Arthritis Care & Research Vol. 68, No. 1, January 2016, pp 36–45 DOI 10.1002/acr.22642 C 2016, American College of Rheumatology V

ORIGINAL ARTICLE

Cause-Specific Mortality in Male US Veterans With Rheumatoid Arthritis BRYANT R. ENGLAND,1 HARLAN SAYLES,1 KALEB MICHAUD,2 LIRON CAPLAN,3 LISA A. DAVIS,4 GRANT W. CANNON,5 BRIAN C. SAUER,5 ELIZABETH B. SOLOW,6 ANDREAS M. REIMOLD,6 GAIL S. KERR,7 PASCALE SCHWAB,8 JOSH F. BAKER,9 AND TED R. MIKULS1

Objective. There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. Methods. Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. Results. There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46–2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20–1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20–3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. Conclusion. Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA.

In addition to experiencing substantial physical impairments and reductions in health-related quality of life, patients with rheumatoid arthritis (RA) have increased mortality (1), which has not improved despite important recent treatment advances (2,3). Standardized mortality

ratios (SMRs) for patients with RA reflect an increase in mortality risk of approximately 30–70% (1). Although both sexes suffer from reduced survival, men with RA appear to have a disproportionately higher absolute mortality risk than affected women (1). We previously observed a greater than 2-fold increased risk of all-cause mortality among male veterans with RA that was associat-

Dr. England’s work was supported by a Rheumatology Research Foundation Resident Research Preceptorship. Dr. Michaud’s work was supported by a Rheumatology Research Foundation Investigator Award. Dr. Davis’ work was supported by a Rheumatology Research Foundation Scientific Development Award. Dr. Mikuls’ work was supported by a Veterans Affairs Merit Award. 1 Bryant R. England, MD, Harlan Sayles, MS, Ted R. Mikuls, MD, MSPH: Veterans Affairs Nebraska–Western Iowa Health Care System, and University of Nebraska Medical Center, Omaha; 2Kaleb Michaud, PhD: Veterans Affairs Nebraska– Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, and National Data Bank for Rheumatic Diseases, Wichita, Kansas; 3Liron Caplan, MD, PhD: Denver VAMC and University of Colorado, Denver; 4Lisa A. Davis, MD, MSCS: Denver VAMC, University of Colorado, and Denver Health Medical Center, Denver, Colorado; 5Grant W.

Cannon, MD, Brian C. Sauer, PhD: Veterans Affairs Salt Lake City Health Care System and University of Utah School of Medicine, Salt Lake City; 6Elizabeth B. Solow, MD, Andreas M. Reimold, MD: Dallas Veterans Affairs and University of Texas Southwestern, Dallas; 7Gail S. Kerr, MD: Washington, DC, Veterans Affairs Medical Center and Georgetown and Howard Universities, Washington, DC; 8Pascale Schwab, MD: Portland Veterans Affairs Health Care System and Oregon Health and Sciences University, Portland; 9Josh F. Baker, MD, MSCE: Philadelphia VAMC and University of Pennsylvania School of Medicine, Philadelphia. Address correspondence to Ted R. Mikuls, MD, MSPH, 986270 Nebraska Medical Center, Omaha, NE 68198-6270. E-mail: [email protected]. Submitted for publication February 4, 2015; accepted in revised form June 16, 2015.

INTRODUCTION

36

Veterans With RA and Cause-Specific Mortality

Significance & Innovations  Men with rheumatoid arthritis (RA) have an approximately 2-fold increase in all-cause mortality and a 3-fold increase in respiratory mortality compared to the general non-RA population.  RA disease characteristics are more closely associated with cardiovascular and respiratory mortality than cancer mortality in men.  After accounting for multiple patient characteristics, including composite measures of disease activity, no associations of biologic or nonbiologic disease-modifying antirheumatic drugs with causespecific mortality were observed.

ed with white race, higher disease activity and inflammation, low body mass index (BMI), extraarticular disease, and select treatments (4). Cause of death was not available for the initial analysis; thus contributions of these factors to specific causes of death has remained unknown. Cause of death in RA mirrors that in the general population, with cardiovascular disease (CVD), cancer, and respiratory disease being among the leading causes (1). Despite the high frequency of CVD and CVD-related mortality in RA, reasons for this increased risk are not well understood. Neither traditional CVD risk factors (5,6) nor inflammation resulting from RA (7,8) appear to fully explain the increased CVD burden in patients with RA. Increased CVD risk in RA appears to impact men and women differentially (9,10), suggesting that risk factors could influence CVD incidence and related outcomes differently in men and women. CVD-related mortality analyses in an RA malepredominant cohort have not been completed to date. Less is known about the risk factors for other causes of death in RA. In a meta-analysis, a small but significant increased incidence of cancer in RA was observed (11), and reduced 5-year cancer survival rates were reported in a cohort of patients with polyarthritis in the UK (12). Male sex (13) and elevated inflammatory markers (14) have been associated with an increased cancer incidence in RA; however, determinants of cancer-related mortality in RA remain largely unknown. Respiratory disease, including interstitial lung disease (ILD), is a common extraarticular manifestation of RA and is more common in men than in women (15,16). It has a dramatic impact on mortality, with a reported 7-year decrease in median survival compared to other patients with RA (16). Increased respiratory mortality has been reported in patients with rheumatoid factor (RF) positivity (17), but little else is known about other risk factors for respiratory-related death in RA. The lack of well-characterized risk factors for causespecific mortality in RA, particularly among male US veterans who have higher mortality rates attributed to high levels of comorbidities (18), is considered a major knowledge gap. We sought to identify the causes of death in this population and to determine risk factors for cause-specific mortality.

