Marc Chevrier

Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR)

IMPORTANCE The efficacy of treatment for psoriasis must be balanced against potential adverse events. OBJECTIVE To determine the effect of treatment on the risk of serious infections in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS A multicenter, longitudinal, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers. Participants were adult patients with psoriasis who were receiving or were eligible to receive conventional systemic or biologic agents. The registry opened on June 20, 2007, and data included herein were collected through August 23, 2013. EXPOSURES Patients were prescribed psoriasis therapies as in standard clinical practice. Patients will be followed for up to 8 years. Data were collected and serious adverse events (including serious infections) were assessed at regular intervals. MAIN OUTCOMES AND MEASURES Cohort characteristics are described based on evaluation at entry into the registry. The cumulative incidence rates of serious infections are reported across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional hazards regression model was used to identify predictors of the time to the first serious infection using the nonmethotrexate/nonbiologics cohort as the reference. RESULTS Data were analyzed from 11,466 patients with psoriasis (22,311 patient-years). Differences in patient characteristics were found between the biologics and nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease characteristics), as well as among the individual biologic groups (eg, a higher prevalence of psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The most commonly reported types of serious infections across the registry were pneumonia and cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection. CONCLUSIONS AND RELEVANCE Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00508547.

Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR).

Psoriasis is associated with several comorbidities and behavioural risk factors.

The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: Results of a prospective, multicenter, open-label study

BACKGROUND In patients with psoriasis and inadequate response (IR) to tumor necrosis factor-α antagonist treatment, the incremental benefit of switching to another tumor necrosis factor-α antagonist is unknown. OBJECTIVE We sought to evaluate the clinical response to an etanercept-to-infliximab switch in patients with psoriasis and IR to etanercept. METHODS Adults with moderate-to-severe plaque psoriasis and IR to etanercept (≥ 4 months) were eligible for this open-label study (called PSUNRISE). Patients had a Physician Global Assessment (PGA) score of at least 2 (mild) on a 5-point scale with etanercept, with or without concomitant oral systemic methotrexate or cyclosporine at baseline and during the study. Patients received intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22. PGA was used to evaluate efficacy at week 10 (primary end point) and week 26 (durability). Safety was evaluated through the end of the study. RESULTS Of 215 patients, only 10 received concomitant immunomodulators. At week 10, 65.4% of patients (138 of 211; 95% confidence interval 58.6%-71.8%) achieved a PGA score of clear (0) or minimal (1) (primary end point). This response was durable through week 26, at which time 61.3% (122 of 199; 95% confidence interval 54.2%-68.1%) achieved a PGA score of clear (0) or minimal (1). There were no unexpected side effects or safety concerns. LIMITATIONS This was an open-label, 26-week study; an incremental change of 1 PGA point, even mild to minimal, was considered clinically significant, as most psoriasis practitioners seek to achieve minimal psoriasis or clear skin. CONCLUSION After switching to infliximab, a substantial proportion of patients with psoriasis and IR to etanercept experienced rapid and durable improvement.

Extension of ustekinumab maintenance dosing interval in moderate‐to‐severe psoriasis: results of a phase IIIb, randomized, double‐blinded, active‐controlled, multicentre study (PSTELLAR)

Phase III studies showed that some patients maintained response for ≥ 6 months following ustekinumab discontinuation.

Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study

BACKGROUND Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohns disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to-severe disease activity despite conventional treatment. METHODS This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18-75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35-55 kg, 390 mg for patients weighing >55 kg and ≤85 kg, and 520 mg for patients weighing >85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061. FINDINGS Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24, 37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10-47], p=0·006). Between week 0 and week 24, 47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment-emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0-24. INTERPRETATION The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. FUNDING Janssen Research & Development, LLC.

