Survival of veterans treated with enzalutamide and abiraterone for metastatic castrate resistant prostate cancer based on comorbid diseases.

BACKGROUND: Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions. METHODS: Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC. RESULTS: Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84-0.96). CONCLUSIONS: Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.

Development and validation of lupus nephritis case definitions using United States veterans affairs electronic health records.

OBJECTIVE: International Classification of Diseases (ICD) codes are commonly used to identify patients with rare diseases in electronic health records (EHRs). However, misclassification is common, impacting the validity of study results. In this study, we compared the accuracies of several ICD-based case definitions of lupus nephritis (LN) in identifying United States veterans with LN. METHODS: Using the Department of Veterans Affairs (VA) EHR, we identified all veterans with ≥1 ICD-9 or 10 diagnostic codes for systemic lupus erythematosus (SLE) between October 1, 1999 and September 30, 2017. A cohort was randomly selected for diagnostic validation and 9 ICD-based LN case definitions were applied to this cohort. The diagnostic accuracy of each definition was assessed against gold standard criterion of biopsy-proven LN. RESULTS: 18,420 veterans had ≥1 ICD-9 or 10 diagnostic codes for SLE; 981 were randomly selected for diagnostic validation. 95 veterans (9.7%) had biopsy-proven LN. The case definitions had high specificity and NPV but variable sensitivity and PPV. The definition containing ≥2 ICD -9 codes for SLE and ≥2 nephritis indicators had the highest combination of sensitivity and specificity (87.4% and 94.6% respectively). ICD-10 code for LN had high specificity (99.8%) and PPV (93.9%). CONCLUSION: ICD-based case definitions of LN in the VA population have high specificity and NPV but variable sensitivity and PPV. Our results may help guide the design of future LN studies in VA cohorts. The choice of specific case definitions depends on the relative importance of different accuracy measures to individual studies.

Longitudinal associations between depressive symptoms and clinical factors in ankylosing spondylitis patients: analysis from an observational cohort.

OBJECTIVES: Although cross-sectional studies have shown that ankylosing spondylitis-specific factors correlate with depressive symptom severity, the association of these factors over time is unresolved. We examined the demographic and clinical factors associated with longitudinal depressive symptom severity in AS patients. METHODS: We analyzed sociodemographic, clinical, behavioral and medication data from 991 patients from the Prospective Study of Outcomes in Ankylosing spondylitis cohort, and measured depression severity with the Center for Epidemiological Studies Depression (CES-D) Scale administered at approximately 6-month visit intervals. Multivariable longitudinal negative binomial regression models were conducted using generalized estimating equation modeling to assess the demographic, clinical, and medication-related factors associated with depression severity by CES-D scores over time. RESULTS: The median baseline CES-D score (possible range 0-60) was 10.0 (interquartile range = 5, 17). In longitudinal multivariable analyses, higher CES-D scores were associated with longitudinal smoking, greater functional impairment, greater disease activity, self-reported depression, and poor global health scores. Marital status (e.g., being married) was associated with lower CES-D. Adjusted mean CES-D scores in our model decreased over time, with a significant interaction between time and gender observed. CONCLUSION: This study identified longitudinal clinical factors such as greater disease activity, greater functional impairment, and poor global health to be associated with longitudinal depression severity. These factors are potentially modifiable and may help manage depressive symptoms in AS.

Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis.

The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans' Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06-5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17-0.74]; p = 0.01 and HR 0.39 [CI 0.20-0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31-1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death.

Environmental factors selectively impact co-occurrence of problem/pathological gambling with specific drug-use disorders in male twins.

