Comparing Efficacy of Guselkumab versus Ustekinumab in Patients with Psoriatic Arthritis: An Adjusted Comparison Using Individual Patient Data from the DISCOVER and PSUMMIT Trials.

INTRODUCTION: Two biologic therapies for psoriatic arthritis (PsA), guselkumab and ustekinumab, have demonstrated superior efficacy versus placebo in clinical trials. However, no head-to-head studies have been conducted comparing these two treatments for PsA. The objective was to indirectly compare guselkumab and ustekinumab on joint and skin efficacy up to week 52, using pooled individual patient-level data (IPD) from PsA trials. METHODS: IPD, including baseline characteristics, American College of Rheumatology (ACR) scores and Psoriasis Area Severity Index (PASI) response from guselkumab (DISCOVER-1 and -2) and ustekinumab (PSUMMIT 1 and 2) trials were pooled. Differences in patient characteristics across trials were adjusted using multivariate logistic regression. Odds ratios (OR) were used to derive absolute response probabilities in the guselkumab trial population and were presented with 95% confidence intervals. RESULTS: Most baseline characteristics for guselkumab-treated patients (100 mg every 8 weeks [Q8W]; 100 mg every 4 weeks [Q4W]) were comparable to ustekinumab-treated patients (45/90 mg). In biologic-naïve patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 1.97; 1.37, 2.84; Q4W: 2.04; 1.40, 2.96) and PASI 90 (Q8W: 2.33; 1.52, 3.56; Q4W: 2.57; 1.67, 3.97) versus ustekinumab from week 16 onwards. In biologic-experienced patients, both guselkumab doses showed significantly higher ACR 20 (Q8W: 2.57; 1.11, 5.93; Q4W: 2.63; 1.12, 6.17) versus ustekinumab from week 24 onwards; for PASI 90, both guselkumab doses were superior to ustekinumab at week 16 and 52 (Q8W: 3.96; 1.39, 11.27; Q4W: 13.10; 4.18, 41.04). Guselkumab efficacy was similar and robust across primary, scenario, and sensitivity analyses. CONCLUSIONS: IPD analysis demonstrated that both guselkumab doses were superior to ustekinumab for ACR 20 from weeks 16 (biologic-naïve) and 24 (biologic-experienced) onwards, and for PASI 90 at weeks 16 and 52 for both subgroups.

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

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

Improvement in patient-reported outcomes and work productivity following 3-year ustekinumab or tumour necrosis factor inhibitor treatment in patients with psoriatic arthritis: results from the PsABio real-world study.

BACKGROUND: To evaluate the real-world effect of the IL-12/23 inhibitor ustekinumab or of a tumour necrosis factor inhibitor (TNFi) on patient-reported outcomes (PRO) and their association with effectiveness endpoints in psoriatic arthritis (PsA) patients over 3 years. METHODS: In PsABio (NCT02627768), a prospective, observational study, patients with PsA that were prescribed first- to third-line ustekinumab or a TNFi, and remained on that drug for 3 years, were analysed for change in baseline in PROs (EuroQol-5 dimensions health state VAS [EQ-5D VAS], 12-item Psoriatic Arthritis Impact of Disease questionnaire [PsAID-12; range 0-10], Work Productivity and Activity Impairment for Psoriatic Arthritis questionnaire [WPAI; results expressed as a percentage for each domain]), and the association between PROs and WPAI with effectiveness endpoints, clinical disease activity index for psoriatic arthritis (cDAPSA), low disease activity (LDA)/remission, minimal disease activity (MDA) and very low disease activity (VLDA). RESULTS: In 437 patients (mean age 49.1 years, 47.8% female), at 3 years, ustekinumab and TNFi treatment led to comparable improvements in EQ-5D VAS; mean change from baseline (95% confidence intervals [CI]) was 11.0 (6.5; 15.4) and 18.9 (14.0; 23.9), respectively. Both groups improved PsAID-12 after 3 years; mean change from baseline (95% CI) was -2.9 (-3.2; -2.5) and -3.5 (-3.9; -3.2), respectively. At baseline, due to their PsA, TNFi-treated patients had lower work productivity compared to ustekinumab-treated patients; mean productivity reduction (95% CI) was 58.8 [52.4; 65.2] and 43.3 [35.6; 51.1]. Over 3 years, TNFi-treated patients had a greater improvement in work productivity compared to ustekinumab-treated patients, ultimately leaving work productivity to be comparable between groups; mean improvement (95% CI) was 44.5% (38.4; 50.6) and 24.9% (15.8; 34.0), respectively. A similar trend was observed in activity impairment. Patients in both treatment groups who achieved effectiveness endpoints, cDAPSA LDA/remission, MDA, and VLDA had greater improvement in PROs and WPAI than patients who did not achieve these endpoints. CONCLUSIONS: At 3 years, improvements in PROs following ustekinumab or TNFi treatment were generally comparable; however, TNFi-treated patients achieved a greater improvement in work productivity, although this group started from a lower baseline. Achievement of effectiveness endpoints, independent of treatment group, also improved PROs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02627768. Registered on 11 December 2015.