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SUBJECTS AND METHODS Study subjects. Participants were enrollees from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. VARA is a longitudinal observational study of US veterans with RA, initiated in 2003 (4). Rheumatology clinics from Veterans Affairs (VA) medical centers in the following 12 US cities have participated: Birmingham, Alabama; Brooklyn, New York; Dallas, Texas; Denver, Colorado; Iowa City, Iowa; Jackson, Mississippi; Little Rock, Arkansas; Omaha, Nebraska; Philadelphia, Pennsylvania; Portland, Oregon; Salt Lake City, Utah; and Washington, DC. All patients reported a disease onset after 18 years of age and fulfilled the 1987 American College of Rheumatology (ACR) classification criteria (19). The registry includes clinical measurements obtained at enrollment and followup visits dictated by usual care as well as by a biological repository of banked DNA, serum, and plasma from enrollment. The registry received institutional review board approval at each site, and study participants provided written informed consent before enrollment. This study was approved by the VARA Scientific Ethics Advisory Committee. Women were excluded from this analysis because they comprised a small proportion of the cohort (,10% of total) and observed deaths (,5% of total). Clinical measurements. At enrollment, age, sex, selfreported race/ethnicity (white, African American or black [not of Hispanic origin], Asian, American Indian or Pacific Islander, Hispanic, or other), education, date of RA diagnosis, smoking status (current, former, never), and BMI are collected. Medications (use, but not dosage) and ACR criteria, including the presence of subcutaneous nodules and radiographic changes, are recorded at enrollment and at followup. At each visit, swollen and tender joint counts (0 to 28 joints), provider and patient global assessments (using 100-mm visual analog scales), and the erythrocyte sedimentation rate (ESR) are collected. Additionally, a pain score (range 0 to 10) is determined and a 10-item Multidimensional Health Assessment Questionnaire (MD-HAQ; range 0 to 3) (20) is collected. The Disease Activity Score in 28 joints (DAS28) (21) and Routine Assessment of Patient Index Data 3 (RAPID-3) are calculated from visit data (22). Using banked serum from enrollment, anti–cyclic citrullinated peptide (anti-CCP) antibody is measured using a second-generation commercial enzyme-linked immunosorbent assay, while RF and high-sensitivity C-reactive protein (hsCRP) are measured by nephelometry (23). Using banked DNA, the HLA–DRB1 shared epitope status was ascertained as previously described (24). Comorbidities. Comorbid conditions were aggregated for the 12 months prior to enrollment from VA national administrative data, using the Healthcare Cost and Utilization Project Clinical Classifications Software (HCUP-CCS) from the Agency for Healthcare Quality and Research. The Rheumatic Disease Comorbidity Index (RDCI) (25) was calculated as an overall comorbidity score from the HCUPCCS categories and features the following comorbid conditions: lung disease, heart attack, other CVD, stroke, hypertension, fracture, depression, diabetes mellitus, cancer, ulcer, and other stomach problem. The RDCI was previously

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England et al

Table 1. Characteristic Demographics Age, years White, % High-school education, % Tobacco use, % Never Former Current Disease duration, years BMI, kg/m2 BMI category, kg/m2, % ,20 20 to 25 .25 to #30 .30 to #35 .35 Mean rheumatology visits per year Comorbidities at enrollment RDCI score (range 0–9) MI or atherosclerosis, % Other CVD, % Stroke, % Hypertension, % Lung disease, % Fracture, % Depression, % Diabetes mellitus, % Ulcer or stomach problem, % Cancer, % RA disease characteristics MD-HAQ (range 0–3) ESR, mm/hour hsCRP, mg/dl DAS28 DAS28 state Remission Low disease activity Moderate disease activity High disease activity Tender joint count (range 0–28) Swollen joint count (range 0–28) Pain (range 0–10) Patient global well-being (range 0–100 mm) Provider global well-being (range 0–100 mm) RAPID-3 score (range 0–10) Subcutaneous nodules, % RF positivity, % RF concentration, IU/ml Anti-CCP positivity, % Anti-CCP concentration, U/ml Shared epitope, % Radiographic changes, % Medications Prednisone, % Methotrexate, % Sulfasalazine, % Hydroxychloroquine, % Leflunomide, % NSAIDs, % Anti-TNF agent, % Any biologic agent, %

Baseline characteristics by cause of death* All patients (n 5 1,652)

CVD death (n 5 105)

Cancer death (n 5 76)

Respiratory death (n 5 50)

Other death (n 5 101)

64.6 6 10.4 79.3 84.4

71.0 6 8.3 90.5 77.5

69.7 6 9.4 84.2 79.0

71.0 6 8.8 90.0 61.4

71.0 6 9.6 85.2 84.8

17.7 55.3 27.1 11.8 6 11.6 28.2 6 5.4

19.1 62.9 18.1 13.8 6 11.2 26.3 6 5.4

9.2 56.6 34.2 13.5 6 12.4 26.3 6 5.1

12.0 58.0 30.0 17.4 6 15.0 26.6 6 5.8

25.7 53.5 20.8 16.5 6 14.2 26.2 6 5.3

4.6 25.0 38.8 21.7 10.1 4.5 6 3.9

12.9 34.4 31.2 14.0 7.5 4.9 6 2.5

13.6 27.3 39.4 12.1 7.6 4.8 6 2.9

12.5 27.1 45.8 6.3 8.3 5.0 6 4.1

11.6 28.1 38.4 14.0 7.0 4.9 6 3.0

2.4 6 1.7 22.3 20.3 3.8 59.9 35.4 1.9 18.0 24.5 4.7 15.1

3.1 6 1.7 46.7 48.6 6.7 71.4 47.6 1.9 15.2 24.8 8.6 11.4

2.7 6 1.7 26.3 19.7 2.6 60.5 48.7 5.3 10.5 11.8 7.9 27.6

3.1 6 1.6 32.0 34.0 8.0 50.0 64.0 0.0 18.0 26.0 0.0 12.0

2.7 6 1.5 18.8 30.7 5.0 65.4 39.6 0.0 17.8 32.7 4.0 15.8

0.9 6 0.6 26.7 6 23.7 1.3 6 2.1 3.7 6 1.5

1.1 6 0.6 37.6 6 29.5 2.0 6 2.8 4.1 6 1.4

1.0 6 0.6 35.0 6 27.5 2.0 6 2.9 3.8 6 1.4

1.1 6 0.6 42.7 6 37.0 1.7 6 2.0 3.9 6 1.6

1.1 6 0.7 33.3 6 24.1 1.6 6 2.2 3.9 6 1.5

22.0 14.7 39.6 23.7 5.4 6 7.0 4.5 6 5.6 4.5 6 2.8 40.8 6 25.3 35.4 6 23.2 3.9 6 2.1 31.4 80.8 354.3 6 739.7 78.6 263.5 6 427.5 72.3 53.6

