Rituximab Therapy for Primary Sjogren's Syndrome: An Open-Label Clinical Trial and Mechanistic Analysis
ABSTRACT OBJECTIVE.: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as investigate its mechanisms. METHODS.: Patients with primary Sjögren's syndrome were enrolled in an open-label trial and received rituximab (1 g) on days 1 and 15 and followed through week 52. The primary endpoint was safety, with secondary endpoints evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibodies and BAFF levels, and analysis of gene expression. RESULTS.: Twelve female subjects with primary Sjögren's syndrome were administered rituximab. They had a median (range) age of 51 (34-69) years and a median (range) disease duration of 8.0 (2-18) years. We observed no unexpected toxicities from 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-muscarinic receptor 3 autoantibodies or in the blood IFN signature. CONCLUSION.: In 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.
- SourceAvailable from: Kenneth Smith
Clinical Immunology 04/2013; 148(1):110-112. DOI:10.1016/j.clim.2013.04.015 · 3.99 Impact Factor
- "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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ABSTRACT: In Sjögren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1(-/-), lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1(+/+) (wild-type) mice, the B6.Aec1Aec2Ifnar1(-/-) (knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.Journal of dental research 03/2013; 92(5). DOI:10.1177/0022034513483315 · 4.14 Impact Factor
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ABSTRACT: Primary Sjögren's syndrome is a systemic autoimmune disease characterized by progressive exocrine gland destruction, resulting clinically in eyes and mouth dryness. To date, no treatment has been proven effective to modify the course of this slow-evolving disease. B cells are now considered to play a central role in the pathogenesis of primary Sjögren's syndrome because their functions are not restrained to antibody production. Thus, several B-cell targeting therapies are under clinical investigation. Rituximab, a monoclonal antibody directed to CD20 and leading to transient blood B-cell depletion, has shown partial improvements in subjective and objective sicca symptoms in small studies. However, the results of two large controlled trials are awaited before considering its use in large populations of patients. Several other therapeutic strategies are being studied, targeting other B-cell surface proteins (epratuzumab and anti-CD22) or major cytokines of B-cell homeostasis (e.g., BAFF, IL-6 and lymphotoxin-β). Although great hope is generated by the trials of these specific therapies, another challenge for clinical researchers is the development of reliable tools to assess the activity of Sjögren's syndrome and its response to treatment.Immunotherapy 06/2013; 5(6):639-646. DOI:10.2217/imt.13.49 · 2.44 Impact Factor