Identification of PsA phenotypes with machine learning analytics using data from two phase III clinical trials of guselkumab in a bio-naïve population of patients with PsA.

OBJECTIVES: Psoriatic arthritis (PsA) phenotypes are typically defined by their clinical components, which may not reflect patients' overlapping symptoms. This post hoc analysis aimed to identify hypothesis-free PsA phenotype clusters using machine learning to analyse data from the phase III DISCOVER-1/DISCOVER-2 clinical trials. METHODS: Pooled data from bio-naïve patients with active PsA receiving guselkumab 100 mg every 8/4 weeks were retrospectively analysed. Non-negative matrix factorisation was applied as an unsupervised machine learning technique to identify PsA phenotype clusters; baseline patient characteristics and clinical observations were input features. Minimal disease activity (MDA), disease activity index for psoriatic arthritis (DAPSA) low disease activity (LDA) and DAPSA remission at weeks 24 and 52 were evaluated. RESULTS: Eight clusters (n=661) were identified: cluster 1 (feet dominant), cluster 2 (male, overweight, psoriasis dominant), cluster 3 (hand dominant), cluster 4 (dactylitis dominant), cluster 5 (enthesitis, large joints), cluster 6 (enthesitis, small joints), cluster 7 (axial dominant) and cluster 8 (female, obese, large joints). At week 24, MDA response was highest in cluster 2 and lowest in clusters 3, 5 and 6; at week 52, it was highest in cluster 2 and lowest in cluster 5. At weeks 24 and 52, DAPSA LDA and remission were highest in cluster 2 and lowest in clusters 4 and 6, respectively. All clusters improved with guselkumab treatment over 52 weeks. CONCLUSIONS: Unsupervised machine learning identified eight PsA phenotype clusters with significant differences in demographics, clinical features and treatment responses. In the future, such data could help support individualised treatment decisions.

Gender-specific differences in patients with psoriatic arthritis receiving ustekinumab or tumour necrosis factor inhibitor: real-world data.

OBJECTIVE: Investigate effects of gender on disease characteristics and treatment impact in patients with PsA. METHODS: PsABio is a non-interventional European study in patients with PsA starting a biological DMARD [bDMARD; ustekinumab or TNF inhibitor (TNFi)]. This post-hoc analysis compared persistence, disease activity, patient-reported outcomes and safety between male and female patients at baseline and 6 and 12 months of treatment. RESULTS: At baseline, disease duration was 6.7 and 6.9 years for 512 females and 417 males respectively. Mean (95% CI) scores for females vs males were: clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA), 32.3 (30.3, 34.2) vs 26.8 (24.8, 28.9); HAQ-Disability Index (HAQ-DI), 1.3 (1.2, 1.4) vs 0.93 (0.86, 0.99); total PsA Impact of Disease-12 (PsAID-12) score, 6.0 (5.8, 6.2) vs 5.1 (4.9, 5.3), respectively. Improvements in scores were smaller in female than male patients. At 12 months, 175/303 (57.8%) female and 212/264 (80.3%) male patients achieved cDAPSA low disease activity, 96/285 (33.7%) and 137/247 (55.5%), achieved minimal disease activity (MDA), respectively. HAQ-DI scores were 0.85 (0.77, 0.92) vs 0.50 (0.43, 0.56), PsAID-12 scores 3.5 (3.3, 3.8) vs 2.4 (2.2, 2.6), respectively. Treatment persistence was lower in females than males (P ≤ 0.001). Lack of effectiveness was the predominant reason to stop, irrespective of gender and bDMARD. CONCLUSIONS: Before starting bDMARDs, females had more severe disease than males and a lower percentage reached favourable disease states, with lower persistence of treatment after 12 months. A better understanding of the mechanisms underlying these differences may improve therapeutic management in females with PsA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02627768.

