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.

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.

Depression and Subsequent Risk for Incident Rheumatoid Arthritis Among Women.

OBJECTIVE: To investigate the association of depression with subsequent risk of rheumatoid arthritis (RA) by serologic phenotype. METHODS: We performed a cohort study using pooled data from the Nurses' Health Study (NHS; 1992-2014) and the NHSII (1993-2015). Depression was defined according to the following composite definition: diagnosis by clinician, regular antidepressant use, or a 5-question Mental Health Inventory score of <60 using time-updated questionnaires during follow-up. Incident RA cases met research criteria by medical record review. Information on covariates, including smoking, diet, and body mass index, was obtained using questionnaires. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for RA risk (overall and by serologic phenotype) according to depression status and adjusted for potential confounders. All analyses included a time separation between assessments of depression and the window for RA risk of at least 4 years to lower the possibility that depressive symptoms due to early RA prior to diagnosis explained any associations. RESULTS: Among 195,358 women, we identified 858 cases of incident RA (65% seropositive) over 3,087,556 person-years (median 17.9 years per participant). Compared to women without depression, those with depression had multivariable HRs as follows: 1.28 (95% CI 1.10-1.48) for all RA; 1.12 (95% CI 0.93-1.35) for seropositive RA; and 1.63 (95% CI 1.27-2.09) for seronegative RA. When analyzing components of the composite depression exposure variable, regular antidepressant use was not associated with subsequent seropositive RA (HR 1.21 [95% CI 0.97-1.49]) and was associated with seronegative RA (HR 1.75 [95% CI 1.32-2.32]). CONCLUSION: Indicators of depression, specifically antidepressant use, were associated with subsequent increased risk for seronegative RA, and this finding was not explained by measured lifestyle factors prior to clinical presentation.

Associations Between Smoking and Systemic Lupus Erythematosus-Related Cytokines and Chemokines Among US Female Nurses.

OBJECTIVE: Smoking has been associated with increased systemic lupus erythematosus (SLE) risk, but the biologic basis for this association is unknown. Our objective was to investigate whether women's smoking was positively associated with SLE-associated proinflammatory chemokines/cytokines (stem cell factor [SCF], B lymphocyte stimulator [BLyS], interferon-γ-inducible 10-kd protein [IP-10], and interferon-α); or negatively associated with antiinflammatory cytokine interleukin-10 (IL-10); and whether associations were modified by SLE-related autoantibody status. METHODS: The Nurses' Health Study (NHS, n = 121,700) and NHSII (n = 116,429) cohorts were begun in 1976 and 1989. In 1988-1990 (NHS) and 1996-1999 (NHSII), ~25% of participants donated blood samples. We identified 1,177 women without SLE with banked samples, and we tested by enzyme-linked immunoassay (ELISA) for chemokines/cytokines as well as anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP. Antinuclear antibodies (ANAs) were detected by HEp-2 cell indirect immunofluorescence, and anti-double-stranded DNA antibodies and were assayed by ELISA. Smoking was assessed until blood draw. Separate tobit and linear regression analyses, adjusted for potential confounders, modeled associations between smoking and log-transformed chemokine/cytokine concentrations. Analyses were stratified by autoantibody status. Effect estimates were calculated as ratios of geometric means expressed as percentage differences. RESULTS: Among the 15% of current/recent versus 85% of past/never smokers, BLyS levels were 8.7% higher (P < 0.01) and were 24% higher (P < 0.0001) among those who were ANA positive. Current/recent smokers had IL-10 concentrations 46% lower (P < 0.01) than past/never smokers; each 10 pack-years of smoking was associated with a 17% decrease in IL-10 level (P < 0.001). Smoking was not associated with IP-10 or SCF. CONCLUSION: Elevated BLyS and lower IL-10 levels among current smokers, particularly among ANA-positive women, may be involved in SLE pathogenesis.

Prenatal Maternal Depression and Neonatal Immune Responses.