AIMS: Multiple forms of drug abuse/dependence frequently co-occur with problem/pathological gambling (PPG). The current study examines the extent to which genetic and environmental factors contribute to their co-occurrence. DESIGN: Bivariate models investigated the magnitude and correlation of genetic and environmental contributions to problem/pathological gambling and its co-occurrence with nicotine dependence, cannabis abuse/dependence and stimulant abuse/dependence. SETTING: Computer-assisted telephone interviews in the community. PARTICIPANTS: Participants were 7869 male twins in the Vietnam Era Twin Registry, a USA-based national twin registry. MEASUREMENTS: Life-time DSM-III-R diagnoses for problem/pathological gambling, nicotine dependence, cannabis abuse/dependence and stimulant abuse/dependence were determined using the Diagnostic Interview Schedule. FINDINGS: All drug-use disorders displayed additive genetic and non-shared environmental contributions, with cannabis abuse/dependence also displaying shared environmental contributions. Both genetic [genetic correlation rA = 0.22; 95% confidence interval (CI) = 0.10-0.34] and non-shared environmental components (environmental correlation rE = 0.24; 95% CI = 0.10-0.37) contributed to the co-occurrence of problem/pathological gambling and nicotine dependence. This pattern was shared by cannabis abuse/dependence (rA = 0.32; 95% CI = 0.05-1.0; rE = 0.36; 95% CI = 0.16-0.55) but not stimulant abuse/dependence (SAD), which showed only genetic contributions to the co-occurrence with problem/pathological gambling (rA = 0.58; 95% CI = 0.45-0.73). CONCLUSIONS: Strong links between gambling and stimulant-use disorders may relate to the neurochemical properties of stimulants or the illicit nature of using 'hard' drugs such as cocaine. The greater contribution of environmental factors to the co-occurrence between problem/pathological gambling and 'softer' forms of drug abuse/dependence (cannabis, tobacco) suggest that environmental interventions (perhaps relating to availability and legality) may help to diminish the relationship between problem/pathological gambling and tobacco- and cannabis-use disorders.

TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis.

Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-α antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA. A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-α antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-α antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy. We conclude that patients with RA who are treated with TNF-α antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.

Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis.

OBJECTIVE: To determine the incidence of and risk factors for non-melanoma skin cancer (NMSC) in a national cohort of veterans with RA. METHODS: We examined skin cancer risk in a cohort of 20 648 patients with RA derived from the Department of Veterans' Affairs (VA) national administrative databases. The cohort was divided into two medication groups: patients treated with non-biologic and TNF-α antagonist DMARDs. We defined skin cancer as the first occurrence of an International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) code for NMSC after initiation of a DMARD. Outcome risk was described using hazard ratios (HRs) with Cox proportional hazards regression for time-to-event analysis and logistic regression. We performed medical record review to validate the diagnosis of NMSC. RESULTS: Incidence of NMSC was 18.9 and 12.7 per 1000 patient-years in patients on TNF-α antagonists and non-biologic DMARDs, respectively. Patients on TNF-α antagonists had a higher risk of developing NMSC (HR 1.42; 95% CI 1.24, 1.63). Risk factors for NMSC included older age, male gender, NSAID and glucocorticoid use and a history of prior malignancies. There was substantial agreement between ICD-9-CM diagnosis of NMSC and medical record validation (κ = 0.61). CONCLUSION: TNF-α antagonist therapy in veterans with RA may be associated with an increased risk of NMSC, compared with therapy with non-biologic DMARDs. Rheumatologists should carefully screen patients receiving TNF-α antagonists for pre-cancerous skin lesions and skin cancer.

Tumor necrosis factor-α blockade, cardiovascular outcomes, and survival in rheumatoid arthritis.

The effect of TNF-α blockade on the risk of cardiovascular outcomes and long-term survival in patients with rheumatoid arthritis (RA) is not known. We assembled a cohort of 20,811 (75,329 person-years) U.S. veterans who were diagnosed with RA between October 1998 and September 2005, and who were treated with a disease-modifying anti-rheumatic drug (DMARD). Cox survival models were built to examine the effect of TNF-α antagonists on the risk of a composite endpoint of cardiovascular outcomes defined as the occurrence of atherosclerotic heart disease, congestive heart failure, peripheral artery disease, or cerebrovascular disease, and on the risk of death. Treatment with TNF-α antagonists was not associated with a significant effect on the composite endpoint of cardiovascular outcomes. When each outcome was examined separately, the use TNF-α antagonists was not associated with an increased risk of atherosclerotic heart disease, congestive heart failure, or peripheral artery disease, but it was associated with decreased risk of cerebrovascular disease (hazard ratio [HR] = 0.83; confidence interval [CI] = 0.70-0.98). The use of TNF-α antagonists did not affect the risk of death (HR = 0.99; CI = 0.87-1.14). In subgroup analyses, the use TNF-α antagonists was associated with a reduced risk of cardiovascular outcomes (HR = 0.90, CI = 0.83-0.98) in patients younger than the median age of our cohort (63 years). The use TNF-α antagonists was not associated with a change in the risk of death in any other subgroup. These results show that the risk of cardiovascular events and survival in patients who receive TNF-α antagonists is not different than those who receive other DMARDs.

