and geography. Indicators for psychiatric disorders include diagnosis of mental illnesses from physician’s visits and hospitalization records (all coded for mental health using ICD-9 and ICD-10 codes). Results 9,991 (66.2%) cases were identified to have at least one visit with a diagnostic code for mental illness compared to 42,276 (56.0%), P < .0001 in the control group. The percentage of people coded for anxiety was 36.50% compared to 28.95%, P < .0001; depression was 37.04% compared to 30.19%, P < .0001; and adjustment disorder was 6.89% versus 5.48%, P < .0001, among those with and without psoriasis, respectively. The greatest risk for anxiety [OR 1.4 (1.20, 1.67)] and depression [OR 1.65 (1.36, 2.00)] among psoriasis patients was between the 0 to 20 age group. Women with psoriasis are more likely to have anxiety [OR 1.08 (1.03, 1.13)], depression [OR 1.04 (1.01, 1.09)] and adjustment disorder [OR 1.07 (0.98, 1.17)] compared to female controls. Conclusion Our result shows that patients with psoriasis have an increased prevalence of mental illness. Using real world data to carry out further investigations will better elucidate this association and provide an increased understanding of the association between psoriasis and mental disorders.

ObjectivesTo evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA).MethodsIn this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs).Results391/500 patients screened were randomised and treated. At W24, 71.4%–79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all pConclusionsTildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

ObjectiveTo report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2 years from COAST-Y.MethodsIn COAST-Y, patients continued with the dose received at the end of the originating study at week 52: 80 mg IXE either every 4 weeks (Q4W) or every 2 weeks (Q2W). Placebo-treated patients from COAST-X received IXE Q4W in COAST-Y. Starting at week 116 (week 64 of COAST-Y), patients receiving IXE Q4W could be escalated to Q2W. Safety for patients receiving ≥ 1 dose of IXE and efficacy for patients receiving ≥ 1 dose of IXE Q4W was assessed. Data are summarized as observed.ResultsFor the 932 patients who received ≥ 1 dose of IXE (Q2W or Q4W) through 3 years, treatmentemergent adverse events (TEAEs) occurred at an incidence rate (IR) of 38.0 per 100 patient-years (PYs). The most frequently reported were infections (IR 25.7 per 100 PYs) and injection site reactions (IR 7.4 per 100 PYs); the majority of TEAEs were mild or moderate in severity. In total, 7.1% of TEAEs led to discontinuation (IR 3.1 per 100 PYs). All patient groups receiving IXE Q4W assessed through 3 years saw sustained improvements in Ankylosing Spondylitis Disease Activity Score, clinically important improvement, and other efficacy end points.ConclusionThe 3-year safety profile of IXE in the COAST program is consistent with the previously established long-term safety profile. IXE Q4W provided sustained improvement of disease activity in patients who received treatment through 3 years. (ClinicalTrials.gov:NCT02696785[COAST-V],NCT02696798[COAST-W],NCT02757352[COAST-X], andNCT03129100[COAST-Y])

Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

Introduction: The growth of global sequencing initiatives and commercial genomic test offerings suggests the public will increasingly be confronted with decisions about sequencing. Understanding public attitudes can assist efforts to integrate sequencing into care and inform the development of public education and outreach strategies. Methods: A 48-item online survey was advertised on Facebook in Eastern Canada and hosted on SurveyMonkey in late 2018. The survey measured public interest in whole genome sequencing and attitudes toward various aspects of sequencing using vignettes, scaled, and open-ended items. Results: While interest in sequencing was high, critical attitudes were observed. In particular, items measuring features of patient control and choice regarding genomic data were strongly endorsed by respondents. Majority wanted to specify upfront how their data could be used, retain the ability to withdraw their sample at a later date, sign a written consent form, and speak to a genetic counselor prior to sequencing. Concerns about privacy and unauthorized access to data were frequently observed. Education level was the sociodemographic variable most often related to attitude statements such that those with higher levels of education generally displayed more critical attitudes. Conclusions: Attitudes identified here could be used to inform the development of implementation strategies for genomic medicine. Findings suggest health systems must address patient concerns about privacy, consent practices, and the strong desire to control what happens to their genomic data through public outreach and education. Specific oversight procedures and policies that are clearly communicated to the public will be required.

Objectives To evaluate the efficacy of guselkumab for the treatment of active PsA utilizing composite indices. Methods Data were pooled from the phase 3 DISCOVER-1 (n = 381) and DISCOVER-2 (n = 739) studies. In both studies, patients were randomized 1:1:1 to subcutaneous guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then Q8W; or placebo Q4W with crossover to guselkumab 100 mg Q4W at week 24. Composite indices used to assess efficacy through week 52 included Disease Activity Index for Psoriatic Arthritis (DAPSA), Psoriatic Arthritis Disease Activity Score (PASDAS), minimal disease activity (MDA), and very low disease activity (VLDA). Through week 24, treatment failure rules were applied. Through week 52, non-responder imputation was used for missing data. Results Greater proportions of guselkumab- than placebo-treated patients achieved DAPSA low disease activity (LDA) and remission, PASDAS LDA and VLDA, MDA, and VLDA at week 24 vs placebo (all unadjusted P Conclusion Treatment with guselkumab provided robust and sustained benefits across multiple PsA domains through 1 year, indicating that guselkumab is an effective therapy for the diverse manifestations of PsA. Trial registration NCT03162796; NCT03158285

Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce.The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach.The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status.Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1β, and MIF (all p ≤ 5.13 × 10GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1β, and MIF levels under homeostatic conditions.