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study.

OBJECTIVES: To evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years. METHODS: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or a TNFi. Persistence and effectiveness (achievement of clinical Disease Activity for PSA (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very LDA (MDA/VLDA)) were assessed every 6 months. Safety data were collected over 3 years. Analyses to compare the modes of action were adjusted on baseline differences by propensity scores (PS). RESULTS: In 895 patients (mean age 49.8 years, 44.7% males), at 3 years, the proportion of patients still on their initial treatments was similar with ustekinumab (49.9%) and TNFi (47.8%). No difference was seen in the risk of stopping/switching; PS-adjusted hazard ratio (95% CI) for stopping/switching ustekinumab versus TNFi was 0.87 (0.68 to 1.11). In the overall population, cDAPSA LDA/remission was achieved in 58.6%/31.4% ustekinumab-treated and 69.8%/45.0% TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63 to 1.26) for cDAPSA LDA; 0.72 (0.50 to 1.05) for remission. MDA/VLDA was achieved in 41.4%/19.2% of ustekinumab-treated and 54.2%/26.9% of TNFi-treated patients with overlapping PS-adjusted ORs. A greater percentage of TNFi-treated patients achieved effectiveness outcomes. Both treatments exhibited good long-term safety profiles, although ustekinumab-treated patients had a lower rate of adverse events (AEs) versus TNFi. CONCLUSION: At 3 years, there was generally comparable persistence after ustekinumab or TNFi treatment, but AE rates were lower with ustekinumab.

Persistence, effectiveness and safety of ustekinumab compared to TNF inhibitors in psoriatic arthritis within the Italian PsABio cohort.

OBJECTIVES: To compare real-world persistence, effectiveness and tolerability of ustekinumab versus TNF inhibitors (TNFi) in psoriatic arthritis (PsA). METHODS: One-year data from Italian subjects enrolled in the PsABio study (PsA patients receiving 1st- to 3rd-line treatment with ustekinumab or TNFi) were evaluated. Treatment persistence was analysed using Kaplan-Meier curves; hazard ratios (HR) of stopping treatment, and the corresponding 95% confidence intervals (CI), were computed through Cox regression models. Proportions of patients reaching clinical effectiveness endpoints were analysed using logistic regression, including propensity score (PS) adjustment for imbalanced baseline covariates, and non-response imputation if treatment was stopped/switched. RESULTS: Among 222 participants with follow-up data (effectiveness set), 101 received ustekinumab and 121 TNFi. In the ustekinumab group, 74.3% continued treatment up to 12±3 months compared to 63.6% in the TNFi group. Ustekinumab showed better persistence than TNFi, overall and in specific subgroups (females, monotherapy without methotrexate, BMI <25 or >30 kg/m2, patients receiving ustekinumab as 2nd-line treatment instead of a second TNFi). Overall, the PS-adjusted HR of treatment discontinuation was 0.46 (95% CI: 0.26-0.82) for ustekinumab vs. TNFi. cDAPSA LDA/remission was achieved in 43.5% of ustekinumab and 43.6% of TNFi-treated patients, while MDA was achieved in 24.2% and 28.0% of patients, respectively. After PS adjustment, odds ratios of clinical effectiveness did not differ significantly. Both treatments showed an acceptable safety profile. CONCLUSIONS: This prospective, real-life study found a better persistence of ustekinumab than TNFi in PsA patients. At 1 year, both treatments showed similar effectiveness.

Guselkumab provides sustained domain-specific and comprehensive efficacy using composite indices in patients with active psoriatic arthritis.

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 < 0.05). At week 52, in the guselkumab Q4W and Q8W groups, respectively, response rates were as follows: DAPSA LDA, 54.2% and 52.5%; DAPSA remission, 18.2% and 17.6%; PASDAS LDA, 45.3% and 41.9%; PASDAS VLDA, 16.9% and 19.5%; MDA, 35.9% and 30.7%; and VLDA, 13.1% and 14.4%. In the placebo-crossover-to-guselkumab group, response rates for all composite indices increased after patients switched to guselkumab, from week 24 through week 52. 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.