An observational study of musculoskeletal pain among patients receiving bisphosphonate therapy.

OBJECTIVE: To seek evidence for the association of bisphosphonate use with diffuse musculoskeletal pain (MSKP) in a large national cohort, controlling for conditions associated with MSKP. PATIENTS AND METHODS: This retrospective cohort study enrolled all US veterans aged 65 years or older with a vertebral or hip fracture who were treated for at least 1 year between October 1, 1998, and September 30, 2006 (N=26,545). All International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes, demographics, and pharmaceutical data were obtained from national databases. A composite end point, based on ICD-9-CM codes compatible with diffuse MSKP, was constructed. The primary outcome was time until MSKP. We performed regression analysis using the Cox proportional hazards model, controlling for age, sex, race, alcoholism, depression, anxiety, smoking, recent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use, rheumatic disease, and comorbidity score. RESULTS: The univariate regression identified an association of bisphosphonate exposure and MSKP (hazard ratio, 1.22; 95% confidence interval, 1.04-1.44). In the multivariate regression, however, patients prescribed a bisphosphonate were not more likely to be assigned an ICD-9-CM code compatible with diffuse MSKP (hazard ratio, 1.10; 95% confidence interval, 0.93-1.30). Consistent with prior studies, we found that female sex, depression, anxiety, comorbidity score, and the presence of a rheumatic disease were all associated with a greater risk of a diagnosis of diffuse MSKP. There was no demonstrable association with statin exposure. CONCLUSION: Bisphosphonate use was not associated with a statistically higher rate of MSKP in this cohort. Individual patients may rarely report MSKP while taking bisphosphonates; however, for our studied cohort, incident MSKP does not appear to explain bisphosphonate discontinuation rates.

Genetic vulnerability and phenotypic expression of depression and risk for ischemic heart disease in the Vietnam era twin study of aging.

OBJECTIVE: To determine if depression contributes to incident heart disease after accounting for genetic, behavioral, and medical factors associated with both conditions. METHODS: We used a prospective twin study with a 12-year follow-up. In 1992, lifetime diagnosis of depression was assessed in 1159 male-male twins and merged with longitudinal health data from the Vietnam Era Twin Registry Study of Aging. Incident heart disease was defined as having myocardial infarction, heart surgery, or angina at 12-year follow-up when twins were 55.4 years (standard deviation, 2.5 years) of age. Risks for heart disease were computed in a logistic regression model that included comparing twins at different levels of phenotypic expression of depression and varying levels of genetic vulnerability at the same time adjusting for pertinent covariates. RESULTS: After adjusting for sociodemographics, co-occurring psychopathology, smoking, obesity, diabetes, hypertension, and social isolation, twins at high genetic risk and exposed to depression remained at greater risk of developing ischemic heart disease (IHD) (odds ratio, 2.55; 95% confidence interval, 1.44-4.49) compared with those at low genetic risk and without phenotypic expression of depression. Odds ratios suggest that twins at genetic liability but without phenotypic expression were at risk of IHD, but the effect was not statistically significant. CONCLUSIONS: A history of depression is a risk factor for incident heart disease after adjusting for numerous covariates. Twins with both high genetic vulnerability and phenotypic expression of depression were at greatest risk of IHD. Trends suggest the genetic contribution to IHD that overlaps with depression may partly explain this association, but studies in larger samples are warranted.

Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis.

BACKGROUND: Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. METHODS: We conducted a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. RESULTS: The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P < .001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). CONCLUSIONS: Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.

Genetic and environmental contributions to nicotine, alcohol and cannabis dependence in male twins.