Background: Total Joint Replacement (TJR) is the most effective treatment for patients with end-stage joint pathologies, such as osteoarthritis (OA). However, this procedure can result in prosthesis failure, consequently requiring an early revision. These revision surgeries come at a high cost to the healthcare system and increase morbidity to patients. Therefore, it is crucial to identify factors associated with revisions to inform surgical decision-making. Methods: This study was a nested-case control study utilizing participants recruited in the he Newfoundland Osteoarthritis Study (NFOAS), initiated in 2011. Study participants were patients who underwent TJR (hip/knee) due to various pathologies, with OA accounting for a large proportion of cases. Revision status was collected through a chart review on the Eastern Health Meditech Health Care Information System. Seventy-two variables collected by general health questionnaires and medical reports were examined for associations with revisions. Results: A total of 1086 patients were recruited in the study; 810 patients were included (41.5% hip and 58.5% knee) in the final analysis; 30 of them underwent revision surgery. Seven factors were identified to be associated with revision status (number of live births, hysterectomy, hypertension, lateral epicondylitis, back pain that radiates to legs, more than five comorbidities, and the surgeon; all pConclusions: Our data suggested that surgeon and patients' health factors were associated with the odds of requiring revision surgery. Therefore, patients' risk of revision surgery could theoretically be calculated prior to TJR, better informing patient treatment decisions.

The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA).Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains.In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W -20.1%, Q8W -19.6%, placebo -10.5%), work productivity (Q4W -20.1%, Q8W -19.2%, placebo -10.6%), and nonwork activity (Q4W -20.5%, Q8W -21.2%, placebo -9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1-25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism.Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment.ClinicalTrials.gov identifier, NCT03158285.

Objectives Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. Methods Two independent cohorts from St John’s, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. Results One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P Conclusions Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

Background/Aims The efficacy of ixekizumab (IXE) and adalimumab (ADA) in patients with psoriatic arthritis (PsA) has been previously reported using ACR 50 and Psoriasis Area and Severity Index (PASI) 100 responses. To minimize confounding effects, in this analysis we assessed the efficacy of either IXE or ADA monotherapy on reduction of pain beyond measurable inflammation in patients with active PsA and low C-reactive protein (CRP) ( Methods SPIRIT-H2H (NCT03151551) was a 52 week (W), multicenter, randomized, open-label, parallel-group, assessor-blinded study evaluating the efficacy and safety of IXE vs ADA. Participants were randomized (1:1) to approved-label dosing of IXE or ADA. This post-hoc analysis included only patients treated with IXE or ADA as monotherapy and with low CRP ( Results 95 monotherapy patients with a CRP Conclusion This analysis suggests a different pattern of pain improvement in patients with low baseline CRP treated with IXE or ADA monotherapy, with a favorable pain reduction outcome for IXE-treated patients, even when inflammation is fluctuating as measured by CRP or SJC improvement. This analysis supports the hypothesis that IXE improves joint pain in PsA patients with and without measurable inflammation. Disclosure N. Maney: None. K. de Vlam: Consultancies; Celgene, Eli Lilly and Company, Galapagos NV, Novartis, Pfizer, and UCB Pharma. Grants/research support; Celgene. G. Gallo: Shareholder/stock ownership; Eli Lilly and Company. P. Mease: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, GlaxoSmithKline. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB Pharma. Grants/research support; Janssen, Merck Sharp & Dohme, Neumentum, Novartis, Pfizer, Sun Pharma, and UCB Pharma. P. Rahman: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. Grants/research support; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. V. Krishnan: Shareholder/stock ownership; Eli Lilly and Company. D. Sandoval Calderon: Shareholder/stock ownership; Eli Lilly and Company. C. Lin: Shareholder/stock ownership; Eli Lilly and Company. D. Zhu: Shareholder/stock ownership; Eli Lilly and Company. R. Bolce: Shareholder/stock ownership; Eli Lilly and Company. P. Conaghan: Consultancies; Amgen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Novartis, Pfizer, and UCB Pharma.

Background/Aims Efficacy of ixekizumab (IXE) in patients (pts) with ankylosing spondylitis (AS) at week (W) 16 in the absence of elevated inflammation as measured by CRP and MRI Spondyloarthritis Research Consortium of Canada (SPARCC) has been previously reported. In this analysis, we evaluated the improvement in pain with IXE based on longitudinal status of objective measures of inflammation by MRI, CRP value, and BASDAI 5/6 over 16W. Methods The Phase III COAST-V (NCT02696785) 52W, multi-center, randomized, double-blind, placebo (PBO)-controlled study examined the efficacy of IXE in pts with active AS. Adalimumab (ADA) was used as an active reference arm for the first 16W. Pts assigned to ADA went through a wash-out period of 6W prior to getting their first dose of IXE. Change in spinal pain at night (SP-N) and Short Form 36 Health Survey Questionnaire (SF-36) Bodily Pain were measured during study visits and analyzed while controlling for inflammation status using MRI, CRP levels and mean of BASDAI 5/6 (Q5: Duration, Q6: Intensity of morning stiffness). Observed data analyses are presented for each group stratified by treatment arm. Initial analysis: ‘controlled inflammation’ is defined as MRI SPARCC SI joint Results When inflammation is controlled per MRI, pts treated (tx) with IXEQ4W (-3.9 p Conclusion This analysis adds support to the hypothesis that IXE improves pain in pts with and without measurable inflammation. Disclosure N. Maney: None. K. de Vlam: Consultancies; Celgene, Eli Lilly and Company, Galapagos NV, Novartis, Pfizer, and UCB Pharma. Grants/research support; Celgene. P.G. Conaghan: Consultancies; Amgen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Novartis, Pfizer, and UCB Pharma. P.J. Mease: Member of speakers’ bureau; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Genentech, Janssen, Pfizer, and UCB Pharma. Grants/research support; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. P. Rahman: Grants/research support; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. V. Krishnan: Shareholder/stock ownership; Eli Lilly and Company. R. Bolce: Shareholder/stock ownership; Eli Lilly and Company. D. Marcelino Sandoval Calderon: Shareholder/stock ownership; Eli Lilly and Company. S. Park: Shareholder/stock ownership; Eli Lilly and Company. G. Gallo: Shareholder/stock ownership; Eli Lilly and Company. W. Maksymowych: Grants/research support; AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Galapagos NV, Janssen, Novartis, Pfizer, and UCB Pharma; and is the Chief Medical Officer of CARE Arthritis Ltd.

