D. Titton

Registro brasileiro de biológicos: processo de implementação e resultados preliminares do BiobadaBrasil

OBJETIVOS: O presente estudo teve por objetivo descrever o processo de implementacao de um registro nacional em um pais em desenvolvimento (Brasil) e relatar os principais resultados preliminares do registro BiobadaBrasil. MATERAL E METODOS: Atraves de um acordo com a PANLAR, o protocolo Biobadaser foi utilizado como modelo para a implementacao de um novo registro no nosso pais. Durante os dois primeiros anos desse esforco, o protocolo original foi adaptado, traduzido e apresentado a todos os reumatologistas brasileiros. Durante dez meses, dados de 1.037 pacientes (750 tratados com biologicos e 287 controles) de 15 centros foram coletados. RESULTADOS: A maioria dos pacientes tinha artrite reumatoide (AR) (n = 723). Infliximabe foi o agente anti-TNF mais usado, e a exposicao total a biologicos foi 2.101 pacientes-ano. A razao mais comum para suspensao da droga foi ineficiencia ou perda de efetividade (50%), e 30% dos pacientes interromperam o tratamento devido a eventos adversos. Tres casos de tuberculose foram observados no grupo biologico, representando maior incidencia do que aquela da populacao brasileira geral. Infeccoes foram observadas em 23% dos pacientes do grupo biologico, sendo o trato respiratorio superior o local mais comumente afetado. Apenas um caso de hanseniase tuberculoide foi observado. Nenhuma morte nem malignidade atribuivel ao efeito dos medicamentos foi observada ate fevereiro de 2010. CONCLUSOES: A implementacao do registro foi bem sucedida. Embora recente, o registro BiobadaBrasil ja forneceu importantes dados.

Incidence of tuberculosis among patients with rheumatoid arthritis using TNF blockers in Brazil: data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas – BiobadaBrasil)

OBJECTIVES To assess the incidence of tuberculosis and to screen for latent tuberculosis infection among Brazilians with rheumatoid arthritis using biologics in clinical practice. PATIENTS AND METHODS This cohort study used data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil), from 01/2009 to 05/2013, encompassing 1552 treatments, including 415 with only synthetic disease-modifying anti-rheumatic drugs, 942 synthetic DMARDs combined with anti-tumor necrosis factor (etanercept, infliximab, adalimumab) and 195 synthetic DMARDs combined with other biologics (abatacept, rituximab and tocilizumab). The occurrence of tuberculosis and the drug exposure time were assessed, and screening for tuberculosis was performed. STATISTICAL ANALYSIS Unpaired t-test and Fishers two-tailed test; p<0.05. RESULTS The exposure times were 981 patient-years in the controls, 1744 patient-years in the anti-TNF group (adalimumab=676, infliximab=547 and etanercept=521 patient-years) and 336 patient-years in the other biologics group. The incidence rates of tuberculosis were 1.01/1000 patient-years in the controls and 2.87 patient-years among anti-TNF users (adalimumab=4.43/1000 patient-years; etanercept=1.92/1000 patient-years and infliximab=1.82/1000 patient-years). No cases of tuberculosis occurred in the other biologics group. The mean drug exposure time until the occurrence of tuberculosis was 27(11) months for the anti-TNF group. CONCLUSIONS The incidence of tuberculosis was higher among users of synthetic DMARDs and anti-TNF than among users of synthetic DMARDs and synthetic DMARDs and non-anti-TNF biologics and also occurred later, suggesting infection during treatment and no screening failure.

