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espanolEn el ano 2015 la Sociedad Espanola de Reumatologia (SER) publico su posicionamiento sobre farmacos biosimilares. En esta actualizacion, la SER, sigue manifestando su compromiso inequivoco con la sostenibilidad del sistema sanitario de nuestro pais y se alinea con las medidas que, sin reducir la calidad asistencial, esten encaminadas a asegurar su sostenibilidad. Desde la publicacion del anterior posicionamiento la Comision Europea ha autorizado la comercializacion de nuevos farmacos biosimilares, lo que abre una excelente oportunidad de avanzar en la eficiencia de la atencion sanitaria. En este nuevo escenario de incremento de la oferta terapeutica de biologicos, la SER considera imprescindible preservar la libertad de prescripcion de los medicos que realizan la indicacion de farmacos basandose exclusivamente en las caracteristicas y circunstancias individuales de cada paciente, sin olvidar los aspectos economicos que se derivan de dicha actuacion. EnglishIn 2015 the Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia [SER]) published its position paper on biosimilar drugs. In this update, the SER, continues to manifest its unequivocal commitment to the sustainability of the health system of our country and is aligned with the measures that, without reducing quality of care, are aimed at ensuring its continuity. Since the publication of the previous position paper, the European Commission has authorized new biosimilar drugs, which provides an excellent opportunity to advance the efficiency of health care. In this new scenario of increased therapeutic offer of biologics, the SER considers it crucial to preserve the freedom of prescription of physicians who prescribe drugs based exclusively on the characteristics and individual circumstances of each patient, without forgetting the economic aspects there of.

In 2015 the Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia [SER]) published its position paper on biosimilar drugs. In this update, the SER, continues to manifest its unequivocal commitment to the sustainability of the health system of our country and is aligned with the measures that, without reducing quality of care, are aimed at ensuring its continuity. Since the publication of the previous position paper, the European Commission has authorized new biosimilar drugs, which provides an excellent opportunity to advance the efficiency of health care. In this new scenario of increased therapeutic offer of biologics, the SER considers it crucial to preserve the freedom of prescription of physicians who prescribe drugs based exclusively on the characteristics and individual circumstances of each patient, without forgetting the economic aspects there of.

Manuel Pombo-Suarez,1 Jose Ramon Maneiro Fernandez,2 Juan Jesus Gomez-Reino3 1Rheumatology Service, Complejo Hospitalario Universitario, Santiago de Compostela, Spain; 2Rheumatology Service, Complejo Hospitalario Universitario, Pontevedra, Spain; 3Fundación Ramón Domínguez, Complejo Hospitalario Universitario, Santiago de Compostela, SpainCorrespondence: Manuel Pombo-Suarez Email mpombosuarez@gmail.comObjective: To evaluate adherence to treatment in a cohort of patients with rheumatoid arthritis in Spain and to identify potential predictors of adherence.Methods: An observational, cross-sectional, multicenter study in outpatient clinics of Rheumatology Departments from 41 centers was conducted. A validated Spanish version of the compliance questionnaire in Rheumatology was used to measure adherence in a cohort of patients with rheumatoid arthritis, representative of the Spanish population. Univariate and multivariate analyses were performed to detect predictors of adherence.Results: A total of 859 patients were recruited. An adherence rate of 79% was established. No differences were detected in adherence in patients receiving biologic disease-modifying antirheumatic drugs compared to conventional disease-modifying antirheumatic drugs, in patients receiving intravenous therapies compared to other routes of administration and in patients treated in specific day hospitals compared to polyvalent day hospitals. The number of drugs and cohabitation were independent predictors of adherence.Conclusion: An inexpensive and useful method was used to measure adherence in Spanish population. The adherence rate in rheumatoid arthritis is still suboptimal. Simpler, more convenient dosing regimens may improve compliance. Increased knowledge of compliance in patients with rheumatoid arthritis and the identification of possible predictors of adherence will allow to develop effective intervention strategies.Keywords: adherence, predictors, questionnaire, rheumatoid arthritis, Spain

OBJECTIVE Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low (

Objectives This report provides data for the extent of B cell depletion and recovery, efficacy, safety and immunogenicity of Sandoz rituximab (SDZ-RTX; GP2013; Rixathon®) compared with reference rituximab (Ref-RTX) up to week 52 of the ASSIST-RA study. Methods Patients were randomized to SDZ-RTX or Ref-RTX in combination with methotrexate according to the RTX label. The primary endpoint was analysed at week 24. Responders (28-joint DAS [DAS28] decrease from baseline >1.2) at week 24 with residual disease activity (DAS28 ≥2.6) were eligible for a second treatment course between week 24 and 52. Endpoints after week 24 included change from baseline in peripheral B cells, DAS28, ACR 20% response rate (ACR20), Clinical and Simplified Disease Activity Indexes (CDAI, SDAI) and HAQ disability index (HAQ-DI). Safety and immunogenicity were assessed by the incidence of adverse events and antidrug antibodies. Results Primary and secondary endpoints up to week 24 were met. Overall, 260/312 randomized patients completed treatment up to week 52. SDZ-RTX resulted in B cell concentrations over time similar to Ref-RTX. The efficacy of SDZ-RTX was similar to Ref-RTX up to week 52, as measured by DAS28, ACR20/50/70, CDAI, SDAI and HAQ-DI. Safety of SDZ-RTX was similar to Ref-RTX regarding frequency, type and severity of adverse events, which were consistent with the known Ref-RTX safety profile. The incidence of antidrug antibodies was low and transient similarly across treatment groups. Conclusion SDZ-RTX demonstrated similar B cell concentrations over time, efficacy, safety and immunogenicity to Ref-RTX over 52 weeks of the ASSIST-RA study.

Background In immune-mediated inflammatory rheumatic diseases (IMIRD), there are differences between cis-men and cis-women in epidemiology, clinical feature, therapeutic approach, treatment response, and prognosis. In transgender individuals, information concerning IMIRD is not substantial. The assessment of information concerning rheumatic diseases in transgenders is crucial because transgenders may undergo treatments with potential impacts on IMIRD. We aim to collect and discuss current knowledge on IMIRD in transgender individuals, determine the coverage of the literature, identify the knowledge gaps, and highlight opportunities for future research. Methods We did a scoping review of publications collected through a systematic search of transgender patients with any IMIRD. Data sources were Medline, Embase, and Web of Knowledge. Synthesis of results and qualitative review of data information was collected in tables. A semi-quantification of the quality of the articles reporting clinical studies was performed. Results There were 11 transwoman, and 3 transmen cases of systemic lupus erythematosus (5 cases), skin lupus erythematosus (2), systemic sclerosis (4), anti-synthetase syndrome (1), rheumatoid arthritis (1) and ankylosing spondylitis (1). Eleven were de novo cases and three had prior history of IMIRD and developed a comorbidity after starting hormone replacement therapy. The clinical expression of the disease was variable. Two transwomen and one transman developed thrombotic events. The lupus skin lesions in one transman improved following testosterone treatment. No clinical studies were identified. Quality of publications was disparate. Conclusion Although the number of cases is small, most cases of IMIRD occur in transwomen. The absence of solid data warrants caution in establishing recommendations regarding hormone replacement therapy in transgenders with IMIRD. There is an essential need for the consideration of cisgender and transgender particularities in future research on IMIRD

Objective Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). Methodology Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase III began on 17 December 2015. Results During the first year, 35 centres participated. The number of patients included in this new phase in December 2016 was 2664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. Conclusions BIOBADASER phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores.

Objectives: To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). Methods: All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young (< 25 years old), adult (25-64 years old), elderly (65-75 years old) or very elderly (> 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Results: 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13-1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01-2.24)] and female gender [HR 1.42 (1.22-1.64)]. Conclusion: Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics., BIOBADASER is supported by the Spanish Agency for Medicine and Health Products (AEMPS), Biogen, Bristol-Myers Squibb (BMS), Celltrion Healthcare, Lilly, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, and Samsung Bioepis.

Objective Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. Methods Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. Results Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. Conclusion Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Patients with systemic autoimmune rheumatic diseases have a higher incidence of infections. This risk is even higher in patients treated with immunosuppressive drugs. The last statement also applies to newer drugs like the biologic disease modifying antirheumatic drugs (bDMARDs). Clinical practice guidelines have been implemented to minimize the risk of infections with the use of bDMARDs. This chapter summarizes the different strategies used to prevent and manage infections in patients being treated with bDMARDs.