Clinical response to golimumab in rheumatoid arthritis patients who were receiving etanercept or adalimumab: results of a multicenter active treatment study

Abstract Objective: Evaluate the efficacy and safety of subcutaneous (SC) golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite etanercept + MTX or adalimumab + MTX therapy and evaluate whether intravenous (IV) golimumab could rescue patients who were nonresponders to SC golimumab. Methods: In this multicenter, assessor-blinded, active-switch study of patients with RA (n = 433) with inadequate response to etanercept or adalimumab + MTX, patients continued MTX and received open-label SC golimumab 50 mg every 4 weeks through week 12. DAS28-ESR good responders at week 16 continued open-label SC golimumab through week 52 (Group 1); nonresponders were randomized to double-blind golimumab SC 50 mg (Group 2-SC) or IV 2 mg/kg (Group 2-IV). Week 14 ACR20 was the primary endpoint; assessments continued through week 52 and for patients in the voluntary long-term extension through week 76. A major secondary endpoint was the proportions of patients with ACR20 response at week 52 relative to week 16 in Group 2-SC and Group 2-IV. Results: At week 14, 34.9% (p < 0.001) achieved an ACR20. At week 52, patients in Group 1 (n = 75) achieved an ACR20 (62.7%). In Groups 2-SC (n = 91) and 2-IV (n = 184), 13.2% and 9.2% had an ACR20 at week 52 relative to week 16, with no significant difference between the randomized groups; 42.9% and 47.8% achieved DAS28-ESR response relative to week 0. Through week 16, 4.6% of patients had a serious adverse event. No differences in the rates or types of adverse events were observed between SC and IV golimumab from weeks 16 to 52. The trial limitations included a higher than expected discontinuation rate as a result of a programming error. Conclusion: SC golimumab + MTX significantly suppressed disease activity in RA patients with inadequate response to etanercept and/or adalimumab + MTX. Patients randomized to Groups 2-SC and 2-IV had lower response rates than Group 1, with no difference between SC or IV mode of administration. The safety profile with IV golimumab was comparable to that established with SC golimumab. Trial registration: NCT01004432, EudraCT 2009-010582-23.

S7A:8 Efficacy and safety of ustekinumab, an interleukin 12/23 inhibitor, in patients with active systemic lupus erythematosus: results of a phase 2, randomised placebo-controlled study

Purpose IL12 and IL23 pathway have been linked to SLE pathogenesis. Anti-IL12/23 monoclonal antibody ustekinumab (UST) previously approved for psoriasis, psoriatic arthritis, and Crohn’s diseasewas evaluated in pts with active SLE. Methods A Ph2, PBO-controlled study in 102 adults with seropositive SLE by SLICC criteria with active disease despite standard-of-care therapy were randomised to UST vs PBO, added to standard care. Primary endpoint was the proportion achieving SLE response index (SRI)−4 response at wk24. Secondary endpoints included change SLEDAI-2K, Physician’s Global Assessment (PGA), and BICLA response. Results The mITT population (includes pts who received at least one dose) at wk24 revealed 60% of UST pts with SRI-4 response vs 31% in PBO (p=0.0046). Pts in UST group had greater median change from wk0 to wk24 in SLEDAI-2K and PGA vs PBO (table 1). No difference was observed in BICLA composite response at wk24, but more UST pts had no BILAG worsening vs PBO. Through wk24, 78% of UST pts and 67% of PBO pts had greater than or equal to 1 AE; 8.3%–9.5%, respectively, had greater than or equal to 1 SAE (table 1). There were no deaths in the study. Safety events were consistent with UST safety profile in other studied indications. Conclusion UST showed efficacy in treatment of active SLE vs PBO and comparable safety warranting further investigation. UST may work via a novel mechanism of action in SLE.Abstract S7A:8 Table 1 Efficacy and safety results at week 24

Longitudinal Study of the Psoriasis-Associated Skin Microbiome during Therapy with Ustekinumab in a Randomized Phase 3b Clinical Trial

Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a phase 3b clinical trial. By sequencing the bacterial 16S ribosomal RNA gene from skin swab samples obtained at six anatomical sites, we identified minor, site-specific differences in microbial diversity and composition between pretreatment lesional and nonlesional skin. During therapy, microbial communities within lesional and nonlesional skin diverged, and body-site dispersion increased, reflecting microbial skin site-specificity. Microbiota demonstrated greater pretreatment heterogeneity in psoriatic lesions than in nonlesional skin, and variance increased as treatment progressed. Microbiota colonizing recurrent lesions did not overlap with pretreatment lesional microbiota, suggesting colonization patterns varied between initial and recurrent psoriatic lesions. While plaque psoriasis does not appear to be associated with specific microbes and/or microbial diversity, this large dataset provides insight into microbial variation associated with (i) disease in different body locations, (ii) initial versus recurrent lesions, and (iii) anti-IL12/23 therapy.

