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Sjogrens Topics => Useful Links => Topic started by: ashler on May 30, 2015, 09:32:29 AM

Title: Novel therapies based upon pathogenesis
Post by: ashler on May 30, 2015, 09:32:29 AM
pSS has long posed a vexing therapeutic dilemma, as the underlying pathophysiologic mechanisms remain obscure, disease activity is challenging to evaluate, and no specific disease modifying treatments known to be effective are well established. Based upon recent convincing evidence that innate immunity, most notably mediated by INF signaling, plays a role in the initial B-cell activation, interest in B cell targeted therapies has increased worldwide. The B lymphocyte pathogenic axis is targeted by numerous drugs currently in evaluation including Epratuzumab a monoclonal antibody directed at the CD22 B cell surface antigen which may preferentially target auto-reactive B cells. Baminercept, a lymphocytotoxin-beta receptor fusion protein which along with BAFF supports the formation of germinal centers within salivary glands is another molecule that is of interest for SS.[32] Particularly promising in pSS is Belimumab, a monoclonal antibody that targets the BAFF receptor specifically and could disrupt the cycle of B cell activation and antibody production.[50] Belimumab appears to be effective for SLE and is undergoing early stage development for pSS. Potential new cytokine therapeutic targets, have been suggested recently by data implicating pro-inflammatory Th17 cells in SS.[51], [52] and [53] IL-for primary SS was 1.43, whereas carriers of five risk alleles have an OR of 6.78. Since IRF5 and STAT4 are components of the type I IFN system, this data emphasizes the importance of this system in the pathogenesis of primary SS.

Ongoing efforts to define the genetic associations that contribute to altered gene expression patterns are likely to reveal additional genes that explain both commonalities and differences between SS and related disorders. In another recent candidate gene association study, which again followed a lead suggesting an important role for the MECP2 gene in the pathogenesis of SLE, Cobb et al. examined the potential role of MECP2 in pSS. MECP2 is critical in DNA methylation-induced transcription silencing.[49] The gene is present on the ?X? chromosome. In their association study of 460 PSS patients compared to 1828 controls, the rs 1743 allele, which was previously associated with Lupus susceptibility, was shown to have an OR in pSS equal to 1.33. Homozygosity for MECP2 was associated with an additive effect (OR 2.17). The discovery of this gene loci in pSS is particularly interesting in that the association is not dependent on the presence of anti-Ro (SSA) or anti-La (SSB) antibody.[49]

The first genome wide association study to be performed in pSS is currently underway and will undoubtedly provide insight into the genetic architectures of this complex syndrome. In the future, the continuing application of genome-wide technologies is likely to identify new genes and molecular pathways in SS that will be useful not only to identify patients at risk for SS, but also to identify subsets of patients at risk for variable levels of disease severity and different extra-glandular features of the disease such as lymphoma. Despite a similar clinical sicca phenotype at presentation, the two disease subsets(anti-Ro(SSA)/anti-La(SSB) positive and seronegative) have a different longitudinal course and are likely to have partly different molecular increased salivary flow with stimulation, symptomatic oral dryness, fatigue and at least one systemic feature. Given the encouraging efficacy data from open label and two small controlled trials, interest in the use of Rituximab and other B cell directed therapies will continue to grow. Particularly exciting was the study by the group led by Devauchelle-Pensec.[31] Using a gene expression profiling approach to the study of salivary gland tissue before and after treatment of pSS with Rituximab, they identified 8 genes that characterized responsiveness to Rituximab suggesting that it will be possible to stratify patients likely to benefit from specific B cell depleting therapy.[31] This study provides a dramatic demonstration of the potential of gene expression profiling to help us identify how to best target new drugs to the right individuals at the right time.