Objective To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs). Methods Articles in Medline, Embase, Cochrane Library, and the Web of Science dated from 2000 to February 2015. Selection criteria were as follows: (1) focus on RCTs or LTEs in RA; (2) treatment with b-DMARDs or tofacitinib; (3) data on malignancies; and (4) a minimum follow-up of 12 weeks. Data included publication details, study design, risk of bias, number and types of malignancies, and patient characteristics and treatments. Data synthesis Of 113 articles and one updated report that were meta-analyzed, overall malignancies in RCTs showed odds ratio (95% confidence intervals) of 1.01 (0.72, 1.42) for all TNF antagonists, 1.12 (0.33, 3.81) for abatacept, 0.54 (0.20, 1.50) for rituximab, 0.70 (0.20, 2.41) for tocilizumab, and 2.39 (0.50, 11.5) for tofacitinib. Network meta-analysis of overall malignancies showed odds ratio (95% predictive intervals) of 1.68 (0.48–5.92) for infliximab, 0.79 (0.44–1.40) for etanercept, 0.93 (0.43–2.03) for adalimumab, 0.87 (0.28–2.75) for certolizumab, 0.87 (0.39–1.95) for golimumab, 1.04 (0.32–3.32) for abatacept, 0.58 (0.21–1.56) for rituximab, 0.60 (0.16–2.28) for tocilizumab, and 1.15 (0.24–5.47) for tofacitinib. Marginal numerical differences in the incidence rate of solid and hematological malignancies and non-melanoma skin cancers appeared in LTEs. Conclusions In RCTs, treatment of RA with b-DMARDs or tofacitinib does not increase the risk for malignancies. Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients.

Background:Abatacept (ABA) is a selective T-cell co-stimulatory modulator. After its approval, changes in therapeutic recommendations, the arrival of new drugs (e.g., biosimilars or Janus kinase inhibitors) and growing focus on comprehensive patient care may have changed prescription patterns, channeling ABA use towards specific patient subtypes. To date, studies analyzing these aspects in clinical practice settings are scarce.Objectives:We aimed to evaluate the epidemiological profile of ABA users and compare it to other DMARD groups included in the register.Methods:We performed an observational study based on the nationwide Spanish register BIOBADASER, which includes patients with rheumatic diseases receiving biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) from 28 tertiary centers. For this analysis, all RA patients included from December 2015 to December 2020 were examined. Baseline features were analyzed descriptively grouping all b/tsDMARDs by mode of action. Clinical effectiveness was assessed through drug survival obtained by the Kaplan-Meier method. Patients were right-censored if data were not available if they were still on treatment at the time of data analysis. The safety profile was assessed by the adverse events (AE) and serious AE incidence rates (IR) expressed as events per 1000 patient-years.Results:There were 628 ABA-treated patients, 471 (75%) using the subcutaneous presentation. Only 142 (23%) were on first-line while 381 (61%) were on third or later-line therapy. ABA users were older and more likely to present certain comorbidities compared to the other b/tsDMARD groups. The biggest relative differences were seen for interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), diabetes and ischemic heart disease. (Table 1)Table 1.This 12-month interim analysis includes 496 patients (336 with axSpA, 98 with RA and 62 with PsA)NABAIL-6CD20JAKiTNFi6287861816691787Mean age, years (SD)64.1 (12.0)50.7 (12.7)63.2 (12.3)59.6 (12.3)60.7 (13.1)Female sex, n (%)482 (77)652 (83)135 (75)537 (80)1418 (79)Median disease duration (p25-p75)10.1 (5.1-16.5)9.4 (4.6-15.9)13.3 (8.3-20.6)10.4 (5.0-17.2)7.4 (3.2-13.7)ACPA, n (%)352 (72)425 (71)113 (79)407 (70)875 (70)RF, n (%)380 (77)454 (75)124 (86)411 (70)915 (72)Current smokers, n (%)98 (16)137 (17)338 (19)90 (20)259 (18)ILD, n (%)64 (13)21 (3)25 (2)8 (2)19 (2)COPD, n (%)38 (6)23(3)52 (3)14 (3)43 (3)Chronic Kidney Disease, n (%)18 (3)13 (2)19 (1)13 (3)18 (1)Diabetes73 (12)66 (8)13 (7)46 (10)100 (7)Ischemic Heart Disease, n (%)36 (6)23 (3)012 (3)30 (2)Hypertension, n (%)197 (31)198 (25)416 (23)131 (30)338 (23)Heart Failure, n (%)19 (4)12 (2)10 (1)6 (2)5 (1)Osteoporosis, n (%)133 (21)141 (18)26 (14)72 (16)215 (15)IL-6: Tocilizumab and Sarilumab; CD20: Rituximab and biosimilars; JAKi: Janus kinase inhibitors (Tofacitinib and Baricitinib); TNFi: TNF inhibitors and biosimilars; ACPA: anti-citrullinated peptide antibodies; RF: rheumatoid factor; ILD: interstitial lung disease; COPD: chronic obstructive pulmonary disease.Overall, 63% of patients remained on ABA at 1 year, 48% at 2 and 31% at 5 years after drug initiation. The corresponding proportions were 79%, 65% and 52% for bionaïve and 59%, 43% and 30% for those in third or later-line therapy. From 394 total discontinuations, loss of efficacy in 225 (57%) and AE in 98 (25%) were the main reasons. This trend was consistent among all therapy lines.The total IR of AE was 886.5 (837.3-938.5) and 156.4 (136.5-179.2) for SAE. Infections were the most frequent AE overall, IR 44.4 (34.4-57.3), and the highest IR was seen among bionaïve patients (69.6 (44.9-107.9)).Conclusion:ABA-treated RA patients in Spain are older and have more comorbidities (vs other b/tsDMARDs), especially ILD, COPD, ischemic heart disease and diabetes and receive ABA as third or later-line therapy. Although these features are associated with worse response to treatment and a higher risk of infection, ABA presents a good drug survival and infectious AE are not the main cause of discontinuation.Acknowledgements:On behalf of the BIOBADASER Working groupDisclosure of Interests:Sebastián C Rodriguez-García Speakers bureau: Sanofi, MSD, UCB-Pharma, Bristol-Myers-Squibb, Novartis, Janssen, Consultant of: Bristol-Myers-Squibb, Galápagos, Carlos Sánchez-Piedra: None declared, Raul Castellanos-Moreira Speakers bureau: Roche, Sanofi, MSD, UCB-Pharma, Bristol-Myers-Squibb, Novartis, Lilly, and Pfizer., Dolores Ruiz-Montesinos: None declared, Manuel Pombo: None declared, Fernando Sánchez-Alonso: None declared, Juan J. Gómez-Reino Consultant of: Pfizer, Grant/research support from: Abbvie, Lilly, MSD, Pfizer, Roche, and UCB.

ObjectivesThe aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment.MethodsIn this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration–time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24.ResultsThe 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.ConclusionsThree-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.Trial registration numberNCT01274182; Results.

Osteoarthritis (OA) is a chronic systemic musculoskeletal disorder involving inflammation, immunity, and metabolic alterations. OA is commonly regarded as non-inflammatory disease; still inflammation is recognized as contributing to the symptoms and progression of OA. New evidence suggests that adipokines are involved in the pathophysiology of OA and might modulate the production of inflammatory mediators including in immune cells. However, the role of immune component in osteoarthritis is still poorly investigated. To gain further insights into the interaction of immune cells in OA and the role of adipokines on these cells, we performed experiments aimed to determine the cytokine profile in activated CD4+ T cells from OA patients. For completeness, we also explored the cross talk between T lymphocytes and chondrocytes in OA by co-culturing human primary chondrocytes with activated CD4+ T cells in two ways: the first by incubating the cells by direct contact (D.C.) or by transwell system. Our results show that the exposure of activated CD4+ T cells to adipokines modulates IL-6, IL-8, and CCL-3 production. In addition, the production of key macromolecules of ECM (aggrecan and collagen-2) and matrix metalloproteinase 13 (MMP-13) in co-cultured chondrocytes with activated CD4+ T cells was altered. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1299-1303, 2017.

The objective of the study was to analyze the impact of TNF antagonists (TNFa) on the total cholesterol and triglycerides on ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In this single-centre observational study of AS and PsA patients, differences in triglyceride and total cholesterol levels and frequency of hypertriglyceridemia and hypercholesterolemia at 3 and 6 months were analysed in patients treated and not treated with TNFa. General estimation equations and linear regression analysis were used to investigate associations between disease activity and lipid levels and to identify predictors of change. One hundred fifty-seven patients treated, and 157 not treated with TNFa, were included in the study. A transient increase in cholesterol level from baseline to 3 months in TNFa-treated patients was the only statistically significant effect (P

Objective.To report on the 5-year efficacy and safety results of the AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) monotherapy study (ClinicalTrials.gov: NCT00109408, NCT00720798).Methods.Patients with rheumatoid arthritis for whom biologics had not failed or who did not discontinue methotrexate because of lack of efficacy or tolerability were followed up for 5 years to assess the efficacy and serious adverse events (SAE) of tocilizumab (TCZ) monotherapy.Results.Longterm efficacy results showed that efficacy was maintained or improved for up to 264 weeks in patients receiving TCZ monotherapy. Serious infection was the most frequent SAE; no new safety signals were reported.Conclusion.Longterm monotherapy with TCZ demonstrated continuing efficacy and safety.