FRI0303 Efficacy and safety of ustekinumab in patients with active systemic lupus erythematosus: results of a phase 2, randomised placebo-controlled study

Background IL12 and IL23 have been linked to SLE pathogenesis. Objectives The anti-IL12/23 monoclonal antibody ustekinumab (UST) was evaluated in pts with active SLE. Methods We conducted a Ph2, PBO-controlled study in 102 pts with active SLE. Pts were randomised(3:2) to UST IV~6 mg/kg or PBO at wk0, followed by UST SC 90 mg or PBO injections q8w, both added to standard care. Primary endpoint was proportion of pts achieving SLE responder index(SRI)−4 response at wk24. Secondary endpoints were change from baseline(BL) in SLEDAI-2K, PGA and BICLA response. Additional pre-specified endpoint analyses included no BILAG worsening(defined as no new BILAG A and ≤1 new BILAG B) and BILAG flare(≥1 new BILAG A or ≥2 new BILAG B). Results SRI-4 response occurred in 60% UST vs 31% PBO pts(p=0.005) at wk24 (table 1). UST pts had greater median change from BL in SLEDAI-2K and PGA vs PBO. No difference was observed in BICLA response at wk24; however, in the UST group vs PBO, more pts had no BILAG worsening, and the risk of a new BILAG flare was significantly lower(HR 0.11 [95% CI 0.01–0.94];p=0.0078). UST demonstrated improvement in musculoskeletal and mucocutaneous disease features vs PBO (table 1). Through wk24, 78% UST vs 67% PBO pts had ≥1 AE; 8.3%–9.5%, respectively, had ≥1 SAE; there were no deaths. The overall safety profile was comparable between UST and PBO.Abstract FRI0303 – Table 1 Efficacy Results at Wk 24. PBO UST Pts randomised, n 42 60 SRI-4 response, n (%) 13 (31.0) 36 (60.0) P value 0.005a Change from baseline SLEDAI-2K, median (range) −2.0 (-20; 10) −6.0 (-10; 3) P value 0.026a,b Change from baseline PGA, median (range) −1.6 (-5.6; 2.7) −2.5 (-6.6; 2.8) P value 0.211a,b BICLA response, n (%) 14 (33.3) 21 (35.0) P value 0.994a Pts with no BILAG worsening, n/N (%) 11 (26.2) 29 (48.3) P value 0.028 Pts with≥50% improvement from baseline in joint activityc,% (95% CI) 63.2 (61.7–64.6) 87.7 (86.8–88.6) P value 0.021d Pts with≥50% improvement from baseline in CLASI activity scored,% (95% CI) 25.2 (23.1–27.4) 58.7 (57.4–60.1) P value 0.043e aPrespecified analyses; all other analyses were post-hoc. bOne-sided test for no difference between treatment groups using a Wilcoxon non-parametric median test for difference of location cPt subpopulation (67% of total) with ≥4 active joints at baseline dPt subpopulation (58% of total) with baseline CLASI activity score ≥4 eProportion of responders and p values based on mITT analysis using a multiple imputation model for missing data from wks 16 to 24 BICLA, BILAG-based Combined Lupus Assessment; BILAG, British Isles Lupus Assessment Group; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SLEDAI-2K, ;Systemic Lupus Erythematosus Disease Activity Index 2000 PGA, physician’s global assessment Conclusions UST treatment showed efficacy in pts with active SLE and was well-tolerated. UST may work via a novel mechanism of action in SLE. Disclosure of Interest R. van Vollenhoven Grant/research support from: Janssen Research and Development, LLC, B. Hahn Grant/research support from: Janssen Research and Development, LLC, G. Tsokos Grant/research support from: Janssen Research and Development, LLC, C. Wagner Employee of: Janssen Research and Development, LLC, P. Lipsky Grant/research support from: Janssen Research and Development, LLC, B. Hsu Employee of: Janssen Research and Development, LLC, M. Chevrier Employee of: Janssen Research and Development, LLC, R. Gordon Employee of: Janssen Research and Development, LLC, M. Triebel Employee of: Janssen Biologics, S. Rose Employee of: Janssen Research and Development, LLC

