Downloaded from http://ard.bmj.com/ on November 14, 2015 - Published by group.bmj.com
ARD Online First, published on September 5, 2014 as 10.1136/annrheumdis-2014-205800 Clinical and epidemiological research
EXTENDED REPORT
Risk of deep venous thrombosis and pulmonary embolism in individuals with polymyositis and dermatomyositis: a general population-based study Erin C Carruthers,1 Hyon K Choi,1,2,3 Eric C Sayre,1 J Antonio Aviña-Zubieta1,3 Handling editor Tore K Kvien 1
Arthritis Research Centre of Canada, Richmond, British Columbia, Canada 2 Division of Rheumatology, Allergy and Immunology, Department of Rheumatology, Harvard Medical School, Boston, Massachusetts, USA 3 Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Correspondence to J Antonio Aviña-Zubieta, 5591 No. 3 Road, Richmond, BC, Canada V6X 2C7; [email protected] Received 23 April 2014 Revised 11 August 2014 Accepted 14 August 2014
ABSTRACT Background/objective Patients with polymyositis (PM) and dermatomyositis (DM) may have an increased risk of venous thromboembolism (VTE); however, no general population data are available to date. The purpose of this study was to estimate the future risk and time trends of new VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) in individuals with incident PM/DM at the general population level. Methods We assembled a retrospective cohort of all patients with incident PM/DM in British Columbia and a corresponding comparison cohort of up to 10 agematched, sex-matched and entry-time-matched individuals from the general population. We calculated incidence rate ratios (IRR) for VTE, DVT and PE and stratified by disease duration. We calculated HRs adjusting for relevant confounders. Results Among 752 cases with inflammatory myopathies, 443 had PM (58% female, mean age 60 years) and 355 had DM (65% female, mean age 56 years); 46 subjects developed both diseases. The corresponding IRRs (95% CI) for VTE, DVT and PE in PM were 8.14 (4.62 to 13.99), 6.16 (2.50 to 13.92) and 9.42 (4.59 to 18.70), respectively. Overall, the highest IRRs for VTE, DVT and PE were observed in the first year after PM diagnosis (25.25, 9.19 and 38.74, respectively). Fully adjusted HRs for VTE, DVT and PE remained statistically significant (7.0 (3.34 to 14.64), 6.16 (2.07 to 18.35), 7.23 (2.86 to 18.29), respectively). Similar trends were seen in DM. Conclusions These findings provide the first general population-based evidence that patients with PM/DM have an increased risk of VTE. Increased vigilance of this serious but preventable complication is recommended.
INTRODUCTION
To cite: Carruthers EC, Choi HK, Sayre EC, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis2014-205800
Inflammatory myopathies, including polymyositis (PM) and dermatomyositis (DM), are rare connective tissue diseases characterised by chronic muscle inflammation and weakness. Prevalence of these conditions is estimated to be between 5.4 and 21.5 per 100 000 in Canada.1 2 These systemic autoimmune rheumatic diseases are associated with increased morbidity and mortality, and a high economic burden.3 Prior to the introduction of corticosteroids in the treatment of PM/DM, the prognosis was extremely poor with a mortality rate as high as 50%–61%.4 Survival rates have significantly improved since then, but the overall risk of mortality is still high,
with recent studies showing a threefold5 to fourfold6 higher risk than the general population. While an increased risk of cardiovascular disease (CVD) has been shown in other autoimmune rheumatic diseases, including rheumatoid arthritis (RA),7–9 scleroderma,10 ankylosing spondylitis11 and systemic lupus erythematosus (SLE),12 13 data on CVD in patients with inflammatory myopathies are scarce and have focused almost entirely on atherosclerotic disease.14 15 Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE), and represents the third most common cardiovascular event after myocardial infarction and stroke.16 PE has a mortality rate of 15% in the first 3 months after diagnosis,17 making it potentially as deadly as acute myocardial infarction, and survivors often experience serious and costly longterm complications.18 The risk of VTE in individuals with inflammatory myopathies has largely been ignored despite several plausible mechanisms. Systemic inflammation associated with PM/DM may modulate thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis.16 Since the link between inflammation and VTE has started to emerge, some hospital-based studies have been conducted to investigate this association for a wide range of autoimmune diseases and have reported an increased risk of VTE in patients with inflammatory myopathies.19–22 However, their findings are limited because they are based on purely hospital-based samples and only one study21 was able to adjust for potential confounding factors and medication use. It is largely unknown whether the increased risk of VTE seen in these inpatient studies is applicable to PM/DM from the general population. Since PE represents a common and often fatal vascular event,23 accurate understanding of this risk among patients with inflammatory myopathies is crucial. To address this issue, we evaluated the risk of incident DVT and PE among incident patients with PM/DM compared with controls in an unselected general population context.
