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Ceramide nanoliposomes treatment promoted the oligomerizations of endogenous MLKL.

Supplementary Materials and Methods

Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knockdown of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pronecroptotic target for ceramide in ovarian cancer models. Mol Cancer Ther; 17(1); 50–59. ©2017 AACR.

Sparse scan partial thermal ablation (TA) with focused ultrasound (FUS) may be deployed to treat solid tumors and increase delivery of systemically administered therapeutics. Further, C6-ceramide-loaded nanoliposomes (CNLs), which rely upon the enhanced permeation and retention (EPR) effect for delivery, have shown promise for treating solid tumors and are being tested in clinical trials. Here, our objective was to determine whether CNLs synergize with TA in the control of 4T1 breast tumors. CNL-monotherapy of 4T1 tumors yielded significant intratumoral bioactive C6 accumulation by the EPR effect, but tumor growth was not controlled. TA increased bioactive C6 accumulation by ∼12.5-fold over the EPR effect. In addition, TA+CNL caused shifts in long-chain to very-long-chain ceramide ratios (i.e., C16/24 and C18/C24) that could potentially contribute to tumor control. Nonetheless, these changes in intratumoral ceramide levels were still insufficient to confer tumor growth control beyond that achieved when combining with TA with control “ghost” nanoliposomes (GNL). While this lack of synergy could be due to increased “pro-tumor” sphingosine-1-phosphate (S1P) levels, this is unlikely because S1P levels exhibited only a moderate and statistically insignificant increase with TA+CNL. In vitro studies showed that 4T1 cells are highly resistant to C6, offering the most likely explanation for the inability of TA to synergize with CNL. Thus, while our results show that sparse scan TA is a powerful approach for markedly enhancing CNL delivery and generating “anti-tumor” shifts in long-chain to very-long-chain ceramide ratios, resistance of the tumor to C6 can still be a rate-limiting factor for some solid tumor types.

Aim: Despite the huge advancements in cancer therapies and treatments over the past decade, most patients with metastasized melanoma still die from the disease. This poor prognosis largely results from resistance to conventional chemotherapies and other cytotoxic drugs. We have previously identified 6 antigenic peptides derived from melanomas that have proven efficacious for activating CD4+ T cells in clinical trials for melanoma. Our aim was to improve pharmacodynamics, pharmacokinetic and toxicological parameters by individually encapsulating each of the 6 melanoma helper peptides within their own immunogenic nanoliposomes. Methods: We modified these liposomes as necessary to account for differences in the peptides’ chemical properties, resulting in 3 distinct formulations. To further enhance immunogenicity, we also incorporated KDO2, a TLR4 agonist, into the lipid bilayer of all nanoliposome formulations. We then conducted in vivo imaging studies in mice and ex vivo cell studies from 2 patient samples who both strongly expressed one of the identified peptides. Results: We demonstrate that these liposomes, loaded with the different melanoma helper peptides, can be readily mixed together and simultaneously delivered without toxicity in vivo. These liposomes are capable of being diffused to the secondary lymphoid organs very quickly and for at least 6 days. In addition, we show that these immunogenic liposomes enhance immune responses to specific peptides ex vivo. Conclusion: Lipid-based delivery systems, including nanoliposomes and lipid nanoparticles, have now been validated for pharmacological (small molecules, bioactive lipids) and molecular (mRNA, siRNA) therapeutic approaches. However, the utility of these formulations as cancer vaccines, delivering antigenic peptides, has not yet achieved the same degree of commercial success. Here, we describe the novel and successful development of a nanoliposome-based cancer vaccine for melanoma. These vaccines help to circumvent drug resistance by increasing a patient’s T cell response, making them more susceptible to checkpoint blockade therapy.

Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870

Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. Vinca alkaloids such as vincristine (VCR), widely used in cancer treatment, are no exception, as their beneficial actions are often supplanted by resistance. In the present work we utilized HL-60 human leukemia cells and a VCR-resistant counterpart, HL-60/VCR, as a model to determine potential interplay between SL metabolism and mitochondrial bioenergetics supportive of multidrug resistance (MDR). Relative to wild-type cells, HL-60/VCR presented with global alterations in SL composition, typified by upregulated expression of sphingosine kinase (SPHK1), which catalyzes formation of sphingosine 1-phosphate (S1P), glucosylceramide synthase (GCS), which catalyzes formation of glucosylceramides (GC), and acid ceramidase, responsible for ceramide hydrolysis. In support of these changes, VCR resistance was also characterized by increases in S1P, several molecular species of ceramide and GC, and changes in sphingomyelin (SM) molecular species. With respect to mitochondria, despite increased basal respiration in HL-60/VCR cells, direct interrogation of the mitochondrial network revealed intrinsic respiratory complex insufficiency, largely localized to complex I (CI). Importantly, forced ceramide accumulation in wild-type cells phenocopied the respiratory insufficiency observed in HL-60/VCR, and co-targeting SL metabolism and CI induced synergistic cytotoxicity in HL-60/VCR cells, as well as in other MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials.MethodsData from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)).ResultsA total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment.ConclusionsIn this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

ObjectiveTo assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies.MethodsIn this posthoc analysis, data were pooled from patients originally randomized to secukinumab 150 mg, 300 mg, or placebo (PBO) from phase III MEASURE 1–4 studies (ClinicalTrials.gov: NCT01358175, NCT01649375, NCT02008916, and NCT02159053). Maastricht AS Enthesitis Score (MASES) was used for assessments of enthesitis through Week 52. Efficacy outcomes were mean change in MASES score and complete resolution (MASES = 0) of enthesitis in patients with baseline MASES > 0.ResultsA total of 693 (71.5%) patients had enthesitis at baseline in secukinumab 300 mg, 150 mg, and PBO groups (58 [76.3%], 355 [70.4%], and 280 [72%], respectively) out of 969 patients pooled in this analysis. At Week 16, mean changes from baseline for overall MASES and enthesitis at axial MASES sites, respectively, were as follows: –2.9 (P < 0.01) and –2.9 (P < 0.01) for secukinumab 300 mg; –2.4 (P < 0.015) and –2.3 (P < 0.05) for secukinumab 150 mg; and –1.9 and –1.8 for PBO, with improvements seen through Week 52. More than one-third of secukinumab-treated patients (300 mg: 36.2%; 150 mg: 40.8%) achieved complete resolution of enthesitis at Week 16.ConclusionSecukinumab improved enthesitis at overall MASES and axial sites in patients with AS.

Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression.We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient.Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI -0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo.Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

Background Enthesitis can be a debilitating extra-articular spondyloarthritis manifestation that causes considerable pain and reduced quality of life. We evaluated the effect of secukinumab on axial and peripheral enthesitis in ankylosing spondylitis (AS) patients with baseline enthesitis (BLE) across all MASES sites (N = 13), axial MASES sites (N = 11; 13 MASES minus Achilles tendons [AT] [AxS]), peripheral sites (N = 6; AT + lateral condyles of humerus/femur [PS]) and the AT (N = 2) at Weeks 16 and 52. Methods This post-hoc analysis pooled data across four AS studies (MEASURE 1-4) from patients originally randomised to secukinumab 150 mg (approved AS dose), 300 mg (MEASURE 3 only) or placebo with BLE (MASES >0). Evaluations included mean change from baseline in MASES score, complete resolution (CR; MASES=0) and improvement from baseline in MASES score ≥5 counts. Mixed-effect model repeat measurement analysis was performed on change from baseline in MASES score and non-responder imputation for resolution of enthesitis at Week 16; data are reported as observed at Week 52. Results 355 (70.4%), 58 (76.3%) and 280 (72%) patients had BLE in the 150 mg, 300 mg and placebo groups, respectively. Baseline characteristics were comparable across groups. At Week 16, mean change from baseline for overall MASES and at AxS was greater for secukinumab 150 mg (−2.4, −2.3) and 300 mg (−2.9, −2.9) vs placebo (−1.9, −1.8; P < 0.05, P < 0.01). At Week 16, patients treated with secukinumab 150 mg (40.8%, 42.7%) and 300 mg (36.2%, 42.1%) vs placebo (28.9%, 30.1%) achieved CR of enthesitis at overall MASES and AxS. Secukinumab 150 mg and 300 mg were consistently associated with a higher mean change in MASES and CR of enthesitis at PS and AT vs placebo. More patients treated with secukinumab 150/300 mg vs placebo achieved a higher threshold of improvement (≥5 counts) in overall MASES at Week 16. Further improvements were observed for all endpoints at Week 52 (Table 1). Conclusion Secukinumab 150 mg and 300 mg were associated with a higher mean change in MASES and CR of enthesitis for overall MASES and at AxS vs placebo in AS patients at Week 16, which further improved through Week 52. Disclosures N. Barkham Grants/research support; Novartis, Eli Lilly, UCB, Celgene. G. Schett None. X. Baraliakos Consultancies; AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Biologics, Novartis, Pfizer, UCB Pharma, Galapagos. Member of speakers’ bureau; AbbVie, Chugai, Janssen, Novartis, Pfizer, UCB Pharma. Grants/research support; AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer, Roche, UCB. F. van den Bosch Consultancies; AbbVie, Bristol-Myers Squibb, Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer, UCB. Member of speakers’ bureau; AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, Pfizer, UCB. A. Deodhar Consultancies; AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Amgen, Eli Lilly, GSK, Janssen, Novartis, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, UCB. L.S. Gensler Consultancies; Novartis, Lilly, Janssen. Grants/research support; AbbVie, Amgen, UCB Pharma. M. Ǿstergaard Consultancies; AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, UCB. Member of speakers’ bureau; AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, UCB. Grants/research support; AbbVie, Celgene, Centocor, Merck, Novartis. S. Agawane Other; Employee of: Novartis. A. Das Gupta Other; Employee of: Novartis. S. Mpofu Other; Employee of: Novartis. T. Fox Other; Employee of: Novartis. A. Winseck Other; Employee of: Novartis. A. Shete Shareholder/stock ownership; Novartis. Other; Employee of: Novartis. B. Porter Shareholder/stock ownership; Novartis. Other; Employee of: Novartis.

Background Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long-term follow-up is needed to evaluate psoriasis therapies fully. Objectives To determine the long-term (3-year) efficacy and safety of secukinumab in moderate-to-severe psoriasis. Methods Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double-blind regimens. Dosing regimens included a fixed-interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. Results In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63·8%, and of PASI 100 responders it was 42·6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality-of-life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. Conclusions Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years.

Background:Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton associated with pain, stiffness, and disability.1Up to 66% of patients (pts) with AS may also have peripheral involvement, including swollen and tender joints (STJs),2,3which are associated with worse overall disease activity.4A previous analysis showed that secukinumab, a selective inhibitor of interleukin 17A, led to significant improvements in efficacy outcomes vs placebo, regardless of peripheral joint involvement.3However, the effect of secukinumab on symptoms of peripheral arthritis in pts with AS was not assessed.Objectives:The objective of this analysis was to assess changes in peripheral symptoms in pts with AS treated with secukinumab vs placebo.Methods:Data from pts with active AS and peripheral symptoms who were enrolled in MEASURE 1 (NCT01358175), 2 (NCT01649375), 3 (NCT02008916), and 4 (NCT02159053) were pooled in this post hoc, hypothesis-generating analysis. No adjustments for multiple comparisons were made. Pts with peripheral symptoms were identified by the presence of STJs, based on 44-joint counts at baseline (BL). Pts received subcutaneous (SC) secukinumab every 4 weeks at doses of 300 mg with an intravenous (IV) loading dose (MEASURE 3 only), 150 mg with an IV or SC loading dose, or placebo. Treatment response through Week 16 was assessed based on the proportions of pts who achieved improvements of 20%, 50%, 70%, or 100% in the number of swollen and number of tender joints and improvements in the BASDAI score for question 3 and Patient Global Assessment (PGA). Changes in the number of swollen and number of tender joints were assessed in pts with swollen or tender joints at BL, respectively.Results:This pooled analysis included 560 pts with AS and STJs at BL (Table). At Week 16, treatment with secukinumab led to significantly greater proportions of pts achieving reductions in the number of swollen (Fig 1A) or tender (Fig 1B) joints compared with placebo; the treatment effect was more pronounced in reduction of swollen joints. Furthermore, a greater proportion of secukinumab-treated pts achieved complete resolution of swollen or tender joints vs placebo (Fig 1). Secukinumab also led to significant improvements in peripheral pain/swelling (Fig 2A) and disease activity (Fig 2B) vs placebo, as assessed using BASDAI question 3 and the PGA, respectively.Table.Patient Characteristics at BaselineSecukinumabPlacebo (n = 252)300 mg (n = 52)150 mg (n = 256)Age, mean, y43.643.744.9Time since diagnosis, mean, y5.67.27.3Male, %63.562.157.5PGA of Disease Activity, mean, mm73.471.770.1BASDAI question 3, mean6.36.66.4Swollen 44-joint count, mean1.92.62.5Tender 44-joint count, mean7.17.87.9Conclusion:In parallel with its previously reported efficacy in axial symptoms,3secukinumab led to significant improvements in symptoms of peripheral arthritis in pts with AS. Significant improvements were seen in both tender and swollen joints.References:[1]Braun J, Sieper J.Lancet. 2007;369:1379-1390.[2]de Winter JJ, et al.Arthritis Res Ther. 2016;18:196.[3]Mease P, et al.Arthritis Rheumatol. 2019;71(suppl 10):1553.[4]de Winter JJ, et al.RMD Open. 2019;5:e000802.Acknowledgments:This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ. The authors thank Amos Race, PhD, of ArticulateScience LLC, Hamilton, NJ, USA, for providing medical writing/editorial support, which was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).Disclosure of Interests:Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Renato Calheiros Shareholder of: Novartis, Employee of: Novartis, Xiangyi Meng Shareholder of: Novartis, Employee of: Novartis, Todd Fox Shareholder of: Novartis, Employee of: Novartis, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen

Objective The aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS). Methods Baseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31–743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640–819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs. Results A total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant. Conclusion Secukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs. Electronic supplementary material The online version of this article (10.1186/s13075-019-1911-1) contains supplementary material, which is available to authorized users.

