Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.

Headache, cognitive dysfunction and mood disorders are common in both diseases, but otherwise there are distinct differences in NP involvement, with cerebrovascular diseases more prevalent in SLE and neuropathies more common in PSS. This indicates that some NP disease mechanisms are shared while others differ between the two diseases.

Background: Neurological manifestations appear to be frequently involved in patients with primary Sjö gren syndrome (PSS). Objective: To investigate the involvement of the peripheral nervous system, including smalldiameter nerve fibers, in an unselected cohort of patients who fulfilled the new international criteria for PSS.

ObjectivesFatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue.MethodsTwenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4.ResultsThere was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group.ConclusionsThis randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS.Trial registrationClinicalTrials.gov NCT00683345

Background and Aims: The present study investigated the prevalence and severity of fatigue in patients with newly diagnosed and untreated ulcerative colitis (UC) and Crohn's disease (CD) and examined relevant disease variables that may influence the severity of fatigue. Methods: Eighty-one patients with inflammatory bowel disease (IBD) (60 with UC and 21 with CD) were assessed for fatigue using two fatigue instruments: the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (fVAS). Cut-off for fatigue was defined as ≥4 for FSS and ≥50 for fVAS. Results were compared with fatigue scores from age-and gender-matched healthy individuals. Disease activity was assessed by symptom scores using the Mayo score in UC patients and the Harvey-Bradshaw index for CD patients, as well as C-reactive protein (CRP) and faecal calprotectin. Results: The prevalence of fatigue based on FSS and fVAS was 47 and 42%, respectively, in UC and 62 and 48% in CD. In multivariate regression models, disease activity markers were not associated with fatigue, while a significant relationship was found with age and depression for both fatigue measures. Conclusions: Close to 50% of patients with IBD reported fatigue at the time of diagnosis. In newly diagnosed patients with active disease, the severity of fatigue was not associated with measures of disease activity.

We performed a candidate gene association study in 540 patients with primary Sjö gren's Syndrome (SS) from Sweden (n ¼ 344) and Norway (n ¼ 196) and 532 controls (n ¼ 319 Swedish, n ¼ 213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P ¼ 9.9 Â 10 À5 , OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P ¼ 4.7 Â 10 À4 , OR 1.37 and the tumor necrosis factor superfamily (TNFSF4 ¼ Ox40L) gene, P ¼ 7.4 Â 10 À4 , OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

Neuropsychiatric symptoms occur frequently in patients with MS. Irritability and apathy are independent of disability and chronic disease and represent unique disease manifestations.

Sjögren’s syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10−14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10−9; odds ratio = 0.75; 95% confidence interval = 0.66–0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.