P. Ravaud

Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study

BACKGROUNDnIncreased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögrens syndrome (pSS).nnnOBJECTIVESnTo evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS.nnnMETHODSnPatients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögrens syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values.nnnRESULTSnAmong 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögrens Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögrens Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmers test did not change.nnnCONCLUSIONSnThese encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial

Objectives To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). Methods Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40u2005mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7u2005mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1u2005mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). Results Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). Conclusions In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1u2005mg/kg of corticosteroids at 6u2005months. Clinical trial registration number NCT00305539.

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.

Efficacy of rituximab in primary Sjögren's syndrome with peripheral nervous system involvement: results from the AIR registry

Objective To evaluate rituximab (RTX) in primary Sjögrens syndrome (pSS) with peripheral nervous system (PNS) involvement. Methods Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. Results 17 patients (age 60 years (44–78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1–5) to 2 (1–5), 2 (1–5) and 2 (1–6) after 3, 6 and 9 months (p=0.02). European Sjögrens Syndrome Disease Activity Index decreased from 18 (10–44) to 11 (5–20), 11 (5–29) and 12 (5–30) after 3, 6 and 9 months (p<0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögrens Syndrome Disease Activity Index scales decreased significantly in group 1. Conclusion RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.

European League Against Rheumatism Sjögren's Syndrome Disease Activity Index and European League Against Rheumatism Sjögren's Syndrome Patient‐Reported Index: A Complete Picture of Primary Sjögren's Syndrome Patients

The European League Against Rheumatism (EULAR) Sjögrens Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient‐Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients symptoms differed between patients with and without systemic involvement and if the disease‐specific indices correlated with each other in primary SS.

Efficacy and safety of belimumab given for 12 months in primary Sjögren’s syndrome: the BELISS open-label phase II study

OBJECTIVEnTo report the efficacy and safety of long-term treatment of SS with belimumab, targeting the B-cell-activating factor.nnnMETHODSnPatients with primary SS were included in the BELISS open-label phase II study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received belimumab, 10 mg/kg i.v., at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Efficacy and safety were analysed during the 1-year period of treatment.nnnRESULTSnAmong the 30 patients recruited, 28 were evaluated at week 28 as already reported. Nineteen terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28. Thirteen of the 15 responders at week 28 also responded at week 52 (86.7%). The improvement in the EULAR Sjögrens Syndrome Disease Activity Index and EULAR Sjögrens Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjögrens Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmers test and the focus score of salivary biopsy did not change. Safety of treatment was good.nnnCONCLUSIONnLong-term treatment with belimumab may be beneficial in SS. Randomized, double-blind, controlled studies in larger populations are encouraged.

Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry.

We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care.

OP0217 Defining Disease Activity Sates and Minimal Clinically Important Improvement (MCII) with the EULAR Primary SjÖGren's Syndrome Disease Activity Index (ESSDAI)

Objectives To determine disease activity levels and clinically important changes with the recently developed and validated [1] EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI), and to assess their relevance for conducting clinical trials. Methods Patients from 2 large prospective cohorts (EULAR [multicenter international] n=395, ASSESS [multicenter French] n=395), have been followed for 6 months and 1 year, respectively. Physician completed ESSDAI, evaluated disease activity according to a 4 point scale, and assessed if the patients were in minimal disease activity (MDA). A ROC curve analysis and an anchoring method using MDA definition was used to determine disease activity levels of ESSDAI. At follow-up visit, physicians assessed whether disease activity has improved or not. An anchoring method based on this evaluation of change was used to estimate the minimum clinically important improvement (MCII) of ESSDAI. Data from recent clinical trials evaluating biologics [2-4] were used to assess the relevance of these thresholds. Results According to data from the 2 cohorts, low (ESSDAI <5), moderate (5 ≤ ESSDAI ≤13) and high (ESSDAI≥14) activity levels were defined. Fifty-four and 37% of patients from EULAR and ASSESS real life cohorts and 70 to 77% of patients from recent trials had at least moderately active disease (ESSDAI≥5). The MCII of the ESSDAI was defined as an improvement of at least 3 to 4 points. Based on recent trial data, the cutoff of 3 could be retained, because it was the best to discriminate between patients from placebo and treated arms. Conclusions In conclusion, this study, involving 2 independent large cohorts of primary SS patients allows determining disease activity levels and clinically relevant changes with ESSDAI. We hope that the results of this study will help to conduct more effectively clinical trials for evaluation of biologics in primary SS. Our proposal is to use the threshold of moderate activity as entry criteria (patients with ESSDAI≥5), and to define response to treatment as a significant improvement of ESSDAI (at least 3 points). References Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjogrens syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2014. Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjogrens syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 2013. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjogrens syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960-8. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Tolerance and efficacy of Rituximab in primary Sjögrens syndrome (TEARS): Results of a randomized controlled trial. Ann Rheum Dis 2012;71:75. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4399

