J. Sibilia

Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry

Objectives Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice. Methods The Orencia and Rheumatoid Arthritis” (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA. Results 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfill inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p< 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months. Conclusions Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity.

Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab

Objective To assess the association between a single nucleotide polymorphism in the gene of FCGR3A and the response to treatment with rituximab (RTX) in rheumatoid arthritis (RA). Methods SMART is a randomised open trial assessing two strategies of re-treatment in patients responding to 1 g infusion of RTX with methotrexate on days 1 and 15 after failure, intolerance or contraindication to tumour necrosis factor (TNF) blockers. Among the 224 patients included, 111 could be genotyped and were included in an ancillary study of SMART. Univariate and multivariate analyses adjusted on disease activity score on 28 joints were performed to assess whether FCGR3A-158V/F polymorphism was associated with European League Against Rheumatism response at week 24. Results Among the 111 patients, 90 (81%) were responders of whom 30 (27%) were good responders. V allele carriage was significantly associated with a higher response rate (91% of responders vs 70%, OR 4.6 (95% CI 1.5 to 13.6), p=0.006). These results were also confirmed in rheumatoid factor-positive patients (93% vs 74%, p=0.025). In multivariate analysis, V allele carriage was independently associated with response to RTX (OR 3.8 (95% CI 1.2 to 11.7), p=0.023). Conclusion The 158V/F polymorphism of FCGR3A seems to influence the response to RTX in patients with RA after failure, intolerance or contraindication to TNF blockers.

Association between -871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients.

OBJECTIVEnTo determine whether a functional single-nucleotide polymorphism in the B-cell activating factor (BAFF) gene correlates with the response to treatment with rituximab (RTX) in RA.nnnMETHODSnSMART is a randomized open trial (NCT01126541) assessing two strategies of re-treatment in patients responding to 1-g infusion of RTX with MTX on days 1 and 15 after failure, intolerance or contraindication to TNF blockers. Among the 224 patients included, 115 provided informed consent, could be genotyped and were included in an ancillary study of SMART assessing European League Against Rheumatism (EULAR) response rate after the first course of RTX according to BAFF-871C>T polymorphism. Baseline clinical factors (patients and disease characteristics) and biologic factors (ESR, CRP, RF, anti-citrullinated peptide antibodies, serum immunoglobulins) were collected. Univariate analyses were performed to assess whether BAFF-871C>T polymorphism was associated with EULAR response at week 24. Results with P < 0.15 obtained in univariate analyses were then included in multivariate analysis adjusted on DAS28 level.nnnRESULTSnNinety-three patients (81%) were responders, of whom 31 (27%) were good responders. CC genotype was significantly associated with a higher response rate [92% of responders vs 64% for TT genotype, odds ratio (OR) = 6.9; 95% CI 1.6, 29.6; P = 0.03]. These results were also confirmed in RF-positive patients (96% vs 58%, P = 0.006). In multivariate analysis, C allele carriage was independently associated with response to RTX (OR = 4.1; 95% CI 1.3, 12.7; P = 0.017).nnnCONCLUSIONnThe BAFF-871C>T polymorphism seems to influence the response to RTX in RA patients after failure or intolerance to TNF blockers.

OP0035 Tolerance of Rituximab, Abatacept and Tocilizumab in Common Practice: Analysis of the 3 Registries of the French Society of Rheumatology (Air, Ora and Regate)