Background Many patients with psoriatic arthritis do not reach minimal disease activity (MDA) on methotrexate alone. This phase 4 open-label study aimed to compare attainment of MDA following introduction of adalimumab with methotrexate escalation in patients with psoriatic arthritis who do not reach MDA after an initial methotrexate course (≤15 mg every week). Methods CONTROL was a phase 4, randomised, two-part, open-label study conducted in 14 countries and 46 sites. We recruited patients with confirmed active psoriatic arthritis, naive to biologic disease-modifying antirheumatic drugs, with an inadequate response to 15 mg or less of methotrexate. In part 1, patients were randomly assigned (1:1) to receive either methotrexate 15 mg (oral or subcutaneous) every week with the addition of adalimumab 40 mg (subcutaneously) every other week (adalimumab plus methotrexate group) or methotrexate (oral or subcutaneous) escalation up to 25 mg every week (escalated methotrexate group). Randomisation was done using Interactive Response Technology and stratified by the duration of methotrexate treatment (≤3 months and >3 months). In this open-label study there was no masking; participants, people giving the interventions, those assessing outcomes, and those analysing the data were aware of group assignment. The primary endpoint was the proportion of patients who reached MDA at 16 weeks. After 16 weeks (part 2), patients who reached MDA (responders) had their current therapy maintained or modified, wheras patients who did not reach MDA (non-responders) had their therapy escalated until 32 weeks. The primary endpoint in part 2 was the proportion of patients who reached MDA at 32 weeks, analysed in all patients who received one or more doses of study drug. The study is registered with ClinicalTrials.gov, NCT02814175. Findings Between Aug 5, 2016, and March 19, 2020, 245 of 287 patients initially assessed were enrolled in the study (50% men and 50% women; 92% of patients were White). 123 patients were randomly assigned to receive adalimumab plus methotrexate and 122 patients to receive escalated methotrexate. All 245 patients were included in the primary analysis, and 227 completed part 1 and entered part 2. A significantly higher proportion of patients reached MDA at 16 weeks in the adalimumab plus methotrexate group (51 [41%] patients) compared with the escalated methotrexate group (16 [13%] patients; p

Metabolic dysfunction has been suggested to be involved in musculoskeletal pain; however, few studies have identified metabolic markers associated with multisite musculoskeletal pain (MSMP). This study sought to identify metabolic marker(s) for MSMP by metabolomic analysis. The Tasmanian Older Adult Cohort Study (TASOAC) provided the discovery cohort with the Newfoundland Osteoarthritis Study (NFOAS) providing the replication cohort. Multisite musculoskeletal pain was assessed by a self-reported pain questionnaire and defined as painful sites ≥4 in both the TASOAC and the NFOAS. Furthermore, MSMP was also defined as painful sites ≥7, whereas non-MSMP was defined as either painful sites7 or ≤1 in the NFOAS. Serum samples of the TASOAC received metabolic profiling using The Metabolomics Innovation Centre Prime Metabolomics Profiling Assay. The data on the identified metabolites were retrieved from NFOAS metabolomic database for the purpose of replication. A total of 409 participants were included in the TASOAC, 38% of them had MSMP. Among the 143 metabolites assessed, 129 passed quality control and were included in the analysis. Sphingomyelin (SM) C18:1 was significantly associated with MSMP (odds ratio [OR] per log µM increase = 3.96, 95% confidence interval, 1.95-8.22; P = 0.0002). The significance remained in multivariable analysis (OR per log µM increase = 2.70, 95% confidence interval, 1.25-5.95). A total of 610 participants were included in the NFOAS, and the association with SM C18:1 was successfully replicated with 3 MSMP definitions (OR ranging from 1.89 to 2.82; all P0.03). Our findings suggest that sphingomyelin metabolism is involved in the pathogenesis of MSMP, and the circulating level of SM C18:1 could serve as a potential marker in the management of MSMP.

Background The objectives of this study were to describe the profile of ankylosing spondylitis (AS) patients treated with either infliximab (IFX) or subcutaneous golimumab (GLM) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. Methods AS patients who were eligible for treatment with IFX or subcutaneous GLM as per their respective Canadian product monographs were enrolled into the BioTRAC registry from 2005 to 2017. The study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in clinical outcomes and acute phase reactants. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. Results A total of 389 IFX- and 421 GLM-treated patients were enrolled. A significant decrease in disease duration at baseline was observed in the IFX cohort, from a median of 8.0 in 2005–2008 to 1.0 years in 2009–2015 (p p = 0.011) and proportion of patients in ASDAS very high disease activity (p = 0.004) was also observed over time. Meanwhile, in the GLM cohort, most disease parameters remained similar from 2010 to 2017. Treatment with both agents significantly improved all disease parameters over time with similar efficacy between the two agents. The incidence of AEs and SAEs were 136 and 131 events/100 PYs and 10.5 and 8.45 events/100 PYs for IFX- and GLM-treated patients, respectively. Conclusion Both IFX and GLM treatment in AS significantly reduced disease activity in most outcome measures in a similar fashion and were well tolerated in Canadian routine care. Trial registration NCT00741793.

