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.

Association of Healthy Lifestyle Behaviors and the Risk of Developing Rheumatoid Arthritis Among Women.

OBJECTIVE: To investigate whether a healthy lifestyle, defined by a healthy lifestyle index score (HLIS), was associated with rheumatoid arthritis (RA) risk, overall and with seropositive/seronegative subtypes. METHODS: We analyzed female nurses in the Nurses' Health Study (NHS, 1986-2016) and NHSII (1991-2017). Lifestyle and medical information were collected on biennial questionnaires. Medical records confirmed incident RA and serostatus. The HLIS index includes 5 modifiable components: smoking, alcohol consumption, body mass index, physical activity, and diet. Cox regression, adjusted for confounders, modeled associations between HLIS and incident RA. The population attributable risk estimated the proportion of incident RA preventable if participants adopted ≥4 healthy lifestyle factors. RESULTS: A total of 1,219 incident RA cases (776 seropositive, 443 seronegative) developed in 4,467,751 person-years. Higher (healthier) HLIS was associated with lower overall RA risk (hazard ratio [HR] 0.86 [95% confidence interval (95% CI) 0.82-0.90]), seropositive RA risk (HR 0.85 [95% CI 0.80-0.91]), and seronegative RA risk (HR 0.87 [95% 0.80-0.94]). Women with 5 healthy lifestyle factors had the lowest risk (HR 0.42 [95% CI 0.22-0.80]). The population attributable risk for adhering to ≥4 lifestyle factors was 34% for RA. CONCLUSION: In this prospective cohort, healthier lifestyle was associated with a lower RA risk. A substantial proportion of RA may be preventable by a healthy lifestyle.

Posttraumatic Stress Disorder and Risk of Systemic Lupus Erythematosus Among Medicaid Recipients.

OBJECTIVE: We studied posttraumatic stress disorder (PTSD), a severe trauma-related mental disorder, and systemic lupus erythematosus (SLE) risk in a large, diverse population enrolled in Medicaid, a US government-sponsored health insurance program for low-income individuals. METHODS: We identified SLE cases and controls among patients ages 18-65 years enrolled in Medicaid for ≥12 months in the 29 most populated US states from 2007 to 2010. SLE and PTSD case statuses were defined based on validated patterns of International Classification of Diseases, Ninth Revision codes. Index date was the date of the first SLE code. Controls had no SLE codes but had another inpatient or outpatient code on the index date and were matched 1:10 to cases by age, sex, and race. Conditional logistic regressions calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of PTSD with incident SLE, adjusting for smoking, obesity, oral contraceptive use, and other covariates. RESULTS: A total of 10,942 incident SLE cases were matched to 109,420 controls. The prevalence of PTSD was higher in SLE cases, at 10.74 cases of PTSD per 1,000 person-years (95% CI 9.37-12.31) versus 7.83 cases (95% CI 7.42-8.27) in controls. The multivariable-adjusted OR for SLE among those with PTSD was 2.00 (95% CI 1.64-2.46). CONCLUSION: In this large, racially and sociodemographically diverse US population, we found patients with a prior PTSD diagnosis had twice the odds of a subsequent diagnosis of SLE. Studies are necessary to clarify the mechanisms driving the observed association and to inform possible interventions.

Association of a Combination of Healthy Lifestyle Behaviors With Reduced Risk of Incident Systemic Lupus Erythematosus.

OBJECTIVE: While previous studies have demonstrated an association between individual factors related to lifestyle and the risk of systemic lupus erythematosus (SLE), it is unclear how the combination of these factors might affect the risk of incident SLE. This study was undertaken to prospectively evaluate whether a combination of healthy lifestyle factors is associated with a lower risk of incident SLE and its subtypes (anti-double-stranded DNA [anti-dsDNA]-positive and anti-dsDNA-negative SLE). METHODS: The study included 185,962 women from the Nurses' Health Study (NHS) and NHSII cohorts, among whom there were 203 incident cases of SLE (96 with anti-dsDNA-positive SLE, 107 with anti-dsDNA-negative SLE) during 4,649,477 person-years of follow-up. The Healthy Lifestyle Index Score (HLIS) was calculated at baseline and approximately every 2 years during follow-up, with scores assigned for 5 healthy lifestyle factors: alcohol consumption, body mass index, smoking, diet, and exercise. A time-varying Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the risk of SLE. In addition, the percentage of partial population attributable risk (PAR%) of SLE development was calculated. RESULTS: A higher HLIS was associated with a lower risk of SLE overall (HR 0.81 [95% CI 0.71-0.94]) and a lower risk of anti-dsDNA-positive SLE (HR 0.78 [95% CI 0.63-0.95]). Women with ≥4 healthy lifestyle factors had the lowest risk of SLE overall (HR 0.42, 95% CI 0.25-0.70) and lowest risk of anti-dsDNA-positive SLE (HR 0.35, 95% CI 0.17-0.75) as compared to women with only 1 healthy behavior or no healthy behaviors. The PAR% of SLE development was 47.7% (95% CI 23.1-66.6%), assuming that the entire population had adhered to at least 4 healthy lifestyle behaviors. CONCLUSION: These results indicate that the risk of developing SLE, a disease in which significant evidence of genetic involvement has been established, might be reduced by nearly 50% with adherence to modifiable healthy lifestyle behaviors.

Interactions Between Genome-Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus.

OBJECTIVE: To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). METHODS: For the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only. RESULTS: The mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry. CONCLUSION: The strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.