AIMS: To compute the common and specific genetic and environmental contributions to nicotine dependence (ND) alcohol dependence (AD) and cannabis dependence (CD). DESIGN: Twin model. PARTICIPANTS: Data from 1874 monozygotic and 1498 dizygotic twin pair members of the Vietnam Era Twin Registry were obtained via telephone administration of a structured psychiatric interview in 1992. MEASUREMENTS: Data to derive life-time diagnoses of DSM-III-R ND, AD and CD were obtained via telephone administration of the Diagnostic Interview Schedule. FINDINGS: The best-fitting model allowed for additive genetic contributions and unique environmental influences that were common to all three phenotypes. Risks for ND and AD were also due to genetic and unique environmental influences specific to each drug. A specific shared environmental factor contributed to CD. CONCLUSIONS: These results suggest that the life-time co-occurrence of ND, AD and CD is due to common and specific genetic factors as well as unique environmental influences, and vulnerability for CD is also due to shared environmental factors that do not contribute to ND and AD. The majority of genetic variance is shared across drugs and the majority of unique environmental influences are drug-specific in these middle-aged men. Because differences between models allowing for specific genetic versus shared environment were small, we are most confident in concluding that there are specific familial contributions-either additive genetic or shared environment-to CD.

Posttraumatic stress disorder; combat exposure; and nicotine dependence, alcohol dependence, and major depression in male twins.

Combat exposure is associated with increased risk of psychiatric and substance use disorders in veterans. However, it is not known whether combat exposure independently increases risk for these disorders or whether this association is accounted for by genetic vulnerability common to posttraumatic stress disorder (PTSD). This article tests competing explanations for the association of combat exposure and PTSD with nicotine dependence (ND), alcohol dependence (AD), and major depression (MD). Data were obtained from 6099 members of the Vietnam Era Twin Registry, a national registry of male-male twin pairs who served in the military during the Vietnam era. Twin models were fit to estimate the genetic and environmental variance common and specific to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, lifetime diagnoses of PTSD, combat trauma, and 3 comorbid conditions: ND, AD, and MD. Variance specific to ND, AD, and MD was due to genetic factors (48%, 36%, and 12%, respectively) and unique environmental factors (36%, 42%, and 58%, respectively). After accounting for variance common to PTSD, no residual genetic and environmental variance overlapped between combat and ND, combat and AD, and combat and MD. Combat exposure is not independently associated with lifetime ND, AD, and MD. The association of combat exposure with these 3 disorders is due to genetic and unique environmental contributions in common with PTSD. These findings suggest comorbid PTSD may represent a genetically mediated vulnerability to psychopathology after trauma.

A twin study of smoking, nicotine dependence, and major depression in men.

This study examined the nature of the relationship among lifetime major depression, smoking, and nicotine dependence. Subjects were 8,169 male twins from the Vietnam Era Twin Registry. Biometrical modeling demonstrated a genetic influence on daily smoking, nicotine dependence, and major depression, and a family environmental influence on daily smoking. Genetic factors influencing nicotine dependence also strongly influenced major depression. We also compared probands with a history of major depression (n = 398) from pairs discordant for major depression, their nondepressed cotwins (n = 364), and controls (n = 1,863) on a number of secondary smoking outcomes. Major depression was associated with current daily smoking and certain nicotine withdrawal symptoms. Individuals with a familial vulnerability for major depression, even without a personal history of major depression, were more likely to smoke despite a serious illness and to report nervousness, restlessness, difficulty concentrating, and depressed mood during past quit attempts. Among the 237 monozygotic pairs discordant for major depression, depressed probands were more likely to have a lifetime history of nicotine dependence than were cotwins. Findings extend Kendler and colleague's (1993) study of female twins by demonstrating in men that shared genetic factors predispose not only to major depression and daily smoking but also to major depression and nicotine dependence.

Common genetic risk of major depression and nicotine dependence: the contribution of antisocial traits in a United States veteran male twin cohort.

Many studies that found associations between depression and nicotine dependence have ignored possible shared genetic influences associated with antisocial traits. The present study examined the contribution of genetic and environmental effects associated with conduct disorder (CD) and antisocial personality disorder (ASPD) to the comorbidity of major depression (MD) and nicotine dependence (ND). A telephone diagnostic interview, the Diagnostic Interview Schedule-III-R, was administered to eligible twins from the Vietnam Era Twin (VET) Registry in 1992. Multivariate genetic models were fitted to 3360 middle-aged and predominantly white twin pairs (1868 monozygotic, 1492 dizygotic pairs) of which both members completed the pertinent diagnostic interview sections. Genetic influences on CD accounted for 100%, 68%, and 50% of the total genetic variance in risk for ASPD, MD and ND, respectively. After controlling for genetic influences on CD, the partial genetic correlation between MD and ND was no longer statistically significant. Nonshared environmental contributions to the comorbidity among these disorders were not significant. This study not only demonstrates that the comorbidity between ND and MD is influenced by common genetic risk factors, but also further suggests that the common genetic risk factors overlapped with those for antisocial traits such as CD and ASPD in men.