Aim: To survey the general public about whole genome sequencing interest, including pharmacogenomic testing, and to identify information important for sequencing decisions. Patients & methods: An online survey of 901 members of the general public in an eastern Canadian province. Results: Interest in whole genome sequencing, including pharmacogenomic testing, was high with few differences among demographic variables. Issues identified as very important to sequencing decisions included familial implications of testing, whether treatment was available for conditions tested and knowing who could access genomic information. Most respondents would value support when interpreting sequencing results. Conclusion: Findings reveal the kind of information and support users of sequencing services would value and could inform the implementation of sequencing into care in ways that accord with public preferences and needs.

Summary Background Secukinumab is an interleukin-17A inhibitor used in the treatment of patients with active psoriatic arthritis. In the phase 3 FUTURE 2 trial, secukinumab showed sustained improvement in clinical outcomes over 2 years. Because scarce data exists on the long-term treatment with biological therapies in patients with psoriatic arthritis, we aimed to assess and describe the 5-year (end-of-study) results on the efficacy and safety of secukinumab 300 mg and 150 mg doses, as well as dose escalation, from the FUTURE 2 study. Methods FUTURE 2 is a phase 3, double-blind, placebo-controlled study done at 76 centres in Asia, Australia, Canada, Europe, and the USA. Patients with active psoriatic arthritis aged 18 years or older were randomly assigned to either secukinumab (300 mg, 150 mg, or 75 mg) or placebo weekly from baseline and then every 4 weeks from week 4. Secukinumab dose was escalated from 150 mg to 300 mg and from 75 mg to 150 mg or 300 mg starting at week 128, if active signs of disease were observed in patients, on the basis of the physician's assessment, with the escalated dose maintained thereafter. We assessed key efficacy endpoints at week 260 (5 years) for secukinumab 300 mg and 150 mg, including American College of Rheumatology (ACR) and Psoriasis Area and Severity Index (PASI) responses. The safety analysis included all patients who received one or more doses of secukinumab. We report data as observed. This study is registered with ClinicalTrials.gov , NCT01752634 . Findings At randomisation, 65% of patients were naive to tumour necrosis factor inhibitors and 47% were receiving concomitant methotrexate. Of 397 patients randomly assigned in FUTURE 2, 248 (62%) completed 5 years of treatment, including 64 (64%) of 100 patients in the original secukinumab 300 mg group, 65 (65%) of 100 in the 150 mg group, 59 (60%) of 99 in the 75 mg group, and 60 (61%) of 98 in the placebo group. Overall, 127 (52%) of 242 patients required dose escalation during the study. ACR responses at 5 years were 71 (74%; ACR20), 50 (52%; ACR50), and 31 (32%; ACR70) of 96 evaluable patients in the secukinumab 300 mg group, and 67 (70%; ACR20), 41 (43%; ACR50), and 28 (29%; ACR70) of 96 evaluable patients in the secukinumab 150 mg group. From 24 to 32 weeks and from 48 to 84 weeks after dose escalation from secukinumab 150 mg to 300 mg, the proportions of ACR and PASI non-responders decreased, whereas the proportions of ACR and PASI responders increased. During the entire treatment period, the most frequent treatment-emergent serious adverse event was serious infection (exposure-adjusted incidence 1·7, 95% CI 1·1–2·5; n=25) in the any secukinumab group. No new or unexpected safety signals were reported. Interpretation Secukinumab 300 mg and 150 mg provided sustained improvement in the signs and symptoms of psoriatic arthritis, with consistent safety over 5 years. This study supports the clinical benefit and safety of long-term treatment with secukinumab in patients with psoriatic arthritis. Funding Novartis.

Introduction: Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis for which effective targeted therapies are now available. However, despite such advances up to 40% of patients fail...

Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes ('psoriatic disease') that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized.

Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (n = 15), a small number of pathogenic, potentially ASD-implicated mutations were identified, notably in TRAK1 and CLSTN3. Furthermore, germline mutations were identified in the same tissue samples in several key ASD genes, including PTEN, SC1A, CDH13, and CACNA1C. The establishment of tissue resources that are available to the scientific community will facilitate the discovery of new mutations for ASD and other neurodevelopmental disorders.

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.

Early and effective detection of severe infection cases during a pandemic can significantly help patient prognosis and resource allocation. We develop a machine learning framework for detecting severe COVID-19 cases at the time of RT-PCR testing. We retrospectively studied 988 patients from a small Canadian province that tested positive for SARS-CoV-2 where 42 (4%) cases wereat-risk(i.e., resulted in hospitalization, admission to ICU, or death), and 8 (< 1%) cases resulted in death. The limited information available at the time of RT-PCR testing included age, comorbidities, and patients’ reported symptoms, totaling 27 features. Vaccination status was unavailable. Due to the severe class imbalance and small dataset size, we formulated the problem of detecting severe COVID as anomaly detection and applied three models: one-class support vector machine (OCSVM), weight-adjusted XGBoost, and weight-adjusted Ad-aBoost. The OCSVM was the best performing model for detecting the deceased cases with an average 95% true positive rate (TPR) and 27.2% false positive rate (FPR). Meanwhile, the XGBoost provided the best performance for detecting the at-risk cases with an average 96.2% TPR and 19% FPR. In addition, we developed a novel extension to SHAP interpretability to explain the outputs from the models. In agreement with conventional knowledge, we found that comorbidities were influential in predicting severity, however, we also found that symptoms were generally more influential, noting that machine learning combines all available data and is not a single-variate statistical analysis.

IntroductionPsoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5–7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA)-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression.Methods and analysisThe PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints.Ethics and disseminationEthics approval for this study was granted by the coordinating centre’s (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations.Trial registration numberNCT05004727.

To assess long-term efficacy and safety of guselkumab, an interleukin-23 p19 subunit (IL-23p19) inhibitor, in patients with active psoriatic arthritis (PsA) from the phase III DISCOVER-2 trial.In the DISCOVER-2 trial, patients with active PsA (≥5 swollen joints and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite prior nonbiologic therapy were randomized to receive the following: guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks; or placebo with crossover to guselkumab 100 mg every 4 weeks, beginning at week 24. Efficacy assessments included American College of Rheumatology ≥20%/50%/70% improvement criteria (ACR20/50/70), Investigator's Global Assessment (IGA) of psoriasis score of 0 (indicating complete skin clearance), resolution of enthesitis (Leeds Enthesitis Index) and dactylitis (Dactylitis Severity Score), and changes in the Sharp/van der Heijde modified radiographic scores for PsA. Clinical data (imputed as no response/no change from baseline if missing) and observed radiographic data were summarized through week 100; safety assessments continued through week 112.Of the 739 randomized and treated patients, 652 (88%) completed treatment through week 100. Across groups of guselkumab-treated patients (including those in the placebo-guselkumab crossover group), the following findings at week 100 indicated that amelioration of arthritis signs/symptoms and extraarticular manifestations was durable through 2 years: ACR20 response (68-76%), ACR50 response (48-56%), ACR70 response (30-36%), IGA score of 0 (55-67%), enthesitis resolution (62-70%), and dactylitis resolution (72-83%). Mean changes in the Sharp/van der Heijde modified score for PsA from weeks 52 to week 100 (range 0.13-0.75) indicated that the low rates of radiographic progression observed among guselkumab-treated patients at earlier time points extended through week 100. Through week 112, 8% (5.8 per 100 patient-years) and 3% (1.9 per 100 patient-years) of the 731 guselkumab-treated patients had a serious adverse event or serious infection, respectively; 1 death occurred (road traffic accident).In biologic-naive PsA patients, guselkumab provided durable improvements in multiple disease domains with no unexpected safety findings through 2 years.

Background This analysis assessed improvements in patients with radiographic axial spondyloarthritis (r-axSpA) treated with ixekizumab in the Assessment of Spondyloarthritis International Society (ASAS) treatment response domains and additional patient-reported outcomes at 1 year of treatment. Methods COAST-V and COAST-W were 52-week, phase 3, randomized controlled trials evaluating the efficacy and safety of ixekizumab in biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced patients with radiographic spondyloarthritis, respectively. Patients were treated with 80-mg ixekizumab either every 2 weeks or every 4 weeks. Patient-reported outcomes included Patient Global Disease Activity, Spinal Pain, stiffness as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Questions 5 and 6, function as measured by the Bath Ankylosing Spondylitis Functional Index, fatigue as measured by the Fatigue Numeric Rating Scale and BASDAI question 1, Spinal Pain at Night, and sleep quality as measured by the Jenkins Sleep Evaluation Questionnaire. Mixed-effects models for repeated measures were used to analyze changes from baseline in patient-reported outcomes from weeks 1 to 16, and descriptive statistics were reported from weeks 20 to 52. Analysis of covariance with Scheffé’s method was used for the ASAS response association analyses. Results This study assessed 341 bDMARD-naïve and 316 TNFi-experienced patients in the placebo-controlled blinded treatment dosing period (weeks 1–16) as well as 329 bDMARD-naïve and 281 TNFi-experienced patients in the dose double-blind extended treatment period (weeks 20–52). bDMARD-naïve or TNFi-experienced patients treated with ixekizumab every 2 weeks and every 4 weeks reported improvements in patient global disease activity, spinal pain, function, stiffness, fatigue, spinal pain at night, and sleep quality through week 52. Greater correlations with improvements in all response domains were seen when comparing ASAS40 responders to ASAS20 non-responders (p Conclusions Ixekizumab-treated bDMARD-naïve and TNFi-experienced patients with radiographic axial spondyloarthritis achieving ASAS40 reported sustained and consistent improvement in all ASAS response domains and other patient-reported outcomes though week 52, with spinal pain, function, and stiffness as major drivers of the response. Trial registration NCT02696785 and NCT02696798, March 2, 2016.

Understanding host cell heterogeneity is critical for unravelling disease mechanism. Utilizing large scale single-cell transcriptomics, we analysed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAM) where genes associated with severe COVID-19 comorbidities are significantly upregulated in broncho-alveolar lavage fluid (BALF) of critical cases. FCGR3B consistently demarcated MoAM subset in different samples from severe COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID-19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis as well as a potential therapeutic target., Graphical Abstract