Background During the last 15 years, the comprehensive understanding of the safety, effectiveness, expanding access, and availability of new biologic disease-modifying antirheumatic drugs (bDMARDs) has likely contributed to the pattern of use of these compounds in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Objectives To assess changes in the baseline characteristics of patients who underwent biological therapy from 2007 to 2018 in a real world setting. Methods Data were obtained from BIOBADASER, the Spanish registry of biologics. Recorded data is obtained from routine clinical practice. Patients diagnosed with RA, PsA and AS and who started biological treatment from 2007 to 2018 were included. Sociodemographic and clinical variables, as well as first bDMARD used, were stratified by the starting year period (2007-2009; 2010-2012; 2013-2015; 2016-2018) and compared using Anova and Chi-square tests. Results 6943 patients (2827 RA patients, 1274 PsA and 1261 AS) were included in this analysis (Table 1). Patient age at the beginning of the first biologic was significantly higher during the period 2016-2018 than in 2007-2009 (48.3 vs 50.6). Disease duration until the use of biologics decreased from 8.6 to 8.1 years. In RA patients, disease activity, as assessed by DAS28 at the start of the biological treatment, was significantly higher in the 2007-2009 period than in the last period analyzed (5.1 vs 4.7). The use of TNF inhibitor as a first option also changed significantly (94.6% vs 58.5%). Regarding comorbidities, the number of rheumatic patients treated with biologics and a past history of cancer (1.8% vs 3.7%), ischemic heart disease (1.8% vs 3.1%), hypercholesterolemia (13.6% vs 26.1%), or hypertension (21.7% vs 23.7%) has increased significantly. Conclusion Our data show that during the last decade the pattern of use of biologics in patients with rheumatic diseases has changed. Nowadays these compounds are used in older patients, with shorter disease duration, with lower disease activity in RA, and with more comorbidities. Disclosure of Interests Carlos Sanchez-Piedra: None declared, Agueda Prior-Espanol: None declared, Mercedes Freire Gonzalez: None declared, Maria Colazo: None declared, Dolores Ruiz-Montesinos: None declared, Yanira Perez-Vera: None declared, Ana Ortiz: None declared, Sagrario Bustabad: None declared, Paloma Vela-Casasempere Grant/research support from: UCB, Abbvie, Pfizer, Roche, Bristol-Myer-Squibb (another research, not BIOBADASER related), Consultant for: UCB, Lilly, Pfizer, Roche, Bristol-Myer-Squibb, Speakers bureau: Roche, UCB, MSD, Pfizer, GSK, BMS, Lilly, Marta Rojas-Gimenez: None declared, Fernando Sanchez-Alonso: None declared, Federico Diaz-Gonzalez Grant/research support from: MSD, Abbvie, Roche, Novartis, Consultant for: Lilly, Novartis, Pfizer, Amgen, Biogen, Celgene, Speakers bureau: MSD, Lilly, Janssen, BMS, Roche, Juan Jesus Gomez-Reino: None declared

Background The advent of biologic therapy (BT) in ankylosing spondylitis (AS) has substantially benefited patients with inadequate response to conventional therapy. However, it is known patients with inadequeate response to a 1st BT have worse response to 2nd and further lines. Objectives To analyze the effectiveness of BT in biologic-naive and biologic-experienced real-world AS patients, measuring response through change in activity indexes (ASDAS-CRP and BASDAI) and percentage of low activity and inactive disease at 12 months. Methods Data were obtained from BIOBADASER III, an ongoing observational longitudinal multicenter cohort of patients with rheumatic diseases treated with BT or targeted synthetic DMARDs. Patients were divided into 2 groups, according to their state before entering the study: BT-naive (BTn) receiving their 1st BT, and BT-experienced (BTe) receiving their 2nd or further BT; regardless of the specific drug they received. Disease activity indexes (DAI) were collected at baseline and after 12 months of BT; mean and SD was calculated for each group and interpreted according to ASDAS disease activity states and, since not established, analogous categories previously used for BASDAI ( Results 846 patients, (29.3% women, mean age 47.6 years) were included, 422 BTn and 424 BTe. Mean DAI results (table 1): at baseline, AS had high disease activity by BASDAI (>4) and ASDAS (>2.1 to 1.3 to Conclusion The mean disease activity on patients starting biologic therapy is high. A clinically important improvement is met after 12 months of therapy, irrespectively of the index used or the prior use of biologics. The delta in DAI is bigger in the biologic-naive group who receive the 1st BT. The biologic-naive group also reaches a higher percentage of low disease activity and inactive disease. Further analysis is needed to see if these tendencies remain after separating the groups per type of biologic drug. References [1] Ramiro S, et al. Ann Rheum Dis2014;73:1455-61. [2] Kviatkovsky MJ, et al. J Rheumatol2016;43:1680-6. Acknowledgement We thank the BIOBADASER group Disclosure of Interests None declared

Background Chronic inflammatory immune-mediated diseases, as rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Ps), ankylosing spondylitis (AS), ulcerative colitis (UC) and Crohn’s disease (CD), have higher risks of morbidity and mortality and a great impact on quality of life of patients1. Drug inhibitors of tumor necrosis factor (TNF inhibitors) have demonstrated an adequate efficacy and security profile in these patients when classical treatments (as disease-modifying antirheumatic drugs) have been failed or patients were intolerant. TNF inhibitors are used to control inflammatory response and to improve quality of life, pain, functional capacity and progression of the disease2. Studies in RA show that smoking habit is related to more articular and extra-articular damage, worse prognosis, higher basal activity and higher risk of seropositive RA. It has been related also to greater number of different treatments and higher doses needed for patients by pharmacokinetic and pharmacodynamic processes. Data published until now suggest that smoking habit decreases efficacy of TNF inhibitors3. Objectives To analyze the smoking habit influence on the efficacy of TNF inhibitors in patients diagnosed of chronic inflammatory immune-mediated diseases (RA, PsA, Ps, AS, UC, CD). Methods It was made a systematic literature search using Cochrane Library, Medline, the Web of Science and Embase databases. Meta-analyses were performed using a random-effects model. Results 37 of 3677 identified articles met the inclusion criteria. No documents with GOL were found. The analysis of all the diseases together gives a significant decrease on the response to TNF inhibitors in smoking patients [OR 0.812 (0.662-0.996), p=0.046]. This response also has a significant decrease in IBD maintained response in smoking patients [OR 0.467 (0.257-0.848), p=0.012]. A non-significant decrease in the treatment response of smoking patients with IBD clinical remission was found, in smoking patients versus ex-smoking and never smoking patients with IBD response, in ex-smoking patients versus never smoking patients with IBD partial response, in current and ex-smoking patients versus never smoking patients with IBD partial response, in current smoking patients versus ex-smoking patients with IBD partial response, in current smoking patients versus never and ex-smoking patients with IBD partial response, in current smoking patients versus never smoking patients with IBD partial response, in patients with AR EULAR and in patients with AR EULAR moderate response. Conclusion Smoking habit is a poor prognosis factor in RA, AS, Ps, PsA, UC and CD. Its leaving will decrease cardiovascular risk, joint and bowel damage, will increase the efficacy of TNF inhibitors and will benefit the health of patients, not only in their particular disease, and it can be the first step on their treatment. References [1] Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008;121(10):9-14. [2] Seymour HE. Anti-TNF agents for rheumatoid arthritis. Br J Clin Pharmacol2001;51(3):201-8. [3] Arnson Y. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun2010;34(3):258-65. Disclosure of Interests None declared

Background JAK inhibitors (JAKi) have been recently authorized in the European Union. JAKi long-term performance in the clinical practice setting still needs to be assessed. Drug survival reflects a drug’s effectiveness, safety, and tolerability; thus, it is an important measurement for real-world studies. Objectives To describe the pattern of use of JAKi in real-world dataset, and to analyze the drug survival as a group (tofacitinib+baricitinib). Methods Information was obtained from BIOBADASER III, an ongoing observational longitudinal multicenter cohort of patients with rheumatic diseases treated with biologic or targeted synthetic (b/ts) DMARDs in Spain. All subjects with current or previous JAKi use were included and followed until September 2018. Clinical characteristics of the patients were analyzed. Drug survival (overall, and for biologic-naive and biologic-experienced patients) was determined using Kaplan-Meier analysis. Results 149 patients, 75.2% women, were treated with JAKi, receiving a total of 152 cycles of treatment (50.7% tofacitinib, 49.3% baricitinib; 3 patients had both). The most frequent diagnosis was rheumatoid arthritis (RA, 92.6%), and there is a small number of off-label uses (6%), depicted at Table 1. Use on psoriatic arthritis is scarce (1.3%). Concomitant use of methotrexate (MTX) was registered in 68 patients (45.6%). Previous use of bDMARDs was high (n=124, 81.6%); drug survival rate for biologic-experienced patients was 81.7% and 78.7% at 6 and 12 months. None of the JAKi treatments in biologic-naive patients (n=18, 18.4%) were discontinued during follow-up. Pooled survival rate of JAKi was 85.0% and 82.5% at 6 and 12 months (Figure 1). Discontinuation was seen in 19 treatments (12.5%); the reasons were inefficacy (n=15, 9.9%) or adverse events (n=4, 2.6%). Conclusion The current use of JAKi in Spain is mainly in RA and as 2nd line after bDMARDs. The use of JAKi in psoriatic arthritis is still scarce and a small group of patients are treated off-label. Less than half use combination therapy with MTX. Overall survival of JAKi is superior to 80% at 12 months. A longer follow-up is needed to continue analyzing the survival of JAKi in a real-world context. Acknowledgement We thank all researchers from the BIOBADASER III group. Disclosure of Interests Valentina Emperiale: None declared, Carlos Sanchez-Piedra: None declared, Eduardo Cuende: None declared, Paloma Vela-Casasempere Grant/research support from: UCB, Abbvie, Pfizer, Roche, Bristol-Myer-Squibb (another research, not BIOBADASER related), Consultant for: UCB, Lilly, Pfizer, Roche, Bristol-Myer-Squibb, Speakers bureau: Roche, UCB, MSD, Pfizer, GSK, BMS, Lilly, Maria del Carmen Castro Villegas Paid instructor for: MSD, Abbvie, Pfizer, Janssen, Lilly, Roche, Sara Manrique Arija Speakers bureau: ABBvie, MSD, Janssen, Lillly, Roche, Pfyzer, Novartis., Cristina Campos Fernandez: None declared, Javier del Pino: None declared, Manuel Pombo: None declared, Fernando Sanchez-Alonso: None declared, Juan Jesus Gomez-Reino: None declared