METHODS Data source Universal health coverage is a feature of the province of British Columbia (BC, population ∼4.7 million) in Canada. Population Data (PopData) BC (formerly known as the British Columbia Linked
EC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205800 1 Copyright Article author (orCarruthers their employer) 2014. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
Downloaded from http://ard.bmj.com/ on November 14, 2015 - Published by group.bmj.com
Clinical and epidemiological research Health Databases or BCLHD) captures population-based administrative data including linkable data files on all provincially funded healthcare professional visits, hospital admissions, interventions, investigations, demographic data, cancer registry and vital statistics since 1990. Furthermore, PopData BC encompasses the comprehensive prescription drug database, PharmaNet, with data since 1996. Numerous general population-based studies have been successfully conducted based on these databases.24–28
Study design We conducted matched cohort analyses for incident VTE (ie, DVT or PE) among individuals with incident PM (PM cohort) or DM (DM cohort) as compared with individuals without PM or DM (comparison cohorts) using data from PopData BC. For the comparison cohorts, we matched up to 10 individuals without PM/DM to each PM/DM case based on age, sex and calendar year of study entry randomly selected from the general population.
Incident PM/DM cohort We created incident PM and DM cohorts with cases diagnosed for the first time between January 1996 and December 2010 with no PM/DM history or diagnosis recorded over the prior 6 years (ie, from January 1990). Our study definition of PM and DM consisted of (a) ≥18 years of age; (b) one International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code by a rheumatologist (710.4 for PM; 710.3 for DM) or from a hospital (ICD-9-CM same as above, or ICD-10-CM M33.0, M33.1 or M33.9 for DM; M33.2 for PM) or (c) two ICD-9-CM codes for PM or DM at least 2 months and no more than 2 years apart by a non-rheumatologist physician. Similar PM/DM case definitions have been used in previous studies in Canada and found to have a specificity of 96.4% in the context of systemic autoimmune rheumatic diseases.29 To further improve specificity, we excluded individuals with at least two visits ≥2 months apart subsequent to the PM/DM diagnostic visit with other inflammatory disease diagnoses (eg, RA, psoriatic arthritis, spondyloarthropathies, SLE, giant cell arteritis).
Ascertainment of DVT and PE Incident DVT and PE cases were defined by a corresponding ICD code and prescription of anticoagulant therapy (heparin, warfarin sodium or a similar agent).30 The codes used were DVT (ICD-9-CM: 453; ICD-10-CM: I82.4, I82.9) and PE (ICD-9-CM: 415.1, 673.2, 639.6; ICD-10-CM: O88.2, I26). Since VTE is a potentially fatal disease, we also included patients with a fatal outcome. Because a patient may have died before anticoagulation treatment, patients with a recorded code of DVT or PE were included in the absence of recorded anticoagulant therapy if there was a fatal outcome within 2 months of diagnosis. These definitions have been successfully used in previous studies and found to have a positive predictive value of 94% in a general practice database.30
Assessment of covariates Covariates consisted of potential risk factors of VTE assessed during the year before the index date. These included relevant medical conditions (alcoholism, hypertension, varicose veins, inflammatory bowel disease, sepsis), trauma, fractures, surgery, healthcare use, and use of glucocorticoids, hormone
2
replacement therapy, contraceptives or COX-2 inhibitors. Additionally, a modified Charlson comorbidity index for administrative data was calculated in the year before index date.31 32
Cohort follow-up Our study cohorts spanned the period 1 January 1996 to 31 December 2010. Individuals with PM/DM entered the case cohort after all inclusion criteria had been met, and matched individuals entered the comparison cohort after a doctor’s visit or hospital admission in the same calendar year. Participants were followed until they either experienced an outcome, died, disenrolled from the health plan (ie, left BC, approximately 1% per year), or follow-up ended (31 December 2010), whichever occurred first.