BackgroundThe interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue.MethodsAcross two phase 3 trials of guselkumab (DISCOVER-1, DISCOVER-2), patients with active PsA despite standard therapy were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W,N= 373); guselkumab 100 mg at week 0, week 4, and then Q8W (N= 375); or placebo (N= 372) through week 24, after which patients in the placebo group crossed over to guselkumab Q4W. Fatigue was measured as a secondary endpoint using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument (range 0–52, higher scores indicate less fatigue). Least-squares mean changes in FACIT-Fatigue scores were compared between treatments using a mixed-effect model for repeated measures. Mediation analysis was used to adjust for indirect effects on fatigue deriving from improvement in other outcomes, including ≥20% improvement in American College of Rheumatology criteria (ACR20; prespecified), minimal disease activity (MDA; post hoc), or C-reactive protein (CRP; post hoc).ResultsBaseline mean (SD) FACIT-Fatigue scores in DISCOVER-1 (N= 381) and DISCOVER-2 (N= 739), ranging from 29.1 (9.5) to 31.4 (10.1), indicated substantial levels of fatigue relative to the United States general population (43.6 [9.4]). Across studies, mean improvements, and proportions of patients with ≥4-point improvements, in FACIT-Fatigue scores at week 24 with guselkumab Q4W and Q8W (5.6–7.6 and 54–63%, respectively) were larger vs placebo (2.2–3.6 and 35–46%). Improvement in FACIT-Fatigue scores with guselkumab was sustained from week 24 to week 52, with moderate-to-large effect sizes (Cohen’sd= 0.52–0.81 at week 24; 0.66–0.91 at week 52). Mediation analyses demonstrated that substantial proportions of the effects of guselkumab vs placebo on fatigue were direct effect, after adjusting for achievement of ACR20 (Q4W 69–70%, Q8W 12–36% direct effect) or MDA (72–92% across dosing regimens) response or for change in serum CRP concentrations (82–88% across dosing regimens).ConclusionsIn patients with active PsA, guselkumab 100 mg Q4W or Q8W led to clinically meaningful and sustained improvements in fatigue through 1 year. A substantial portion of the improvement in FACIT-Fatigue scores induced by guselkumab was independent of effects on the achievement of other select outcomes.Trial registrationName of the registry: ClinicalTrials.govTrial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017URLs of the trial registry record:DISCOVER-1,https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1DISCOVER-2,https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1

To identify serum biomarker(s) for predicting knee cartilage volume loss over time, we studied 139 knee osteoarthritis (OA) patients from a previous 24-month clinical trial cohort. Targeted metabolomic profiling was performed on serum collected at baseline. The pairwise metabolite ratios as proxies for enzymatic reaction were calculated and used in the analysis. Cartilage volume loss between baseline and 24 months was assessed quantitatively by magnetic resonance imaging (MRI). Data revealed an association between the serum ratio of lysophosphatidylcholine 18:2 (lysoPC 18:2) to phosphatidylcholine 44:3 (PC44:3) and the cartilage volume loss in the lateral compartment (β = −0.21 ± 0.04, p = 8.53*10−7) and with joint degradation markers, COMP (r = 0.32, p = 0.0002) and MMP1 (r = 0.26, p = 0.002). The significance remained after adjustment for age, sex, BMI, diabetes, hypertension, dyslipidemia, and the treatment taken in the original study. As the ratio indicated the over activation of the conversion pathway of PC to lysoPC catalyzed by phospholipase A2 (PLA2), we assessed and found that a specific PLA2, PLA2G5, was significantly increased in human OA cartilage and synovial membrane (85% and 19% respectively, both p

Objective To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).

Background: The treat-to-target (T2T) strategy has become established in several medical specialties as a key guidance to optimal therapeutic decision making. T2T may be effective in the assessment of the biologic class of agents called interleukin (IL)-17 inhibitors, which are emerging as a safe and effective treatment option for autoimmune inflammatory conditions such as plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Objective: The objective of this article is to use a T2T approach for the evaluation of the effectiveness and safety of IL-17 inhibitors in the management of patients with plaque psoriasis, PsA, and AS. Methods: Following a comprehensive literature search, a full-day meeting was convened to discuss and identify the T2T targets for psoriasis, PsA, and AS. Clinical trial evidence was presented for the approved IL-17 inhibitors—secukinumab, ixekizumab, and brodalumab—to assess whether these data meet T2T safety and efficacy targets. Results: All 3 approved agents were significantly superior to placebo and active controls in the achievement of T2T targets for psoriasis. Secukinumab and ixekizumab were likewise associated with significantly better outcomes than controls in the PsA targets, and secukinumab resulted in significant AS target improvements vs placebo. The IL-17 inhibitors were also associated with low rates of serious adverse events and exacerbations of common comorbid conditions. Conclusion: Phase III trial results support the T2T benefit and safety of IL-17 inhibitors according to their specific indications for the management of patients with plaque psoriasis, PsA, and AS.

Genetic and environmental factors are critical elements in most common complex disease. Genetics is increasingly being recognized to play a substantive role in the susceptibility, prognosis, and treatment of common diseases. Due to recent and rapid advancements in characterization of genetic variants and large-scale genotyping platforms, multiple genes and genetic variants have now been identified for common, complex diseases. The most efficient method for gene identification at present appears to be large-scale association-based studies, which integrate genetic and epidemiological principles. As the strategy for gene identification studies has shifted toward genetic association-based methods rather than traditional linkage analysis, epidemiological methods are increasingly being integrated into genetic investigations and in public health research. Consequently, the disciplines of genetics and epidemiology, which historically have functioned separately, have been integrated into a hybrid discipline referred to as genetic epidemiology. In this chapter, we review methods for establishing the genetic burden of complex genetic disease, followed by methods for gene and/or genetic variant identification. When appropriate, we will highlight the epidemiological issues and clinical applications that guide these methods.

