Increased risk of adverse events among patients with vs. without systemic autoimmune rheumatic disease prescribed sodium-glucose cotransporter 2 inhibitors: a retrospective cohort study.

BACKGROUND: Systemic autoimmune rheumatic disease (SARD) patients have been excluded from sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials given putative risks, but this risk magnitude is unknown. We aimed to quantify SGLT2i adverse event risks among patients with vs. without SARD.   METHODS: In a retrospective cohort study, patients with SARD at Mass General Brigham, a multihospital system in Boston, Massachusetts, prescribed SGLT2i were age-, self-reported race-, and sex-matched to patients prescribed the same SGLT2i between 1/1/2016 and 12/10/2021. Cumulative incidence and Cox models, overall and sex-stratified, estimated patient-reported adverse event risks from prescription date, censoring for discontinuation, death, or study end (12/12/2022). RESULTS: Four hundred sixty-eight SARD and 420 matched non-SARD patients were compared: mean age 64 years (SD 11.3), 61% female, and 70% White. SARD patients had shorter SGLT2i use duration (8.4 vs. 12.7 months; p < 0.0001) and time to adverse event (0.59 vs. 0.85 years; p 0.04). Yeast infections (9.8% vs. 6.2%; p 0.047) and muscular symptoms (3.4% vs. 1.0%, p 0.01) were more prevalent among those with SARD. Adjusting for baseline demographics, adverse event risk was higher (MV HR 1.68; 95% CI 1.28, 2.21), in patients with vs. without SARD. Risk was higher in women than men overall and in women with SARD vs. without (adjusted HR 1.86; 95% CI 1.36, 2.54). CONCLUSION: Patients with vs. without SARD had 68% higher adverse event risk with SGLT2i use. Women with vs. without SARD had > 85% higher adverse event risks, although most were not serious. Trials of safety and efficacy of SGLT2i among SARD patients are warranted. Key Points •To our knowledge, this is the first study to compare adverse events associated with SGLT2i utilization in patients with vs. without SARD, despite RCT exclusion and documented SGLT2i use in the population. •In our comparison of 468 patients with SARD and 420 patients without, we identified a greater than 65% increase in risk of adverse event outcomes among patients with SARD. •Furthermore, we found that this risk disproportionately affected female patients, with a 4.4-fold increased risk among women with SARD compared to men without.

Cost-Related Medication Behaviors for Patients With and Without Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: Medication nonadherence challenges the management of systemic autoimmune rheumatic diseases (SARDs). We investigated cost-related medication behaviors among patients with SARDs, and compared them to those of patients without SARDs, in a large diverse cohort across the United States. METHODS: As part of the All of Us (version 7), a nationwide diverse adult cohort with linked electronic health records begun in 2017, participants completed questionnaires concerning cost-related medication behaviors. Chi-square tests compared responses between patients with SARDs, by disease and medication type, and to those without SARDs. Logistic regression analyses were used to calculate odds ratios (95% confidence intervals [CIs]). RESULTS: We analyzed data from 3,997 patients with SARDs and 73,990 participants without SARDs. After adjustment, patients with versus without SARDs had 1.56 times increased odds of reporting unaffordability of prescription medicines (95% CI 1.43-1.70), 1.43 times increased odds of cost-related medication nonadherence (95% CI 1.31-1.56), and 1.23 times increased odds of using cost-reducing strategies (95% CI 1.14-1.32). Patients with SARDs who reported unaffordability were 16.5% less likely to receive a disease-modifying drug (95% CI 0.70-0.99) but 18.1% more likely to receive glucocorticoids (95% CI 0.99-1.42). In addition, unaffordability of prescription medicines was likely to have 1.27 times increased odds of one to two emergency room visits per year (95% CI 1.03-1.57) and 1.38-fold increased odds of three or more emergency room visits per year (95% CI 0.96-1.99). CONCLUSION: In this large diverse cohort, patients with versus without SARDs had more self-reported cost-related medication behaviors, and those who reported medication unaffordability received fewer disease-modifying drugs and had more emergency room visits.

Earlier vs. later time period of COVID-19 infection and emergent autoimmune signs, symptoms, and serologies.

OBJECTIVE: Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities. METHODS: Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses. RESULTS: 57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic. CONCLUSION: In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic.

Ultraprocessed Food Intake and Risk of Systemic Lupus Erythematosus Among Women Observed in the Nurses' Health Study Cohorts.

