Efficacy and safety of rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study

Abstract

IntroductionPrimary Sjögren’s syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of disease prognosis. Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX. The aim of this study was to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients.MethodsForty-one patients with early pSS and active disease (EULAR Sjogren’s syndrome disease activity index, ESSDAI ≥ 6) were enrolled in the study. Patients were treated with either RTX or DMARDs in two different Rheumatology centers and followed up for 120 weeks. Clinical assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-reported global disease activity pain, sicca symptoms and fatigue on visual analogic scales, unstimulated saliva flow and Schirmer’s I test at week 12, 24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to week 120. Two labial minor salivary gland (MSG) biopsies were obtained from all patients at the time of inclusion in the study and at week 120.ResultsOur study demonstrated that RTX treatment results in a faster and more pronounced decrease of ESSDAI and other clinical parameters compared to DMARDs treatment. No adverse events were reported in the two groups. We also observed that RTX is able to reduce glandular infiltrate, interfere with B/T compartmentalization and consequently with the formation of ectopic lymphoid structures and germinal center-like structures in pSS-MSGs.ConclusionsTo our knowledge, this is the first study performed in a large cohort of early active pSS patients for a period of 120 weeks. We showed that RTX is a safe and effective agent to be employed in pSS patients with systemic, extra-glandular involvement. Furthermore, our data on pSS-MSGs provide additional biological basis to employ RTX in this disease.

The value of rituximab treatment in primary Sjögren's syndrome

“…Plasma cells are not directly depleted by rituximab, because expression of CD20 is downregulated when B cells differentiate towards plasma cells, but formation of new plasma cells may be impaired by B cell depletion therapy. Although initial studies in pSS showed improvement of both subjective and objective parameters [4][5][6][7], two large placebo-controlled trials [8,9] did not confirm all promising results of the earlier studies. Possible explanations for this discrepancy are heterogeneity in patient characteristics, primary end points and background medication use, which will all be discussed in this review.…”

“…While three studies did not find significant changes in anti-SS-A/Ro or anti-SS-B/La autoantibodies after treatment [7,15,16], we found a significant reduction of ±25% in anti-SS-A/Ro and anti-SS-B/La titers at 16 weeks after treatment (Table 1) [17]. The discrepancy between studies may be explained by differences in study population size, baseline systemic disease activity, time point of measurements, or differences in reliability of the immunoassay, but methods for anti-SS-A/Ro and anti-SS-B/La measurement were not specified in most studies.…”

“…Meijer et al and Carubbi et al showed significant improvement in UWS after rituximab treatment [4,7]. In other trials, including the TEARS trial, no effect on UWS was observed [6,8,11,15].…”

“…Importantly, rituximab clearly reduces the total number and proportion of infiltrating B cells in both minor and major salivary glands (Table 1) [7,25,26]. In addition, as shown in minor salivary gland tissue, rituximab decreases mRNA expression of lymphotoxin (LT)-α and -β, important for lymphoid organogenesis [7].…”

“…Only one out of seven studies showed significant improvement in Schirmer's test after treatment (Table 3) [7]. The TEARS study showed a stable Schirmer's test result in the rituximab group, whereas the placebo group tended to deteriorate [8].…”