THU0388 Combining RNA-SEQ and Machine Learning to Classify an Sle-Specific Gene Signature and in Vitro Responses to IFN-I Pathway Inhibition

Background Type I IFN (IFN-I) is elevated in SLE and is thought to play a role in its pathogenesis. In this study, we utilized RNA sequencing (RNA-Seq) to evaluate whole blood gene expression profiles from a cohort of SLE patients and from age- and sex- matched African American and Hispanic controls in an effort to create more selective biomarkers associated with IFN-I activation. Objectives We generated a transcriptional signature from SLE patient blood associated with in vitro IFN-I pathway inhibition. We then tested whether IFN-I inhibition could reverse SLE-specific gene expression signatures in an effort to predict which individuals with SLE may be most likely to respond to IFN-I inhibition treatment. Methods Paired-end strand specific RNA-Seq was used for gene expression profiling of healthy donors and lupus patients. For each sample, almost 100 million reads were sequenced for a total of ∼50 million fragments. A Support Vector Machine (SVM), a powerful classification algorithm in machine learning, was trained on multiple datasets to classify SLE patients and identify genes responsive to IFN-I inhibition. Results RNA-Seq analysis of 23 healthy donors (23H) versus 25 SLE patients (25L) identified ∼200 differentially expressed transcripts. Approximately 95% of these transcripts were up-regulated, and Ingenuity® Pathway Analysis (IPA) confirmed that IFN-I was the most enriched pathway in this SLE cohort. To characterize the molecular contribution of the IFN-I pathway in SLE, we treated a subgroup of SLE patient blood samples in vitro with an IFN-I inhibitor and examined the effect of treatment on the transcriptome. SVM was trained on these data and identified a gene signature in SLE donors that was normalized to a healthy donor profile after in vitro treatment. SVM identified a signature of down modulated transcripts after IFN-I inhibition. We next tested this signature in a larger cohort (23H and 25L) to verify the relevance of these genes in SLE and to examine the potential of this signature to identify lupus patients most likely to respond to IFN-I inhibition. SVM correctly classified 21 out of 23 Healthy donors and 23 out of 25 SLE patients. Of note, two misclassified Healthy donors had positive Antinuclear Antibodies titer, one of which also exhibited specific Lupus-related autoantibodies (anti-Smith, and anti-Ro). Comparison with other SLE signatures suggests that the genes identified by our approach better represent the larger cohort of SLE patients examined in our study. Conclusions We identified ∼200 SLE-specific transcripts and showed that the IFN-I pathway was the most prevalent canonical pathway enriched in this SLE cohort. Applying a machine learning approach using an in vitro interventional dataset from this same cohort, we were able to identify SLE-specific signature that was down-modulated after treatment. This signature correctly classified ∼92% of SLE patients. Applying this approach to larger data sets may enable the development of more precise biomarkers for patient stratification and pharmacodynamic assessment for therapies targeting IFN-I. Acknowledgements We acknowledge Tanesha Cash-Mason for her support with processing these samples Disclosure of Interest M. Cesaroni Employee of: Janssen, J. Jordan Employee of: Janssen, J. Schreiter Employee of: Janssen, M. Chevrier Employee of: Janssen, W.-H. Shao Grant/research support from: Janssen, B. Hilliard Grant/research support from: Janssen, P. Cohen Grant/research support from: Janssen, R. Caricchio Grant/research support from: Janssen, J. Benson Employee of: Janssen