BiobadaBrasil: Brazilian biologic registry

109 Rev Bras Reumatol 2011;51(2):109-112 In this volume, the article Brazilian Biologic Registry: BiobadaBrasil implementation process and preliminary, the authors described the implementation of the registry “Monitoring the Brazilian Registry of Biological Therapies in Rheumatic Diseases – BiobadaBrasil” promoted by the Brazilian Society of Rheumatology (BSR), and presented data from the first ten months of the study providing this registry available to all rheumatologists and the Brazilian Society. The registry implementation was a proposal from the “First Forum of New Resources Rheumatology”, held in Sao Paulo in July 2007, to create a national database of biological agents. Afterwards, a contract was signed with the BSR, PANLAR and Spanish Society of Rheumatology (SSR) in order to participate in BIOBADAMERICA in November of that year. This action was the result of the vision of President of SBR (2006-08), Fernando Neubarth, that participate in a registry already consolidated as BIOBADASER and rely on its support and advice would facilitate the implementation and consolidation of the Brazilian registry. Using a simple online platform makes this registry accessible to all study centers with internet access and all rheumatologists interested in participating. The implementation process is described in the article, with a training phase, the BiobadaBrasil I, with the system and documents adaptation from Spanish to Portuguese, staff training, and gradual implementation. In April 2009, it was officially presented in the “XX Brazilian Conference Rheumatology” in Natal, and rheumatologists were invited to participate. Throughout this period, the study was presented and discussed in all SBR events and its disclosure was made at the company website and magazine. The President of BSR (2008-10), Ieda Laurindo, actively supported the study, encouraged and guided the implementation team, and was the main responsible for implementing the study in 23 centers and including 1,037 patients until February 2010. BiobadaBrasil: Brazilian Biologic Registry

AB0232 Disease activity state in patients with rheumatoid arthritis included in the biobadabrasil registry

Objectives to analyse disease activity of RA patients at the start of treatment with a biologic agent (adalimumab, infliximab, certolizumab, etanercept, golimumab, abatacept, rituximab and tocilizumab -bDMARDs), target (tofacitinib-tsDMARDs) therapy or conventional DMARDs (comparison cohort of RA patients – csDMARDs). Methods BiobadaBrasil is a prospective observational cohort study, part of an international initiative (biobadaAmerica) in collaboration with BiobadaSeR; established in 2009, is an ongoing study supported by the Brazilian Society of Rheumatology (29 public centres located at academic instituitions and 2 in private practice) focused on the study of adverse events in patients on biologic therapy. Additionally, by decision of its investigators, disease activity scores were also recorded at the beginning of each treatment. Sex, age, disease duration, RA -DAS-28, concomitant treatments at baseline were collected. Results expressed in mean ±SD,%(n) Results -Data from 1984 RA patients (67% on ts/bDMARDs) were analysed: 86% of the patients were women; mean age=56.6±14.95 years; disease duration=14.4±9.42; 87% RF positive. There were 3802 treatment courses, 67% with aTNF (Adalimumab-ADA, Certolizumab-CTZ, Etanercept-ETA, Golimumab-GOL, Infliximab-INFL), 33% non-aTNF (Abatacept-ABA, Rituximab-RIT, Tocilizumab-TCL) including Tofacitinib-TOF. The table 1 below depicted the medications prescribed at the initiation of a new treatment course:Abstract AB0232 – Table 1 n courses ADA(855) CTZ(85) ETA(708) GOL(113) INFL(772) ABA(163) RIT(184) TCL(192) TOF(70) cDMARDs(660) DAS28 5.1±1.6 4.9±1.5 5.1±1.6 4.9±1.7* 5.3±1.6 5.3±1.4 5.3±1.6 5.4±1.4* 5.3±1.3 5.2±2.8 CE (%) 58 76 60 61 58 68 74 71 83 78 MTX (%) 55 57 53 56 59 54 51 62 49 83 LFN (%) 27 42 27 31 23 31 25 18 27 45 Chlor (%) 14 15 11 10 15 11 19 17 11 30 Considering the more recent medications patients beginning TCL have more active disease than the ones beginning GOL and CTZ (p<0,006); anti-TNF are prescribed in association with MTX in less than 60% of the treatments. Extensive use of corticosteroids was identified besides consistent use of leflunomide and of hydroxychloroquine. Starting of new treatments was related to moderate/high levels of disease activity. Conclusions patterns of bDMARDS, csDMARDS and corticosteroid use clearly surfaced. Possibilities of improvement can be addressed. Acknowledgements for data monitoring P Cabral; contributing to BiobadaBrasil registry, R. Giorgi, H. Pereira, M. Scheinberg, F. Sztajnbok, W. Vieira Disclosure of Interest None declared

FRI0195 Switching from anti-TNF To Non anti-TNF Therapy Yield Better Survival in Rheumatoid Arthritis (RA): Results from Brazilian Register of Biological Agents in Rheumatic Diseases – Biobadabrasil