9.8 11.8 46.1 32.4 5.8 6 7.4 5.0 6 5.9 4.7 6 2.7 44.0 6 27.1 41.6 6 22.0 4.2 6 2.1 47.6 87.1 455.4 6 910.7 76.2 286.9 6 415.9 62.0 62.0

16.0 16.0 48.0 20.0 4.8 6 6.8 4.1 6 6.0 4.9 6 2.7 41.2 6 25.7 26.4 6 19.6 4.1 6 2.1 32.9 77.8 410.3 6 681.6 75.0 381.6 6 614.2 75.0 55.1

16.3 22.5 34.7 26.5 4.6 6 6.0 4.6 6 5.0 4.3 6 3.0 43.5 6 26.8 47.2 6 21.5 4.1 6 2.1 48.0 86.0 406.8 6 630.8 76.0 276.3 6 459.9 79.2 60.5

22.5 9.2 39.8 28.6 5.6 6 7.2 4.2 6 5.0 4.8 6 2.8 42.4 6 24.7 40.6 6 22.2 4.2 6 2.0 47.5 79.8 337.9 6 646.5 76.8 373.1 6 657.6 73.7 66.7

43.5 54.6 15.5 33.6 12.2 35.3 25.2 26.2

60.4 48.5 15.8 31.7 18.8 35.2 29.5 29.5

46.5 46.5 11.3 32.4 8.5 25.0 19.7 22.4

51.0 53.1 14.3 34.7 12.2 38.0 24.0 28.0

48.4 52.6 13.7 27.4 15.8 31.7 19.8 19.8

* Values are the mean 6 SD unless otherwise indicated. CVD 5 cardiovascular disease; BMI 5 body mass index; RDCI 5 Rheumatic Disease Comorbidity Index; MI 5 myocardial infarction; RA 5 rheumatoid arthritis; MD-HAQ 5 Multidimensional Health Assessment Questionnaire; ESR 5 erythrocyte sedimentation rate; hsCRP 5 high-sensitivity C-reactive protein; DAS28 5 Disease Activity Score in 28 joints; RAPID-3 5 Routine Assessment of Patient Index Data 3; RF 5 rheumatoid factor, anti-CCP 5 anti–cyclic citrullinated peptide; NSAID 5 nonsteroidal antiinflammatory drug; anti-TNF 5 anti–tumor necrosis factor.

Veterans With RA and Cause-Specific Mortality demonstrated to be a robust predictor of mortality in the VARA registry (25). Vital status. Patients were followed longitudinally from the time of enrollment to death or through December 31, 2013, whichever occurred first. Vital status and cause of death were determined through linkage with the National Death Index (NDI) (National Center for Health Statistics, US Department of Health and Human Services). Primary cause of death was obtained from the NDI and coded according to the International Classification of Diseases, Tenth Edition (ICD-10). Cause of death was assigned to CVD-related for ICD-10 codes within Chapter IX (I00–I99), cancer for codes within Chapter II (C00–D48) and respiratory-related for codes within Chapter X (J00–J99). Cause of death was determined to be “other” if ICD-10 codes were not within one of the previously mentioned categories. COD was further detailed within CVD-related, cancer, and respiratory-related causes by using the HCUP-CCS. Statistical analysis. Crude mortality rates, age-adjusted SMRs, and corresponding 95% confidence intervals (95% CIs) were calculated for all-cause, CVD-related, cancer, and respiratory-related deaths using US life tables for men from 2000 through 2012. Life tables were obtained from the Centers for Disease Control and Prevention Wonder Online Database (http://wonder.cdc.gov). To explore associations of disease activity level with cause-specific mortality, we calculated SMRs based on DAS28 categories defined as scores ,2.6 (remission), $2.6 and ,3.2 (low), $3.2 and #5.1 (moderate), and .5.1 (high) at enrollment for all-cause mortality and the previously mentioned causes. Population values were not available for ages $85 years, so death rates from the 80- to 84-year-old age group were used. Life tables specific to US veterans were not available for these analyses. Age-adjusted associations with all-cause mortality were examined using Cox proportional hazards regression for patient characteristics (race, education [high school graduate/ nonhigh-school graduate], enrollment BMI, RDCI score, smoking status), disease characteristics (joint counts, disease activity measures, inflammatory markers, radiograph changes, subcutaneous nodules), and medications (methotrexate [MTX], biologic agents, hydroxychloroquine, sulfasalazine, leflunomide, prednisone, and nonsteroidal antiinflammatory drugs [NSAIDs]). Age-adjusted associations with cause-specific mortality were examined using competing-risks regression with the same previously mentioned variables to account for the obscuring of associations between risk factors and independent causes of death (26). Disease characteristics (ESR, DAS28, RAPID-3, etc.) were examined as time-varying covariates, except for those collected only at enrollment (RF, anti-CCP, shared epitope, and hsCRP). Medications were examined at enrollment and as time-varying covariates. Standard error adjustment was applied to all models to account for clustering by enrollment site (n 5 12 sites). Covariates included in multivariable analyses of allcause mortality were selected based on prior work from this cohort (4) with the exception that the RDCI was used as the measure of comorbidity. Additionally, we examined enrollment DAS28 categories rather than RAPID-3 and

