Understanding, Diagnosing, and Treating Sjogren Syndrome
Understanding, Diagnosing, and Treating Sjogren Syndrome
Patients with SS have higher risk for lymphoma, which is characterized by antigen driven B-cell lymphoma. Nocturne and colleagues further emphasized the role of A20 protein impairment, which influences NF-k signaling in B cells, in the progression from lymphoproliferation to frank lymphoma. Multiple groups of researchers presented exciting data on the cytokine and chemokine profiles that occur at the level of the salivary gland biopsy and offer new targets for therapy by targeting the T cells, B cells, and dendritic cells that constitute the inflammatory infiltrate. Teos and colleagues reported on changes in acinar cell function in SS. Their study emphasized that the salivary gland is only partially destroyed in SS and that dysfunction of the residual gland is mediated by processes such intracytosolic calcium transport in acinar cells that may result from cytokines released from the lymphoid infiltrates including interleukin (IL)-14, TNF-α, and IL-20.
GWA studies have begun to identify genetic risk loci for SS, such as those conducted by the Sjogren's Genetics Network. Future efforts are being directed at expanding these GWA studies and determining how different risk variants contribute to different clinical manifestations of SS. Alteration of DNA methylation may have an important role in the pathogenesis of primary SS, as reported by Imgenberg-Kreuz and colleagues and Orsia and colleagues. They found that several of the alteration sites identified corresponded to genes involved in viral infection and lymphomas. In another study, Norheim and colleagues noted methylation pattern alterations in the MAP3K5 gene associated with patient-reported fatigue levels. This gene was also associated with innate immune response and apoptotic signaling. In a different session, Gottenberg and colleagues demonstrated that changes in overall metabolism can be detected in SS, most likely representing the increased metabolic activity of the immune system and the response of the target tissues. As with information on genetic risk variants, identification of these metabolic pathways will increase our understanding of the causal mechanisms in the pathogenesis of SS and may also help identify biomarkers and therapeutic targets.
Carsons and colleagues presented clinical practice guidelines for treatment of musculoskeletal pain, fatigue, and the use of biologics. Currently, no biologics are currently approved for use in SS, although certain manifestations of SS, such as arthritis, might fall under approved indications. In Europe, rituximab remains the most widely used biologic, despite not having regulatory approval for SS. Although rituximab has shown benefit in treating extraglandular manifestations, little objective benefit in either tear flow or saliva increase has been observed, except in patients with early onset of disease. Blokland and colleagues reviewed novel targets such CCR9 expressed on follicular T cells and CCL25, a thymus expressed chemokine. This chemokine and its corresponding receptor have shown promising results in early trials of Crohn disease and may be a promising therapeutic target in SS. Nocturne and colleagues noted that other members of the chemokine family, in particular CXCL13 and CCL11, are elevated in serum of patients with high disease activity or lymphoma, suggesting that these are additional potential therapeutic targets.
Potential Therapeutic Targets
Patients with SS have higher risk for lymphoma, which is characterized by antigen driven B-cell lymphoma. Nocturne and colleagues further emphasized the role of A20 protein impairment, which influences NF-k signaling in B cells, in the progression from lymphoproliferation to frank lymphoma. Multiple groups of researchers presented exciting data on the cytokine and chemokine profiles that occur at the level of the salivary gland biopsy and offer new targets for therapy by targeting the T cells, B cells, and dendritic cells that constitute the inflammatory infiltrate. Teos and colleagues reported on changes in acinar cell function in SS. Their study emphasized that the salivary gland is only partially destroyed in SS and that dysfunction of the residual gland is mediated by processes such intracytosolic calcium transport in acinar cells that may result from cytokines released from the lymphoid infiltrates including interleukin (IL)-14, TNF-α, and IL-20.
GWA studies have begun to identify genetic risk loci for SS, such as those conducted by the Sjogren's Genetics Network. Future efforts are being directed at expanding these GWA studies and determining how different risk variants contribute to different clinical manifestations of SS. Alteration of DNA methylation may have an important role in the pathogenesis of primary SS, as reported by Imgenberg-Kreuz and colleagues and Orsia and colleagues. They found that several of the alteration sites identified corresponded to genes involved in viral infection and lymphomas. In another study, Norheim and colleagues noted methylation pattern alterations in the MAP3K5 gene associated with patient-reported fatigue levels. This gene was also associated with innate immune response and apoptotic signaling. In a different session, Gottenberg and colleagues demonstrated that changes in overall metabolism can be detected in SS, most likely representing the increased metabolic activity of the immune system and the response of the target tissues. As with information on genetic risk variants, identification of these metabolic pathways will increase our understanding of the causal mechanisms in the pathogenesis of SS and may also help identify biomarkers and therapeutic targets.
Carsons and colleagues presented clinical practice guidelines for treatment of musculoskeletal pain, fatigue, and the use of biologics. Currently, no biologics are currently approved for use in SS, although certain manifestations of SS, such as arthritis, might fall under approved indications. In Europe, rituximab remains the most widely used biologic, despite not having regulatory approval for SS. Although rituximab has shown benefit in treating extraglandular manifestations, little objective benefit in either tear flow or saliva increase has been observed, except in patients with early onset of disease. Blokland and colleagues reviewed novel targets such CCR9 expressed on follicular T cells and CCL25, a thymus expressed chemokine. This chemokine and its corresponding receptor have shown promising results in early trials of Crohn disease and may be a promising therapeutic target in SS. Nocturne and colleagues noted that other members of the chemokine family, in particular CXCL13 and CCL11, are elevated in serum of patients with high disease activity or lymphoma, suggesting that these are additional potential therapeutic targets.
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