Statistical analysis We compared baseline characteristics between PM/DM and control cohorts. We calculated incidence rates (IR) per 1000 person-years (PY) for respective outcomes for PM/DM and corresponding comparison cohorts. The associations between PM/ DM and study outcomes are expressed as incidence rate ratios (IRR) with 95% CIs. To evaluate the time-trend of VTE risk according to the time since PM/DM diagnosis, we estimated IRRs in 1-year intervals, starting in the first year after diagnosis and up to 5 years after diagnosis. We conducted Cox proportional hazard regressions33 to assess the adjusted relative risk (RR) of VTE, DVT and PE associated with PM/DM after stratifying by matched variables (baseline age and sex). These multivariable analyses were adjusted for all covariates listed above and the effect of PM/DM on study outcomes was expressed as HRs with 95% CIs. We also performed subgroup analyses according to sex. We performed three sensitivity analyses. First, analysis with a stricter definition of PM/DM exposure was used, limited to subjects with ICD codes for PM/DM and the use of antirheumatic medications including glucocorticoids, antimalarials, methotrexate and immunosuppressives between 1 month before and 6 months after the index date. Second, we estimated the cumulative incidence of each event accounting for the competing risk of death according to Lau et al34 and expressed the results as subdistribution HRs with 95% CIs. Third, to quantify the potential impact of unmeasured confounders, we performed sensitivity analyses, which assessed how a hypothetical unmeasured confounder might have affected our estimates of the association between PM/DM and risk of VTE.35 We simulated unmeasured confounders with their prevalences ranging from 10% to 20% in the PM/DM and comparison cohorts, and ORs for the associations between the unmeasured confounder and both VTE and the exposures ranging from 1.3 to 3.0. Analyses were performed with SAS software V.9.3 (SAS Institute, Cary, North Carolina, USA). For all RRs, we calculated 95% CIs. All p values are two-sided.
RESULTS Baseline characteristics We identified 443 new cases with PM and 355 cases with DM. For each case, 10 controls matched by birth year, sex and calendar year of follow-up were randomly selected from the general population to create control cohorts for PM (N=4603) and DM (N=3577). Table 1 summarises the baseline characteristics of the cohorts.