Risk Management Plans: reassessment of safety concerns based on Good Pharmacovigilance Practices Module V (Revision 2)-a company experience.

INTRODUCTION: In the European Union (EU), a Risk Management Plan (RMP) is submitted as part of the dossier for initial marketing authorization of a medicinal product or with an application involving a significant change to an existing marketing authorization. A comprehensive revision of the EU Guideline on Good Pharmacovigilance Practices (GVP) Module V-Risk Management Systems (Revision [Rev] 2), adopted in March 2017, provides a framework for developing more focused, actionable, and risk-proportionate RMPs. This paper describes the Janssen experience with the interpretation and application of GVP Module V (Rev 2) regarding the evaluation of safety concerns in an RMP. METHODS: Janssen convened a cross-functional working group to promote consistent interpretation of the GVP Module V (Rev 2) guidance across therapeutic areas. The group created 3 algorithms to support implementation of the guidance related to removal or reclassification of safety concerns by product-specific RMP teams. RESULTS: Following implementation of the GVP Module V (Rev 2) guidance, the algorithm-driven process led to a substantial decrease in the number of safety concerns for most products. With few exceptions, EU health authorities agreed with the proposed safety concern removals or reclassifications, resulting in RMPs that were focused on only those safety concerns that required further characterization or specific risk minimization. CONCLUSIONS: The algorithm-driven process allows for consistent interpretation and application of the GVP Module V (Rev 2) guidance, which enables product teams to develop an actionable RMP using a thoughtful, evaluative, science-based approach that considers all available evidence.

Persistence and effectiveness of the IL-12/23 pathway inhibitor ustekinumab or tumour necrosis factor inhibitor treatment in patients with psoriatic arthritis: 1-year results from the real-world PsABio Study.

OBJECTIVE: We evaluated real-world treatment persistence and effectiveness at 1 year following initiation of IL-12/23 inhibitor ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis (PsA). METHODS: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or TNFi. Drug persistence, effectiveness (achievement of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very low disease activity (MDA/VLDA)), and safety were assessed every 6 months. In addition to descriptive statistics, propensity score (PS)-adjusted comparisons across cohorts were performed. RESULTS: At 1 year, overall persistence was similar in the ustekinumab (n=317/438, 72.4%) and TNFi (n=321/455, 70.5%) groups. PS-adjusted HR (95% CI) for stopping/switching ustekinumab versus TNFi was 0.82 (0.60; 1.13). cDAPSA LDA (including remission)/remission was achieved in 55.9%/22.1% of ustekinumab-treated and 67.1%/31.7% of TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.80 (0.57; 1.10) for cDAPSA LDA and 0.73 (0.49; 1.07) for remission. MDA/VLDA was achieved in 34.2%/11.9% of ustekinumab-treated and 43.1%/12.6% of TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63; 1.26) for MDA and 0.90 (0.54; 1.49) for VLDA. The safety profiles were similar in both groups. CONCLUSION: In the real-world PsABio Study, after 1 year of treatment, although unadjusted persistence was numerically slightly higher for ustekinumab versus TNFi and unadjusted effectiveness was numerically slightly higher for TNFi versus ustekinumab, the PS-adjusted comparisons demonstrated comparable overall persistence, effectiveness and safety for both modes of action in PsA.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who are inadequate responders to tumour necrosis factor inhibitors: results through one year of a phase IIIb, randomised, controlled study (COSMOS).