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

THU0392 Efficacy and Safety of Belimumab Given for 12 Months in Primary sjögren's Syndrome: The Beliss Open-Label Phase II Study

Background Belimumab, a monoclonal antibody against BAFF registered for the treatment of systemic lupus erythematosus (SLE), was recently employed in primary SS in the BELISS trial (1), with encouraging results reported at 6 months of treatment. Objectives To report the efficacy and safety of long term treatment of Sjögrens syndrome (SS) with belimumab, targeting the B-cell activating factor. Methods Patients with primary SS were included in this 1-year open-label trial if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. Efficacy and safety were analyzed during the 1-year period of treatment. Limitedly to the Italian BELISS protocol, to evaluate a possible delayed response, treatment with belimumab could be also continued up to W48 if both the clinician and the patient agreed to complete the study despite the lack of response at W28, but in the absence of clinical worsening or side effects. A final evaluation was scheduled at W52. Response was defined as the improvement in at least 2 of the 5 following items: ≥30% reduction in dryness score on a visual analogue scale (VAS), ≥30% reduction in fatigue score on a VAS, ≥30% reduction in musculoskeletal pain score on a VAS, ≥30% reduction in systemic activity score on a VAS assessed by the physician, and/or ≥25% reduction in serum levels of any of the following B-cell activation biomarkers (free light chains of immunoglobulin, beta2-microglobulin, immunoglobulin monoclonal component, cryoglobulins, IgG) or ≥25% increase in C4 level. Results Nineteen out of 30 patients terminated the 52-week study, 15 of them being responders while 4 non-responders at W28. Thirteen of the 15 responders at W28 also responded at W52 (86.7%). Overall, fatigue, and pain appeared to improve with time from W28 to W52, although without any statistical significance, while dryness symptoms remained stable. However, a significant improvement in the physician VAS systemic activity score was recorded (3.2±1.2 at W28 vs. 2.5±1.1 at W52; p=0.04). In the 15 responders at W28, the ESSDAI was 7.5±4.0 at baseline, 3.9±3.1 at W28 (p<0.0001 vs. baseline), with a trend of further improvement at W52, i.e., 3.1±3.2 (p<0.0001 vs. baseline). In the same 15 responders, the ESSPRI was 6.0±1.0 at baseline, 4.5±1.8 at W28 (p=0.003 vs. baseline), and 4.3±2.3 at W52 (p=0.01 vs. baseline) (p=0.7, between W28 and W52). A moderate disease activity (i.e., an ESSDAI score ≥5) was observed in 5/15 (33.3%) patients at W52 vs. 6/15 (40%) at W28 and vs. 10/15 (66.7%) at baseline. Decreases of B-cell biomarkers observed at W28 persisted unchanged until W52, with the exception of the rheumatoid factor, which appeared to further decrease [64.8±78.7 IU/mL at baseline, 51.1±56.8 IU/mL at W28 (p=0.028, W28 vs. baseline) and 42.6±47.3 IU/ml at W52 (p=0.048, W52 vs. baseline)]. The safety of treatment was good at W52. Conclusions Long-term treatment with belimumab may be beneficial in SS. Randomised, controlled studies in larger populations are encouraged. References Mariette X, et al. Ann Rheum Dis 2013. Disclosure of Interest None declared