Background Enthesitis can be a debilitating extra-articular spondyloarthritis (SpA) manifestation and cause of considerable pain and reduced quality of life/physical function.1,2 Objectives To evaluate the effect of secukinumab (SEC) on axial and peripheral enthesitis in ankylosing spondylitis (AS) patients (pts) with baseline enthesitis (BLE) across all Maastricht AS EnthesiS (MASES) sites (N=13), axial MASES sites [N=11; 13 MASES minus Achilles tendons (AT); AxS], peripheral sites (N=6; AT + lateral condyles of humerus/femur; PS) and the AT (N=2; AT) at Weeks (W) 16 and 52. Methods This post hoc analysis pooled data across 4 SEC studies in AS (MEASURE 1-4) from pts originally randomised to SEC 150mg (approved dose in AS), 300mg (MEASURE 3 only), or placebo (PBO) with BLE (MASES >0). Study designs have been reported previously. Evaluations include mean change from BL in MASES score, complete resolution (CR; MASES=0) and improvement from BL in MASES score of ≥5 counts. Mixed-effect model repeat measurement (MMRM) analysis was done on change from BL in MASES score and non-responder imputation for resolution of enthesitis at W16; data are reported as observed at W52. Results A total of 355 (70.4%), 58 (76.3%), and 280 (72%) pts had BLE in 150mg, 300mg and PBO groups, respectively. BL characteristics were generally comparable across groups. At W16, mean change from BL for overall MASES and at AxS was greater for SEC 150mg (-2.4 and -2.3) and 300mg (-2.9 and -2.9) vs PBO (-1.9 and -1.8; P Conclusion Secukinumab was associated with higher mean change in MASES and complete resolution of enthesitis compared to placebo at Week 16, which further improved through Week 52. References [1] Braun J, et al.Nat Clin Pract Rheumatol. 2006;2:536-45; 2. Schett G, et al. Nat Rev Rheumatol. 2017;13:731-741. Disclosure of Interests Georg Schett: None declared, Xenofon Baraliakos Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer Inc, Roche and UCB, Grant/research support from: AbbVie, Pfizer, Merck Sharp & Dohme, UCB Pharma, Novartis, Consultant for: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Biologics, Novartis, Pfizer, UCB Pharma, Galapagos, Speakers bureau: AbbVie, Chugai, Janssen, Novartis, Pfizer, UCB Pharma, Filip van den Bosch Consultant for: AbbVie, BMS, Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, BMS, Janssen, Lilly, Merck, Novartis, Pfizer and UCB., Atul Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, GSK, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Lianne S. Gensler Grant/research support from: Abbvie, Amgen, UCB Pharma , Consultant for: Novartis, Lilly, Janssen, Mikkel Ǿstergaard Grant/research support from: Abbvie, Celgene, Centocor, Merck, Novartis, Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Speakers bureau: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, Shital Agawane Employee of: Novartis, Ayan Das Gupta Employee of: Novartis, Shephard Mpofu Employee of: Novartis, Todd Fox Employee of: Novartis, Adam Winseck Employee of: Novartis, Abhijit Shete Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Brian Porter Shareholder of: Novartis, Employee of: Novartis

Background: Ankylosing spondylitis (AS) is an inflammatory disease resulting in progressive disability due to structural damage in the spine. The identification of predictors of progression would allow treating physicians to personalize treatments but requires an approach accounting for a relatively short follow-up of clinical studies, large between-patient variability, and low sensitivity of X-ray images which generate intra-patient variability when repeated measurements are taken. Objectives: 1) To identify patient characteristics predicting faster structural damage progression. 2) To quantify the progression over four years of secukinumab treatment, depending on dose/exposure. Methods: Data came from the phase 3 randomized placebo-controlled trial MEASURE 1 (NCT01358175)1 in which patients were treated with secukinumab (intravenous loading of 10 mg/kg at weeks 0, 2, and 4, followed by secukinumab subcutaneously at a dose of either 75 mg or 150 mg every 4 weeks) over 208 weeks. Only patients treated with secukinumab with at least two assessments of structural damage were included. We explored the effect of multiple baseline demographic traits, disease stage, severity, bone cartilage biomarkers as well as prior and current treatment on change in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) using a longitudinal Bayesian mixture model with random effects, which accounted simultaneously for the probability of progression, magnitude of progression and inter-patient variability. Posterior predictive check was performed. Results: Out of 249 patients randomized to secukinumab, 167 had their structural damage assessed at least twice. These patients contributed in total 409 assessments of change in structural damage between weeks 0, 52, 104 and 208. Of the factors tested, a higher baseline BASMI score was associated with faster progression rate in a statistically significant way (+0.60 in mSASSS/year for each additional standard deviation of baseline BASMI (SD=1.74), 95% interval 0.03 to 1.14). Trends were also detected for association between faster mSASSS progression and younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin levels. Increased exposure to secukinumab was associated with slower structural damage progression (-0.23 in mSASSS/year for each additional standard deviation in exposure, 95% interval -0.58 to 0.10). Model estimation suggested that secukinumab 150 mg was associated with a yearly progression of -0.2 (95% interval -1.2 to 0.8) in the first two years of treatment and 0.1 mSASSS (95% interval -0.8 to 1.0) in the third and fourth year of treatment. Analogously, secukinumab 75mg (currently not approved for clinical use) was associated with a progression of -0.2 mSASSS/year (95% interval -1.3 to 0.9) in the first two years of treatment and 0.5 mSASSS/year (95% interval -0.5 to 1.6) in the third and fourth year of treatment. Conclusion: Potential predictors of structural progression suggested by the model were higher baseline BASMI, younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin at baseline, although only baseline BASMI showed statistical significance. Further analyses using larger, deeper and real-world data are needed to confirm these findings and to estimate progression rates in AS patients in daily practice. Reference [1] Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med. 2015;373(26):2534-2548. Disclosure of Interests: Olivier Luttringer Shareholder of: Novartis, Employee of: Employee of Novartis Pharma AG, Todd Fox Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Abhijit Shete Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Hanno Richards Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Witold Wiecek Consultant for: Employee of CERTARA Strategic Consulting., Zuzanna Angehrn Shareholder of: Owns funds which might occassionaly invest in pharmaceutical companies’ stocks., Consultant for: Employee of CERTARA strategic consulting., Helene Karcher Consultant for: Former employee of Analytica Laser, a Certara company. Former independent consultant. Current employee of PAREXEL., Employee of: Former employee of Novartis., Billy Amzal Consultant for: Employee of CERTARA Strategic Consulting., Employee of: Former employee of Novartis.

Background Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). Methods The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. Results A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. Conclusions Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions. Electronic supplementary material The online version of this article (10.1186/s13075-019-1882-2) contains supplementary material, which is available to authorized users.

Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously. Objectives: To report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies. Methods: The moderate-to-severe plaque psoriasis and active PsA data pool consisted of 15 Phase 2 and 3 Phase 3 studies. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75-300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were rerandomised to SEC at 12-24 weeks depending on study design. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIR) per 100 patientyears and analyses included all patients who received ≥1 dose of SEC. Results: A total of 5,181 and 1,380 patients from psoriasis and PsA studies representing an exposure of 10,416.9 and 3,866.9 patient-years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (Table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease and major adverse cardiac events were low and similar in both psoriasis and PsA indications (Table 1). No cases of tuberculosis were reported. Conclusion: SEC demonstrated a favourable safety profile during long-term treatment (up to 5 years) in patients with moderate-to-severe plaque psoriasis or PsA, hence, supporting long-term use. The safety profile of SEC was consistent with previous reports and comparable across psoriasis and PsA patients.

TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-β1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-β1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α–neutralized by Etanercept but not Adalimumab–in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity., Author summary Mycobacterium tuberculosis (Mtb) is the world’s leading infectious killer. Multi-cellular immune structures called granulomas may constitute a latent form of Mtb infection and a potential reservoir for future cases. Post-marketing surveillance data suggested that Mtb protective immunity is unequally impacted by different TNF-α-targeting drugs used to treat inflammatory disorders. We used an in-vitro granuloma model to reproduce these clinical observations and gain mechanistic insights and, in addition, to assess the risk of tuberculosis reactivation associated with the use of other immunomodulatory drugs. These results may inspire pharmacologists to design future drug-development strategies of biologics in particular, while immunologists and microbiologists will find a relevant experimental approach to disentangle the complex interactions involved in Mtb protective immunity and immunopathogenesis.

Background Secukinumab, a fully human interleukin 17A (IL-17A) inhibitor, improved signs and symptoms of ankylosing spondylitis (AS) in patients (pts) in the MEASURE 1 core trial at 2 years and through 4 years in the extension study.1,2 A low radiographic progression rate was reported for the modified Stoke Ankylosing Spondylitis Spinal Score (Δ mSASSS at Yr 2=0.3).1 Comparison of anti-TNF agents with historical NSAID-treated cohorts have not shown a significant benefit at 2 years in reducing radiographic progression.3,4 Objectives This retrospective analysis compared spinal radiographic progression over 2 years in the MEASURE 1 cohort of secukinumab-treated AS patients (C1; NCT01358175) vs a historical cohort of biologic-naive AS pts (ENRADAS [C2; NCT00715091]).5 Methods Baseline (BL) and 2 year X-ray data from the 2 cohorts were compared. Only data from pts with X-rays at BL and Yr 2 (data capture window for Yr 2 X-rays: 31–744 days) were included (n=168 [C1], n=69 [C2]). X-rays were independently re-evaluated using the mSASSS by 2 reviewers and an adjudicator blinded to the timing and cohorts; averaged values were analysed. Cases with the highest difference in Δ mSASSS between readers (top 10%) were adjudicated. The primary outcome was to compare the% pts with no radiographic progression (Δ mSASSS at Year 2≤0) in C1 vs C2. The difference between C1 and C2 was analysed using a logistic regression with cohort as a factor and BL mSASSS as a covariate. Results BL demographics were comparable across cohorts, with mean age 40.9 vs 42.6 years, and gender 72.8% vs 66.7% male in C1 vs C2, respectively. Over 2 years, least squares (LS) mean Δ mSASSS was 0.55 for C1 vs 0.89 for C2 (p=0.185) and% pts with no radiographic progression (Δ mSASSS at Year 2≤0) was slightly higher in C1 vs C2 (table 1). Conclusions Over 2 years, a numerically lower rate of progression was seen in secukinumab-treated pts vs a control cohort of biologic-naive AS pts. Further research is needed to understand the impact of IL-17A inhibition with secukinumab on spinal disease progression in AS pts; SURPASS (NCT03259074), an ongoing H2H study powered to compare differences in spinal radiographic progression with secukinumab vs biosimilar adalimumab, will help answer these questions. References [1] Braun J, et al. Ann Rheum Dis Ann Rheum Dis2017;76:1070–77. [2] Braun J, et al. Arthritis Rheumatol2017;69(10). [3] van der Heijde D, et al. Arthritis Rheum2008;58:1324–31. [4] van der Heijde D, et al. Arthritis Res Ther2009;11:R127. [5] Sieper J, et al. Ann Rheum Dis2016;75:1438–43. Disclosure of Interest J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis and UCB, H. Haibel: None declared, M. de Hooge Employee of: MdH Research, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth, Employee of: Rheumatology Consultancy BV, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth, M. Rudwaleit Speakers bureau: Abbvie, BMS, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, UCB, T. Fox Shareholder of: Novartis, Employee of: Novartis Pharma AG, A. Readie Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, H. Richards Shareholder of: Novartis, Employee of: Novartis Pharma AG, B. Porter Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, R. Martin Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, D. Poddubny Grant/research support from: Abbvie, Janssen, MSD, Novartis and Pfizer, Consultant for: AbbVie, Bristol-Myers Squibb, MSD, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer, Roche and UCB, J. Sieper Grant/research support from: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Merck, Lilly, Pfizer, and UCB, Consultant for: AbbVie, Janssen, Novartis, Merck, Lilly, Pfizer, Sun and UCB, Speakers bureau: AbbVie, Janssen, Novartis, Merck, Pfizer, Roche and UCB, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB, Employee of: Imaging Rheumatology BV

Background Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously.1 Objectives To report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies. Methods The moderate to severe plaque psoriasis and active PsA data pool consisted of 15 and 3 Phase III studies, respectively. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75–300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were re-randomised to SEC at 12–24 weeks depending on study design. Adverse events (AEs) were reported as exposure adjusted incident rates (EAIR) per 100 patient-years and analyses included all patients who received ≥1 dose of SEC. Results A total of 5181 and 1380 patients from psoriasis and PsA studies representing an exposure of 10416.9 and 3866.9 patient years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease (IBD) and major adverse cardiac events (MACE) were low and similar in both psoriasis and PsA indications (table 1). No cases of tuberculosis were reported. Conclusions SEC demonstrated a favourable safety profile during long-term treatment (up to 5 years) in patients with moderate to severe plaque psoriasis or PsA, hence, supporting long-term use. The safety profile was consistent with previous reports and comparable across psoriasis and PsA patients. Reference [1] Mease, et al. Arthritis Rheumatol2017; 69(suppl 10):A606. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, BMS, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, UCB,, Speakers bureau: AbbVie, Amgen, BMS, Janssen, Lilly, Pfizer, and UCB, I. McInnes Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, K. Reich Consultant for: Abbvie, Affibody, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Sanofi, Takeda, UCB Pharma, Xenoport, Speakers bureau: Abbvie, Affibody, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Sanofi, Takeda, UCB Pharma, Xenoport., P. Nash Grant/research support from: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, Consultant for: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, A. Widmer Shareholder of: Novartis Stock, Employee of: Novartis, K. Abrams Shareholder of: Novartis Stock, Employee of: Novartis, L. Pricop Shareholder of: Novartis Stock, Employee of: Novartis, T. Fox Shareholder of: Novartis Stock, Employee of: Novartis

Background: Therapeutic advances have made the achievement of clear/almost clear skin possible for many patients with moderate-to-severe plaque psoriasis. Objective: To determine patient perceptions of the impact of psoriasis and of attaining clear/almost clear skin. Methods: Global survey of patients with moderate-to-severe psoriasis. Results: A total of 8338 patients from 31 countries participated. The majority (57%) had not achieved self-assessed clear/almost clear skin with their current therapy, and 56% of those who had not met this goal believed it would be impossible to do so. Among the patients who had clear/almost clear skin, 73% had not initiated their current treatment until >1 year after psoriasis diagnosis, and 28% had to wait >5 years. Eighty-four percent of all respondents experienced discrimination and/or humiliation due to psoriasis, and many reported negative effects on work, intimate relationships, sleep and mental health. Patients without clear/almost clear skin reported that such achievement would open new possibilities, such as swimming (58%), a wider choice of clothing (40%), and meeting new people (26%). A limitation of this study, as with any survey-based research, is that selection and recall bias may have been present. Additionally, respondent definitions of clear/almost clear skin were subjective and may have varied. Conclusion: Despite the importance of clear/almost clear skin to psoriasis patients, most are still not achieving it, and many are unaware it is possible.