Most reports on serious infections (SI) in rheumatoid arthritis (RA) patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) are from the USA and Western Europe. Data from other regions are largely missing. We report data from South American countries with different backgrounds and health-care systems but similar registries.We merged 2010-2016 data from two registries, BIOBADABRASIL (Brazil) and BIOBADASAR (Argentina), which share the same protocol, online platform and data monitoring process. Patients with active RA were included when they began the first bDMARD or a conventional synthetic DMARD (csDMARD, control group). The SI incidence rate (IR) per 1000 patient/years and adjusted IR ratio (aIRR) were estimated for bDMARDs and csDMARDs.Data were analysed for 3717 RA patients with an exposure of 13,380 patient/years. The 2591 patients treated with bDMARDs (64% tumour necrosis factor-α inhibitors (TNFi)) had a follow-up of 9300 years, and the 1126 treated with csDMARDs had an exposure of 4081 patient/years. The SI IR was 30.54 (CI 27.18-34.30) for all bDMARDs and 5.15 (CI 3.36-7.89) for csDMARDs. The aIRR between the two groups was 2.03 ([1.05, 3.9] p = 0.034) for the first 6 months of treatment but subsequently increased to 8.26 ([4.32, 15.76] p 0.001). The SI IR for bDMARDs decreased over time in both registries, dropping from 36.59 (28.41-47.12) in 2012 to 7.27 (4.79-11.05) in 2016.While SI remains a major concern in South American patients with RA treated with bDMARDs, a favourable trend toward a reduction was observed in the last years.Key Points• New comprehensive data on biologic drugs safety from international collaboration in South America.• First proposal for national registries data merging in South America.• Serious infections remain a major concern in RA patients treated with biologics.• A significant reduction of serious infections in RA patients exposed to biologics was observed over a 7 years period.

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs., This work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed the efficacy of tofacitinib using pooled data from two phase 3 studies of patients with active PsA. Methods Data were pooled from OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439). Patients had active PsA and either an inadequate response (IR) to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) and were tumor necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden), or had IR to ≥ 1 TNFi (OPAL Beyond). Pooled data included tofacitinib 5 or 10 mg twice daily (BID; to month 6) and placebo (to month 3; patients then switched to tofacitinib 5 or 10 mg BID). Patients also received one background csDMARD. Endpoints included American College of Rheumatology (ACR)20 response and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at month 3 (primary endpoints), ACR50/70 response, HAQ-DI response (decrease from baseline ≥ 0.35) and improvements in painful and swollen joint counts, psoriasis, enthesitis and dactylitis to month 6. Results A total of 710 patients were included (tofacitinib 5 mg BID: 238; tofacitinib 10 mg BID: 236; placebo: 236). Primary endpoints showed significant improvements at month 3 in patients receiving tofacitinib 5 or 10 mg BID vs. placebo. Significant improvements in HAQ-DI response, painful and swollen joints, psoriasis, enthesitis and dactylitis vs. placebo were observed for both tofacitinib doses at month 3. Efficacy was maintained to month 6 (final pooled time point). Conclusions In a pooled analysis of csDMARD-IR/TNFi-naïve and TNFi-IR patients, tofacitinib was superior to placebo at month 3 across four PsA domains: peripheral arthritis, psoriasis, enthesitis and dactylitis. Trial Registration OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439). Funding Pfizer Inc. Electronic supplementary material The online version of this article (10.1007/s40744-018-0131-5) contains supplementary material, which is available to authorized users.

Peter C Taylor,1 Rieke Alten,2 Juan J Gomez Reino,3 Roberto Caporali,4 Philippe Bertin,5 Emma Sullivan,6 Robert Wood,6 James Piercy,6 Radu Vasilescu,7 Dean Spurden,8 Jose Alvir,9 Miriam Tarallo10 1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 2Department of Internal Medicine II, Rheumatology, Clinical Immunology, and Osteology, Schlosspark Klinik, University Medicine Berlin, Berlin, Germany; 3Experimental and Observational Rheumatology and Rheumatology Unit, Fundacion Ramon Dominguez and Rheumatology, Hospital Clinico Universitario, Santiago de Compostela, Spain; 4Division of Rheumatology, IRCCS Foundation Policlinico S. Matteo, University of Pavia, Pavia, Italy; 5Service de Rhumatologie, CHU Dupuytren, Limoges, France; 6Real-World Evidence and Epidemiology, Adelphi Real World, Bollington, UK; 7Medical Affairs, International Developed Markets, Pfizer, Brussels, Belgium; 8Health Economics and Outcomes Research, Pfizer Ltd, Tadworth, UK; 9Statistical Research and Data Science Center, Global Product Development, Pfizer Inc, New York, NY, USA; 10Patient and Health Impact, Pfizer Italia Srl, Rome, Italy Objective: The aim of this study was to identify factors that influence treatment adjustments and adoption of a treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA) in European practices.Methods: Cross-sectional data were drawn from the Adelphi 2014 RA Disease Specific Programme. Treatment patterns and clinical characteristics were investigated in patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) vs non-bDMARDs. For the T2T analysis, patients were subdivided into two subsets (RA diagnosis

ObjectivesThis post-hoc analysis explored the impact of body mass index (BMI) on tofacitinib efficacy/safety in patients with active psoriatic arthritis (PsA).MethodsData were pooled from two phase 3 studies (NCT01877668;NCT01882439). Analyses included patients randomised to tofacitinib 5/10 mg two times a day or placebo, stratified by baseline BMI: 2, ≥25–2, ≥30–2or ≥35 kg/m2. Endpoints (month 3): American College of Rheumatology (ACR20/50/70), Health Assessment Questionnaire-Disability Index (HAQ-DI) and Psoriasis Area and Severity Index (PASI) 75 response rates; dactylitis/enthesitis resolution rates; changes from baseline Short Form-36 Health Survey version 2 (SF-36v2) Physical/Mental Component Summary (PCS/MCS) scores and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score. Safety was also reported.ResultsAnalysis included 710 patients; 43.8% were obese (BMI ≥30 kg/m2). Tofacitinib demonstrated higher efficacy response rates at month 3, compared with placebo, regardless of baseline BMI. Generally, ACR20/50/70 and HAQ-DI response rates, enthesitis resolution rates and changes from baseline in SF-36v2 PCS score and FACIT-F total score (month 3) were reduced in patients with baseline BMI ≥35 kg/m2versus patients with lower BMIs. Elevated alanine aminotransferase/aspartate aminotransferase levels were reported in patients with baseline BMI ≥35 kg/m2receiving tofacitinib 5 mg but not 10 mg two times a day.ConclusionTofacitinib demonstrated greater efficacy than placebo in patients with PsA, regardless of baseline BMI. For all treatment arms, reduced efficacy was observed in patients with baseline BMI ≥35 kg/m2. Safety was generally comparable across BMI categories, although the effect of tofacitinib on liver enzymes in patients with baseline BMI ≥35 kg/m2was inconclusive.

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.