Carruthers EC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205800
Downloaded from http://ard.bmj.com/ on November 14, 2015 - Published by group.bmj.com
Clinical and epidemiological research Table 1 Characteristics of PM, DM and comparison cohorts at baseline Variable
PM n=443
Non-PM n=4603
p Value
DM n=355
Non-DM n=3577
p Value
Age, mean (SD) years Female Alcoholism Hypertension Sepsis Varicose veins Inflammatory bowel disease Trauma Fracture Surgery Glucocorticoids Hormone replacement therapy Contraceptives Cox-2 inhibitors Charlson’s comorbidity index, mean (SD) Number of hospitalisations, mean (SD) Number of outpatient visits, mean (SD)
60.39 (15.62) 257 (58.0) 5 (1.1) 136 (30.7) 3 (0.7) 3 (0.7) 3 (0.7) 1 (0.2) 14 (3.2) 4 (0.9) 203 (45.8) 30 (6.8) 7 (1.6) 33 (7.4) 1.39 (1.94) 0.9 (1.4) 129.54 (108.83)
60.53 2678 41 1222 8 49 8 19 69 30 186 220 89 145 0.44 0.3 38.33
NS NS NS NS NS NS NS NS 0.017 NS
ARD Online First, published on September 5, 2014 as 10.1136/annrheumdis-2014-205800 Clinical and epidemiological research
EXTENDED REPORT
Risk of deep venous thrombosis and pulmonary embolism in individuals with polymyositis and dermatomyositis: a general population-based study Erin C Carruthers,1 Hyon K Choi,1,2,3 Eric C Sayre,1 J Antonio Aviña-Zubieta1,3 Handling editor Tore K Kvien 1
Arthritis Research Centre of Canada, Richmond, British Columbia, Canada 2 Division of Rheumatology, Allergy and Immunology, Department of Rheumatology, Harvard Medical School, Boston, Massachusetts, USA 3 Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Correspondence to J Antonio Aviña-Zubieta, 5591 No. 3 Road, Richmond, BC, Canada V6X 2C7; [email protected] Received 23 April 2014 Revised 11 August 2014 Accepted 14 August 2014
ABSTRACT Background/objective Patients with polymyositis (PM) and dermatomyositis (DM) may have an increased risk of venous thromboembolism (VTE); however, no general population data are available to date. The purpose of this study was to estimate the future risk and time trends of new VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) in individuals with incident PM/DM at the general population level. Methods We assembled a retrospective cohort of all patients with incident PM/DM in British Columbia and a corresponding comparison cohort of up to 10 agematched, sex-matched and entry-time-matched individuals from the general population. We calculated incidence rate ratios (IRR) for VTE, DVT and PE and stratified by disease duration. We calculated HRs adjusting for relevant confounders. Results Among 752 cases with inflammatory myopathies, 443 had PM (58% female, mean age 60 years) and 355 had DM (65% female, mean age 56 years); 46 subjects developed both diseases. The corresponding IRRs (95% CI) for VTE, DVT and PE in PM were 8.14 (4.62 to 13.99), 6.16 (2.50 to 13.92) and 9.42 (4.59 to 18.70), respectively. Overall, the highest IRRs for VTE, DVT and PE were observed in the first year after PM diagnosis (25.25, 9.19 and 38.74, respectively). Fully adjusted HRs for VTE, DVT and PE remained statistically significant (7.0 (3.34 to 14.64), 6.16 (2.07 to 18.35), 7.23 (2.86 to 18.29), respectively). Similar trends were seen in DM. Conclusions These findings provide the first general population-based evidence that patients with PM/DM have an increased risk of VTE. Increased vigilance of this serious but preventable complication is recommended.
INTRODUCTION
To cite: Carruthers EC, Choi HK, Sayre EC, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis2014-205800
Inflammatory myopathies, including polymyositis (PM) and dermatomyositis (DM), are rare connective tissue diseases characterised by chronic muscle inflammation and weakness. Prevalence of these conditions is estimated to be between 5.4 and 21.5 per 100 000 in Canada.1 2 These systemic autoimmune rheumatic diseases are associated with increased morbidity and mortality, and a high economic burden.3 Prior to the introduction of corticosteroids in the treatment of PM/DM, the prognosis was extremely poor with a mortality rate as high as 50%–61%.4 Survival rates have significantly improved since then, but the overall risk of mortality is still high,
with recent studies showing a threefold5 to fourfold6 higher risk than the general population. While an increased risk of cardiovascular disease (CVD) has been shown in other autoimmune rheumatic diseases, including rheumatoid arthritis (RA),7–9 scleroderma,10 ankylosing spondylitis11 and systemic lupus erythematosus (SLE),12 13 data on CVD in patients with inflammatory myopathies are scarce and have focused almost entirely on atherosclerotic disease.14 15 Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE), and represents the third most common cardiovascular event after myocardial infarction and stroke.16 PE has a mortality rate of 15% in the first 3 months after diagnosis,17 making it potentially as deadly as acute myocardial infarction, and survivors often experience serious and costly longterm complications.18 The risk of VTE in individuals with inflammatory myopathies has largely been ignored despite several plausible mechanisms. Systemic inflammation associated with PM/DM may modulate thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis.16 Since the link between inflammation and VTE has started to emerge, some hospital-based studies have been conducted to investigate this association for a wide range of autoimmune diseases and have reported an increased risk of VTE in patients with inflammatory myopathies.19–22 However, their findings are limited because they are based on purely hospital-based samples and only one study21 was able to adjust for potential confounding factors and medication use. It is largely unknown whether the increased risk of VTE seen in these inpatient studies is applicable to PM/DM from the general population. Since PE represents a common and often fatal vascular event,23 accurate understanding of this risk among patients with inflammatory myopathies is crucial. To address this issue, we evaluated the risk of incident DVT and PE among incident patients with PM/DM compared with controls in an unselected general population context.