OBJECTIVE: The aim of the study was to examine the association of lifetime maternal depression with regulation of immune responses in the infant, measured by cytokine levels and lymphocyte proliferation (LP) in cord blood mononuclear cells collected at delivery. METHODS: We studied women recruited in early pregnancy into the Project Viva longitudinal cohort who had cord blood assayed after delivery (N = 463). Women reported about depressive symptoms in midpregnancy (Edinburgh Postnatal Depression Scale) and depression history by questionnaire. Immune responses were assayed by an index of LP, and concentrations of five cytokines (interleukin [IL]-6, IL-10, IL-13, tumor necrosis tumor necrosis factor factor α, and interferon γ) after incubation of cord blood mononuclear cells either in medium alone or stimulated with phytohemagglutinin (PHA), cockroach extract, or house dust mite extract. We examined associations of maternal depression with these sets of cytokine measures using multivariable linear or tobit regression analyses. RESULTS: After adjustment for confounders (mother's age, race/ethnicity, education, household income, season of birth, and child sex), levels of IL-10 after stimulation with cockroach or dust mite allergen were lower in cord blood from ever versus never depressed women, and a similar trend was evident in IL-10 stimulated with PHA (percentage difference: cockroach extract = -41.4, p = .027; house dust mite extract = 1-36.0, p = .071; PHA = -24.2, p = .333). No significant differences were seen in levels of other cytokines or LP. CONCLUSIONS: Maternal depression is associated with offspring immune responses at birth, which may have implications for later life atopic risk or immune function.

Comprehensive treatment of late-onset tibia vara.

BACKGROUND: Late-onset tibia vara (Blount disease) can be difficult to treat because of frequent morbid obesity and associated deformities, including distal femoral varus, proximal tibial procurvatum, and distal tibial valgus, that contribute to lower extremity malalignment. We present a comprehensive approach that addresses all components of the deformity and allows restoration of the anatomic and mechanical axes. METHODS: Fifteen consecutive patients (nineteen lower extremities) with late-onset tibia vara were managed with this comprehensive approach. The mean age of the patients at the time of surgery was 14.9 years, and the mean weight was 113 kg. Standing anteroposterior and lateral radiographs were made preoperatively and at the time of the final follow-up. Preoperatively, the mean mechanical axis deviation was 108 mm, the mean lateral distal femoral angle was 95 degrees , and the mean mechanical medial proximal tibial angle was 71 degrees . In all nineteen extremities, the proximal tibial varus deformity was corrected by means of a valgus osteotomy and application of an Ilizarov ring external fixator. Distal femoral varus was corrected by means of either hemiepiphyseal stapling or valgus osteotomy with blade-plate fixation in thirteen of the nineteen extremities. Distal tibial valgus was treated either with hemiepiphyseal stapling or with varus osteotomy and gradual correction with use of the Ilizarov external fixator in eleven of the nineteen extremities. RESULTS: After a mean duration of follow-up of 5.0 years, the mean mechanical axis deviation had improved to 1 mm (range, 20 to -30 mm), the lateral distal femoral angle had improved to 87 degrees (range, 83 degrees to 98 degrees), and the mechanical medial proximal tibial angle had improved to 88 degrees (range, 83 degrees to 98 degrees ). The mean time required for correction of the proximal tibial varus deformity was thirty-one days, and the external fixator was removed at a mean of 4.5 months postoperatively. All patients had development of one or more superficial pin-track infections (mean, 1.9 pin-site infections per patient). No wound infections, nonunions, or neurovascular complications occurred. Eighteen of the nineteen extremities were pain-free at the time of the final follow-up. CONCLUSIONS: This comprehensive approach allowed restoration of the mechanical and anatomic axes of the lower extremity in patients with late-onset tibia vara, resulting in a resolution of symptoms as a result of normalization of the weight-bearing forces across the knee and ankle. We believe that this approach will decrease the risk of early degenerative arthritis of the knee.