Concerns have emerged over the potential for brodalumab, a monoclonal antibody that binds to the human interleukin (IL)-17 receptor A and blocks the activity of multiple IL-17 isoforms, to increase risk of suicidal ideation and behaviour. Although the validity of this association has been questioned,1,2 brodalumab has a boxed warning regarding suicidality in its US label and is only available through a Risk Evaluation and Mitigation Strategy. Regardless of the true association between suicidality and brodalumab, the demonstrated adverse impact of psoriasis on mental health necessitates careful assessment for possible psychiatric adverse effects of psoriasis therapies, including those that inhibit the IL-17 pathway. This article is protected by copyright. All rights reserved.

pBACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle missing efficacy data. This methodological challenge may not be understood by clinicians, yet can have a significant effect on the interpretation of clinical trials./ppOBJECTIVE Evaluate the effects of different data imputation methods on apparent secukinumab response rates./ppMETHODS: Post hoc analyses were conducted on efficacy data from 2 phase III, multicenter, randomized, double-blind trials (FIXTURE and ERASURE) of secukinumab in moderate to severe plaque psoriasis. Per study protocols, missing data were imputed using strict non-response imputation (NRI), a highly conservative method that assumes non-response for all missing data. Alternative imputation methods (observed data, last observation carried forward [LOCF], modified NRI, and multiple imputation [MI]) were applied in this analysis and the resultant response rates compared./ppRESULTS: Response rates obtained with each imputation method diverged increasingly over 52-weeks of follow-up. Strict NRI response estimates were consistently lower than those using the other methods. At week 52, Psoriasis Area and Severity Index (PASI) 90 rates for secukinumab 300 mg based on strict NRI were 9.2% (FIXTURE) and 8.7% (ERASURE) lower than estimates obtained using the least conservative method (observed data). Estimates obtained through LOCF and modified NRI were closest to those produced by MI, currently regarded as the most methodologically sophisticated approach available./ppCONCLUSION: Awareness of differences in assumptions and limitations among imputation methods is necessary for well-informed interpretation of trial data./ppemJ Drugs Dermatol. 2017;16(8):734-742./em/p.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

Background No data are available from head-to-head RCTs between secukinumab 150 mg (SEC; an anti-IL-17A) and golimumab 50 mg (GOL; a TNFi) in patients with active ankylosing spondylitis (AS). Matching-Adjusted Indirect Comparison (MAIC) can be used to estimate comparative effectiveness and enables treatment outcomes to be compared across effectively balanced trial populations. MAIC is an established method in health technology assessments and NICE have published guidance on appropriate methodology, and especially for addressing imbalances in observed covariates between trials. 1 Objectives To assess the comparative effectiveness of SEC and GOL up to week 24 using MAIC with pooled individual patient data (IPD) from the RCTs MEASURE 1 (M1) and MEASURE 2 (M2) and published aggregate data from the RCT GO-RAISE. Methods Pooled M1 and M2 data were used to maximize the effective sample size (ESS) for SEC. IPD from the SEC arms of M1 and M2 (n=197) were weighted to match the published baseline characteristics of the GOL arm of GO-RAISE (n=138). Placebo arms were matched in the same way; placebo-adjusted comparisons were possible only until week 16 because patients could receive active treatment from this time onwards. Logistic regression was used to determine weights for age, sex, BASFI, disease duration, CRP and previous TNFi therapy. Recalculated outcomes from M1 and M2 (SEC, ESS=102; placebo, ESS=81) were compared with data from GO-RAISE (GOL, n=138; placebo, n=78). Pairwise comparisons – reported as odds ratios (ORs [95% CIs]) – were performed for ASAS 20, ASAS 40 and ASAS PR responses at nearest-equivalent time points across trials: week 12 (SEC)/14 (GOL), week 14 (GOL)/16 (SEC) and week 24 (SEC and GOL). Non-responder imputation (NRI) was available for all binary outcome data. Strict thresholds were avoided when interpreting p values, in line with American Statistical Association 2016 guidance. Results There was no evidence of differences in ASAS 20 and ASAS 40 responses between SEC and GOL at weeks 12/14 and 14/16 (both placebo-adjusted). At week 24, non-placebo-adjusted ASAS 20 and ASAS 40 responses using NRI were higher with SEC than GOL (OR [95% CI]: 1.58 [0.93–2.69], p =0.089 and 1.58 [0.94–2.64], p =0.084, respectively). There was no evidence of differences in ASAS PR responses between SEC and GOL at weeks 12/14, 14/16 and 24. A sensitivity analysis conducted after adding BASDAI score to the matching parameters yielded similar results. Conclusions There was no evidence of differences in ASAS responses between SEC and GOL in placebo-adjusted analyses. In non-placebo-adjusted analyses, SEC showed higher ASAS 20 and ASAS 40 responses than GOL at week 24. References Phillippo DM et al. (2016) NICE DSU Technical Support Document 18. Available from: http://www.nicedsu.org.uk. Disclosure of Interest W. Maksymowych Grant/research support from: AbbVie, Pfizer and Sanofi, Consultant for: AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi and UCB, E. Choy Grant/research support from: Pfizer, Roche and UCB, Consultant for: Chugai Pharma, Eli Lilly, Janssen, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi, Y. Yazici Grant/research support from: Celgene, BMS and Genentech, Consultant for: Celgene, BMS and Novartis, J. Walsh Consultant for: Novartis, H. Thom Consultant for: Eli Lilly, F Hoffman-La Roche, Novartis Pharma AG and Pfizer, C. Kalyvas Employee of: Paid employee of the Mapi Group. The Mapi Group received funding from Novartis Pharma AG for this study, T. Fox Employee of: Novartis employee with stock, K. Gandhi Employee of: Novartis employee with stock, S. Jugl Employee of: Novartis employee with stock

