Oklahoma Medical Research Foundation Oklahoma City, OK, United States
Astrid Rasmussen1, R. Hal Scofield2, Kiely Grundahl1, Lida Radfar2, Christopher Lessard1 and A. Darise Farris1, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, 2University of Oklahoma Health Sciences Center, Oklahoma City, OK
Background/Purpose: Metformin (dimethyl biguanide, Met) is a widely used, first-line antidiabetic drug with AMPK-dependent anti-inflammatory and immunomodulatory effects. In vitro studies and human trials in SLE and multiple sclerosis have shown that Met associates with reduced Th17 cells, IL-17, IL-1b, IL-6, IFN-g, and TNF-a, while restoring or increasing regulatory T-cells (Treg). Sjögren's Disease (SjD) is a systemic autoimmune disorder characterized by autoantibody production and lymphocytic infiltration of the exocrine glands. In SjD, T cells participate in target organ inflammation and promote B cell activation; it has been proposed that an imbalance between pro-inflammatory Th17 and Tfh cells and their regulatory counterparts, Treg and Tfr cells, is a key component of pathogenesis. A study of an SjD mouse model treated with Met showed improved salivary gland function and re-establishment of the T cell equilibrium. Based on this premise, we reviewed the potential impact of Met on SjD in a large cohort.
Methods: The clinical and serologic features of patients meeting the ACR-EULAR classification criteria for SjD in the OMRF SjD cohort were retrospectively reviewed. Cases were defined as SjD diabetic patients treated with Met (SjD-Met) at the time of evaluation (n=31). The comparison groups were 1) SjD non-diabetic, not on Met matched by age, sex, and race 1:4 to the cases (SjD-match, n=124); 2) SjD diabetic patients not treated with Met (SjD-DM-notMet, n=59); 3) All diabetic SjD, irrespective of treatment (SJD-DM, n=84); and 4) All non-diabetic SjD in the cohort (SjD-nonDM, n=375).
Results: 459 participants that met SjD classification had sufficient data for analysis. No significant differences in sociodemographic features were observed across groups. SjD-Met subjects had lower rates of (+) Schirmer's and OSS than SjD-match (OR 0.40, p=0.028; and OR 0.24, p=0.004, respectively). Interestingly, while no differences were observed in salivary flow, SjD-Met also showed significantly lower focus scores on salivary gland biopsy than SjD-match (1.88±1.32 vs. 3.26±2.91, p=0.0002). This pattern persisted when SjD-Met was compared to SjD-DM-notMet but the effects disappear when comparing all diabetics to non-diabetics so this seems directly associated with Met. The differences that could be attributed to diabetes, since they were observed when comparing all diabetics (irrespective of treatment) to non-diabetics, were lower salivary flow volumes and higher ESR in SjD-DM. No differences were identified in disease activity, autoantibodies, complement, or immunoglobulin levels. Limited ESSPRI data precluded drawing conclusions despite a consistent trend toward lower ESSPRI scores in the SjD-Met group.
Conclusion: Our retrospective study shows that SjD patients receiving Met have lower rates of abnormal ocular tests (Schirmer's and OSS) and less extensive focal lymphocytic infiltration of the minor salivary glands (Focus Score) than their counterparts not on Met. These results justify the design of prospective, randomized, double-blind control trials of Met, an accessible and safe drug for SjD, a disease with great unmet therapeutic needs.
Disclosures: A. Rasmussen, None; R. Scofield, None; K. Grundahl, None; L. Radfar, None; C. Lessard, Janssen; A. Farris, Janssen.
