Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: In the 5.3-year randomized, 2 × 2 factorial, double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61-0.99). Omega-3 (n-3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67-1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation. METHODS: Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant-reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods. RESULTS: A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83-1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n-3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70-0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70-1.04) for vitamin D and HR 0.87 (95% CI 0.71-1.06) for n-3 fatty acids. CONCLUSION: Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n-3 fatty acids had a sustained effect in reducing AD incidence.

Bereavement, Memorial Attendance, and Mental Health During the COVID-19 Pandemic: Longitudinal Results from the Nurses' Health Study.

BACKGROUND: Mortality increased during the COVID-19 pandemic. Many bereaved individuals were not able to gather to memorialize their loved ones, yet it is unknown if this contributed to worsening mental health. OBJECTIVE: Examine the association of bereavement in the early part of the COVID-19 pandemic with subsequent psychological distress and the role of memorial attendance in reducing psychological distress among the bereaved. DESIGN, SETTINGS, SUBJECTS: In May 2020, 39,564 older females from the Nurses' Health Study II enrolled in a longitudinal COVID-19 substudy (meanage = 65.2 years, SD = 4.5). METHODS: Linear regression analyses estimated associations of bereavement reported between March and October, 2020 with subsequent psychological distress between January and October 2021, adjusting for sociodemographic and prepandemic depression symptoms. Secondary models examined associations between memorial attendance and psychological distress. RESULTS: Bereavement during the early part of the COVID-19 pandemic was associated with higher psychological distress (adjusted ß = 0.21, 95% CI: 0.15, 0.26) assessed over the next year. Among the bereaved, memorial attendance was associated with lower psychological distress (in-person: adjusted ß = -0.41, 95% CI: -0.53, -0.29; online: adjusted ß = -0.24, 95% CI: -0.46, --0.02). CONCLUSION: Attending memorials was associated with lower subsequent psychological distress among bereaved older females.

Adolescent endocrine disrupting chemical exposure and academic achievement.

BACKGROUND: Epidemiologic studies support associations of exposure to endocrine disrupting chemicals (EDCs), such as some phthalates, phenols, and parabens with a wide range of cognitive and behavioral traits. While many of these traits are associated with academic achievement, the relationship of EDC exposure specifically with academic achievement in adolescence has not yet been studied. OBJECTIVE: We assessed the association of urinary biomarker concentrations of EDCs with academic achievement in adolescents as well as the potential for psychosocial factors to modify associations. METHODS: We quantified urinary concentrations of select EDCs in 205 adolescent participants from the New Bedford Cohort (NBC), a prospective birth cohort of children born to mothers residing near the New Bedford Harbor Superfund site in Massachusetts, and estimated associations between EDCs and adolescent academic achievement assessed with the Wide Range Achievement Test (WRAT). Measures of socioeconomic status and the home environment were used to estimate psychosocial stress. RESULTS: Urinary concentrations of antiandrogenic phthalates were inversely associated with Math Computation scores. For example, each doubling of the concentration of antiandrogenic phthalate metabolites in urine was associated with a 1.94 point decrease (95% CI: 3.84, -0.05) in Math Computation scores, indicating poorer performance. For the most part, associations were stronger in adolescents with more, as compared to less, social disadvantage, but most of these differences did not achieve statistical significance. CONCLUSION: Our findings support the potential for adolescents' exposure to antiandrogenic phthalates to correlate with poorer academic achievement in math, particularly among participants with greater psychosocial stress.

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.

Pre-pandemic resilience to trauma and mental health outcomes during COVID-19.

PURPOSE: The stress-sensitization hypothesis posits that individuals with prior trauma are at elevated risk for poor mental health when faced with subsequent stressors. Little work has examined whether those who have demonstrated psychological resilience to prior trauma would show either increased resilience or vulnerability to subsequent stressors. We examined pre-pandemic psychological resilience to lifetime trauma in relation to mental health outcomes amid the coronavirus disease 2019 (COVID-19) pandemic, a major societal stressor. METHODS: The sample included 16,900 trauma-exposed women from the Nurses' Health Study II. Pre-pandemic resilience was defined by psychological health in 2017-2019 (characterized by levels of both distress and positive emotional well-being) relative to lifetime trauma. Resilience was defined categorically by cross-classifying unfavorable, adequate, and favorable psychological health by higher versus lower trauma burden, and continuously as the residual difference in predicted versus actual psychological health regressed on trauma burden. Mental health outcomes as of May-August 2020 included psychological distress symptoms and overall positive emotional well-being. Associations were assessed using covariate-adjusted regression models. RESULTS: Pre-pandemic resilience was associated with lower distress and higher well-being early in the COVID-19 pandemic. Relative to the women showing highest resilience (favorable psychological health despite higher trauma), only those with lower trauma and favorable prior psychological health had significantly lower distress and higher positive emotional well-being during the pandemic. Higher continuous pre-pandemic resilience was also significantly associated with lower distress and higher positive emotional well-being during the pandemic. CONCLUSION: Preventing mental health problems following trauma may contribute to protecting population well-being amid major stressors.

Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.

OBJECTIVE: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk. DESIGN: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design. SETTING: Nationwide in the United States. PARTICIPANTS: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment. INTERVENTIONS: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence. MAIN OUTCOME MEASURES: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others. RESULTS: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease. CONCLUSIONS: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo). STUDY REGISTRATION: ClinicalTrials.gov NCT01351805 and NCT01169259.