39 ESR scores. Enrollment BMI was modeled in categories (#20, .20 to #25, .25 to #30, .30 to #35, and .35 kg/ m2) with the .20 to #25 kg/m2 group serving as the reference group, recognizing its U-shaped relationship with survival (4,27). Enrollment medications were used in multivariable regression to mitigate channeling bias, which was most evident in age-adjusted cancer mortality analyses. For disease-modifying antirheumatic drugs (DMARDs), a hierarchical model was constructed, with drug categories being MTX, biologic agents, and non-MTX/nonbiologic DMARDs (reference group). To allow for comparisons across models, the same covariates used in the all-cause analysis were adopted in analyses of cause-specific mortality with the addition of pertinent enrollment comorbidities for each cause of death as suggested by Michaud and Wolfe (28). These comorbidities were prior myocardial infarction, atherosclerosis, or other heart disease for CVD-related mortality; prior cancer for cancer mortality; and prior lung disease for respiratory-related mortality. A Cox proportional hazards model was used for all-cause mortality and a competing-risks regression model was used for causespecific mortality. All analyses were conducted using Stata, version 12.1.

RESULTS Baseline characteristics. There were 1,652 men with RA included in the study and 332 deaths occurred over a cumulative followup period of 6,141 patient-years. Baseline patient characteristics, RA disease features, and medications for the overall cohort in addition to each cause of death group are shown in Table 1. Patients had a mean age of 64.6 years, were predominantly white (79.3%), had frequent smoking history (82.4% current or former), high levels of comorbidity (mean RDCI 2.4), and long disease duration (mean 11.8 years). A majority of patients were seropositive for RF (80.8%) or anti–CCP antibody (78.6%). Cause of death and mortality rates. Cause of death is summarized in Figure 1. CVD-related was the leading cause of death category (n 5 105, 31.6%), followed by cancer (n 5 76, 22.9%) and respiratory-related causes (n 5 50, 15.1%). CVD-related death was most commonly due to coronary artery disease (n 5 45), congestive heart failure (n 5 13), and stroke (n 5 13). Cancer death was most commonly due to lung cancer (n 5 34), leukemia (n 5 7), lymphoma (n 5 6), and prostate malignancy (n 5 6). Respiratoryrelated death was most commonly due to chronic obstructive pulmonary disease (COPD; n 5 28) and ILD (n 511). RA was listed as the cause of death in 5.4% of deaths. Crude mortality rates per 1,000 patient-years were 54.1 (95% CI 48.6–60.2) for all-cause, 17.1 (95% CI 14.1–20.7) for CVD-related, 12.4 (95% CI 9.9–15.5) for cancer, and 8.1 (95% CI 6.2–10.7) for respiratory-related disease. Corresponding SMRs were 1.97 (95% CI 1.77–2.19) for all-cause, 1.77 (95% CI 1.46–2.14) for CVD-related, 1.50 (95% CI 1.20–1.89) for cancer, and 2.90 (95% CI 2.20– 3.83) for respiratory-related deaths (Figure 2). SMRs were lowest for each cause of death in patients who were in DAS28 remission at enrollment. SMRs for those in remis-

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England et al

Figure 1. Cause of death among male US veterans with rheumatoid arthritis. Cause of death for the 332 patients who died during followup was obtained from the National Death Index and coded according to the International Classification of Diseases, Tenth edition. COPD 5 chronic obstructive pulmonary disease.

sion were 1.26 (95% CI 0.96–1.65) for all-cause, 0.68 (95% CI 0.37–1.27) for CVD-related, 0.97 (95% CI 0.55–1.70) for cancer, and 1.85 (95% CI 0.92–3.69) for respiratory-related deaths. The highest SMRs for both all-cause (2.59 [95% CI 2.10–3.19]) and CVD-related (2.75 [95% CI 1.96–3.87])

deaths were for those in high disease activity at enrollment. For cancer and respiratory-related deaths, SMRs were similar and demonstrated overlapping CIs for low, moderate, and high disease activity categories, with patients in the low disease activity category having the

Figure 2. Standardized mortality ratios for cause-specific mortality by enrollment DAS-28 state in men with rheumatoid arthritis. Age-adjusted SMRs and 95% confidence intervals (95% CIs) were calculated for all-cause, cardiovascular, cancer, and respiratory deaths using US life tables for men from 2000 through 2012 from the Centers for Disease Control and Prevention. SMR 5 standardized mortality ratio; DAS-28 5 Disease Activity Score in 28 joints.

Veterans With RA and Cause-Specific Mortality

Table 2.

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Age-adjusted associations with all-cause and cause-specific mortality*

Characteristic Demographics White High-school education Tobacco use at enrollment Former Current Disease duration at enrollment, years BMI, kg/m2 BMI category, kg/m2 ,20 20 to 25 .25 to #30 .30 to #35 .35 Mean rheumatology visits per year Comorbidities RDCI score MI or atherosclerosis Other CVD Cancer Lung disease RA disease characteristics MD-HAQ ESR per 10 mm/hour hsCRP per 1 mg/dL§ DAS28 DAS28, enrollment Remission Low disease activity Moderate disease activity High disease activity Tender joint count Swollen joint count Pain Patient global well-being per 10 mm Provider global well-being per 10 mm RAPID-3 score Subcutaneous nodules RF positivity§ RF concentration per 100 IU/ml§ Anti-CCP positivity§ Anti-CCP concentration per 100 U/ml§ Shared epitope§ Radiographic changes Enrollment medications Prednisone Methotrexate Sulfasalazine Hydroxychloroquine Leflunomide NSAIDs Anti-TNF agent Any biologic agent Time-varying medications Prednisone Methotrexate Sulfasalazine Hydroxychloroquine Leflunomide NSAIDs Anti-TNF agent Any biologic agent

