OP0065 Tolerance and efficacy of rituximab in primary sjogren syndrome (TEARS): Results of a randomized controlled trial

Abstract

Background Current pharmacological treatments can improve the sicca symptoms but they are unable to modify the course of of primary Sjogren’s syndrome (pSS). There is evidence for a critical role of B cells in the pathogenesis of pSS. Both open labelled and small controlled studies suggested the efficacy of Rituximab (RTX) in specific subgroups of pSS. Objectives We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of RTX in a large group of patients with active primary Sjögren’s syndrome (pSS). Methods 122 Patients were assigned to receive either RTX infusions (1g) or placebo (P) at weeks 0 and 2. They were followed up for 24 weeks. All patients fulfilled the new American-European Consensus Group criteria for pSS, had an active disease as assessed by mean values of the 2 highest visual analog scales (VAS) ≥50 evaluating dryness, pain, fatigue and global (disease activity assessed by the patient), and had either a recent (less than 10 years since first clinical sign) and a biologically active pSS [Auto antibodies (SSA or RF) or cryoglobulinaemia, or hypergammaglobulinaemia, or high level of beta 2-microglobulinemia or hypo-complementaemia] or at least one extra-glandular manifestation. The primary end point was an improvement of at least a 30 mm on 2 of 4 VAS between weeks 0 and 24. Secondary end points included values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, Schirmer test, the focus score on labial salivary gland biopsy, biological and extra glandular improvement evaluated from baseline to week 24. Results 24 of 122 patients (19.5%) had a recent pSS without systemic symptoms, 67 (54.9%) had a recent pSS with systemic signs and 31 (25.4%) had a chronic systemic pSS. Concerning systemic manifestations, 33 (28%) had pulmonary involvement, 63 (53%) articular involvement and 34 (28.5%) parotidomegaly. 113 patients had an evaluation at week 24. 11/53 (20.7%) patients receiving P and 13/60 (21.7%) treated with RTX had a favourable overall response (P=0.9). The 30 points VAS improvement for fatigue and sicca were numerically better in the RTX than in the P group [11/60 (18%) vs 5/53 (9%) (p: 0.16) and 15/60 (25%) vs 6/53 (11%) (p:0.06), respectively] but the differences did not reach significance. 9/54 (16.7%) and 9/61 (14.7%) were considered as improved by physicians in P and RTX group, respectively. The two groups did not differ in term of salivary unstimulated flow rate improvement in both recent and chronic pSS. Conclusions This randomized, double blind, placebo controlled study suggest that the efficacy of RTX is not sufficient enough to allow its prescription in a large population of pSS. Further studies are needed to select which subgroups may justify this treatment. Disclosure of Interest V. Devauchelle-Pensec Speakers Bureau: Roche, X. Mariette Consultant for: Roche, Speakers Bureau: Roche, S. Jousse-Joulin: None Declared, J.-M. Berthelot: None Declared, A. Perdriger: None Declared, E. Hachulla Consultan...

Rituximab Therapy for Primary Sjögren's Syndrome: An Open‐Label Clinical Trial and Mechanistic Analysis

“…Previous studies have investigated the potential clinical efficacy and safety of rituximab therapy for primary Sjögren’s syndrome (6–9), but they too are limited by their small sample size, open-label design in some cases, and the lack of standardized treatment outcomes. These results are consistent with those reported in an abstract describing the results of a 122-patient, randomized, placebo-controlled study of rituximab therapy in primary Sjögren’s syndrome (34). In this study, rituximab therapy was not significantly more effective than placebo in improving by 30 mm or more at least two of the four 100 mm VAS scales evaluating dryness, pain, fatigue, and global disease activity.…”

“…The results of the present study are consistent with those of a 122‐patient, randomized, placebo‐controlled study of rituximab therapy in primary Sjögren's syndrome, which was reported in the form of an abstract (33). In that study, rituximab therapy was not significantly more effective than placebo in improving by ≥30 mm the scores on at least 2 of the 4 100‐mm VAS scales evaluating dryness, pain, fatigue, and global disease activity.…”

“…In addition to detailed studies of blood B cell subsets, exploratory analyses of gene transcripts and pathways in the peripheral blood suggest rituximab therapy substantially alters B cells, while having little impact on the IFN signature. Larger randomized placebo‐controlled clinical trials such as those reported by Devauchelle‐Pensec and colleagues (33) are needed to further evaluate the clinical efficacy and safety of rituximab therapy for primary Sjögren's syndrome.…”

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)

“…The objective is to select the patients who are most likely to benefit from the treatment in order to increase the chances of demonstrating treatment efficacy. For biologics or immunosuppressants, they might be a combination of factors, such as the inclusion of patients with active systemic complications, very early and/or biologically active disease 16 30. An alternative, or complementary, approach is to require a minimal ESSDAI score, such as moderate activity threshold (ESSDAI≥5), to ensure inclusion of patients with active disease.…”

Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)

“…This observation has some major implication for the conduct of clinical trials, particularly when assessing the effect of immunosuppressive therapy. First, this might explain why previous trials failed to demonstrate any effect of immunosuppressive or biologic treatments 18 19. Also, when evaluating such treatments, it might be preferable to assess its effect on the systemic manifestations for which it has been prescribed.…”