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.

Air Pollution, Neonatal Immune Responses, and Potential Joint Effects of Maternal Depression.

Prenatal maternal exposure to air pollution may cause adverse health effects in offspring, potentially through altered immune responses. Maternal psychosocial distress can also alter immune function and may increase gestational vulnerability to air pollution exposure. We investigated whether prenatal exposure to air pollution is associated with altered immune responses in cord blood mononuclear cells (CBMCs) and potential modification by maternal depression in 463 women recruited in early pregnancy (1999-2001) into the Project Viva longitudinal cohort. We estimated black carbon (BC), fine particulate matter (PM2.5), residential proximity to major roadways, and near-residence traffic density, averaged over pregnancy. Women reported depressive symptoms in mid-pregnancy (Edinburgh Postnatal Depression Scale) and depression history by questionnaire. Immune responses were assayed by concentrations of three cytokines (IL-6, IL-10, and TNF-α), in unstimulated or stimulated (phytohemagglutinin (PHA), cockroach extract (Bla g 2), house dust mite extract (Der f 1)) CBMCs. Using multivariable linear or Tobit regression analyses, we found that CBMCs production of IL-6, TNF-a, and IL-10 were all lower in mothers exposed to higher levels of PM2.5 during pregnancy. A suggestive but not statistically significant pattern of lower cord blood cytokine concentrations from ever (versus never) depressed women exposed to PM2.5, BC, or traffic was also observed and warrants further study.

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.

Associations between daily alcohol consumption and systemic lupus erythematosus-related cytokines and chemokines among US female nurses without SLE.

OBJECTIVES: Moderate alcohol consumption has been associated with decreased systemic lupus erythematosus risk, but the biologic basis for this association is unknown. We aimed to determine whether moderate alcohol consumption was associated with lower concentrations of systemic lupus erythematosus-associated chemokines/cytokines in an ongoing cohort of female nurses without systemic lupus erythematosus, and whether the association was modified by the presence of systemic lupus erythematosus-related autoantibodies. METHODS: About 25% of participants from the Nurses' Health Study (n = 121,700 women) and Nurses' Health Study 2 (n = 116,429) donated a blood sample; of these, 1177 women were without systemic lupus erythematosus at time of donation. Cumulative average and current (within 4 years) intakes of beer, wine or liquor were assessed from pre-blood draw questionnaires. Chemokine/cytokine concentrations (stem cell factor, B-lymphocyte stimulator, interferon-inducible protein-10, interferon-alpha, interleukin-10) and antibodies against dsDNA and extractable nuclear antigens were obtained using enzyme-linked immunosorbent assays. Antinuclear antibodies were detected by indirect immunofluorescence on HEp-2 cells. RESULTS: At blood draw, the women's mean age was 56 years and 22% were antinuclear antibody positive; 36% were African-American. About half (46%) reported consuming 0-5 g/day of alcohol. Stem cell factor levels were 0.5% lower (p < 0.0001) for every gram per day increase in cumulative average alcohol consumption. Women who consumed >5 g/day had mean stem cell factor levels 7% lower (p = 0.002) than non-drinkers. Other cytokines were not significantly associated with alcohol intake. Autoantibody status did not modify observed associations. CONCLUSION: In this study of female nurses, moderate alcohol consumption was associated with lower stem cell factor levels, suggesting a plausible mechanism through which alcohol may lower systemic lupus erythematosus risk might be by decreasing circulating stem cell factor.

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.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1ß, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

Socioeconomic disadvantage and neural development from infancy through early childhood.

BACKGROUND: Early social experiences are believed to shape neurodevelopment, with potentially lifelong consequences. Yet minimal evidence exists regarding the role of the social environment on children's neural functioning, a core domain of neurodevelopment. METHODS: We analysed data from 36 443 participants in the United States Collaborative Perinatal Project, a socioeconomically diverse pregnancy cohort conducted between 1959 and 1974. Study outcomes included: physician (neurologist or paediatrician)-rated neurological abnormality neonatally and thereafter at 4 months and 1 and 7 years; indicators of neurological hard signs and soft signs; and indicators of autonomic nervous system function. RESULTS: Children born to socioeconomically disadvantaged parents were more likely to exhibit neurological abnormalities at 4 months [odds ratio (OR) = 1.20; 95% confidence interval (CI) = 1.06, 1.37], 1 year (OR = 1.35; CI = 1.17, 1.56), and 7 years (OR = 1.67; CI = 1.48, 1.89), and more likely to exhibit neurological hard signs (OR = 1.39; CI = 1.10, 1.76), soft signs (OR = 1.26; CI = 1.09, 1.45) and autonomic nervous system dysfunctions at 7 years. Pregnancy and delivery complications, themselves associated with socioeconomic disadvantage, did not account for the higher risks of neurological abnormalities among disadvantaged children. CONCLUSIONS: Parental socioeconomic disadvantage was, independently from pregnancy and delivery complications, associated with abnormal child neural development during the first 7 years of life. These findings reinforce the importance of the early environment for neurodevelopment generally, and expand knowledge regarding the domains of neurodevelopment affected by environmental conditions. Further work is needed to determine the mechanisms linking socioeconomic disadvantage with children's neural functioning, the timing of such mechanisms and their potential reversibility.

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.