All-cause

CVD

Cancer

Respiratory

1.62 (1.37–1.91)† 0.85 (0.55–1.30)

2.13 (1.49–3.05)† 0.91 (0.51–1.63)

1.18 (0.76–1.84) 0.94 (0.33–2.71)

1.94 (0.93–4.03) 0.39 (0.33–0.47)†

1.10 (0.85–1.42) 1.73 (1.49–2.00)† 1.01 (1.00–1.02)† 0.95 (0.94–0.96)†

1.08 (0.44–2.64) 1.02 (0.40–2.64) 1.00 (0.99–1.01) 0.96 (0.93–0.99)‡

2.02 (1.13–3.59)‡ 4.29 (1.91–9.63)† 1.00 (0.98–1.02) 0.95 (0.92–0.99)†

1.53 (0.72–3.29) 3.14 (1.54–6.38)† 1.02 (1.01–1.04)† 0.97 (0.94–1.01)

2.75 (2.15–3.52)† Reference 0.94 (0.69–1.29) 0.64 (0.47–0.88)† 0.96 (0.73–1.25) 1.05 (1.03–1.07)†

1.91 (1.34–2.70)† Reference 0.66 (0.33–1.34) 0.66 (0.31–1.39) 0.86 (0.61–1.22) 1.05 (1.03–1.08)†

2.55 (1.48–4.40)† Reference 1.06 (0.64–1.75) 0.69 (0.41–1.19) 0.95 (0.52–1.74) 1.05 (1.03–1.06)†

2.39 (1.08–5.30)‡ Reference 1.26 (0.68–2.36) 0.38 (0.12–1.19) 1.20 (0.68–2.13) 1.06 (1.03–1.08)†

1.15 (1.12–1.19)† — — — —

1.23 (1.11–1.36)† 2.68 (2.00–3.61)† 3.14 (2.52–3.91)† — —

1.06 (0.98–1.15) — — 1.92 (1.56–2.37)† —

1.20 (1.15–1.25)† — — — 2.94 (2.42–3.58)†

2.12 1.19 1.11 1.26

1.49 1.12 1.12 1.28

(1.16–1.90)† (1.08–1.16)† (1.05–1.19)† (1.15–1.43)†

1.44 (1.24–1.67)† 1.19 (1.13–1.25)† 1.12 (1.07–1.17)† 1.11 (0.98–1.24)

2.68 1.19 1.06 1.23

Reference 1.55 (1.22–1.95)† 1.58 (1.22–2.04)† 2.06 (1.62–2.63)† 1.02 (1.01–1.03)† 1.02 (1.01–1.03)† 1.08 (1.03–1.13)† 1.20 (1.15–1.26)† 1.25 (1.20–1.30)† 1.24 (1.17–1.32)† 1.65 (1.29–2.11)† 1.21 (0.94–1.55) 1.01 (1.00–1.02)‡ 1.03 (0.96–1.11) 1.02 (1.01–1.03)† 0.96 (0.81–1.13) 1.19 (1.06–1.33)†

Reference 2.09 (1.30–3.34)† 2.68 (1.36–5.26)† 3.71 (1.89–7.27)† 1.02 (0.98–1.05) 1.05 (1.02–1.09)† 1.03 (0.99–1.08) 1.10 (1.06–1.14)† 1.15 (1.11–1.19)† 1.12 (1.09–1.15)† 1.75 (1.33–2.31)† 1.73 (1.23–2.43)† 1.02 (1.01–1.03)† 1.01 (0.74–1.38) 1.00 (0.98–1.03) 0.61 (0.38–0.97)‡ 1.18 (0.86–1.62)

Reference 1.67 (0.88–3.19) 1.69 (1.08–2.64)‡ 1.27 (0.78–2.07) 0.99 (0.93–1.05) 0.98 (0.96–1.01) 1.02 (0.93–1.12) 1.18 (1.13–1.24)† 1.15 (1.05–1.25)† 1.13 (1.03–1.23)‡ 1.23 (0.85–1.78) 0.86 (0.60–1.23) 1.01 (0.99–1.04) 0.94 (0.53–1.65) 1.03 (1.00–1.07) 1.16 (0.85–1.58) 1.05 (0.77–1.42)

Reference 2.36 (1.31–4.26)† 1.17 (0.65–2.11) 1.78 (0.92–3.45) 0.99 (0.96–1.02) 0.98 (0.92–1.04) 1.14 (1.03–1.26)‡ 1.17 (1.10–1.24)† 1.26 (1.22–1.30)† 1.29 (1.12–1.48)† 2.35 (1.03–5.38)‡ 1.60 (0.80–3.17) 1.01 (0.99–1.04) 1.00 (0.75–1.34) 1.00 (0.96–1.03) 1.51 (0.81–2.81) 1.05 (0.60–1.85)

1.35 (1.16–1.57)† 0.68 (0.52–0.87)† 0.97 (0.71–1.33) 0.94 (0.79–1.11) 1.11 (0.71–1.71) 0.83 (0.73–0.94)† 1.01 (0.85–1.20) 1.05 (0.86–1.27)

1.72 (1.08–2.74)‡ 0.72 (0.60–0.85)† 1.13 (0.72–1.77) 0.88 (0.67–1.15) 1.52 (0.67–3.48) 1.03 (0.58–1.80) 1.38 (1.09–1.75)† 1.39 (1.07–1.81)‡

1.00 (0.65–1.54) 0.63 (0.42–0.93)‡ 0.82 (0.43–1.55) 0.96 (0.74–1.26) 0.56 (0.28–1.12) 0.59 (0.34–1.01) 0.81 (0.50–1.31) 0.92 (0.54–1.57)