Background:Obesity is highly prevalent in PsA (~45%)1and is associated with a reduced response to TNF inhibitors.2Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA.Objectives:This post hoc analysis assessed tofacitinib efficacy and safety in patients (pts) with PsA by baseline (BL) body mass index (BMI) category.Methods:Data were pooled from two placebo (PBO)-controlled, double-blind, Phase 3 studies in pts with active PsA and an inadequate response to ≥1 conventional synthetic DMARD (OPAL Broaden [12 months;NCT01877668]) or to ≥1 TNF inhibitor (OPAL Beyond [6 months;NCT01882439]).3,4This analysis included pts randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or PBO, stratified by BL BMI: 2, ≥25–2, ≥30–2, or ≥35 kg/m2. Efficacy and safety were reported to Month (M)3. M3 efficacy outcomes included ACR20/50/70 and HAQ-DI responses, dactylitis and enthesitis resolution rates and changes from BL in HAQ-DI, Short Form-36 Version 2 (SF-36v2) Physical (PCS) and Mental Component Summary (MCS) scores, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores. Safety outcomes included adverse events (AEs), such as cardiovascular (CV) events and changes in lipid levels and liver function tests (LFTs).Results:This analysis included 710 pts; 43.8% were obese (BMI ≥30). At BL, 161 (22.7%) pts had a BMI 2.87 mg/L (49.1% in BMI Conclusion:Regardless of BL BMI, tofacitinib demonstrated greater efficacy than PBO at M3 in pts with PsA. Similar to other advanced therapies,2reduced efficacy was generally observed in tofacitinib and PBO pts with a BL BMI ≥35. Tofacitinib safety appeared consistent across all BL BMI categories.References:[1]Labitigan et al. Arthritis Care Res (Hoboken) 2014;66:600-07.[2]Singh et al. PLoS One 2018;13:e0195123.[3]Mease et al. NEJM 2017;377:1537-50.[4]Gladman et al. NEJM 2017;377:1525-36.Acknowledgments:Medical writing support was provided by Mark Bennett of CMC Connect, McCann Health Medical Communications, and funded by Pfizer Inc.Disclosure of Interests:Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Alexis Ogdie Shareholder of: Amgen, Novartis, Pfizer Inc, Grant/research support from: Novartis, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Novartis, Pfizer Inc, Jon T Giles Grant/research support from: Pfizer Inc, Juan Jesus Gomez-Reino Grant/research support from: AbbVie, Novartis, Pfizer Inc, Roche, UCB, Consultant of: Pfizer Inc, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc, Roche, UCB, Philip Helliwell: None declared, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Pamela Young Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Wael Joseph Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rajiv Mundayat Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Daniela Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background:Persistence in treatment with a biological drug can be considered an indirect measure of efficacy,safety and tolerabilityObjectives:We assessed the probability of persistence of golimumab treatment in patients with rheumatic diseases and the factors associated with persistence up to 7 years of follow-upMethods:BIOBADASER is the Spanish registry of biological drugs of the Spanish Society of Rheumatology and the Spanish Medicines Agency.A data-base analysis was done in Dec 2019 on all the patients aged 18 years or older who had initiated golimumab for rheumatoid arthritis (RA),psoriatic arthritis (PsA) and axial spondyloarthritis (SpA).The probability of persistence was calculated with a Kaplan-Meier test.Factors related to persistence were analyzed with a Cox-regression modelResults:There were 685 patients included (195 [28.5%] RA, 294 [42.9%] axial SpA and 196 [28.6%] PsA) in the analysis (Mean age 51.3 [12.6] years, 53.7% women). Median duration of disease at the onset of golimumab therapy was 7.6 (3.0-14.5) years. Golimumab was prescribed as first biological drug in 36.4%, as second in 31.7% and as third or further in 31.9% of the patients. Concomitant medication at golimumab initiation included methotrexate (40.0%), corticosteroids (34.2%), leflunomide (17.8%) and sulphasalazine (8.1%). The probability of persistence with golimumab treatment was 71.7% (95% CI 68.1–74.9) at year 1,60.5% (56.5–64.2) at year 2, 55.6% (51.5–59.5) at year 3, 50.6% (46.2–54.8) at year 4, 45.1% (40.1–50.0) at year 5, 44.2% (39.0–49.3) at year 6 and 39.5% (32.8–46.2) at year 7. As the first biological agent the probability of persistence was 83.2% at year 1 and 60.0% at year 5. As a second biological drug persistence was 70.4% and 39.9% (year 1 and 7). Cox-regression analysis (table) showed that the probability of persistence with golimumab treatment was higher in first vs second or third biological line (Hazard Ratio[HR] for discontinuation: 1.45 for second and 3.04 for third or further vs first line), in SpA and PsA patients (HR discontinuation vs RA:0.56 and 0.49 respectively) and in patients with methotrexate (HR:0.61) and lower in those needing corticosteroids(HR:1.71) or DMARDs different to methotrexate (HR:1.88) and in patients with higher disease activity at golimumab onset (HR:1.45)Conclusion:The probability of persistence on golimumab therapy was high and remained relatively stable up to 7 years of follow-up. A lower risk of treatment discontinuation was observed in patients who received golimumab as first biological agent and in PsA and SpA patients. Persistence was lower in patients needing corticosteroids, DMARDs different to methotrexate and in those with higher disease activity at golimumab onsetCox-regression analysis.HR for discontinuation of golimumabHR95% CIpAge at golimumab initiation1.01(0.99-1.02)0.480Gender (women vs men)1.15(0.69-1.90)0.595Smoking habit (smoker vs non-smoker)1.46(0.90-2.37)0.128Smoking habit (past smoker vs non-smoker)0.94(0.48-1.84)0.859Overweight (vs normal)1.10(0.63-1.93)0.728Obesity (vs normal)0.90(0.51-1.59)0.708SpA vs RA0.56(0.31-1.00)0.050PsA vs RA0.49(0.28-0.87)0.015Second vs first biological drug1.45(0.85-2.46)0.171Third or further vs first biological drug3.04(1.86-4.98)0.001MTX0.61(0.38-0.97)0.037Other DMARD1.88(0.90-3.93)0.091Corticosteroids1.71(1.04-2.83)0.036Activity higher than median1.45(0.96-2.19)0.078Acknowledgments:BIOBADASER is a multi-funded registry of The Spanish Society of Rheumatology (SER) and this specific analysis was funded by MSD Spain.Disclosure of Interests:Manuel Pombo: None declared, Carlos Sánchez-Piedra: None declared, Luis Cea-Calvo Employee of: MSD Spain, Sara Manrique Arija: None declared, Blanca Garcia-Magallon Consultant of: MSD, Speakers bureau: Pfizer, Amgen, Celgene, MSD, Cristina Campos Fernández: None declared, Irene Notario: None declared, Federico Diaz-Gonzalez: None declared, Juan Jesus Gomez-Reino: None declared

Background:Respiratory tract infections are among the leading causes of hospitalization in rheumatoid arthritis (RA) and Streptococcus Pneumoniae (Sp) is one of the most frequent pathogens involved. For these patients, the CDC recommends a combined vaccination scheme (CVS) using two types of Sp vaccines but evidence on its effectiveness remains insufficient.1Objectives:To assess the impact of the combined vaccination scheme on the incidence of Sp infections in patients with RA treated with DMARD.Methods:A cohort was nested in a register including patients with RA who were prescribed a bDMARD or tsDMARD -either naïve or switch- from 2000 to March 2019.The target outcomes were invasive pneumococcal disease (IPD) and all-cause community-acquired pneumonia (CAP), as defined by relevant MedDRA codes. Demographic and clinical features were also retrieved. Each participant centre informed about the date when they implemented a systematic Sp vaccination protocol and whether they were using the CVS. Those not adopting this practice were excluded from the analysis.Crude incidence rates (IRs) were calculated for each outcome as well as for its combination (combined variable defined as “Sp infections”). Exposure was split into two periods, considering the date when the CVS was officially recommended in Spain (May 2015). The incidence rate ratio (IRR) comparing pre and post implementation periods was estimated with a Poisson regression model adjusted for sex, age and comorbidities (Charlson Index).Results:1704 patients were included, their characteristics are shown in table 1. One centre was excluded for not using any Sp vaccination protocol while the remaining ones reported using the CVS. Crude IRs by periods (pre and post CVS implementation) and age groups are shown in table 2. The IRR of the post-vaccination period after adjusting for age, sex and comorbidities (Charlson index) was 0.40 (95% CI: 0.29 - 0.56), pTable 1.Baseline features of the cohort.DemographicsAge, years *60.6 (12.5)Female1356 (79.6%)Current smoking287 (16.8%)RA clinical characteristicsDisease duration, years*9.1 (7.9)RF positive875 (74%)ACPA positive831 (71%)DAS28*4.6 (1.4)Other clinical characteristicsBody Mass Index*27.5 (5.2)Charlson index*2.3 (1.5)Chronic pulmonary Disease125 (9.3%)Diabetes mellitus147 (9%)*Data presented as mean (standard deviation).Table 1Characteristics of patients with RA at time of RA diagnosis and patients with SAB with/without RA at time of SAB diagnosisCharacteristic, n (%)At RA diagnosisAt first-time SABRA (n=34,627)RA (n=228)Non-RA (n=25,268)Age, years (IQR)59.8 (48.8-70.3)71.8 (62.3-79.2)69.7 (57.7-79.7)Female, %69%59%38%Diabetes mellitus2,467 (7.1%)51 (22.4%)5,678 (22.5%)Heart failure1,018 (2.9%)42 (18.4%)4,718 (18.7%)Liver disease454 (1.3%)12 (5.3%)2,189 (8.7%)Chronic obstructive pulmonary disease1,677 (4.8%)36 (15.8%)3,412 (13.5%)Cancer2,124 (6.1%)60 (26.3%)6,742 (26.7%)HIV11 (0.0%)0 (0%)127 (0.5%)Solid organ transplant8 (0.0%)0 (0%)357 (1.4%)Alcohol abuse642 (1.9%)12 (5.3%)3,356 (13.3%)Chronic dialysis29 (0.1%)11 (4.8%)2,256 (8.9%)Orthopedic implant3,807 (11.0%)89 (39.0%)5,422 (21.5%)Cardiac or vascular implant731 (2.1%)18 (7.9%)1,940 (7.7%)Glucocorticoid (0-90 days prior)7,062 (20.4%)99 (43.4 %)2,911 (11.5%)Invasive surgery (0-30 days prior)1,962 (5.7%)62 (27.2%)8,451 (33.5%)Table 2.Crude IRs (95% CI) of the outcomes of interest split by age.Overall≥65PrePostPrePostPrePostSP-Infections33 (27.4-39.9)12.7 (9.8-16.4)28 (22.4-35)11.8 (8.9-15.6)60.3 (42.4-85.8)19.5 (10.8-35.2)IPD–0.4 (0.1-1.6)–0.4 (0.1-1.8)––All cause CAP23.6 (19.0-29.3)11.5 (8.8-15)18.7 (14.4-24.4)10.4 (7.7-14)50.8 (34.8-74)19.5 (10.8-35.2)Conclusion:The incidence of Sp infections experienced a decrease in RA patients taking bDMARD or tsDMARD after the introduction of the stepwise combined vaccination scheme that is not related to age, sex or comorbidities.References:[1] Furer V,et al.Ann Rheum Dis2019;0:1–14Disclosure of Interests:Sebastian C Rodriguez-García Speakers bureau: Novartis Farmaceutica, S.A., Merck Sharp & Dohme España, S.A., Sanofi Aventis, UCB Pharma, Carlos Sánchez-Piedra: None declared, Raul Castellanos-Moreira Speakers bureau: Lilly, MSD, Sanofi, UCB, Dolores Ruiz-Montesinos: None declared, Victoria Hernandez: None declared, Manuel Pombo: None declared, Fernando Sánchez-Alonso: None declared, Loreto Carmona Grant/research support from: Novartis Farmaceutica, SA, Pfizer, S.L.U., Merck Sharp & Dohme España, S.A., Roche Farma, S.A, Sanofi Aventis, AbbVie Spain, S.L.U., and Laboratorios Gebro Pharma, SA (All trhough institution), Juan Jesús Gómez-Reino: None declared