OBJECTIVE: To evaluate efficacy and safety of guselkumab, an anti-interleukin-23p19-subunit antibody, in patients with psoriatic arthritis (PsA) with prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFi). METHODS: Adults with active PsA (≥3 swollen and ≥3 tender joints) who discontinued ≤2 TNFi due to IR (lack of efficacy or intolerance) were randomised (2:1) to subcutaneous guselkumab 100 mg or placebo at week 0, week 4, then every 8 weeks (Q8W) through week 44. Patients receiving placebo crossed over to guselkumab at week 24. The primary (ACR20) and key secondary (change in HAQ-DI, ACR50, change in SF-36 PCS and PASI100) endpoints, at week 24, underwent fixed-sequence testing (two-sided α=0.05). Adverse events (AEs) were assessed through week 56. RESULTS: Among 285 participants (female (52%), one (88%) or two (12%) prior TNFi), 88% of 189 guselkumab and 86% of 96 placebo→guselkumab patients completed study agent through week 44. A statistically significantly higher proportion of patients receiving guselkumab (44.4%) than placebo (19.8%) achieved ACR20 (%difference (95% CI): 24.6 (14.1 to 35.2); multiplicity-adjusted p<0.001) at week 24. Guselkumab was superior to placebo for each key secondary endpoint (multiplicity-adjusted p<0.01). ACR20 response (non-responder imputation) in the guselkumab group was 58% at week 48; >80% of week 24 responders maintained response at week 48. Through week 24, serious AEs/serious infections occurred in 3.7%/0.5% of 189 guselkumab-randomised and 3.1%/0% of 96 placebo-randomised patients; the guselkumab safety profile was similar through week 56, with no deaths or opportunistic infections. CONCLUSION: Guselkumab significantly improved joint and skin manifestations and physical function in patients with TNFi-IR PsA. A favourable benefit-risk profile was demonstrated through 1 year. TRIAL REGISTRATION NUMBER: NCT03796858.

Effectiveness of IL-12/23 inhibition (ustekinumab) versus tumour necrosis factor inhibition in psoriatic arthritis: observational PsABio study results.

OBJECTIVES: To evaluate 6-month effectiveness of ustekinumab versus tumour necrosis factor inhibitor (TNFi), analysing predictors of low disease activity (LDA)/remission. METHODS: PsABio is a prospective, observational cohort study of patients with psoriatic arthritis (PsA) at 92 sites in eight European countries, who received first-line to third-line ustekinumab or a TNFi. Comparative achievement at 6 months of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) LDA/remission, and minimal disease activity (MDA)/very LDA using propensity score (PS)-adjusted multivariate logistic regression was assessed. RESULTS: In the final analysis set of 868 participants with 6-month follow-up data (ustekinumab, n=426; TNFi, n=442), with long-standing disease and a high mean cDAPSA score (31.0 vs 29.8, respectively), proportions of patients in ustekinumab/TNFi treatment groups achieving cDAPSA LDA at 6 months were 45.7%/50.7%. cDAPSA remission was achieved in 14.9%/19.2%, and MDA in 26.4%/30.8% of patients. PS-adjusted odds ratios (OR; 95% confidence interval (CI)) of reaching cDAPSA LDA and MDA were 0.73 (0.46 to 1.15) and 0.87 (0.61 to 1.25) with ustekinumab versus TNFi, indicating no significant difference. High baseline body mass index or high cDAPSA were associated with a lower chance (OR (95% CI)) of reaching cDAPSA LDA with TNFi (0.94 (0.89 to 0.99) and 0.64 (0.52 to 0.79), respectively). Predictive factors were similar to previously published evidence, with cDAPSA and 12-item Psoriatic Arthritis Impact of Disease scores and chronic widespread pain at baseline appearing as new risk factors for unfavourable outcome. Safety data were similar between groups. CONCLUSION: Treatment targets were reached similarly after 6 months of treatment with ustekinumab and TNFi.

Corrigendum to: Persistence of biologic treatments in psoriatic arthritis: a population-based study in Sweden.

[This corrects the article DOI: 10.1093/rap/rkaa070.][This corrects the article DOI: 10.1093/rap/rkaa070.].

Post-approval Safety Surveillance Study of Golimumab in the Treatment of Rheumatic Disease Using a United States Healthcare Claims Database.

BACKGROUND AND OBJECTIVE: Golimumab is a fully human anti-tumor necrosis factor monoclonal antibody approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). This study estimated rates of prespecified outcomes in patients with RA, PsA or AS initiating golimumab versus matched patients initiating non-biologic systemic (NBS) medications. METHODS: Patients enrolled in a US health plan with rheumatic disease who initiated a study medication were accrued between April 2009 and November 2014. Golimumab initiators were matched by propensity score to NBS initiators in a 1:4 ratio. Outcomes were identified through September 2015. As-treated, as-matched, and nested case-control (NCC) analyses were conducted in the matched cohorts. Sensitivity analyses evaluated the impact of residual confounding and nondifferential misclassification of exposure and outcomes. RESULTS: Risks of outcomes were similar between golimumab and NBS initiators. In the as-treated analysis, the rate ratio (RR) for depression was elevated during current golimumab use versus golimumab non-use in the NBS cohort [RR 1.45, 95% confidence interval (CI) 1.31-1.61]. This finding was not replicated in as-matched (RR 1.08, 95% CI 0.97-1.19) or NCC (odds ratio 1.01, 95% CI 0.78-1.31) analyses, which focused on incident cases. Sensitivity analyses suggest that depression was sensitive to misclassification, and the RR changed from greater than to less than one across a plausible range of specificity. CONCLUSIONS: This study suggests that there is no association between exposure to golimumab and an increased risk of prespecified outcomes. Increased depression risk in the as-treated analysis was not replicated in other analyses and may be associated with residual imbalance in baseline history or severity of depression.