Background Pain remains a major clinical challenge in the treatment of psoriatic arthritis (PsA). Secukinumab (SEC) has demonstrated significant efficacy in PsA patients (pts), across a range of quality of life related outcome measures. 1,2 Objectives This post-hoc analysis evaluated change in pain scores from baseline (BL) to Week (Wk) 104 in PsA pts receiving SEC in the FUTURE 2 study. Methods FUTURE 2 study design has been reported. 2 Mean change from BL in pain VAS and SF-36 bodily pain domain scores were evaluated using mixed-effect model for repeated measures (MMRM) through Wk 16 and as observed through Wk 104. Proportion of pts reporting improvements ≥clinically meaningful differences in pain VAS (mean change from BL ≥20%) was assessed. Results are reported for SEC 300 and 150mg in overall population and stratified by prior use of TNF inhibitor (TNFi; TNFi-naive vs. inadequate responder/intolerant [TNFi-IR]). EQ–5D-3L pain item scores (no-, moderate- or extreme-pain/discomfort) were assessed as proportions. Results Mean changes from BL in pain VAS were greater with SEC vs. placebo (PBO) by Wk 3 (least squares mean [LSM]: -16.9, -12.6 with SEC 300 and 150mg, respectively vs. -5.75 with PBO; P P 50% pts reported improvements of ≥20% by Wk 3 and this increased through Wk 104. Similarly, SF-36 bodily pain domain scores improved from BL by Wk 4 and 16 with SEC vs. PBO, exceeding minimum clinically important differences of 5.0 (Wk 4: LSM: 16.2 and 16.3 for SEC 300 and 150mg, respectively vs. 5.9 with PBO; P P Conclusions SEC provides rapid and sustained pain relief through 104 wks in pts with PsA as assessed by multiple clinically relevant patient-reported measures of pain. Improvements were reported by pts regardless of their prior TNFi therapy status. References Strand V, et al. Ann Rheum Dis 2017;76:203–7. McInnes IB, et al. Lancet 2015;386:1137–46. Disclosure of Interest I. McInnes Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, P. Mease Grant/research support from: Abbvie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB, Consultant for: Abbvie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB, Speakers bureau: Abbvie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB, G. Schett: None declared, B. Kirkham Grant/research support from: AbbVie, Eli Lilly, Novartis, Roche and UCB, Consultant for: Abbott, Eli Lilly and Novartis, Speakers bureau: Abbott, Janssen, Novartis and Pfizer, V. Strand Consultant for: AbbVie, Amgen, BMS, Celgene, Celltrion, Corrona, Genentech/Roche, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi and UCB, N. Williams Consultant for: Novartis through employment at RTI, Employee of: RTI Health Solutions, T. Fox Shareholder of: Novartis, Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, S. Jugl Shareholder of: Novartis, Employee of: Novartis, K. Gandhi Shareholder of: Novartis, Employee of: Novartis

Background Pooled safety data from secukinumab psoriasis (PsO) and psoriatic arthritis (PsA) clinical trial programs after ∼1 year of exposure have been reported.1,2 Objectives To report updated longer-term secukinumab exposure safety data from PsO and PsA studies (data cut-off: 25 June 2016). Methods The PsO data pool consisted of 9 Phase III studies in moderate-to-severe plaque PsO and PsA pool consisted of 3 Phase III studies in active PsA. Secukinumab doses differed in the studies and included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75–300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were re-randomised to secukinumab at 12–24 weeks depending on study design. Only data for approved secukinumab 300 and 150mg doses were included in analysis. Exposure adjusted incident rates (EAIR) were used to adjust for differences in exposure. Results In both PsO and PsA, the most frequently reported adverse events (AEs) with secukinumab were non-serious infections of the upper respiratory tract, headache and arthralgia (Table). The EAIRs of AEs of special interest with secukinumab including Crohn9s disease, Candida infections, serious infections, inflammatory bowel disease, major adverse cardiac events and neutropenia (reported in the Table) were similar in both PSO and PsA indications, and comparable to those reported previously.1,2 No cases of tuberculosis (new onset or reactivation) were reported. Conclusions The safety profile of secukinumab was similar for PsO and PsA patients supporting its long-term use in these chronic conditions. Secukinumab long-term exposure safety data is consistent with that previously reported with shorter-term exposure, including being well tolerated, and without any new safety signals identified. References Van de Kerkhof PC, et al. J Am Acad Dermatol 2016;75:83–98. Mease PJ, et al. Arthritis Rheumatol 2015; 67:A2886. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, I. McInnes Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, K. Reich Grant/research support from: AbbVie, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cliag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Takeda, UCB Pharma, Xenoport, Speakers bureau: AbbVie, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cliag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Takeda, UCB Pharma, Xenoport, P. Nash Grant/research support from: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche; Consultancy fees: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, M. Andersson Employee of: Novartis, K. Abrams Shareholder of: Novartis, Employee of: Novartis, L. Pricorp Shareholder of: Novartis, Employee of: Novartis, T. Fox Shareholder of: Novartis, Employee of: Novartis

Background Disease Activity index for Psoriatic Arthritis (DAPSA) states are associated with functional impairment levels in patients (pts) with psoriatic arthritis (PsA).1 Secukinumab demonstrated sustained improvements in disease activity assessed with DAS28-CRP, physical function and pt-reported outcomes (PROs) among active PsA pts over 104 weeks (wks) in the FUTURE 2 study.2 Objectives To explore the relationship between DAPSA states and function, health-related quality of life and PROs, and the individual DAPSA components in the different states in pts treated with secukinumab through 104 wks using post-hoc analysis. Methods FUTURE 2 study design has been reported.3 DAPSA was derived as sum of five core components: tender joint and swollen joint counts (TJC 68, SJC 66), pt global assessment (PtGA) and pain (PP) assessed by a 10cm VAS and CRP (mg/dl). Four DAPSA states were: remission (REM:≤4), low (LDA:>4–≤14), moderate (MDA:>14–≤28) or high disease activity (HDA:>28). Mean±SD of each core component of DAPSA were analysed at Wks 16, 24, 52 and 104 using observed data. The relationship between HAQ-DI, SF-36 PCS and MCS, PsAQoL, DLQI and FACIT-Fatigue with DAPSA states was assessed in the pooled treatment arms at each time point using a mixed-effect model for repeated measures (MMRM) analyses. Results Baseline characteristics were similar across treatment groups.3 DAPSA scores at baseline (mean±SD) were 42.0±17.4, 46.8±24.3 and 44.9±25.3 in the secukinumab 300mg, 150mg and placebo groups, respectively. Mean scores of each component by DAPSA states at Wk 16 are shown in table and were sustained through Wk 104. Significant differences were observed among secukinumab treated pts between REM vs. HDA and LDA vs. HDA states for PRO scores through Wk104 (Figure). Conclusions In pts treated with secukinumab 300 or 150mg, the five individual components related to DAPSA REM were References Schoels MM, et al. Ann Rheum Dis 2016;75:811–8. McInnes IB, et al. Arthritis Rheumatol 2016;68(suppl 10). McInnes IB, et al. Lancet 2015;386:1137–46. Disclosure of Interest J. Smolen Grant/research support from: AbbVie, Janssen, Eli Lilly, MSD, Pfizer, Roche, Amgen, AstraZeneca, Astro, Celgene, Celltrion, GSK, ILTOO, Medimmune, Novartis-Sandoz, Pfizer, Samsung, Sanofi and UCB., Consultant for: AbbVie, Janssen, Eli Lilly, MSD, Pfizer, Roche, Amgen, AstraZeneca, Astro, Celgene, Celltrion, GSK, ILTOO, Medimmune, Novartis-Sandoz, Pfizer, Samsung, Sanofi and UCB., I. McInnes Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, L. Gossec Grant/research support from: UCB, Eli Lilly and Pfizer; Consultant for AbbVie, BMS, Celgene, Janssen, Novartis, Pfizer and Roche, V. Strand Consultant for: AbbVie, Amgen, BMS, Celgene, Celltrion, Corrona, Genentech/Roche, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sanofi and UCB, L. Pricop Shareholder of: Novartis, Employee of: Novartis, T. Fox Shareholder of: Novartis, Employee of: Novartis, S. Jugl Shareholder of: Novartis, Employee of: Novartis, C. Gaillez Shareholder of: Novartis and BMS, Employee of: Novartis