Background There are few studies evaluating switching strategies of biological therapy in RA1. Survival studies are indirect evidence of treatment efficacy and safety besides being an useful tool to evaluate switching options in the real life2. Objectives To compare the survival of different strategies of switching to a second biological therapy. Methods Data from a population-based cohort including 1,109 RA patients biological therapy were analyzed at baseline (beginning of the first biologic therapy) up to 7 years (2009–2015). Sex, age, disease duration, DAS-28 and concomitant treatments at baseline were recorded. Kaplan-Meier estimates, Chi-square, Kruskal-Wallis and Wilcoxon-Mann-Whitney tests, Cox regression analysis were applied when appropriate. Results expressed in mean±SD, % (n). Small sample precluded golimumab (GOL) and certolizumab (CER) from the survival analysis. Results 85% of the patients were women; mean age=50.10±11.81yrs; 86,56% rheumatoid factor positive. At baseline, mean DAS28=5.36±1.35; 77% receiving methotrexate, 78% prednisone, and 40% leflunomide. Regarding biological therapy, 32.1% (356) started with infliximab (INF), 33.36% (370) with adalimumab (ADA), 23.26% (258) with etanercept (ETA), 4.33% (48) with rituximab (RTX), 3.15% (35) with tocilizumab (TOC), 1.26% (14) with abatacept (ABA), 1.70% (19) with GOL and 0.81% (09) with CER. 32.28% (358) switched to second biological therapy. Of those, 65.92% (236) switched from anti-TNF to anti-TNF (INF=33, ETA=105, ADA=83) vs 27.93% (100) from anti-TNF to non anti-TNF (RTX=38, TOC=32, ABA=30), 6.13% from non anti TNF to anti-TNF (n=15) or to non anti-TNF (n=7). Discontinuation of first anti-TNF therapy was due to inefficacy (57%, n=134), adverse effects (31%, n=73) or other (12%, n=29). Better switching strategy was from anti-TNF to non-anti-TNF: 50.72±3.00 (95%CI 44.84,56.60) vs 44.67± 2.46,(95%CI 39.85,49.49)months; p=0.010. Patients that switched to TOC were using less corticosteroid, had higher DAS28 at baseline, and yield better survival (55.80±4.74 95%CI 46.51,65.09 months, p=0.029) as second biological therapy compared to ETA (50.06±3.61 95%CI 42.99–57.14), RIT (47.75±4.93 95%CI 38.10,57.40), ABA (44.89±5.94 95%CI 33.25,56.53), ADA (39.45±3.89 95%CI 31.83,47.08), and INF (34.43±4.65 95%CI 25.31,43.55). Conclusions Switching from anti-TNF to non anti-TNF therapy seems to be a better option in the treatment of RA patients. Tocilizumab showed a better survival as second biological therapy, especially in severe disease. References Emery P, et al. Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previus TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study. Ann Rheum Dis 2015;74:979–984. Chatzzidionysiou K, et al. Effectiveness of TNF inhibitor switch in RA: results from the national Swedish register. Ann Rheum Dis 2015;74:890–896. Disclosure of Interest None declared

THU0631 Incidence of Serious Adverse Events in Patients with Rheumatoid Arthritis Exposed To Biologic Therapies. Results from Biobadabrasil Registry