Persistence of biologic treatments in psoriatic arthritis: a population-based study in Sweden.

OBJECTIVES: TNF inhibitors (TNFis) and IL inhibitors are effective treatments for PsA. Treatment non-persistence (drug survival, discontinuation) is a measure of effectiveness, tolerability and patient satisfaction or preferences in real-world clinical practice. Persistence on these treatments is not well understood in European PsA populations. The aim of this study was to compare time to non-persistence for either ustekinumab (IL-12/23 inhibitor) or secukinumab (IL-17 inhibitor) to a reference group of adalimumab (TNFi) treatment exposures in PsA patients and identify risk factors for non-persistence. METHODS: A total of 4649 exposures of adalimumab, ustekinumab, and secukinumab in 3918 PsA patients were identified in Swedish longitudinal population-based registry data. Kaplan-Meier curves were constructed to measure treatment-specific real-world risk of non-persistence and adjusted Cox proportional hazards models were estimated to identify risk factors associated with non-persistence. RESULTS: Ustekinumab was associated with a lower risk of non-persistence relative to adalimumab in biologic-naïve [hazard ratio (HR) 0.48 (95% CI 0.33, 0.69)] and biologic-experienced patients [HR 0.65 (95% CI 0.56, 0.76)], while secukinumab was associated with a lower risk in biologic-naïve patients [HR 0.65 (95% CI 0.49, 0.86)] but a higher risk of non-persistence in biologic-experienced patients [HR 1.20 (95% CI 1.03, 1.40)]. Biologic non-persistence was also associated with female sex, axial involvement, recent disease onset, biologic treatment experience and no psoriasis. CONCLUSION: Ustekinumab exhibits a favourable treatment persistency profile relative to adalimumab overall and across lines of treatment. The performance of secukinumab is dependent on biologic experience. Persistence and risk factors for non-persistence should be accounted for when determining an optimal treatment plan for patients.

Effectiveness of the golimumab educational program in ensuring healthcare professionals' awareness of risks described in the European risk management plan.

BACKGROUND: The golimumab safety awareness study commenced in 2010 to measure, periodically, the awareness of golimumab prescriber healthcare professionals (HCPs) of specific risks associated with golimumab as well as awareness of the requirement to provide a patient alert card to each patient treated with golimumab, as described in the European golimumab educational program. The aim of this study was to measure the awareness of HCPs who prescribe or who intend to prescribe SIMPONI® (golimumab) of the risks potentially related to golimumab and of the requirements for distributing the patient alert card, as described in the golimumab educational program. METHODS: A structured, quantitative Web-based survey was conducted in 2010, 2012, 2014, and 2016 in eight European countries among HCPs who were at that time current or future prescribers of golimumab for patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, or ulcerative colitis. RESULTS: The overall golimumab risk awareness was high for golimumab prescriber HCPs across the risk statement categories (median awareness in 2016 across categories: 91%). The awareness of the golimumab risks was generally slightly higher among rheumatologists (75-98%) and gastroenterologists (73-97%) than among dermatologists (67-94%). Overall, the awareness of the requirements for handing out the patient alert card to golimumab-treated patients remained steady or increased slightly in 2016 relative to the other surveys. CONCLUSIONS: The results of this study show that the awareness of risks associated with golimumab by golimumab prescriber HCPs is high. The information made available to golimumab prescriber HCPs appears to have been sufficient with respect to golimumab risk awareness education.

Alternatively activated myeloid cells limit pathogenicity associated with African trypanosomiasis through the IL-10 inducible gene selenoprotein P.