Objectives To perform a joint analysis of the safety of abatacept (ABA), rituximab (RTX) and tocilizumab (TCZ) in real life. Methods The AIR, ORA and REGATE French Society of Rheumatology registries follow up prospectively patients with rheumatoid arthritis treated with RTX, ABA or TCZ. The analyses took into account serious infections that occurred in the 12 months that followed an infusion of rituximab in the absence of initiation of a new biologic or those who occurred under abatacept or tocilizumab or in the 3 months that followed their discontinuation, in the absence of initiation of a new biologic. Serious infections and cancers were validated by the review of the charts of patients. Results 1980 patients treated with RTX (current follow up of 6844 patient-years), 1024 patients with ABA (2882 patient-years), and 1503 patients with TCZ (1552 patient-years) (database of January 2013 for RTX and ABA and August 2013 for TCZ). – Serious infections: 309 serious infections occurred under RTX (4.5 serious infections/100 patient/years). 102 serious infections occurred under ABA (3.5 serious infections/100 patient/years). 55 serious infections occurred under TCZ (5.2 serious infections/100 patient/years). 3 tuberculosis infections (0.04/100 patient/years) occurred under RTX, 2 (0.07/100 patient/years) under ABA and no tuberculosis under TCZ. – Cancers: 85 cancers occurred under RTX (1.2/100 patient-years) including 14 non-melanoma skin cancers (0.2/100 patient/years), 71 solid cancers and haematological malignancies (1.0/100 patient/years) including 8 haematological malignancies (0.1/100/patient/years with 1 lymphoma).40 cancers occurred under ABA (1.4/100 patient/years) including 13 non-melanoma skin cancers (0.5/100 patient/years), 27 solid cancers and hematological malignancies (0.9/100 patients/year) including 4 haematological malignancies (0.14/100 patient/years, without lymphoma). 10 cancers were observed under TCZ (1.0/100 patient/years) including 2 non melanoma skin cancers (0.19/100/patient/years) 8 solid cancers and haematological malignancies 0.8/100 patient/years) including 3 haematological malignancies (0.29/100 patient/years) with 3 lymphomas. Conclusions Incidences of serious adverse events in real life patients with comorbidities were similar under ABA, RTX and TCZ to what is expected in rheumatoid arthritis treated with anti-TNF. With ABA, RTX and TCZ, the incidence of tuberculosis is low. Adjusted statistical comparisons of safety, efficacy and drug retention rate of these 3 biologics are currently performed. Disclosure of Interest None declared

THU0173 Retention Rates of Adalimumab, Etanercept and Infliximab as First and Second-Line Biologic Therapy in Patients with Rheumatoid Arthritis in Daily Practice: The Maintain Study

Background Efficacy and safety of TNFα inhibitors (TNFi) in rheumatoid arthritis (RA) have been evaluated in randomized controlled trials. The analysis of observational studies and registries provides additional real-world information. Drug survival rate reflects the real world balance between efficacy and safety. Objectives The primary objective of this study was to compare the retention rates (RR) of adalimumab (ADA), etanercept (ETN) and infliximab (IFX) as 1st-line biologic therapy in RA. The secondary objectives were to determine causes of discontinuation, factors associated with a better retention, and RR of 2d-line TNFi. Methods This is a retrolective, multicentre study in 8 French Rheumatology centres. The medical charts of all pts with RA who started TNFi therapy between March 1st 2005 and April 30th 2009 were reviewed, based on diagnosis and treatment (TT) codes, with a follow-up duration of min. 2 to max. 6 yrs. The RR was estimated using the Kaplan-Meier method. TNFi were compared after adjusting the inverse of a propensity score, using a Cox model. Factors associated with a better RR were identified by multivariate analysis. Results 706 pts were included in the study. The first TNFi was ADA in 203 (28.8%), ETN in 404 pts(57.2%) and IFX in 99 pts (14%). The percentage of pts still on TT after 2 yrs was 54.9%, 61.9% and 48.7% for ADA, ETN and IFX respectively. The median duration of trt was 31 mths for ADA (95% CI [19-38]), 45 mths for ETN (95% CI [35-51]) and 23 mths for IFX (95% CI [16-36]). The Hazard ratios (HRs) for discontinuing the first TNFi were significantly greater with ADA and IFX than with ETN (1.315, 95% CI [1.050-1.648] and 1.380, 95% CI [1.041-1.828] respectively). There was no significant difference between the 2 monoclonal antibodies. The HR for TT discontinuation due to lack of efficacy was significantly higher with ADA than ETN (1.511, 95% CI [1.152-1.982]). The HR for stopping trt due to adverse events was significantly higher with IFX than ETN (2.175 (95% CI [1.402-3.374]). Baseline characteristics associated with a better retention of the first TNFi were a higher number of previous DMARDs and a higher ESR. A second TNFi was administered to 231 pts: ADA in 105, ETN in 106, and IFX in 20 pts. The median retention period was 11 mths for ADA (95% CI [7-17]), 43 mths for ETN (95% CI [19.1-58]), and 19.1 mths for IFX (95% CI [5-NE]). The HR for discontinuing ADA was significantly greater than for ETN (2.023, 95% CI [1.393-2.937]). The HRs for stopping due to lack of efficacy or adverse events (AE) were significantly greater for ADA than for ETN (1.998, 95% CI [1.321-3.024] and 2.188, 95% CI [1.017-4.708] respectively). Conclusions ETN had a better RR as a first-line biotherapy in RA, with a HR for discontinuing ADA or IFX that was about 30% greater than that of ETN. As first-line biologic therapy, ETN had fewer withdrawals for inefficacy than ADA, and fewer withdrawals for AE than IFX. As a 2d-line TNFi, ETN also had a better RR than ADA. Disclosure of Interest A. Frazier-Mironer Consultant for: Pfizer, A. Cantagrel Grant/research support from: Chugai, Pfizer, UCB, Consultant for: Laboratoires BMS, Chugai, MSD France, Novartis, Pfizer, Roche, UCB, Speakers bureau: Laboratoires Abbott, BMS, Chugai, MSD France, Nordic-Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, B. Combe Grant/research support from: Pfizer, Roche, Chugai, Consultant for: BMS, Celgene, Merck, Novartis, Pfizer, Roche, Chugai, UCB, Speakers bureau: Merck, Pfizer, UCB, V. Deschamps Employee of: PFIZER, M. Dougados Grant/research support from: Pfizer, Abbott, Roche, BMS, Merck, Lilly, Novartis, Consultant for: Pfizer, Abbott, Roche, BMS, Merck, Lilly, Novartis, R.-M. Flipo Grant/research support from: Pfizer, Roche, Chugaï, Consultant for: Abbott, Astra-Zeneca, BMS, Ipsen-Ménarini, MSD, Pfizer, Roche, Chugaï, UCB, Janssen-Cilag, Paid instructor for: Abbott, Astra-Zeneca, BMS, Expansciences, Ipsen-Ménarini, MSD, Nordic-Pharma, Pfizer, Roche, Chugaï, Genzyme, UCB, I. Logeart Employee of: Pfizer, X. Mariette Consultant for: BMS, Pfizer, Roche et UCB, T. Schaeverbeke Consultant for: Roche, Chugai, Pfizer, J. Sibilia Grant/research support from: Roche, Pfizer, Merck Sharp, Bristol Myers Squibb, Speakers bureau: Roche, Chugai, Bristol Myers Squibb, Abbott, UCB, GSK, LFB, Actelion, Pfizer, Merck Sharp, Novartis, X. Le Loët Consultant for: MSD, Pfizer, Roche