Background Safety data for secukinumab in the treatment of ankylosing spondylitis (AS) have been reported from three Phase 3 studies: MEASURE 1 (NCT01358175) 1 , MEASURE 2 (NCT01649375) 1 and MEASURE 3 (NCT02008916). 2 Objectives To report long-term (up to 3 years) pooled safety and tolerability data for secukinumab in AS (data cut-off: 25 June 2016). Methods Overall, 371, 219 and 226 patients with active AS were randomised in MEASURE 1, MEASURE 2 and MEASURE 3, respectively. Study design, efficacy and safety results of these studies have been published earlier. 1,2 Secukinumab doses differed in the studies and included intravenous 10 mg/kg or subcutaneous (75–300mg) multi-dose loading, followed by subcutaneous (s.c.) maintenance dosing (75, 150, or 300mg). Data collected up to the last patient performing the Wk 156 visit in MEASURE 1, the Wk 104 visit in MEASURE 2, and the Wk 52 visit in MEASURE 3 were pooled at the patient level. Exposure-adjusted incidence rates were calculated to account for differences in treatment exposure and analyses included all patients who received ≥1 dose of secukinumab 150 or 300mg. Results A total of 510 patients were included in the analysis (968.9 patient-years of exposure). The exposure-adjusted AE and SAE rates with secukinumab across the entire safety period were 159.2 and 5.4 per 100 patient-years, respectively. Nasopharyngitis, diarrhoea and headache were the most frequently reported AEs. The incidences of Candida infections, serious infections, inflammatory bowel disease, major adverse cardiac events, neutropenia and uveitis were low and consistent with previous reports over shorter exposure periods 1 (Table). No cases of suicidal ideation or depression were reported. Conclusions This longer-term safety assessment of secukinumab in the treatment of AS was consistent with previous reports and did not identify any new safety signals. References Baeten D, et al. N Engl J Med 2015;373:2534–48. Kivitz A, et al. XIX PANLAR 2016, Panama City, Panama. Poster No. P-081. Disclosure of Interest A. Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, GSK, Janssen, Novartis, Pfizer, and UCB; advisory board member: Eli Lilly, Janssen, Novartis, Pfizer, and UCB., X. Baraliakos Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, and Werfen, Consultant for: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, and Werfen, H. Marzo-Ortega Grant/research support from: Janssen and Pfizer, Consultant for: AbbVie, Celgene, Janssen, Novartis and UCB, Speakers bureau: Abbvie, Celgene, Janssen and UCB, J. Sieper Grant/research support from: for AbbVie, Boehringer Ingelheim, Janssen, Novartis, Merck, Lilly, Pfizer, and UCB, Consultant for: for AbbVie, Boehringer Ingelheim, Janssen, Novartis, Merck, Lilly, Pfizer, and UCB, M. Andersson Employee of: Novartis, B. Porter Shareholder of: Novartis, Employee of: Novartis, T. Fox Shareholder of: Novartis, Employee of: Novartis

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

Background Sparse information is available concerning mental health issues in psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS) patients. Objective To estimate risk of depression, suicidal ideation, and suicide attempt in patients with psoriasis, PsA, and AS, respectively, compared with the general population. Methods This population-based cohort study analyzed 36,214 psoriasis patients, 5,138 PsA patients, and 1,878 AS patients who were frequency-matched with a general population cohort. Annual incidence rate of depression, suicidal ideation, and suicide attempt was calculated separately for psoriasis, PsA and AS. Results There was an increased risk of depression in the three cohorts; adjusted IRR: psoriasis, 1.14 (95% CI, 1.11, 1.17); PsA, 1.22 (95% CI, 1.16, 1.29); AS, 1.34 (95% CI, 1.23, 1.47). There was no significantly increased risk for suicidal ideations or suicide attempt among psoriasis, PsA, or AS patients. Limitations Patients were not excluded if previously diagnosed with depression, suicidal ideation, or suicide attempt. Suicide attempt and completed suicide analyses were not adjusted for presence of depression. Use of systemic psoriasis treatment to measure severe psoriasis could lead to psoriasis severity misclassification. Conclusion The risk of depression, but not suicidal ideation or suicide attempt, was significantly increased in patients with psoriasis, PsA, and AS. This article is protected by copyright. All rights reserved.

Background: The emergence of new biological therapies showing high and sustained level of Psoriasis Area and Severity Index (PASI) 90 response has provided the possibility of both greater skin clearance and increased quality of life (QOL). Objective: To evaluate the association of greater response in skin clearance with improvements in skinrelated QOL up to 52 weeks. Methods: Subjects achieving various levels of skin clearance (PASI 90-100 or PASI 75-89) and Dermatology Life Quality Index (DLQI) (0/1) response were compared using ERASURE and FIXTURE trial data. Similar analyses with IGA ratings of Clear or Almost Clear were performed. Results: Significantly more PASI 90-100 responders at week 12 had DLQI 0/1 response than PASI 75-89 (69.4% vs. 47.1%; p

Introduction Secukinumab (SEC), anticorps monoclonal humain neutralisant selectivement l’IL-17A, est efficace dans le traitement du psoriasis en plaques modere a severe et du rhumatisme psoriasique. Les donnees des effets sur la grossesse d’un traitement du psoriasis par biotherapie sont peu nombreuses. Bien que les etudes sur l’animal ne montrent pas d’effet deletere sur le developpement embryofœtal, l’accouchement ou le developpement postnatal, les femmes enceintes etaient exclues des etudes de developpement clinique du SEC. Les protocoles d’etudes exigeaient l’utilisation de contraceptifs efficaces chez les femmes en âge de procreer. En cas de survenue d’une grossesse au cours d’un essai clinique, la patiente devait arreter le traitement de l’etude. Nous rapportons ici les cas de grossesses connues, lorsque la patiente ou son partenaire avait recu SEC, cas issus de la base de donnees de tolerance de Novartis. Materiel et methodes La base de donnees [essais cliniques et postcommercialisation (PC)] a ete analysee et tous les cas de grossesse avec une exposition maternelle (EM) ou paternelle (EP) a SEC ont ete inclus dans cette analyse (analyse arretee au 25/12/2015). Resultats L’exposition a SEC est estimee a plus de 21 500 patientes–annees. Dans tous les cas, SEC etait interrompu ou arrete des confirmation de la grossesse, dans la plupart des cas dans les premieres semaines du 1er trimestre. Parmi les grossesses confirmees, 63 ont eu lieu lors d’essais cliniques, 11 en PC et 10 ont ete rapportees spontanement. Soixante-six correspondaient a une EM et 18 a une EP. Les 15 EM arrivees a terme ont abouti a la naissance de nouveau-nes vivants et sans malformation congenitale, 11 grossesses etaient toujours en cours. Dans 32 cas d’EM, une interruption de grossesse etait programmee ou les informations etaient incompletes. Un avortement spontane est survenu dans 8 cas, tous lors du premier trimestre ; des antecedents de fausse couche ou mort neonatale ou des facteurs de risque potentiel (infection ou traitement concomitants) etant presents dans 6 cas. Les EP ont donne le meme profil de resultats que les EM. Parmi les grossesses menees a terme, toutes ont conduit a la naissance de nouveau-nes vivants sans anomalie congenitale. Discussion Les donnees sur les grossesses en cas d’exposition a SEC ont montre que toutes celles menees a terme ont conduit a la naissance de nouveau-nes vivants sans anomalie congenitale. Le taux d’avortement spontane se trouve dans l’intervalle attendu, tous s’etant produits lors du 1er trimestre et la majorite etant associee a d’autres facteurs de risque potentiels. Conclusion Ces resultats sont rassurants car ils ne montrent aucune evidence de teratogenicite ou de risque pour le fœtus avec SEC. Cependant, en l’absence de donnees pour certaines grossesses, la securite d’emploi de SEC pendant la grossesse necessite des etudes supplementaires.