Uncontrolled inflammation is a major cause of tissue injury/pathogenicity often resulting in death of a host infected with African trypanosomes. Thus, comparing the immune response in hosts that develop different degrees of disease severity represents a promising approach to discover processes contributing to trypanosomiasis control. It is known that limitation of pathogenicity requires a transition in the course of infection, from an IFN-gamma-dependent response resulting in the development of classically activated myeloid cells (M1), to a counterbalancing IL-10-dependent response associated with alternatively activated myeloid cells (M2). Herein, mechanisms and downstream effectors by which M2 contribute to lower the pathogenicity and the associated susceptibility to African trypanosomiasis have been explored. Gene expression analysis in IL-10 knockout and wild-type mice, that are susceptible and relatively resistant to Trypanosoma congolense infection, respectively, revealed a number of IL-10-inducible genes expressed by M2, including Sepp1 coding for selenoprotein P. Functional analyses confirm that selenoprotein P contributes to limit disease severity through anti-oxidant activity. Indeed, Sepp1 knockout mice, but not Sepp1(Delta)(240-361) mice retaining the anti-oxidant motif but lacking the selenium transporter domain of selenoprotein P, exhibited increased tissue injury that associated with increased production of reactive oxygen species and increased apoptosis in the liver immune cells, reduced parasite clearance capacity of myeloid cells, and decreased survival. These data validate M2-associated molecules as functioning in reducing the impact of parasite infection on the host.

African trypanosomiasis: naturally occurring regulatory T cells favor trypanotolerance by limiting pathology associated with sustained type 1 inflammation.

Tolerance to African trypanosomes requires the production of IFN-gamma in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-gamma by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-alpha production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis.

Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions.

Compared with type I cytokine-associated myeloid (M1) cells, the molecular repertoire and mechanisms underlying functional properties of type II cytokine-associated myeloid (M2) cells are poorly characterized. Moreover, most studies have been limited to in vitro-elicited M2 cells. Here, comparative gene expression profiling of M1 and M2 cells, elicited in murine models of parasitic infections and cancer, yielded a common signature for in vivo-induced M2 populations independent of disease model, mouse strain, and organ source of cells. Some of these genes, such as cadherin-1, selenoprotein P, platelet-activating factor acetylhydrolase, and prosaposin, had not been documented as associated with M2. Overall, the common signature genes provide a molecular basis for a number of documented or suggested properties of M2, including immunomodulation, down-regulation of inflammation, protection against oxidative damage, high capacity for phagocytosis, and tissue repair. Interestingly, several common M2 signature genes encode membrane-associated markers that could be useful for the identification and isolation of M2. Some of these genes were not induced by IL-4/IL-13 or IL-10 under various in vitro settings and thus were missed in approaches based on in vitro-activated cells, validating our choice of in vivo models for expression profiling of myeloid cells.

Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection.

Understanding the role of CD11b(+)GR-1(+) myeloid suppressor cells in the immune suppression and immunoregulation associated with a variety of diseases may provide therapeutic opportunities. In this article, we show, in a model of helminth infection, that CD11b(+)GR-1(+) myeloid suppressor cells but not CD11b(+)F4/80(high) mature macrophages expanded in the peritoneal cavity of BALB/c mice implanted with Taenia crassiceps. Peritoneal cell populations from early stage-infected animals impaired T cell proliferation by secreting NO. Yet, they lost their ability to secrete NO in the late stage of infection. Concomitantly, their capacity to exert arginase activity and to express mRNAs coding for FIZZ1 (found in inflammatory zone 1), Ym, and macrophage galactose-type C-type lectin increased. Furthermore, cells from early stage-infected mice triggered T cells to secrete IFN-gamma and IL-4, whereas in the late stage of infection, they only induced IL-4 production. These data suggest that CD11b(+)GR-1(+) myeloid suppressor cells displaying an alternative activation phenotype emerged gradually as T. crassiceps infection progressed. Corroborating the alternative activation status in the late stage of infection, the suppressive activity relied on arginase activity, which facilitated the production of reactive oxygen species including H(2)O(2) and superoxide. We also document that the suppressive activity of alternative myeloid suppressor cells depended on 12/15-lipoxygenase activation generating lipid mediators, which triggered peroxisome proliferator-activated receptor-gamma. IL-4 and IL-13 signaling contributed to the expansion of myeloid suppressor cells in the peritoneal cavity of T. crassiceps-infected animals and to their antiproliferative activity by allowing arginase and 12/15-lipoxygenase gene expression.