Background/Purpose: Primary Sjögren’s syndrome (pSS) is the second most frequent systemic autoimmune disease affecting 0.1% of the general population. No specific immunomodulatory drug has demonstrated efficacy for this disease, and no biomarker is available to identify patients at risk of developing systemic complications. To enable a precision medicine approach, we explored the molecular stratification of the disease in an unsupervised systems biological manner.

Methods: Blood transcriptomes and genotypes of 351 pSS patients from a multi-center prospective clinical ASSESS cohort were analyzed. Clinical phenotype, immunological profile and yearly follow-up of disease course for 5 years of these patients were carefully assessed. Replication of the transcriptomic results was performed using 3 independent cohorts (n= 523 patients). Circulating IFN-alpha (IFNɑ) and IFN-gamma (IFNγ) protein concentrations were determined using ultrasensitive digital ELISA (SIMOA) and patients were genotyped using Immunochip in the ASSESS cohort.

Results: Transcriptomic analysis of the prospective cohort enabled patient stratification that matched clinical assessments, and showed a strong IFN gene signature in more than half of the patients. This finding was replicated in three independent cohorts. As gene expression analysis did not discriminate between type I and II interferons, we applied digital ELISA to assess serum levels of IFNγ. The IFN transcriptomic signature was regulated by circulating IFNɑ, and not IFNγ, protein levels. 95% of the interferon-inducible genes (1552 genes) were specifically modulated by serum IFNα concentration, while only 7 genes were specifically regulated by serum IFNγ concentration. 70 genes were regulated by both IFNα and IFNγ concentrations (Figure 1).

IFNɑ protein levels, detectable in 75% of patients, were significantly associated with clinical and immunological features of disease activity at enrollment (association with anti-SSA: p= 5.09*10^-28, anti-SSB: p= 2.45*10^-14, RF: R=0.662, p = 1.19 × 10^–41) . At enrolment, the mean ESSDAI was higher (4 [0-31] versus 2[1-18], p=0.0004) in patients with detectable IFNɑ blood levels. During the 5-year follow-up, patients with detectable IFNɑ blood levels more frequently developed systemic complications (OR 1.54 [1.14; 2.13]). Genetic analysis revealed a significant association between a specific MHC-II HLA-DQ locus genotype (HLA-DQA1*05:01 allele), anti-SSA antibody (p=4.31 × 10^–12) and circulating IFNɑ protein (p=1.70 × 10^–8). In multivariate analysis, both HLA DQA1*05:01 and anti-SSA positivity were independently associated with IFNɑ blood concentrations (OR 3.24 [1.78-5.88], p< 0.001, OR 3.08 [1.80-5.29], p< 0.001, respectively). Analyses in healthy controls, and in anti-SSA positive patients using Cytof, suggested that this HLA gene polymorphism acts through upregulation of HLA II molecules on conventional DCs (Figure 2).

Conclusion: This large systems biology analysis emphasizes the crucial role of circulating IFNα in pSS. In addition, we report a new pathogenic mechanism underlying the associations between HLA predisposition, autoantibody production, cytokine secretion and systemic complications of autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systems-biology-in-874-patients-with-primary-sjogrens-syndrome-indicates-the-predominant-role-of-interferon-alpha-compared-to-interferon-gamma-its-association-with-systemic-complications-and-a-new/