Background The safety profile of biologic drugs might have substantial regional differences. Since 2009, the Brazilian Society of Rheumatology runs BiobadaBrasil, a registry for monitoring of biologic therapies in rheumatic diseases, in collaboration with other Latin America countries (BiobadaAmerica) and with Biobadaser Objectives To report the incidence of serious adverse events (SAE) in Rheumatoid Arthritis (RA) patients exposed to biologic drugs in Brazil Methods BiobadaBrasil counts on thirty two centers, from almost all Brazilian states, that prospectively include patients with active rheumatic diseases who started a biologic drug or a synthetic DMARD as a parallel control group. A constant three level monitory of data quality is maintained (online, by phone and “in situ”). This study focuses on SAE (for definition: Protocolo 1.1 at https://biobadaser.ser.es/biobadamerica/Brasil/cgi-bin/upload/documentacion.aspx) in RA patients exposed to biologics from January 2009 to June 2015. Time of exposure was set from start of the drug to the date of last administration or censorship. Continuous variables were expressed as mean with standard deviation (SD). SAE incidence rate was calculated per 1000 patient/years with 95%CI Results Out of a total of 1649 subjects with RA, 1121 were exposed to biologics (4735 p/y), 91% a-TNFs, follow-up 2.8 (2.2) yrs, 85% females, at baseline: age 50 (14) yrs, disease duration 9 (8) yrs, DAS28 5.4 (1.4). Controls were 528 (1971 p/y), follow-up 3.6 (2.2) yrs, 86% females, at baseline: age 54 (13) yrs, disease duration 6 (8) yrs, DAS28 5.1 (3.1). The incidence rates of SAE in the biologics and control groups were 86 [78, 94] vs 34 [27, 44] (ratio 2.5 [1.9, 3.3], p<0.001). There was no statistical difference in SAE incidence between a-TNFs and non-a-TNF biologics. Among a-TNFs, Adalimumab was associated with less SAE (64 [53,79]) compared with Etanercept (93 [77,113] p<0.01) and Infliximab (102 [86,122] p=0.0003). SAE were more frequent with subsequent a-TNF than with the first, 107 [87, 132] vs 79 [70, 90] (ratio 1.4 [1.1, 1.7] p=0.0078). Among SAEs with biologics, serious infections account for half of the events (43 [37–49]) Conclusions In the BiobadaBrasil registry the incidence of SAE is 2 fold higher with biologics than with synthetic DMARDs, and higher with subsequent a-TNF than with the first Acknowledgement for data monitoring P Cabral, for contributing to BiobadaBrasil registry, L.Barbosa, W.Chahade, A.Hayata, A.Kakehasi, M.Pinheiro, A.Ranzolin, M.Scheinberg, F.Sztajnbok, I.Silveira Disclosure of Interest None declared

SAT0586 Herpes Zoster in The Brazilian Register -Biobadabrasil

Background Herpes Zoster has been reported with increased frequency in association with rheumatic diseases and biologic therapy. Objectives To study herpes zoster (HZ) in patients with rheumatic diseases included in the Brazilian Register for monitoring of biologic therapies in rheumatic diseases - BiobadaBrasil, Methods BiobadaBrasi is a prospective observational cohort study, part of an international initiative (biobadaAmerica) in collaboration with BiobadaSer. Patients with rheumatic diseases are enrolled at the moment of introduction of their first biologic therapy; a comparison cohort of patients with active RA receiving traditional disease-modifying antirheumatic drugs (DMARDs) was recruited in parallel in each center. This register was established in 2009 and is an ongoing study ran by the Brazilian Society of Rheumatology comprising 32 centers (30 public, located at academic centres, 2 private) in almost all states of the country. Data quality is under constant monitoring (online, by phone and “in situ”). In this report all biologic administered to more than a hundred patients were included: abatacept, adalimumab, etanercept, infliximab, rituximab and tocilizumab. Data was expressed as mean (SD); crude incidence rates (IR) were calculated as number of HZ episodes per 1000 patient-years- IR (1000 patient-years). Results Up to January 2016, 2715 patients were included in the register, 70% female, mean age 51 (14.3) yrs, submitted to 3770 treatments; 1721 patients with diagnosis of RA;

Drug survival and causes of discontinuation of the first anti-TNF in ankylosing spondylitis compared with rheumatoid arthritis: analysis from BIOBADABRASIL

54 with AS and APs=181. 61 HZ episodes were related including only one relapse reported in a 44years-old female patient with AR and in use of rituximab. The crude IR (95% CI) of HZ in the study population (biologic agentes) was 8.3 (1000 patient-years) vs 4.45 (1000 patient-years) in the control population (traditional DMARds), (p=0,7 95%CI-3,7–4,7). Only 6 cases were considered severe by the investigators, two of them were HZ ophthalmicus, one periorbital and all lead to some impairment. These patients were taking different biologic agents (etanercept, adalimumab, infliximab – 2 patients) and one was using traditional DMARDS. Treatment with steroids (HR 1.99; 95%CI 1.092–3.6) was the only factor associated with zoster development. There was no difference in age, sex, specific disease or biologic agent associated with HZ episodes. Conclusions In our database, the risk of HZ was significantly increased in association with corticosteroid treatment but neither with biologic agents nor with inflammatory rheumatic diseases. Acknowledgement for monitor P Cabral, for contribution to the BiobadaBrasil registry, L.Barbosa, W.Chahade, A.Hayata, A.Kakehasi, M.Pinheiro, A.Ranzolin, M.Scheinberg, F.Sztajnbok, I.Silveira Disclosure of Interest None declared