METHODS Data source Universal health coverage is a feature of the province of British Columbia (BC, population ∼4.7 million) in Canada. Population Data (PopData) BC (formerly known as the British Columbia Linked
EC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205800 1 Copyright Article author (orCarruthers their employer) 2014. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
Downloaded from http://ard.bmj.com/ on November 14, 2015 - Published by group.bmj.com
Clinical and epidemiological research Health Databases or BCLHD) captures population-based administrative data including linkable data files on all provincially funded healthcare professional visits, hospital admissions, interventions, investigations, demographic data, cancer registry and vital statistics since 1990. Furthermore, PopData BC encompasses the comprehensive prescription drug database, PharmaNet, with data since 1996. Numerous general population-based studies have been successfully conducted based on these databases.24–28
Study design We conducted matched cohort analyses for incident VTE (ie, DVT or PE) among individuals with incident PM (PM cohort) or DM (DM cohort) as compared with individuals without PM or DM (comparison cohorts) using data from PopData BC. For the comparison cohorts, we matched up to 10 individuals without PM/DM to each PM/DM case based on age, sex and calendar year of study entry randomly selected from the general population.
Incident PM/DM cohort We created incident PM and DM cohorts with cases diagnosed for the first time between January 1996 and December 2010 with no PM/DM history or diagnosis recorded over the prior 6 years (ie, from January 1990). Our study definition of PM and DM consisted of (a) ≥18 years of age; (b) one International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code by a rheumatologist (710.4 for PM; 710.3 for DM) or from a hospital (ICD-9-CM same as above, or ICD-10-CM M33.0, M33.1 or M33.9 for DM; M33.2 for PM) or (c) two ICD-9-CM codes for PM or DM at least 2 months and no more than 2 years apart by a non-rheumatologist physician. Similar PM/DM case definitions have been used in previous studies in Canada and found to have a specificity of 96.4% in the context of systemic autoimmune rheumatic diseases.29 To further improve specificity, we excluded individuals with at least two visits ≥2 months apart subsequent to the PM/DM diagnostic visit with other inflammatory disease diagnoses (eg, RA, psoriatic arthritis, spondyloarthropathies, SLE, giant cell arteritis).
