Efficacy and safety of abatacept in active primary Sjogren's syndrome:results of a phase III, randomised, placebo-controlled trial

Objectives To evaluate efficacy and safety of abatacept in adults with active primary Sjogren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial. Methods Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjogren's Syndrome Disease Activity Index [ESSDAI] >= 5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored. Results Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI - 3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified. Conclusions Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity

DNA sequence variation and haplotype structure of the ICAM1 and TNF genes in 12 ethnic groups of India reveal patterns of importance in designing association studies

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies

Frequent Deletion and Methylation in SH3GL2 and CDKN2A Loci are Associated with Early- and Late-onset Breast Carcinoma

This study attempts to understand the association of candidate tumour suppressor genes SH3GL2, CDKN2A (p16–p14) and CDKN2B (p15) in development of earlyonset (group A) and late-onset (group B) breast carcinoma (BC). Deletion, methylation, and mutation of the candidate tumour suppressor genes (TSGs) were analysed in 47 group A and 59 group B samples. Immunohistochemical analysis was used to identify the expression status of SH3GL2 and p16. Clinicopathological correlation of the alterations was analysed by the chi-square and log-rank tests. Higher frequency of overall alterations (46–62%) in SH3GL2 and p16-p14 than p15 (22–26%) indicated their importance in BC. Deletion frequencies were in the following order: group A: p14 (43%) > p16 (42%) > SH3GL2 (38%) > p15 (33%) and group B: p14 (36%) > p16 (33%) > SH3GL2 (31%) > p15 (14%) while, methylation frequencies were: group A: SH3GL2 (34%) > p16 (28%) > p14 (26%) > p15 (15%) and group B: SH3GL2 (36%) > p16 (31%) > p14 (29%) > p15 (15%). Infrequent mutation was observed only in CDKN2A common exon-2. Immunohistochemical analysis showed significant association between expression of SH3GL2 and p16 with their deletion (P = 0.01 and 0.02, respectively) and methylation status (P = 0.007 and 0.01, respectively). In group A, overall alterations of SH3GL2 showed significant association with CDKN2A locus with significant prognostic implications, whereas CDKN2A and CDKN2B loci were associated in both groups.The molecular mechanisms involving CDKN2A inactivation seem to follow similar pathway in the pathogenesis of both age groups of BC while significant association of SH3GL2 with CDKN2A might play a synergistic role in the development of group A