OBJECTIVE: We assessed ultraprocessed food (UPF) intake and systemic lupus erythematosus (SLE) incidence within the prospective Nurses' Health Study (NHS) cohorts. METHODS: A total of 204,175 women were observed (NHS 1984-2016; NHSII 1991-2017). Semiquantitative food frequency questionnaires were completed every two to four years. UPF intake was determined as per the Nova classification. Nurses self-reported new doctor-diagnosed SLE, confirmed by medical records. Time-varying Cox regressions estimated hazard ratios (HRs; 95% confidence intervals [CIs]) for patients with incident SLE and SLE by anti-double-stranded DNA (dsDNA) antibody at diagnosis, according to cumulatively updated daily (a) UPF servings, (b) total intake (in grams and milliliters), and (c) percentage of total intake. Analyses adjusted for age, race, cohort, caloric and alcohol intakes, household income, smoking, body mass index (BMI), physical activity, menarchal age, and oral contraceptive use. We tested for interaction with BMI and examined UPF categories. RESULTS: Mean baseline age was ~50 years (NHS) and ~36 years (NHSII); 93% self-reported White race. A total of 212 patients with incident SLE were identified. SLE risk was higher in the third versus first UPF tertile (servings per day pooled multivariable [MV] HR 1.56, 95% CI 1.04-2.32; P = 0.03). Results were stronger for dsDNA antibody in patients with SLE (servings per day pooled MV HR 2.05, 95% CI 1.15-3.65; P = 0.01) and for absolute (servings or total) than percentage of total intake. Sugar-sweetened/artificially sweetened beverages were associated with SLE risk (third vs first tertile MV HR 1.45, 95% CI 1.01-2.09). No BMI interactions were observed. CONCLUSION: Higher cumulative average daily UPF intake was associated with >50% increased SLE risk and with doubled risk for anti-dsDNA antibody in patients with SLE. Many deleterious effects on systemic inflammation and immunity are postulated.

Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial.

OBJECTIVES: We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. METHODS: Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. RESULTS: Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. DISCUSSION: Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Posttraumatic stress disorder symptoms in systemic autoimmune rheumatic disease patients during the early COVID-19 pandemic.

AIM: Given reports of increased prevalence of PTSD symptoms at COVID-19 pandemic onset, we aimed to assess the prevalence of posttraumatic stress disorder (PTSD) symptoms at pandemic onset in individuals with and without systemic autoimmune rheumatic disease (SARD). METHODS: In May 2020, we invited 6678 patients to complete the Brief Trauma Questionnaire and the Posttraumatic Stress Disorder Checklist (PCL-5), validated PTSD symptom screenings. We compared responses from patients with and without SARD using multivariable logistic regression. RESULTS: We received 1473 responses (22% response rate) from 5/2020 to 9/2021 (63 with prior PTSD diagnoses, 138 with SARD history). The SARD population was more female (p .0001) and had a higher baseline prevalence of stress disorders (56% vs. 43%, p .004). SARD subjects reported more experiences with life-threatening illness, 60%, versus 53% among those without SARD (p .13), and more antidepressant or anxiolytic medication use pre-pandemic (78% vs. 59%, p .0001). Adjusting for pre-pandemic PTSD diagnosis, younger age and history of stress disorder were the most significant predictors of PCL-5 positivity. There were no significant differences in PCL-5 score or positivity among those with or without SARD. CONCLUSION: In this population, patients with SARD had a higher pre-COVID-19 prevalence of stress-related conditions, but it was not the case that they had an increased risk of PTSD symptoms in the early pandemic. Younger individuals, those with baseline depression, anxiety, or adjustment disorders, and those taking antidepressant or anxiolytic medications were more likely to have PTSD symptoms in the first waves of the COVID-19 pandemic.

Over-the-counter fish oil supplementation and pro-resolving and pro-inflammatory lipid mediators in rheumatoid arthritis.

OBJECTIVE: Little is known about the effects of over-the-counter fish oil (FO) supplements on circulating omega-3 polyunsaturated fatty acid (n-3 PUFA)-derived specialized pro-resolving mediators (SPMs), nor about whether having a chronic inflammatory disease such as rheumatoid arthritis (RA) influences SPM levels. We investigated associations between over-the-counter n-3 PUFA FO supplementation and circulating SPMs among patients with vs. without RA. METHODS: We studied 104 participants: 26 with RA taking FO matched by age and sex to 26 with RA not taking FO, 26 without RA taking FO, and 26 without RA not taking FO. Targeted-liquid chromatography-tandem mass spectroscopy was performed on patient plasma to identify and quantify 27 lipid mediators (including eicosanoids and SPMs). We performed t-tests and then multivariable linear regression analyses to assess whether having RA or taking FO supplements was associated with circulating lipid mediator concentrations, adjusting for age, race, sex, smoking, body mass index, and current medication use (statins, prednisone and immunomodulators among RA cases only). We tested for interactions between FO supplementation and RA status. We also conducted Spearman's correlations between EPA, DHA, and ARA and their downstream metabolites. RESULTS: Among patients who were taking FO compared to those who were not, in multivariable- adjusted analyses, SPM substrates EPA and DHA were both elevated as were several of their pro-resolving bioactive products, including 15- and 18-HEPE from EPA, and 14- and 17-HDHA from DHA, which are substrates for specific SPMs. While E-series and D-series resolvins were present and identified, we did not find statistical elevations of other SPMs. Results were similar among patients with RA and patients without RA, taking vs. not taking FO supplementation (no formal statistical interaction observed). There was a strong positive correlation between EPA and DHA and their immediate downstream SPM precursors (18-HEPE and15-HEPE from EPA; 17-HDHA and 14-HDHA from DHA) among all patients. CONCLUSION: Patients taking FO supplements, regardless of RA status, not only had higher blood levels of EPA and DHA, but also of their enzymatic products 18-HEPE (E-series resolvin precursors), 15-HEPE and 17-HDHA (D-series resolvin and protectin precursors). Patients with RA, an inflammatory autoimmune disease, may be able to augment some SPM precursor reserves, similarly to matched controls without RA, by taking oral FO supplements.