Background Tofacitinib and other new treatments approved for use in psoriatic arthritis have only recently been included in psoriatic arthritis treatment guidelines, and studies evaluating the relative efficacy of available therapies are important to inform treatment decisions by healthcare professionals. Objective To perform a network meta-analysis to evaluate the efficacy and safety profiles of tofacitinib, biologic disease-modifying antirheumatic drugs (bDMARDs), and apremilast in patients with psoriatic arthritis naive to tumor necrosis factor inhibitor therapy (TNFi-naive) or with an inadequate response (TNFi-IR). Methods A systematic literature review used searches of MEDLINE, Embase, and The Cochrane Library on October 9, 2017. Randomized controlled trials including adult patients with psoriatic arthritis receiving treatment administered as monotherapy or with conventional synthetic DMARDs were selected. Efficacy outcomes included American College of Rheumatology 20 response, change from baseline in Health Assessment Questionnaire-Disability Index, ≥75% improvement in Psoriasis Area and Severity Index, and change from baseline in Dactylitis Severity Score and Leeds Enthesitis Index. Treatment effects were evaluated during placebo-controlled phases, using a binomial logit model for binary outcomes and a normal identify link model for other outcomes. Discontinuations due to adverse events and serious infection events were assessed as safety outcomes. Results The network meta-analysis included 24 published randomized controlled trials, of which 13 enrolled TNFi-naive patients only, 3 enrolled TNFi-IR patients only, and 8 enrolled both TNFi-naive and TNFi-IR patients. Placebo-controlled treatment durations ranged from 12 to 24 weeks. Indirect comparisons showed tofacitinib 5 and 10 mg BID to have similar efficacy compared with most bDMARDs and apremilast in improving joint symptoms (based on American College of Rheumatology 20 response), and with some bDMARDs in improving skin symptoms (based on Psoriasis Area and Severity Index) (tofacitinib 10 mg BID only in TNFi-IR) in patients with psoriatic arthritis who were TNFi-naive or TNFi-IR. Results also showed that, compared with placebo, the improvement in physical functioning (based on Health Assessment Questionnaire-Disability Index) with tofacitinib 5 and 10 mg BID was similar to that observed with most bDMARDs and apremilast in TNFi-naive patients, and similar to that observed with all bDMARDs with available data in the TNFi-IR population. Improvements in Dactylitis Severity Score and Leeds Enthesitis Index scores were comparable between treatments. Tofacitinib 5 and 10 mg BID were median-ranked 8 and 15, respectively, for discontinuation due to any adverse events, and 5 and 16, respectively, for a serious infection event out of a total of 20 treatments in the network (lower numbers are more favorable). Conclusions Tofacitinib provides an additional treatment option for patients with psoriatic arthritis, both in patients naive to TNFi and in those with TNFi-IR. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)

[Objective]: Recognition of a new type of rheumatoid arthritis (RA)-specific autoantibody, the anti-carbamylated protein antibodies (anti-CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti-CarP antibodies and HLA-DRB1 alleles in RA. [Methods]: Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme-linked immunosorbent assay. HLA-DRB1 alleles were determined using either hybridization techniques or imputation from HLA-dense genotypes. Results of these analyses were combined in a meta-analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA-DRB1 alleles were compared between the antibody-positive RA subgroups and the double-negative subgroup of RA patients stratified by anti-citrullinated protein antibody (ACPA)/anti-CarP antibody status, and also between the 4 RA patient strata and healthy controls. [Results]: Meta-analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA-DRB1*03 carriers in the ACPA-/anti-CarP+ subgroup as compared to ACPA-/anti-CarP- RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA-/anti-CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti-CarP- and ACPA+/anti-CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA-DRB1*03) were associated with protection from ACPA+ RA. [Conclusion]: These findings indicate a specific association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility., Supported by the Instituto de Salud Carlos III and FEDER (grant RD16/0012/0012 to Dr. Balsa, grants PI14/00442 and RD16/0012/0011 to Dr. Gonzalez-Alvaro, and grants RD16/0012/0014 and PI17/01606 to Dr. Gonzalez). Ms Regueiro's work was supported by the Ministerio de Educacion Cultura y Deporte (FPU pre-doctoral fellowship FPU15/03434)

Registries characterize the effectiveness and safety of therapeutic interventions in daily clinical practice. Data from registries enable mining the records of tens of thousands of patients towards determining the effectiveness, safety, and cost-benefit of any given therapeutic. The strengths of registries include real-life settings, greater power than clinical trials to detect rare events, and the study of multiple outcomes and several research questions. Registries also have their weaknesses. They are expensive, less accurate than clinical trials, affected by channelling bias, often require links to external sources or use historic and selected control cohorts or combine datasets to increase power, and have the risk of multiple confounders. Since the beginning of biological era, registries were developed to profile emerging treatments. This article reviews the role of registries in the treatment of rheumatoid arthritis with biologic disease-modifying anti-rheumatic drugs.

Background ACTIVE is the first apremilast (APR) study to demonstrate onset of response to APR starting at Week 2 in biologic-naive subjects with psoriatic arthritis (PsA) who may have had exposure to 1 prior conventional disease-modifying anti-rheumatic drug. Objectives To determine the efficacy and safety of APR through Week 104 in the ACTIVE study. Methods Subjects were randomised (1:1) to receive APR 30 mg BID or placebo (PBO) for 24 weeks; thereafter, all subjects received active treatment with APR. The long-term durability of APR treatment on various PsA manifestations was evaluated. Along with safety data, adverse events (AEs) of diarrhoea were further characterised. Results A total of 219 subjects were randomised (APR: n=110; PBO: n=109); 89% (142/160) of subjects entering year 2 of the study completed the Week 104 visit, and 64.8% (142/219) of randomised subjects completed the Week 104 visit, including 60.9% (67/110) of subjects randomised to APR at baseline. Early onset of response to APR was observed for ACR20 response and improvements in DAS-28 (CRP), HAQ-DI, enthesitis (in subjects with enthesitis at baseline), and morning stiffness severity. With continued APR exposure, the Week 104 ACR20 response rate was 62.9%; ACR50 and ACR70 response rates were 33.3% and 20.1%, respectively. Mean percent change in swollen joint count was −75.9%, and mean percent change in tender joint count was −68.3%. In all, 65.7% of APR subjects with baseline enthesitis reached a Gladman Enthesitis Index score of 0 (table 1). More than half of the APR subjects had improvements in morning stiffness severity. Sustained improvements in physical function were also observed, with a mean change of 5.9 in the SF-36v2 Physical Functioning score and a mean change in HAQ-DI score of −0.37 at Week 104. Safety findings for the APR-exposure period were consistent with previous reports. The most commonly reported AEs (≥5% of subjects) during the APR-exposure period were bronchitis (5.3%), headache (6.3%), hypertension (6.3%), nasopharyngitis (8.3%), upper respiratory tract infection (8.3%), nausea (8.7%), and diarrhoea (16.5%). New incidences of protocol-defined diarrhoea (≥2 watery/liquid stools/day) decreased during long-term APR exposure. Over the APR-exposure period, serious AEs occurred in 7.3% of subjects; 8.3% of subjects discontinued treatment due to an AE. No serious opportunistic infections, including tuberculosis reactivation, or cases of serious depression were seen. Week 52 and Week 104 analyses were data as observed among all subjects who received APR, regardless of when APR treatment started (baseline, Week 16 or Week 24); actual number of subjects may vary for each end point depending on availability of data. *Evaluated in subjects with enthesitis at baseline (Gladman Enthesitis Index score >0). ACR20/50/70=≥20%/≥50%/≥70% improvement in modified American College of Rheumatology response criteria; n/m=number of responders/number of subjects with sufficient data for evaluation; DAS-28=28 joint count Disease Activity Score; CRP=C reactive protein; SF-36v2=36 item Short-Form Health Survey version 2; HAQ-DI=Health Assessment Questionnaire-Disability index; MCID=minimal clinically important differences. Conclusions In biologic-naive subjects treated with APR, early onset of effect was observed across PsA manifestations, including morning stiffness severity and enthesitis, with sustained improvements through Week 104 in the subjects continuing APR therapy. AEs were consistent with those reported for other APR phase 3 PsA and psoriasis studies. Disclosure of Interest P. Nash Grant/research support from: Celgene Corporation, K. Ohson Grant/research support from: Celgene Corporation, J. Walsh Grant/research support from: Amgen, Pfizer, UCB, Celgene Corporation, Novartis, N. Delev Employee of: Celgene Corporation, D. Nguyen Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, M. Paris Employee of: Celgene Corporation, J. Gomez-Reino Grant/research support from: Roche, Schering-Plough, Consultant for: BMS, Pfizer, Roche, Schering-Plough, UCB, J. Aelion Grant/research support from: AbbVie, Ardea Biosciences, AstraZeneca, BMS, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda Pharmaceuticals, UCB, Vertex Pharmaceuticals