Background/Aims Tumor necrosis factor inhibitors (TNFis) are effective treatments for radiographic axial spondyloarthritis (r-axSpA), but may be less effective in patients (pts) without elevated C-reactive protein (CRP). This study evaluated the efficacy of ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting interleukin-17A, in pts with r-axSpA at 52 weeks (wks) with nonelevated (≤5mg/L) and elevated (>5mg/L) baseline (BL) CRP. Methods COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomised, double-blind, PBO-controlled trials investigating efficacy of 80-mg IXE every 4 wks and every 2 wks in pts who met ASAS criteria for raxSpA, had radiographic sacroiliitis according to mNY criteria, and were biological diseasemodifying antirheumatic drug (bDMARDs)-naïve (COAST-V) or TNFiexperienced (COAST-W). Data from 157 COAST-V pts and 188 COAST-W pts treated with IXE from Wk0 to 52 were analyzed. Patients were stratified based on nonelevated (≤5mg/L) vs elevated (>5 mg/L) BL CRP. Additional analysis was done with BL CRP ≤10.0mg/L vs > 10.0mg/L. Efficacy was assessed by ASAS40, ≥50% improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), and change in Short Form 36 physical component summary (SF36 PCS) score. Missing data were imputed by nonresponder imputation for binary measures and modified BL observation carried forward for continuous measure. Week 16 data are presented for comparison. Results Of pts treated with IXE through Wk52, 34.4% had CRP ≤5.0mg/L, 65.6% had CRP >5.0mg/L, 61.8% had CRP ≤10.0mg/L, and 38.2% had CRP >10.0mg/L at BL in COASTV and 33.0% had CRP ≤5.0mg/L, 67.0% had CRP >5.0mg/L, 55.9% had CRP ≤10.0mg/L, and 44.1% had CRP >10.0mg/L at BL in COAST-W.At Wk16, the proportion of pts achieving ASAS40 in COAST-V was numerically higher with IXE in the ≤5mg/L group and significantly higher with IXE in the >5mg/L group vs PBO, as previously shown, and was significantly higher with IXE in the ≤10mg/L and >10mg/L groups vs PBO. Results were similar in COAST-W and significant in the >5mg/L and ≤10mg/L groups vs PBO. At Wk52, greater than 45% of COAST-V pts and greater than 35% of COAST-W pts treated with IXE achieved an ASAS40 response, greater than 40% of COAST-V pts and greater than 25% of COAST-W patients treated with IXE achieved a BASDAI50 response, and change from baseline in SF-36 PCS score in patients treated with IXE was greater than 5 points in both studies regardless of the BL CRP cutoffs evaluated. Conclusion A higher proportion of ASAS40 responders was observed in IXE treated arms versus PBO among bDMARD-naïve and TNFi-experienced pts with r-axSpA when the CRP cutoff of 10mg/L was evaluated, and the responses were consistent through Wk52. Furthermore, similar proportions of pts achieved BASDAI50 and SF-36 responses within each patient population regardless of the BL CRP cutoff evaluated. Disclosure J.D. Reveille: None. P. Rahman: None. D.M. Sandoval Calderon: Shareholder/stock ownership; D. Sandoval Calderon is a shareholder and employee of Eli Lilly and Company. T. Muram: Shareholder/stock ownership; T. Muram is a shareholder and employee of Eli Lilly and Company. A. Kronbergs: Shareholder/stock ownership; A. Kronbergs is a shareholder and employee of Eli Lilly and Company. R. Bolce: Shareholder/stock ownership; R.Bolce is a shareholder and employee of Eli Lilly and Company. V. Geneus: Shareholder/stock ownership; V. Geneus is a shareholder and employee of Eli Lilly and Company. T. Hunter: Shareholder/stock ownership; T. Hunter is a shareholder and employee of Eli Lilly and Company. S. Liu-Leage: Shareholder/stock ownership; S.L. League is a shareholder and employee of Eli Lilly and Company. M. Rudwaleit: None. J.A. Maldonado-Cocco: None. F. van den Bosch: None.

Objective Guselkumab, a human monoclonal antibody specific to interleukin-23p19, demonstrated efficacy and safety versus placebo through week 24 of the phase III DISCOVER-2 trial in biologic-naive patients with psoriatic arthritis (PsA). Here we report 1-year DISCOVER-2 findings.Methods Adults with active PsA (>= 5 swollen and >= 5 tender joints; C-reactive protein level >= 0.6 mg/dl) despite standard nonbiologic treatment were randomized to receive subcutaneous injections of guselkumab 100 mg every 4 weeks, guselkumab 100 mg at week 0, week 4 and every 8 weeks thereafter, or placebo with crossover to guselkumab 100 mg every 4 weeks at week 24. We primarily evaluated clinical efficacy through week 52 by imputing missing data (nonresponse for categorical end points; no change/using multiple imputation for continuous end points). Observed radiographic scores and adverse events (AEs) were summarized.Results Of 739 randomized, treated patients, 93% completed week 52. The proportions of patients in whom a >= 20% improvement from baseline in American College of Rheumatology criteria (ACR20) was achieved were maintained after week 24, reaching 71% (173 of 245) and 75% (185 of 248) for patients randomized to receive treatment every 4 weeks or every 8 weeks, respectively, by week 52. The proportions of patients in whom ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were achieved at week 24 were also maintained through week 52. Further, low levels of radiographic progression, along with improvements in physical function and health-related quality of life, were sustained through week 52 with continued guselkumab treatment. Few patients experienced serious infections through week 52, with no evidence of a dosing regimen response or increase from weeks 0-24 (4 of 493 [0.8%]) to weeks 24-52 (3 of 493 [0.6%]) among guselkumab-randomized patients. No patient developed an opportunistic infection or died.Conclusion In biologic-naive PsA patients, guselkumab provided sustained improvements across diverse manifestations and maintained a favorable risk-benefit profile through week 52.