OP0237 Polymorphisms of Gene Implicated in Type 1 Interferon Pathway Are Associated with The Clinical Response of Rituximab at 24 Weeks in Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) treatment may target B-cells using rituximab (RTX), a chimeric monoclonal antibody directed against the B-cell marker CD20. Transcriptome of PBMCs from RA patients before RTX has suggested that responders differs from non-responders on the expression of genes regulated by type 1 interferon (IFN) (1) suggesting a possible contribution of type 1 IFN pathway genes such as interferon regulatory factor 5 (IRF5), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4), osteopontin (SPP1) and interferon regulatory factor 7 (IRF7). Objectives To study 8 IRF5, TYK2, STAT4, SPP1 and IRF7 variants as candidate predictors of the clinical response to RTX in RA at 6 months defined by a good or moderate EULAR response. Methods Patients from the SMART study who signed consent for genetic studies were included (2). The association between the EULAR response at 24 weeks and the polymorphism of the 8 chosen SNPs was analyzed by logistic regression. Response rates were compared across risk genotypes using the χ2 test or the Fisher exact test, when appropriate. Significant variables after univariate regression (P<0.15) were entered into a stepwise multivariate model adjusted to the sex, the age and the DAS28-CRP score. Results Among the 115 included patients, 92 were women, mean age was 56 years, 93 patients were anti-CCP positive. At M6, 30 patients were considered as good responders (26.1%), 62 as moderate responders (53.9%) and 22 as non-responders (19.1%). Univariate analysis showed that IRF5 rs2004640 was significantly associated with a good/moderate EULAR response at week 24 (P=0.038) whereas IRF7 rs1131665 and SPP1 rs9138 were near statistical significance (P=0.092 and P=0.089, respectively). Since it was previously reported an association between TNFSF13B (the gene coding the BAFF cytokine) rs9514828 and RTX response in RA in the same cohort (2), this variant was also included in the multivariate analysis. The multivariate analysis with logistic regression analysis including IRF5, SPP1, IRF7 and TNFSF13B revealed that a genotypic combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate response to RTX at M6: P=9.34x10–6, OR =11.37 [4.03–35.28] with a PPV of 91% and a NPV of 53% (Fig. 1). Conclusions We found an association between a combination of type 1-interferon genes and response to RTX treatment in RA. To further validate the magnitude of the association detected an independent replication in a larger cohort is required. If validated, our model could be helpful before the decision of initiating RTX in RA. References Vosslamber S, et al. Ann Rheum Dis 2011. Ruyssen-Witrand A, et al. Rheumatology 2013. Acknowledgement Unrestricted grant from Roche-Chugai and SFR Disclosure of Interest None declared