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). In a pooled analysis of data from 2 Phase 3 trials in patients (pts) with active PsA, tofacitinib 5 and 10 mg twice daily (BID) significantly improved American College of Rheumatology (ACR) 20 response rates vs placebo (PBO) (50.0, 53.0 vs 28.0%, respectively; p Objectives To compare the efficacy of tofacitinib 5 and 10 mg BID vs PBO in predefined pt subgroups based on differences in BL demographics, disease activity and concomitant medication. Methods This was an analysis of pooled efficacy data from 2 Phase 3, randomised, double-blind, PBO-controlled studies (OPAL Broaden [12 months; NCT01877668] and OPAL Beyond [6 months; NCT01882439]) in pts with active PsA (defined as ≥3 swollen and ≥3 tender joints). Pts in OPAL Broaden were tumour necrosis factor inhibitor (TNFi)-naive with an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Pts in OPAL Beyond had an IR to ≥1 TNFi. Pts were randomised to receive tofacitinib 5 or 10 mg BID, subcutaneous adalimumab 40 mg every 2 weeks (OPAL Broaden; data not included) or PBO. Pts continued to receive a stable dose of a single csDMARD. ACR20 response rates and LSM change from BL in HAQ-DI at Month 3 (primary endpoint data) were evaluated by subgroup category (demographic and disease characteristics at BL or at screening). Analyses were based on the full analysis set (table 1). Results In total, 238, 236 and 236 pts received tofacitinib 5 mg BID, 10 mg BID, or PBO, respectively. Across all subgroups analysed, tofacitinib 5 and 10 mg BID were generally associated with greater improvements at Month 3 in ACR20 and change from BL in HAQ-DI score than PBO (table 1). In pts classified as current smokers, slightly lower ACR20 response rates and similar changes from BL in HAQ-DI score to corresponding PBO at Month 3 were observed relative to never- or ex-smokers; however, the sample size was small. Statistical methods: ACR20 response was defined as achieving a≥20% improvement in ACR criteria components Missing ACR20 response was considered a non-response to treatment LSMs were calculated based on a mixed model for repeated measures without imputation for missing values ACR, American College of Rheumatology; BID, twice daily; BMI, body mass index; BSA, body surface area; CRP, C-reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DSS, Dactylitis Severity Score; HAQ-DI, Health Assessment Questionnaire-Disability Index; LEI, Leeds Enthesitis Index; LSM, least squares mean; MTX, methotrexate; N, number of patients in full analysis set (randomised and received ≥1 treatment dose); n, number of responders; N1, number of patients in the full analysis set by category of subgroup and treatment; N2, number of patients included in the repeated measures model by category of subgroup and treatment; NC, analysis not conducted; PASDAS, Psoriatic Arthritis Disease Activity Score; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; pts, patients; ROW, rest of world (Brazil, Mexico and Taiwan); SPARCC, Spondyloarthritis Research Consortium of Canada (enthesitis index) Conclusions In this analysis of pooled data from 2 Phase 3 studies in pts with active PsA, tofacitinib 5 and 10 mg BID consistently improved efficacy at Month 3 compared with PBO across all predefined subgroups evaluated, with the exception of current smoking; however, as this was not a pre-specified analysis and some subgroups (including smoking status) were small, interpretation should be made with caution. Reference [1] Nash P, et al. Arthritis Rheumatol2017;69(suppl 10):619. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by K Nicholson of CMC and funded by Pfizer Inc. Disclosure of Interest F. Behrens Grant/research support from: AbbVie, Chugai, Novartis, Pfizer Inc, Prophylix, Roche, Consultant for: AbbVie, Biotest, BMS, Celgene, Chugai, Eli Lilly, Genzyme, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, Speakers bureau: AbbVie, Biotest, BMS, Celgene, Chugai, Eli Lilly, Genzyme, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, J. Gomez-Reino Grant/research support from: AbbVie, MSD, Pfizer Inc and Roche, Consultant for: Pfizer Inc, Speakers bureau: AbbVie, Biogen, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc and Roche, P. Nash Grant/research support from: AbbVie, BMS, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, BMS, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, BMS, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, O. FitzGerald Grant/research support from: AbbVie, BMS, Novartis, Pfizer Inc, Consultant for: Amgen, Celgene, Eli Lilly, Janssen, C. Ritchlin Grant/research support from: AbbVie, Amgen and UCB, Consultant for: AbbVie, Amgen, Celgene, Janssen, Novartis, Pfizer Inc, Sun and UCB, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is an oral JAK inhibitor for the treatment of psoriatic arthritis (PsA). Objectives To perform a systematic literature review (SLR) and network meta-analysis (NMA) to evaluate the efficacy of tofacitinib 5 and 10 mg BID relative to biologic disease-modifying antirheumatic drugs (bDMARDs) or a targeted synthetic DMARD (apremilast [APR]) in tumour necrosis factor inhibitor-naive (TNFi-N) patients with active PsA. Methods The SLR identified randomised controlled clinical trials (RCTs) evaluating tofacitinib, bDMARDs or APR to treat patients with active PsA who were TNFi-N. Outcomes included American College of Rheumatology (ACR)20 response and change from baseline in Health Assessment Questionnaire-Disability Index (ΔHAQ-DI), Dactylitis Severity Score (ΔDSS) and Leeds Enthesitis Index (ΔLEI). Treatment effects were only evaluated during placebo (PBO)-controlled trial phases. The Bayesian NMA (with non-informative priors) was conducted using WinBUGs. The binomial logit model was used for ACR20. ΔHAQ-DI, ΔDSS and ΔLEI were analysed using the normal identify link model. A fixed-effect model was fitted to the data. Median treatment rankings represent data from each iteration of the model from which inferences are based, following model convergence. Results The SLR identified 25 RCTs and 21 were included in the NMA (see treatments in table 1). All trials allowed methotrexate use. PBO-controlled treatment durations ranged from 12–24 weeks. In general, patient characteristics were similar across trials. All treatments were associated with improvements in ACR20 and ΔHAQ-DI vs PBO. Tofacitinib 5 mg BID was associated with substantially decreased odds ratios (ORs) for ACR20 vs golimumab 50 and 100 mg Q4W, etanercept 25 mg BW, infliximab 5 mg/kg and secukinumab 150 mg QW-Q4W (table 1); ORs for all remaining comparators were not substantially different. Tofacitinib 10 mg BID was associated with a substantially increased OR for ACR20 vs APR 20 mg BID. Etanercept was associated with an improvement in ΔHAQ-DI vs tofacitinib 5 and 10 mg BID. There was no difference in ΔHAQ-DI for tofacitinib vs other bDMARDs. For ACR20, tofacitinib 5 and 10 mg BID were median ranked 14 (95% credible interval: 8, 17) and 9,5, 14 respectively, among 18 comparators. For ΔHAQ-DI, tofacitinib 5 and 10 mg BID were median ranked 114, 13 and 8,2, 13 respectively, among 14 comparators. Two studies evaluated ΔDSS and ΔLEI; there were no substantial differences in ΔDSS and ΔLEI for tofacitinib 5 and 10 mg BID vs adalimumab 40 mg Q2W and ixekizumab 80 mg Q2W and Q4W. Conclusions Based on the NMA of published RCTs in TNFi-N patients with PsA, tofacitinib 5 and 10 mg BID had similar efficacy vs many, but not all, bDMARDs and APR in improving ACR20 and ΔHAQ-DI. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by P Scutt of CMC and funded by Pfizer Inc. Disclosure of Interest D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, A.-M. Orbai Grant/research support from: Celgene, Eli Lilly, Horizon, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, J. Gomez-Reino Grant/research support from: AbbVie, MSD, Pfizer Inc, Roche, Consultant for: Pfizer Inc, Speakers bureau: AbbVie, Biogen, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc and Roche, S. Chang-Douglass Employee of: Decision Resources Group, E. Leoncini Employee of: Decision Resources Group, H. Burton Employee of: Decision Resources Group, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M.-A. Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Persistence to treatment may be used as a surrogate marker for long-term treatment success Objectives To assess the probability of persistence on golimumab (GOL) up to 5 years after treatment initiation and the factors associated to longer persistence Methods BIOBADASER is the Spanish registry of biological drugs of the Spanish Society of Rheumatology and the Spanish Medicines Agency. A data-base analysis was done in October 2017 on all the patients who had initiated GOL for one of the approved indications (rheumatoid arthritis [RA], axial spondyloarthritis [SpA] or psoriatic arthritis [PsA]). The probability of persistence was calculated with a Kaplan-Meier test. Factors related to persistence were analysed with a Cox-regression model. Results 353 patients were included (105 [29.8%] RA, 147 [30.6%] axial SpA and 101 [28.6%] with PsA), mean age 52 11 years, 55% women). Median duration of disease at the onset of GOL was 8.0 [2.8–15.0] years. GOL was the first biological drug in 40.1% of the patients, second in 30.1% and third or further biological in 29.8%. Concomitant medication at GOL initiation was methotrexate (MTX) (33.7%), sulphasalazine (SSZ) (6.1%), leflunomide (LEF) (12.7%), steroids (CS) (26.0%). At the last observation on GOL, 32.0% were on MTX, 5.8% on SSZ, 12.8% on LEF, 16.3% on CS. The probability of persistence on GOL since treatment initiation was 85.9% at year 1 (95% CI 81.4–89.5), 73.7% at year 2 (67.1–79.1), 68.5% at year 3 (60.5–75.1), 60.6% (50.2–69.5) at year 4% and 57.1% (44.9–67.5) at year 5. Persistence was similar for RA, axial SpA or PsA patients (p log-rank 0.070), and higher when GOL was used as first biological agent (p log-rank Conclusions In patients with RA, axial SpA or PsA, the probability of persistence on GOL after initiation was high. The retention rate was higher both in patients with GOL as first biological drug and in those with concomitant therapy with MTX, and lower in those needing CS. Acknowledgements This study was funded by Merck Sharp and Dohme of Spain Disclosure of Interest None declared