Objective To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. Methods Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0–6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. Results Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70–75%), moderate (LEI = 2; 69–73%) or severe (LEI = 3–6; 42–44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. Conclusion Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. Clinical trial registration DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285)

BackgroundTo prevent the spread of COVID-19 in Newfoundland & Labrador (NL), NL implemented a wide travel ban in May 2020. We estimate the effectiveness of this travel ban using a customized agent-based simulation (ABS).MethodsWe built an individual-level ABS to simulate the movements and behaviors of every member of the NL population, including arriving and departing travellers. The model considers individual properties (spatial location, age, comorbidities) and movements between environments, as well as age-based disease transmission with pre-symptomatic, symptomatic, and asymptomatic transmission rates. We examine low, medium, and high travel volume, traveller infection rates, and traveller quarantine compliance rates to determine the effect of travellers on COVID spread, and the ability of contact tracing to contain outbreaks.ResultsInfected travellers increased COVID cases by 2-52x (8-96x) times and peak hospitalizations by 2-49x (8-94x), with (without) contact tracing. Although contact tracing was highly effective at reducing spread, it was insufficient to stop outbreaks caused by travellers in even the best-case scenario, and the likelihood of exceeding contact tracing capacity was a concern in most scenarios. Quarantine compliance had only a small impact on COVID spread; travel volume and infection rate drove spread.InterpretationNL’s travel ban was likely a critically important intervention to prevent COVID spread. Even a small number of infected travellers can play a significant role in introducing new chains of transmission, resulting in exponential community spread and significant increases in hospitalizations, while outpacing contact tracing capabilities. With the presence of more transmissible variants, e.g., the UK variant, prevention of imported cases is even more critical.

Background: Improved understanding of the genetic architecture of psoriatic disease (PsD) and reduction in genotyping costs provide an opportunity to assess the application of genetic testing for psoriatic arthritis (PsA) diagnosis. The study aimed to assess the performance of a multi-marker genetic kit in classifying patients as PsD and PsA and to assess whether the performance has improved by combining genetic and clinical data.Methods: 328 patients with psoriasis and musculoskeletal symptoms (78 PsA and 250 psoriasis alone) who were referred to rheumatology for suspected PsA and 341 non-psoriatic controls were analyzed. A custom multi-SNP genetic assay, including 41 variants based on large scale association genome-wide association studies in PsA, was genotyped. Machine-learning methods were used to identify the optimal classification model by area under the receiver operating curve (AUC). Results: The performance of all three classifiers to distinguish PsD from non-psoriatic controls was moderate with similar AUC (range 0.64 to 0.69). Logistic regression had the highest AUC and showed moderate specificity (61.9%) and specificity (67.9%). The ability of the models to correctly classify PsA among all psoriasis patients was suboptimal with AUC ranging from 0.55 to 0.60 with low sensitivity (1.3% to 34.6%) and moderate to high specificity (69.2% to 99.6%). The combination of genetic and clinical data resulted in an improvement in the performance of the models (AUC 0.65 to 0.69), however, the information contributed by the genetic markers was only marginal. Conclusions: Genetic testing has marginal effect on correctly classifying PsA among psoriasis patients in clinical setting.

ObjectiveEvaluate the safety of guselkumab (monoclonal antibody targeting interleukin [IL]-23p19) in patients with psoriatic arthritis (PsA) through 1 year (1Y) of the phase III DISCOVER-1 and DISCOVER-2 trials.MethodsPatients with active PsA (n = 1120; biologic-naïve except 118 patients treated with tumor necrosis factor inhibitors in DISCOVER-1) were randomized to subcutaneous guselkumab 100 mg every 4 weeks (Q4W) or at Week 0, Week 4, then every 8 weeks (Q8W); or placebo. At Week 24, patients in the placebo group switched to guselkumab 100 mg Q4W. Treatment continued through 1Y and 2 years for DISCOVER-1 and DISCOVER-2, respectively. In this pooled analysis, patients with ≥ 1 adverse event (AE) through 1Y were standardized for 100 patient-years [100 PYs] of follow-up.ResultsThrough Week 24, adverse events (AEs) were consistent between patients treated with placebo and guselkumab (Q4W + Q8W). AEs were 142.8/100 PYs and 150.6/100 PYs, serious AEs were 7.1/100 PYs and 4.4/100 PYs, and AEs leading to study agent discontinuation were 4.1/100 PYs and 3.8/100 PYs, respectively. Through 1Y in patients treated with guselkumab, no uveitis, active tuberculosis, opportunistic infections, or inflammatory bowel disease were observed, and low rates of malignancy and major adverse cardiovascular (CV) events were observed. Injection-site reactions occurred in 1.7%, and antibodies to guselkumab in 4.5% of patients treated with guselkumab through 1Y; the vast majority of antibodies to guselkumab were nonneutralizing. Serum hepatic transaminase elevations (more common with Q4W than Q8W dosing) and decreased neutrophil counts were generally mild, transient, and did not require treatment discontinuation, with minimal change from Week 24 to 1Y.ConclusionGuselkumab 100 mg Q4W and Q8W were well tolerated in patients with PsA, with no new safety concerns through 1Y of the phase III DISCOVER trials. Guselkumab safety through 1Y in patients with PsA is consistent with that established in patients with psoriasis who were treated with guselkumab. [ClinicalTrials.gov:NCT03162796andNCT03158285]