1.42 (1.04–1.93)‡ 0.94 (0.57–1.55) 1.15 (0.45–2.97) 1.29 (0.98–1.71) 0.88 (0.44–1.76) 1.09 (0.57–2.09) 1.11 (0.64–1.91) 1.20 (0.69–2.08)

1.57 (1.37–1.79)† 0.56 (0.49–0.63)† 0.90 (0.68–1.19) 1.11 (0.93–1.32) 0.99 (0.68–1.44) 0.79 (0.65–0.96)‡ 0.65 (0.55–0.76)† 0.65 (0.54–0.79)†

1.91 (1.61–2.28)† 0.62 (0.52–0.74)† 1.01 (0.70–1.45) 1.27 (0.78–2.06) 1.22 (0.71–2.09) 0.68 (0.45–1.03) 1.06 (0.85–1.33) 0.95 (0.77–1.18)

1.17 (0.83–1.64) 0.48 (0.26–0.88)‡ 0.90 (0.52–1.53) 1.08 (0.66–1.79) 0.78 (0.47–1.28) 0.71 (0.39–1.30) 0.40 (0.28–0.58)† 0.44 (0.32–0.60)†

1.39 (1.06–1.83)† 0.66 (0.35–1.26) 0.76 (0.25–2.44) 1.16 (0.77–1.75) 1.08 (0.45–2.61) 1.27 (0.75–2.13) 1.04 (0.68–1.58) 1.04 (0.66–1.64)

(1.86–2.41)† (1.14–1.24)† (1.08–1.15)† (1.19–1.33)†

(1.69–4.25)† (1.12–1.27)† (1.00–1.12)‡ (1.07–1.42)†

* Values are the hazard ratio (95% confidence interval), calculated using Cox proportional hazards for all-cause and competing-risks regression for cardiovascular, cancer, and respiratory deaths. CVD 5 cardiovascular disease; BMI 5 body mass index; RDCI 5 Rheumatic Disease Comorbidity Index; MI 5 myocardial infarction; RA 5 rheumatoid arthritis; MD-HAQ 5 Multidimensional Health Assessment Questionnaire; ESR 5 erythrocyte sedimentation rate; hsCRP 5 high-sensitivity C-reactive protein; DAS28 5 Disease Activity Score in 28 joints; RAPID-3 5 Routine Assessment of Patient Index Data 3; RF 5 rheumatoid factor; anti-CCP 5 anti–cyclic citrullinated peptide; NSAIDs 5 nonsteroidal antiinflammatory drugs; antiTNF 5 anti–tumor necrosis factor. † P , 0.01. ‡ P , 0.05. § Measured off banked serum from enrollment.

42

England et al

Table 3.

Multivariable associations with all-cause and cause-specific mortality*

Characteristic Demographics Age White Tobacco use at enrollment Never Former Current BMI, kg/m2 ,20 20 to 25 .25 to # 30 .30 to # 35 .35 Mean rheumatology visits per year Comorbidities RDCI score MI or atherosclerosis Other CVD Cancer Lung disease RA disease characteristics Enrollment DAS28 Remission Low Moderate High Subcutaneous nodules RF concentration per 100 IU/ml§ Enrollment medications Prednisone DMARDs Non-MTX/nonbiologic agent MTX Biologic agent

All-cause

CVD

Cancer

Respiratory

1.08 (1.05–1.10)† 1.69 (1.48–1.93)†

1.05 (1.02–1.08)† 2.62 (1.34–5.13)†

1.06 (1.02–1.10)† 1.04 (0.57–1.89)

1.06 (1.00–1.12)‡ 2.62 (1.04–6.64)†

Reference 1.25 (0.88–1.77) 1.54 (1.08–2.20)‡

Reference 0.94 (0.42–2.10) 0.57 (0.17–1.87)

Reference 3.44 (1.98–5.97)† 6.98 (3.02–16.14)†

Reference 1.62 (0.62–4.23) 2.10 (0.70–6.35)

2.39 (1.84–3.09)† Reference 0.89 (0.67–1.18) 0.60 (0.47–0.75)† 1.03 (0.81–1.30) 1.06 (1.03–1.08)†

1.42 (0.52–3.90) Reference 0.60 (0.39–0.93)‡ 0.48 (0.21–1.08) 0.75 (0.54–1.03) 1.06 (1.04–1.09)†

1.74 (0.78–3.90) Reference 0.86 (0.36–2.10) 0.67 (0.30–1.49) 0.88 (0.22–3.56) 1.04 (1.02–1.07)†

2.39 (1.12–5.10)‡ Reference 1.07 (0.44–2.61) 0.34 (0.08–1.40) 1.53 (0.70–3.34) 1.07 (1.04–1.11)†

1.14 (1.09–1.20)† — — — —

1.07 (0.93–1.22) 1.73 (1.16–2.57)† 2.50 (1.73–3.62)† — —

0.97 (0.89–1.05) — — 2.03 (1.49–2.75)† —

1.00 (0.87–1.15) — — — 2.40 (1.52–3.78)†

Reference 1.40 (1.12–1.76)† 1.35 (1.04–1.75)‡ 1.50 (1.24–1.81)† 1.48 (1.07–2.05)‡ 1.01 (0.99–1.02)

Reference 2.76 (1.41–5.41)† 2.92 (1.60–5.36)† 3.62 (1.66–7.88)† 1.63 (1.00–2.65)‡ 1.02 (1.00–1.04)‡

1.01 1.51 0.91 0.86 1.00

1.30 (1.06–1.59)‡

1.41 (0.86–2.31)

0.96 (0.40–2.32)

1.32 (0.87–2.01)

Reference 0.86 (0.55–1.32) 1.04 (0.77–1.40)

Reference 0.83 (0.49–1.41) 1.25 (0.78–1.99)

Reference 1.12 (0.48–2.60) 1.44 (0.92–2.25)