Background Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in childhood. The early disease recognition and treatment is critical to prevent long-term complications and disability in childhood. During the last decade the arrivals of biologics has dramatically changed the prognosis of these patients. A number of well-designed clinical trials, as well as cohort studies have demonstrated that biologics are an effective option for JIA patients who do not respond or cannot tolerate treatment with synthetic disease modifying drugs (DMARDs). JIA is not confined to childhood, and a 41% had active disease are on medication after 30 years and 28% had a high symptom state. Objectives The aim of this work was to study the pattern of use, drug survival and adverse events of biologic therapy in JIA patients during the transition period from the diagnostic to the adulthood. Methods Information was obtained from BIOBADASER, a safety multicenter prospective registry. All patients included in the registry diagnosed of JIA between 2000 and 2015 were analysed. Proportions, means and standard deviations (SD) were used to describe population. Incidence rates and 95% confidence intervals were calculated to assess adverse events. Kaplan-Meier analysis was used to compare the drug survival. Results 469 patients, 46.1% women were included in this study. Age at diagnosis was 9.4 (SD=5.3) and years of disease evolution 24.1 (SD=14.1). The age at biological treatment initiation was 23.9 years (SD=13.9). The pattern of use of biologics in JIA patients in the paediatric age shows a linear increase from 24% in 2000 to 65% in 2014. Interestingly, the biologic suspension for disease remission was higher in patients who initiated its use under 16 years (25.7%) than in those who began at 16 years or later (7.9%, p Conclusions The biologic survival and suspension by remission was higher when the biologic therapy started before 16 years old in JIA patients. The incidence rate severe adverse events in the childhood and adulthood in JIA patients treated with biologics was similar, however, a significant increment of infection was observed in patients under 16 years old. Disclosure of Interest None declared

To demonstrate the efficacy of the anti-interleukin-6 receptor monoclonal antibody tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy (GO).Double-masked randomized clinical trial.Setting and Participants: Thirty-two adults with moderate-to-severe corticosteroid-resistant GO from 10 medical centers in Spain were randomized (1:1).Randomization to either 8 mg/kg body weight tocilizumab or placebo administered intravenously at weeks 0, 4, 8, and 12, and follow-up for an additional 28 weeks. Main Outcomes and Measures: The primary outcome was the proportion of patients with a change from baseline to week 16 of at least 2 in the clinical activity score (CAS).The primary outcome was met by 93.3% (95% confidence interval [CI] 70.1%-98.8%) of the patients receiving tocilizumab and 58.8% (36%-78.3%) receiving placebo (P = .04; odds ratio, 9.8 [CI 1.3-73.2]). A significant difference was also observed in the proportion of patients achieving a CAS3 (86.7% [CI 62.1%-96.2%] vs 35.2% [CI 17.3%-58.7%], P = .005; OR 11.9 [CI 2.1-63.1]) at week 16. Additionally, a larger proportion of patients with improvement in the European Group on GO-proposed composite ophthalmic score at week 16 (73.3% [CI 48%-89.1%] vs 29.4% [CI 13.2%-53.1%]; P = .03), and exophthalmos size change from baseline to week 16 (-1.5 [-2.0 to 0.5] mm vs 0.0 [-1.0 to 0.5] mm; P = .01) were seen with tocilizumab. One patient experienced a moderate increase in transaminases at week 8; another had an acute pyelonephritis at week 32 in the tocilizumab-treated group.Tocilizumab offers a meaningful improvement in activity and severity in corticosteroid-resistant GO. This trial justifies further studies to characterize the role of tocilizumab in GO.

Background: Despite the wide array of treatments available for rheumatoid arthritis (RA), some patients continue to report unmet clinical needs. We investigated the extent of inadequate disease control in patients with RA. Methods: Data were drawn from the Adelphi 2014 RA Disease Specific Program in France, Germany, Italy, Spain and the UK. Rheumatologists provided patient demographics, comorbidities, satisfaction with RA control and other clinical details. Patients reported their level of satisfaction and completed the EuroQoL 5-Dimensions health questionnaire and Work Productivity and Activity Impairment questionnaire. Patients had been on their current therapy ≥3 months and had 28-joint disease activity scores (DAS28) reported. Adequately controlled (DAS28 ≤3.2) and inadequately controlled (DAS28 >3.2) patient cohorts were compared using univariate tests. Results: Of 1147 patients, 74% were female, the mean age was 52 years and the mean time since RA diagnosis was 7 years. Twenty-seven percent of patients had inadequately controlled RA whereas 73% had adequately controlled RA. Inadequately controlled patients were more affected clinically versus adequately controlled patients; 69% versus 13% had moderate/severe RA, the current level of pain was 4.6 versus 2.3, and 67% versus 41% experienced flares, respectively (all p Conclusion: RA was insufficiently controlled in over a quarter of patients despite their current therapy and this had a negative impact on the patients.

Objective The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. Methods Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. Results At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (−1.3 vs −0.9; p

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.

ObjectiveEvaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA.MethodsPatients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52.ResultsAmong 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (PConclusionsIn biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports.Trial registration numberNCT01925768; Results.

Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis.We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759.Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred.Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis.Janssen ResearchDevelopment.

Background The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. Aims To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. Sources Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Content Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti- Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles–mumps–rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. Implications Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

Objetivo Establecer recomendaciones para el manejo de pacientes con artritis reumatoide (AR) centrado en el papel de los farmacos antirreumaticos modificadores de enfermedad (FAME) sinteticos y biologicos disponibles, que sirvan de referencia para todos los profesionales implicados en la atencion de estos pacientes. Metodos Las recomendaciones se consensuaron a traves de un panel de 14 expertos previamente seleccionados por la Sociedad Espanola de Reumatologia (SER). Se recogio la evidencia disponible mediante la actualizacion de las 3 revisiones sistematicas (RS) que se utilizaron para las recomendaciones EULAR 2013, a las que se anadio una nueva RS para dar respuesta a una pregunta adicional. Todas fueron realizadas por miembros del grupo de revisores de la SER. La clasificacion del nivel de la evidencia y del grado de la recomendacion se realizo utilizando el sistema del Centre for Evidence-Based Medicine de Oxford. Se utilizo la metodologia Delphi para evaluar el grado de acuerdo entre los panelistas para cada recomendacion. Resultados Se emiten un total de 13 recomendaciones sobre el manejo terapeutico de pacientes con AR del adulto. El objetivo terapeutico debe ser tratar al paciente en fases precoces de la enfermedad, con el objetivo de la remision clinica, teniendo un papel central el metotrexato como FAME sintetico de referencia. Se actualizan las indicaciones de los FAME biologicos disponibles, se enfatiza la importancia de los factores pronosticos y se incide en el concepto de optimizacion de biologicos. Conclusiones Se presenta la quinta actualizacion de las recomendaciones SER para el manejo de la AR con FAME sinteticos y biologicos.

ObjectivesTo evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.MethodsPhase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).ResultsWe identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15–161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).ConclusionsWithin the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.