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Objective: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS)., Methods: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration., Results: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8 + CD103 + CD69 + cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8 + CD103 + Trm contributed to the secretion of granzyme-B and interferon-γ, CD8 + Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3 + CD8 + SG T cells. In the SG of ESS, CD8 + CD69 + CD103 + Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow., Conclusions: CD103 + CD8 + Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted., Competing Interests: Competing interests: RT has filed provisional patents surrounding technology for targeting DCs for antigen-specific tolerance (US patent 9017697 B2: 2006, PCT/AU2013/000303) and is developing immunotherapy to target DCs to suppress autoimmune disease in collaboration with CSL. AB-M and AB are employees of CSL. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis., Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed., Results: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69)., Conclusions: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs)., Methods: Patients with RA <12 months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy., Results: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events., Conclusions: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: The RCA alpha block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA alpha block haplotype associations with both disease susceptibility and diversification of the anti-Ro/La autoantibody response in primary Sjögren syndrome (pSS)., Methods: 115 patients with pSS and 98 controls were included in the study. 93 of 109 (85%) of the patients with pSS were seropositive for Ro/La autoantibodies. The Genomic Matching Technique (GMT) was used to define RCA alpha block ancestral haplotypes (AH)., Results: RCA alpha block haplotypes, AH1 and AH3, were both associated with autoantibody-positive pSS (p = 0.0003). Autoantibody associations with both HLA DR3 and DR15 have been previously defined. There was an epistatic interaction (p = 0.023) between RCA alpha AH1 and HLA DR3, and this genotypic combination was present in 48% of autoantibody-positive patients with pSS compared with 8% of controls. This epistasis is most simply attributable to an interaction between C4 and its receptor, CR1, encoded within the RCA alpha block. Both DR3 and a relative C4 deficiency are carried on the major histocompatibility complex 8.1 ancestral haplotype. Only four of 92 (4%) autoantibody-positive patients with pSS did not carry any risk RCA alpha or HLA haplotype, compared with 36 of 96 (38%) controls, and there were differences in haplotype frequencies within autoantibody subsets of pSS., Conclusions: Normal population variation in the RCA alpha block, in addition to the major histocompatibility complex, contributes genetic susceptibility to systemic autoimmune disease and the autoantibody response. This finding provides evidence for the role of regulation of complement activation in disease pathogenesis.

Background: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS)., Objective: To examine genetic variation in the promoter region of the Fas gene in pSS., Methods: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls., Results: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04)., Conclusion: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.