Reference 0.79 (0.49–1.27) 0.83 (0.41–1.65)

Reference (0.49–2.09) (0.90–2.55) (0.44–1.89) (0.50–1.49) (0.97–1.03)

Reference 2.23 (1.08–4.61)‡ 0.90 (0.42–1.92) 1.37 (0.66–2.84) 1.89 (0.96–3.72) 0.98 (0.92–1.03)

* Values are the hazard ratio (95% confidence interval), calculated using Cox proportional hazards for all-cause and competing-risks regression for CVD, cancer, and respiratory mortality. CVD 5 cardiovascular disease; BMI 5 body mass index; RDCI 5 Rheumatic Disease Comorbidity Index; MI 5 myocardial infarction; RA 5 rheumatoid arthritis; DAS28 5 Disease Activity Score in 28 joints; RF 5 rheumatoid factor; DMARDs 5 diseasemodifying antirheumatic drugs; MTX 5 methotrexate. † P , 0.01. ‡ P , 0.05. § Measured off banked serum from enrollment.

highest SMRs (cancer 1.76 [95% CI 1.00–3.10]; and respiratory 4.86 [95% CI 2.69–8.77]) (Figure 2). Age-adjusted associations with all-cause and causespecific mortality. Age-adjusted associations of patient characteristics with all-cause and cause-specific mortality are shown in Table 2. After accounting for age, white race was associated with an increased risk of all-cause mortality (hazard ratio [HR] 1.62 [95% CI 1.37–1.91]; P , 0.01), a risk that appeared to be greatest for CVD-related mortality. Current smoking was associated with an increased risk of all-cause, cancer, and respiratory-related deaths but not CVD-related mortality, while former smoking was associated only with cancer-specific mortality. Factors associated with both all-cause and cause-specific mortality in ageadjusted analyses included low body weight (BMI #20 kg/ m2), increased visit frequency, and measures indicative of

higher disease activity (MD-HAQ, ESR, hsCRP, DAS28, disease activity categories at enrollment, RAPID-3, and both patient and provider global well-being scores). A lower all-cause mortality risk was seen in association with BMI .30 kg/m2 and #35 kg/m2 and high school or greater education level was associated with a lower respiratory mortality risk. Enrollment and time-varying prednisone use were associated with an increased risk of all-cause, CVD-related, and respiratory-related mortality. Enrollment and time-varying NSAID use were associated with decreased risk of all-cause mortality. Both enrollment and time-varying MTX use were also associated with decreased risk of all-cause, CVD-related, and cancer mortality. Enrollment biologic agent use was associated with an increased risk of CVD-related mortality, whereas time-varying biologic agent use was associated with a decreased risk of allcause and cancer mortality.

Veterans With RA and Cause-Specific Mortality Multivariable associations with cause-specific mortality. Multivariable associations of patient factors with all-cause and cause-specific mortality are shown in Table 3. After multivariable adjustment, patient characteristics associated with increased risk of all-cause mortality were older age, white race, current smoking, a BMI #20 kg/m2, visit frequency, RDCI score, disease activity at enrollment, subcutaneous nodules, and prednisone use at enrollment. Associations of these factors with cause-specific mortality were more variable, with age and visit frequency being the only factors consistently associated with individual causes of death. White race was associated with CVD- and respiratory-related mortality, and current and former smoking were associated with only cancer mortality. A BMI of .25 to #30 kg/m2 was associated with decreased risk of CVD-related mortality, and a BMI of .30 to #35 kg/m2 trended toward a protective association but did not reach statistical significance. A BMI #20 kg/m2 was associated with increased risk of respiratory death. Individual comorbidities, rather than the RDCI score, were more closely associated with cause-specific mortality. In examining RA disease characteristics, we observed that subcutaneous nodules were associated with an increased risk of CVD-related and a trend toward an association with respiratory-related mortality, while RF concentration was associated with an increased risk of CVD-related mortality. Low, moderate, and high disease activity were associated with increased risk of CVD-related mortality while low disease activity alone was associated with increased risk of respiratory-related death referent to those in remission. After adjusting for multiple covariates, prednisone use at enrollment was associated with increased risk of CVD-related mortality, although this did not reach statistical significance (HR 1.41 [95% CI 0.86– 2.31]; P 5 0.17). No association was seen between prednisone use and cancer or respiratory-related mortality. There were no associations of MTX or biologic agent use at enrollment with either all-cause or cause-specific mortality referent to non-MTX/nonbiologic DMARD use. Sensitivity analyses were conducted, dividing those taking biologic agents into those also taking MTX and those taking biologic agents in the absence of MTX (biologic monotherapy) groups. Fifty-two percent of patients taking biologic agents at enrollment were also taking MTX. In our multivariable model we found biologic monotherapy to be associated with an increased risk of all-cause mortality (HR 1.46 [95% CI 1.14–1.87]; P 5 0.003).

DISCUSSION To our knowledge, this is the first study to examine both the rates and determinants of all-cause and cause-specific mortality in men with RA. In this high-risk population of male US veterans with established RA, we observed an approximately 2-fold increase in all-cause mortality risk. As anticipated, we found CVD-related mortality to be the leading cause of death in this group, accounting for approximately 1 of every 3 deaths observed. Notably, we identified respiratory-related mortality as being the most overrepresented cause of death in men with RA, with a corresponding mortality risk that was almost 3 times that of age- and

