To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms.
Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression.
Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature.
In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.
"Subjects with primary SjS, as defined by the revised American-European Consensus Group criteria, were enrolled in an open-label Autoimmunity Centers of Excellence-sponsored clinical trial of the B cell-depleting antibody, rituximab (anti-CD20). Clinical features of the study subjects have been described previously . Subjects received two 1-gram doses of rituximab and 100 mg of methylprednisolone on days 0 and 15. "
[Show abstract][Hide abstract] ABSTRACT: Subjects with primary Sjogren's Syndrome (SjS) have an increased risk of developing B cell lymphoma and may harbor monoclonal B cell expansions in the peripheral blood. Expanded B cell clones could be pathogenic, and their persistence could exacerbate disease or predispose towards the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B cell clones in the blood of subjects with primary SjS who were treated with rituximab.
To determine if circulating B cell clones in subjects with primary SjS emerge or remain following B cell depleting therapy with rituximab, we studied the antibody heavy chain repertoire. We performed single memory B cell and plasmablast sorting and antibody heavy chain sequencing in six rituximab-treated SjS subjects over a one-year follow-up period.
Expanded B cell clones were identified in four out of the six rituximab treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH and JH gene segments. We identified one SjS subject with a large expanded B cell clone that was present prior to therapy and persisted following therapy. Somatic mutations in the clone were numerous, but did not increase in frequency over the course of the one-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection.
For some subjects with primary SjS, these data show that: 1) expanded B cell clones are readily identified in the peripheral blood; 2) some clones are not eliminated by rituximab, and 3) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B cell populations in humans.
"Although few data are present in the literature to date, evidence from both open-label studies and randomized clinical trials provide the clue that RTX is effective in reducing different disease manifestations of pSS patients, such as sicca symptoms, extraglandular manifestations, fatigue and improving saliva production and eventually HR-QoL [28,30,31,36,38-40]. "
[Show abstract][Hide abstract] ABSTRACT: Primary 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.
Forty-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.
Our 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.
To 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.
"Considering known treatments   (see Fig. 1 for possible areas for intervention), while belimumab (anti-BLyS) is a promising new treatment for SLE; it is unclear whether or not it alters the clonal turnover presented in this work. Rituximab (anti-CD20) has no effect on antibody secreting cells, and although it may cause the death of precursor memory cells, it may not be effective at reducing the amount of autoantibody and has shown only modest clinical impact in Sjögren's syndrome to date . Epratuzumab (anti-CD22) has been shown to be efficacious in 50% of trial participants with primary Sjögren's in a small phase I/II open label study  and may help to reduce auto-stimulation of memory cells. "
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