Secukinumab, a human monoclonal antibody that selectively targets interleukin-17A, is highly efficacious in the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favorable safety profile.Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg, or placebo self-administered by prefilled syringe at baseline, weeks 1, 2, and 3, and then every four weeks from week 4 to 48. Efficacy responses (≥ 75/90/100% improvement in Psoriasis Area and Severity Index [PASI 75/90/100] and clear/almost clear skin by Investigator's Global Assessment 2011 modified version [IGA mod 2011 0/1]) were measured to week 52. Patient-reported usability of the prefilled syringe was evaluated by the Self-Injection Assessment Questionnaire to week 48.The efficacy of secukinumab increased to week 16 and was maintained to week 52. With secukinumab 300 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 83.5%/68.0%/47.5% and 71.5% of patients when analyzed by multiple imputation, respectively, and by 75.9%/62.1%/43.1% and 63.8% of patients when analyzed by nonresponder imputation, respectively. With secukinumab 150 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 63.5%/50.3%/31.1% and 43.6% of patients when analyzed by multiple imputation, respectively, and by 61.0%/49.2%/30.5% and 42.4% of patients when analyzed by nonresponder imputation, respectively. Self-reported acceptability of the prefilled syringe was high throughout the study. The incidence of adverse events (AE) was well balanced between groups, with AEs reported in 74.4% of patients receiving secukinumab 300 mg and 77.3% of patients receiving secukinumab 150 mg. Nasopharyngitis was the most common AE across both secukinumab groups.Self-administration of secukinumab by prefilled syringe was associated with robust and sustained efficacy and a favorable safety profile up to week 52.br /br /emJ Drugs Dermatol./em2016;15(10):1226-1234.

Background User satisfaction is an important factor associated with treatment adherence in chronic diseases including moderate-to-severe psoriasis. Objective To evaluate the efficacy, safety and patient acceptability of 300 and 150 mg secukinumab – a fully human anti-interleukin-17A monoclonal antibody that has demonstrated efficacy in the treatment of patients with moderate-to-severe plaque psoriasis – self-administered by autoinjection. Methods Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg or placebo self-administered by autoinjection at baseline, Weeks 1, 2 and 3 and then every 4 weeks from Week 4 to Week 48. Efficacy responses [≥75/90/100% improvement in Psoriasis Area and Severity Index (PASI 75/90/100) and clear/almost clear skin by Investigator's Global Assessment 2011 modified version (IGA mod 2011 0/1)] were measured at Week 52. Patient-reported usability of the autoinjector was evaluated by the self-injection assessment questionnaire to Week 48. Results At Week 52 with secukinumab 300 mg, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 81.4/64.1/38.8% and 69.6% of patients, respectively, by multiple imputation. At Week 52 with secukinumab 150 mg, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 75.2/57.4/33.1% and 60.2% of patients, respectively, by multiple imputation. Patient-assessed acceptability of the autoinjector remained high to Week 48. The proportion of patients experiencing adverse events was greater with secukinumab 300 mg (88.6%) than with secukinumab 150 mg (78.7%). Conclusion Self-administration of secukinumab using an autoinjector was associated with robust and sustained efficacy, a good safety profile and high acceptability.

Psoriasis is a chronic condition with negative impact on patients' quality of life that most often requires lifelong effective and safe treatment.This analysis focused on the effect of secukinumab treatment on patient-reported health-related quality of life as assessed by the Dermatology Life Quality Index (DLQI) in patients with moderate to severe psoriasis.The proportion of subjects achieving DLQI score 0/1 response at week 24, time to DLQI score 0/1 response, and sustained DLQI score 0/1 response up to week 52 were compared between secukinumab and etanercept.Of 1470 subjects, 1144 received secukinumab and 326 received etanercept. DLQI score 0/1 response rates were significantly higher for secukinumab than for etanercept at week 24. The median time to DLQI score 0/1 response was significantly shorter for secukinumab versus etanercept (12 vs 24 weeks; P .01). The majority of secukinumab-treated subjects achieved DLQI score 0/1 response at week 24 and sustained it through week 52 along with a 90% to 100% reduction in the Psoriasis Area and Severity Index total score response.Placebo comparisons are limited during the maintenance period because of rerandomization at week 12.Secukinumab treatment provided faster and greater sustained improvements in quality of life than etanercept over 52 weeks, consistent with greater clinical response.

Item does not contain fulltext BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate to severe plaque psoriasis. OBJECTIVE: We reviewed safety data from the secukinumab psoriasis phase II/III program. METHODS: Data were pooled from 10 phase II/III secukinumab psoriasis studies. RESULTS: Analysis included 3993 subjects; 3430 received secukinumab, representing 2725 subject-years (SYs) of exposure. Over 52 weeks, for secukinumab 300 mg, 150 mg, and etanercept, respectively, exposure-adjusted incidence rates (IRs) per 100 SYs were comparable across treatments for total adverse events (AEs; 236.1, 239.9, and 243.4, respectively); infections (91.1, 85.3, and 93.7, respectively); serious AEs (7.4, 6.8, and 7.0, respectively); serious infections (1.4, 1.1, and 1.4, respectively); malignant or unspecified tumors (0.77, 0.97, and 0.68, respectively); and adjudicated major adverse cardiovascular events (0.42, 0.35, and 0.34, respectively). AEs were not dose-related except for nonserious, mild/moderate, skin/mucosal candidiasis (IRs 3.55, 1.85, and 1.37 for secukinumab 300 mg, 150 mg, and etanercept, respectively). LIMITATIONS: There was a limited number of patients in comparator groups and the exposure to placebo was short. CONCLUSION: Secukinumab had a favorable safety profile, had no meaningful difference between the 300- and 150-mg doses and, in terms of safety, was comparable to etanercept over 52 weeks in patients with moderate to severe plaque psoriasis.