43 race-matched men from the general population. Likewise, cancer deaths were 50% higher in this cohort than in population controls. Importantly, we identified several potentially modifiable factors to be associated with mortality in this analysis, including factors such as smoking, BMI, prednisone use, and increased disease activity. In contrast with those with higher disease activity, those in disease remission at enrollment demonstrated mortality risks that were not substantially elevated compared to population norms. Higher disease activity at enrollment was associated with both all-cause and cause-specific mortality, demonstrating a striking dose-dependent relationship with cardiovascular death, i.e., results not apparent among the individuals dying from cancer and respiratory-related causes. This may reflect a lack of power in the cancer and respiratory subgroups or, more interestingly, suggest that the mechanisms underlying disease activity in RA contribute more to CVD than malignant and respiratory processes. Together, these findings suggest that interventions focused on smoking cessation, optimizing body weight, reducing prednisone use, and achieving and maintaining tight disease control may prolong survival. There has been substantial investigation into the potential benefits of DMARDs in RA with respect to mortality (29–32). Aside from the previously mentioned association with prednisone use, no significant mortality benefit with either MTX or biologic agent use (including anti–tumor necrosis factor [anti-TNF] drugs), was observed after accounting for other factors, including disease activity. Referent to other non-MTX/nonbiologic DMARDs, RA patients taking MTX in our study demonstrated a 15% lower risk of all-cause and CVD-related mortality, although neither of these associations reached statistical significance. In sensitivity analyses, biologic monotherapy was associated with a 46% increased risk of all-cause mortality. These results differ from previous work showing an approximately 70% reduction in CVD-related deaths associated with MTX use (30) and a more recent study showing an approximately 60% reduction in composite CVD outcomes associated with anti-TNF use, including, but not limited to, fatal events (31). These discrepancies may relate to the striking differences in study populations examined, as prior studies included predominantly women (with women comprising ;70% to 75% of the study population) with substantially lower rates of comorbidity and smoking (30,31). In addition, this study included more than 100 CVD-related deaths, whereas the former studies were smaller in comparison, with 84 (30) and 17 (31) reported CVD-related deaths, respectively. Statistical analyses also differed between studies, with a competingrisks regression model rather than a Cox proportional hazards regression model being used in this study of causespecific mortality. Although the sample size was reduced, our sensitivity analyses suggest that biologic therapy in combination with MTX may have more benefit in reducing mortality than biologic monotherapy. Consistent with a prior report from this population (4) and others (33,34), we found that all-cause mortality was approximately 2-fold higher among whites than nonwhites. Further insight provided by this analysis suggests that the increased overall risk appears to be driven by

44 CVD- and respiratory-related mortality, with a nearly 3fold corresponding risk. We observed no difference in the risk of cancer death based on race. The reasons underpinning the higher CVD- and respiratory-related mortality observed among white men with RA are unknown, but it clearly warrants further study. In contrast to prior studies showing that respiratory disease accounts for only #9% of all deaths (1), we found this to be the most overrepresented cause of death, accounting for approximately 1 of every 6 deaths (15%) among male veterans with RA. While this could in part be explained by the high prevalence of smoking and existing lung disease, multivariable analyses revealed that RA characteristics, including disease activity and subcutaneous nodules (but not smoking), were most strongly associated with the risk of respiratory mortality. The most common respiratory causes of death were COPD (56% of all respiratory deaths) followed by ILD (22%), conditions that are known to be overrepresented in RA (16,35) with disease-related ILD in particular reported to disproportionately affect men (15). It is important to note, however, that these findings parallel recent preliminary observations from a large prospective cohort of women with RA, recently reported to have a 4-fold increased risk of respiratory mortality compared to unaffected women (36). In this study, malignancy accounted for nearly onefourth of all deaths, with lung cancer accounting for almost half of the mortality in this category. This appears to reflect, again, the high frequency of smoking in this population. Indeed, we observed robust associations of both current and former smoking with cancer mortality. In addition to smoking, prevalent malignancy and older age were independently associated with cancer mortality. In contrast to prior reports (34,37), we observed no relationship between anti–CCP antibody (concentration or positivity) or shared epitope status with mortality. In addition to disease activity, other RA-related factors independently associated with mortality were subcutaneous nodules and higher RF concentration. Examinations of cause-specific mortality suggest that the association of RF titers and nodules with mortality appears to be driven by their associations with CVD-related mortality, though nodules also approached an association with respiratory-related deaths. Additional studies will be needed in order to identify whether RF is directly pathogenic in CVD or simply serves as a surrogate marker of disease severity and hence increased risk. Likewise, further study will be needed to understand the potential links between subcutaneous nodules and long-term mortality outcomes in RA. There are limitations to this study. Because of the unique attributes of the VA (38), results from this study may not be readily generalizable to other male RA cohorts. However, as the largest integrated health system in the US, the VA provides a unique setting for the study of health outcomes in RA, because it is an environment with relatively uniform benefits that serve to mitigate the confounding effects of differences in health care access. The NDI obtains cause of death from death certificates and this may serve as a source of misclassification. Despite this limitation, the NDI frequently serves as the gold standard for vital status assessment and cause of death ascertain-

England et al ment, correctly classifying vital status in .95% of veterans in a previous study (39). With more than 1,600 male veterans available for this study and more than 330 deaths observed, we were able to examine both all-cause and cause-specific mortality. An additional strength of this cohort is the wealth of information that was available, including longitudinal followup of disease activity, data from standardized assays using banked biospecimens, and a robust linkage with national VA administrative data sets and the NDI. The findings in this study begin to fill important gaps in our understanding of patient characteristics associated with mortality in men with RA. Further studies investigating other potentially modifiable risk factors for causespecific mortality are needed. It is possible, for instance, that novel biomarkers could help optimize models examining cause-specific mortality risk, particularly when incorporated with the clinical characteristics that have been identified in this study. In turn, this may help to identify those at highest risk for premature mortality and allow implementation of targeted screening and therapies earlier in the disease course.

AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Mikuls had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. England, Caplan, Cannon, Mikuls. Acquisition of data. Caplan, Davis, Cannon, Reimold, Kerr, Mikuls. Analysis and interpretation of data. England, Sayles, Michaud, Caplan, Cannon, Sauer, Solow, Kerr, Schwab, Baker, Mikuls.

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