Nicotine dependence subtypes: association with smoking history, diagnostic criteria and psychiatric disorders in 5440 regular smokers from the Vietnam Era Twin Registry.

Studies suggest empirically derived subtypes of nicotine dependence exist in young adult populations with short smoking careers. It is not known if classes of dependence exist in middle aged smokers with longer smoking careers and whether these classes reflect quantitative or qualitative differences. It is not known if psychiatric disorders are associated with classes of nicotine dependence. Nicotine dependence symptoms were obtained from a 1992 administration of the Diagnostic Interview Schedule. Latent Class Analyses (LCA) was computed using data from 5440 members of the Vietnam Era Twin Registry. LCA was used to derive significantly different classes of nicotine dependence, which were assessed for their association with smoking history, nicotine dependence, and other psychiatric disorders. The LCA model which best fit the data was a 4 class solution characterized by severity. Age onset of regular smoking decreased with more severe classes. Cigarette consumption, failed cessation and psychiatric disorders were associated with more severe classes. Empirically derived subtypes of nicotine dependence are mostly characterized by increasing severity. Suggestions for refinement of nicotine dependence diagnostic criteria are discussed.

Posttraumatic stress disorder and late-onset smoking in the Vietnam era twin registry.

Epidemiological and clinical studies have consistently reported associations between smoking and posttraumatic stress disorder (PTSD). This study analyzed diagnostic interview data on 6,744 members of the Vietnam Era Twin Registry to clarify the PTSD-smoking relation and to examine whether genetic liability for smoking moderated this relation. Preexisting active (unremitted) PTSD increased risk of late-onset daily smoking. Remitted PTSD decreased risk. Active PTSD increased risk of smoking at all levels of genetic liability; the effect was strongest for those with least genetic liability. This suggests PTSD represents a nongenetic pathway to late-onset smoking among individuals who were nonsmokers prior to developing PTSD. If replicated, these results identify PTSD as a risk factor for smoking that should lead to early tobacco control treatment in this population.

A twin registry study of the relationship between posttraumatic stress disorder and nicotine dependence in men.

CONTEXT: Recent studies indicate a strong association between posttraumatic stress disorder (PTSD) and nicotine dependence (ND). However, the explanation for the association remains unclear. OBJECTIVE: To test competing explanations for the association between PTSD and ND. DESIGN, SETTING, AND PARTICIPANTS: Analysis of data on 6744 members of the Vietnam Era Twin Registry, a national registry of all male-male twin pairs who served in the military during the Vietnam era interviewed in 1991-1992. MAIN OUTCOME MEASURES: Risk of PTSD and ND using the Diagnostic Interview Schedule for the DSM-III-R. RESULTS: The prevalence of ND was elevated among trauma-exposed individuals (52.0%) and those with PTSD (71.7%) compared with unexposed individuals (40.5%). This association was significant for ND and for trauma without PTSD (odds ratio, 1.31; 95% confidence interval [CI], 1.18-1.45) and for PTSD (odds ratio, 2.34; 95% CI, 1.92-2.84) and was not entirely explained by shared risk factors. Shared genetic effects explained 63% of the PTSD-ND association; the remaining covariance was explained by individual-specific environmental effects. Using survival analysis with time-dependent covariates, ND was associated with a substantially increased risk of PTSD among trauma-exposed men (hazard ratio, 1.98; 95% CI, 1.61-2.42). Trauma (hazard ratio, 1.49; 95% CI, 1.35-1.64) and PTSD (hazard ratio, 1.36; 95% CI, 1.14-1.61) were less strongly but significantly associated with increased risk of ND onset after controlling for shared risk factors. CONCLUSIONS: Most of the PTSD-ND association is explained by shared genetic effects. However, there is a substantial, robust PTSD-ND association not explained by shared risk factors. Multiple explanations for the association were supported; however, the strongest association was consistent with preexisting ND increasing the risk of PTSD onset. These data suggest that male veterans with a history of ND may be at increased risk for PTSD. Further research on the biological mechanisms underlying PTSD-ND comorbidity is needed.