Improvement of Sjögren's syndrome after two infusions of rituximab (anti‐CD20)

Abstract

Objective. There is evidence to support a dominant role for B cells in the pathophysiology of primary Sjö gren's syndrome (SS). Therefore, we evaluated the safety and efficacy of anti-CD20 monoclonal antibody.

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS)

“…In particular, further recruitment of B cells into the SG with higher degrees of lymphoid organization of ectopic GCs could be observed over 48 weeks in the placebo arm, associated with the increase in transcriptomic signatures critical for B and T cell recruitment, activation, and costimulation, which was efficiently prevented by rituximab. These findings are in line with the existing evidence that rituximab reduces the total number of SG-infiltrating B cells, both in LSGs [28][29][30][31] and parotid SGs, 32,33 despite the different rituximab dosage and administration regimen. This observation should prompt a rethinking of the notion that SG immunopathology is stable over time 34 and focus the longitudinal assessment of SGs in clinical trials both in terms of amelioration from baseline but also lack of progression.…”

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS)

“…In particular, further recruitment of B cells into the SG with higher degrees of lymphoid organization of ectopic GCs could be observed over 48 weeks in the placebo arm, associated with the increase in transcriptomic signatures critical for B and T cell recruitment, activation, and costimulation, which was efficiently prevented by rituximab. These findings are in line with the existing evidence that rituximab reduces the total number of SG-infiltrating B cells, both in LSGs [28][29][30][31] and parotid SGs, 32,33 despite the different rituximab dosage and administration regimen. This observation should prompt a rethinking of the notion that SG immunopathology is stable over time 34 and focus the longitudinal assessment of SGs in clinical trials both in terms of amelioration from baseline but also lack of progression.…”

BAFF‐modulated repopulation of B lymphocytes in the blood and salivary glands of RITUXIMAB‐TREATED patients with Sjögren's syndrome

“…B cell depletion was defined as a reduction in the proportion of CD19+ cells to <0.1% of circulating lymphocytes. In PB, B cells started to decline during the first week of treatment, as reported previously (23). On day 8, B cells dropped to 0.0% in 12 patients, 0.4% in 1 patient, 0.7% in 1 patient, and 4.2% in 1 patient.…”

Potential of epigenetic therapies in non-cancerous conditions

“…In the same study, an in vitro co-culture experiment showed that DNA hypomethylation in SGECs may be in part due to B cells causing alterations to the PKCδ/Erk/DNMT1 pathway. Therefore, the authors concluded that infiltrating B cells may be contributing to the demethylation process—congruent to the findings from an older study that showed that SS patients treated with rituximab (an anti-CD20 antibody that depletes B cells) led to higher global DNA methylation levels after 4 months of drug administration ( Devauchelle-Pensec et al, 2007 ).…”

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS)

“…In particular, further recruitment of B cells into the SG with higher degrees of lymphoid organization of ectopic GCs could be observed over 48 weeks in the placebo arm, associated with the increase in transcriptomic signatures critical for B and T cell recruitment, activation, and costimulation, which was efficiently prevented by rituximab. These findings are in line with the existing evidence that rituximab reduces the total number of SG-infiltrating B cells, both in LSGs [28][29][30][31] and parotid SGs, 32,33 despite the different rituximab dosage and administration regimen. This observation should prompt a rethinking of the notion that SG immunopathology is stable over time 34 and focus the longitudinal assessment of SGs in clinical trials both in terms of amelioration from baseline but also lack of progression.…”

BAFF‐modulated repopulation of B lymphocytes in the blood and salivary glands of RITUXIMAB‐TREATED patients with Sjögren's syndrome

“…B cell depletion was defined as a reduction in the proportion of CD19+ cells to <0.1% of circulating lymphocytes. In PB, B cells started to decline during the first week of treatment, as reported previously (23). On day 8, B cells dropped to 0.0% in 12 patients, 0.4% in 1 patient, 0.7% in 1 patient, and 4.2% in 1 patient.…”

Potential of epigenetic therapies in non-cancerous conditions

“…In the same study, an in vitro co-culture experiment showed that DNA hypomethylation in SGECs may be in part due to B cells causing alterations to the PKCδ/Erk/DNMT1 pathway. Therefore, the authors concluded that infiltrating B cells may be contributing to the demethylation process—congruent to the findings from an older study that showed that SS patients treated with rituximab (an anti-CD20 antibody that depletes B cells) led to higher global DNA methylation levels after 4 months of drug administration ( Devauchelle-Pensec et al, 2007 ).…”

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS)

“…In particular, further recruitment of B cells into the SG with higher degrees of lymphoid organization of ectopic GCs could be observed over 48 weeks in the placebo arm, associated with the increase in transcriptomic signatures critical for B and T cell recruitment, activation, and costimulation, which was efficiently prevented by rituximab. These findings are in line with the existing evidence that rituximab reduces the total number of SG-infiltrating B cells, both in LSGs [28][29][30][31] and parotid SGs, 32,33 despite the different rituximab dosage and administration regimen. This observation should prompt a rethinking of the notion that SG immunopathology is stable over time 34 and focus the longitudinal assessment of SGs in clinical trials both in terms of amelioration from baseline but also lack of progression.…”

BAFF‐modulated repopulation of B lymphocytes in the blood and salivary glands of RITUXIMAB‐TREATED patients with Sjögren's syndrome

“…B cell depletion was defined as a reduction in the proportion of CD19+ cells to <0.1% of circulating lymphocytes. In PB, B cells started to decline during the first week of treatment, as reported previously (23). On day 8, B cells dropped to 0.0% in 12 patients, 0.4% in 1 patient, 0.7% in 1 patient, and 4.2% in 1 patient.…”

Potential of epigenetic therapies in non-cancerous conditions

“…In the same study, an in vitro co-culture experiment showed that DNA hypomethylation in SGECs may be in part due to B cells causing alterations to the PKCδ/Erk/DNMT1 pathway. Therefore, the authors concluded that infiltrating B cells may be contributing to the demethylation process—congruent to the findings from an older study that showed that SS patients treated with rituximab (an anti-CD20 antibody that depletes B cells) led to higher global DNA methylation levels after 4 months of drug administration ( Devauchelle-Pensec et al, 2007 ).…”