SAT0044 Five-Year Favourable Outcome of Patients with Early Rheumatoid Arthritis in the 2000S: Data from the Espoir Cohort

Objectives To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify predictive factors of outcome. Methods Patients were recruited if they had early arthritis of less than 6 months’ duration, a high probability of developing RA, and had never been prescribed DMARDs or steroids. Patients were followed every 6 months during the first 2 years, then every year. Logistic regression analysis was used to determine predictive factors of outcome. Results 813 patients were included from December 2012 to april 2005: age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, DAS28 5.1 ± 1.3, HAQ 1.0 ± 0.7; 44.2 and 38.8% had IgM Rheumatoid Factor or anti-CCP2 antibodies; 22% had hands or feet erosions; 78.5% fulfilled the ACR/EULAR criteria for RA at baseline and 93.8% during follow-up. 573 patients were evaluated at 5 years. The outcome was mild for most patients: disease activity (median DAS28 2.5) and HAQ (median 0.3) were well controlled over time; 47.6% achieved DAS28 remission and 64.6% low disease activity in the first 2 years. Radiographic progression was low (2.9 Sharp unit / year). Only a few patients required joint surgery, but some developed new co-morbidities (eg, hyperlipemia, cardiovascular diseases). During the 5 years, 82.7% of patients had received at least one DMARD (methotrexate: 65.9%) usually as monotherapy, 18.3% a biological DMARD, and about 60% prednisone at least once (mean dosage 8.8 ± 7.7 mg/day). Anti-CCP2 antibodies was the best predictor of 5-year remaining in the cohort, prescription of synthetic or biologic DMARDs, and radiographic progression. Conclusions The generally good 5-year outcome of this cohort could be related to early referral, early effective treatment and close monitoring which are key processes in the management of early RA in daily practice. Disclosure of Interest B. Combe: None Declared, N. Rincheval: None Declared, J. Benessiano: None Declared, F. Berenbaum: None Declared, A. Cantagrel: None Declared, J.-P. Daures: None Declared, M. Dougados: None Declared, P. Fardellone: None Declared, B. Fautrel: None Declared, R.-M. Flipo: None Declared, P. Goupille: None Declared, F. Guillemin: None Declared, X. Le Loet: None Declared, I. Logeart Employee of: Pfizer, X. Mariette: None Declared, O. Meyer: None Declared, P. Ravaud: None Declared, A. Saraux: None Declared, T. Schaeverbeke: None Declared, J. Sibilia: None Declared

FRI0246 Serious infusion-related reactions after rituximab in patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry

Objectives To evaluate the prevalence of serious infusion-related reactions after rituximab (RTX) in a large prospective registry of patients with rheumatoid arthritis. Methods The Autoimmunity and Rituximab registry (AIR) is an independent registry promoted by the French Society of Rheumatology that included 1983 patients with rheumatoid arthritis treated with rituximab and followed-up prospectively for seven years. An infusion-related reaction (IRR) was defined as occurring during or in the 24 hours following an infusion. Results Overall, 45 IRR resulted in RTX discontinuation [2.2% of all patients with RA, 0.4% of all infusions]. These serious IRR occurred after the first cycle in 17 patients, the second cycle in 18, the third cycle in 7, the fourth cycle in 2 patients and after the fifth cycle in 1 patient. Serious IRR mainly occurred after the first infusion of the cycle (71% of the 45 IRR vs 39% after the second infusion). 32 patients (73%) had allergic or anaphylactic manifestations such as a skin rash (18 patients), a throat irritation (8 patients), an anaphylaxis (3 patients), a bronchospasm (2 patients) or an angioedema (1 patient), 5 (11%) hypertension, 3 patients (7%) fever, 4 patients (8.5%) other symptoms and 1 missing data. Among the 30 patients who had a serious IRR after the second or subsequent infusions, 15 (50%) had previously had a milder IRR requiring a transient interruption or a reduction in the infusion flow. There was no fatal infusion-related reaction, and all infusion-related reactions resolved after discontinuation of RTX and symptomatic treatment. Conclusions The real life frequency of IRR resulting in RTX discontinuation is similar to that observed in clinical studies, approximately 0.5 %. Allergic manifestations were the most frequent. These reactions mainly occurred during the first two cycles, but nearly a quarter of them occurred after the 3d or subsequent cycles. Last, severe reactions had been preceded by a milder infusion reaction to a former infusion in 50% of patients Disclosure of Interest: None Declared

FRI0247 Serum level of interleukin 33, a novel independent predictive biomarker of clinical response to rituximab in rheumatoid arthritis: results from the smart trial

Background Interleukin-33 (IL33) is a recently identified member of the interleukin-1 family that binds to its ST2 receptor expressed on various cells including mast cells, T-cells and also B1-cells in mice (1). IL-33 may activate B-cell, immunoglobulin secretion (IgA and IgG) and induce immunoglobulin class switching. We previously demonstrated in a whole-blood transcriptomic analysis performed in 69 patients (pts) with rheumatoid arthritis (RA) included in the SMART trial that baseline IL-33 mRNA upregulation was associated with subsequent clinical response to rituximab (RTX) (2). Objectives To investigate whether baseline serum level of IL-33 may predict response to RTX in RA. Methods Before treatment, serum level of IL-33 using ELISA and of B-cell activation biomarkers (rheumatoid factor [RF], anti-CCP antibodies, free light chains, IgG, IgA, IgM, and BAFF levels) were assessed in 205 RA pts participating to the SMART study and treated by a first course of RTX (1g day 1 and 15). Association between IL-33 level and RA features were determined. Results are presented in median and interquartiles. Uni and multivariate (clinical features, auto-antibodies status and IL33 level) analyses were performed to identify factors associated with a EULAR response at 24 weeks. Results Serum IL-33 level was higher in pts with anti-CCP (anti-CCP+: 359 [87; 1619] vs anti-CCP-: 102 [39; 368]; p=0.001) and in those with RF (RF+: 365 [95; 1677] vs RF-: 131 [38; 602]; p=0.001). IL-33 level was not modulated by anti-TNF prior exposure (n=140) or current steroid use (n=161) (anti-TNF +: 216 [73; 978] vs anti-TNF -: 359 [78; 1874] pg/mL; NS) and steroid +: 254 [70; 1348] vs steroid -: 258 [79; 1345] pg/mL; NS). Serum IL-33 level was not correlated to DAS28-CRP (r=-0.04; NS). There were 146 (71%) responders (i.e. 44 good and 102 moderate). IL-33 level was associated with EULAR response (IL33 level: 361 [87; 1654] vs 131 [46; 475] pg/mL in responders and non responders to RTX, respectively; p=0.006). After adjustment on baseline DAS28-CRP, multivariate analysis indicated that IL33 level was independently associated with subsequent response to RTX (OR [95% CI]: 1.3 [1.02; 1.6]), as well as the presence of anti-CCP antibodies or RF (OR [95% CI]: 2.7 [1.2; 6.0]). The combination of the 2 parameters further increased the likelihood of response. Conclusions Serum IL33 level is increased in RA pts with anti-CCP and/or RF. Moreover, we confirm our transcriptomic analysis and demonstrate for the first time that serum IL-33 level represents a novel simple useful biomarker predicting clinical response to RTX, independently of auto-antibodies status, which usually displays a strong impact on rituximab response. The role of the IL-33/ST2 axis in B-cell immunopathology in RA needs to be further addressed. References Komai-Koma M et al. J Immunol 2011;186:2584-91 Sellam et al ACR congress 2011 Disclosure of Interest: J. Sellam Grant/research support from: Roche, S. Rouanet Employee of: Roche, H. Hendel-Chavez: None Declared, S. Marion-Thore: None Declared, C. Miceli-Richard: None Declared, B. Combe Grant/research support from: Roche, J. Sibilia Grant/research support from: Roche, X. Le Loët Grant/research support from: Roche, J. Tebib Grant/research support from: Roche, G. Chiocchia: None Declared, R. Jourdan Employee of: Roche, M. Dougados Grant/research support from: Roche, Y. Taoufik: None Declared, X. Mariette Grant/research support from: Roche