Ascertainment of DVT and PE Incident DVT and PE cases were defined by a corresponding ICD code and prescription of anticoagulant therapy (heparin, warfarin sodium or a similar agent).30 The codes used were DVT (ICD-9-CM: 453; ICD-10-CM: I82.4, I82.9) and PE (ICD-9-CM: 415.1, 673.2, 639.6; ICD-10-CM: O88.2, I26). Since VTE is a potentially fatal disease, we also included patients with a fatal outcome. Because a patient may have died before anticoagulation treatment, patients with a recorded code of DVT or PE were included in the absence of recorded anticoagulant therapy if there was a fatal outcome within 2 months of diagnosis. These definitions have been successfully used in previous studies and found to have a positive predictive value of 94% in a general practice database.30
Assessment of covariates Covariates consisted of potential risk factors of VTE assessed during the year before the index date. These included relevant medical conditions (alcoholism, hypertension, varicose veins, inflammatory bowel disease, sepsis), trauma, fractures, surgery, healthcare use, and use of glucocorticoids, hormone
2
replacement therapy, contraceptives or COX-2 inhibitors. Additionally, a modified Charlson comorbidity index for administrative data was calculated in the year before index date.31 32
Cohort follow-up Our study cohorts spanned the period 1 January 1996 to 31 December 2010. Individuals with PM/DM entered the case cohort after all inclusion criteria had been met, and matched individuals entered the comparison cohort after a doctor’s visit or hospital admission in the same calendar year. Participants were followed until they either experienced an outcome, died, disenrolled from the health plan (ie, left BC, approximately 1% per year), or follow-up ended (31 December 2010), whichever occurred first.
Statistical analysis We compared baseline characteristics between PM/DM and control cohorts. We calculated incidence rates (IR) per 1000 person-years (PY) for respective outcomes for PM/DM and corresponding comparison cohorts. The associations between PM/ DM and study outcomes are expressed as incidence rate ratios (IRR) with 95% CIs. To evaluate the time-trend of VTE risk according to the time since PM/DM diagnosis, we estimated IRRs in 1-year intervals, starting in the first year after diagnosis and up to 5 years after diagnosis. We conducted Cox proportional hazard regressions33 to assess the adjusted relative risk (RR) of VTE, DVT and PE associated with PM/DM after stratifying by matched variables (baseline age and sex). These multivariable analyses were adjusted for all covariates listed above and the effect of PM/DM on study outcomes was expressed as HRs with 95% CIs. We also performed subgroup analyses according to sex. We performed three sensitivity analyses. First, analysis with a stricter definition of PM/DM exposure was used, limited to subjects with ICD codes for PM/DM and the use of antirheumatic medications including glucocorticoids, antimalarials, methotrexate and immunosuppressives between 1 month before and 6 months after the index date. Second, we estimated the cumulative incidence of each event accounting for the competing risk of death according to Lau et al34 and expressed the results as subdistribution HRs with 95% CIs. Third, to quantify the potential impact of unmeasured confounders, we performed sensitivity analyses, which assessed how a hypothetical unmeasured confounder might have affected our estimates of the association between PM/DM and risk of VTE.35 We simulated unmeasured confounders with their prevalences ranging from 10% to 20% in the PM/DM and comparison cohorts, and ORs for the associations between the unmeasured confounder and both VTE and the exposures ranging from 1.3 to 3.0. Analyses were performed with SAS software V.9.3 (SAS Institute, Cary, North Carolina, USA). For all RRs, we calculated 95% CIs. All p values are two-sided.
RESULTS Baseline characteristics We identified 443 new cases with PM and 355 cases with DM. For each case, 10 controls matched by birth year, sex and calendar year of follow-up were randomly selected from the general population to create control cohorts for PM (N=4603) and DM (N=3577). Table 1 summarises the baseline characteristics of the cohorts.
Carruthers EC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205800
Downloaded from http://ard.bmj.com/ on November 14, 2015 - Published by group.bmj.com
Clinical and epidemiological research Table 1 Characteristics of PM, DM and comparison cohorts at baseline Variable
PM n=443
Non-PM n=4603
p Value
DM n=355
Non-DM n=3577
p Value
Age, mean (SD) years Female Alcoholism Hypertension Sepsis Varicose veins Inflammatory bowel disease Trauma Fracture Surgery Glucocorticoids Hormone replacement therapy Contraceptives Cox-2 inhibitors Charlson’s comorbidity index, mean (SD) Number of hospitalisations, mean (SD) Number of outpatient visits, mean (SD)
60.39 (15.62) 257 (58.0) 5 (1.1) 136 (30.7) 3 (0.7) 3 (0.7) 3 (0.7) 1 (0.2) 14 (3.2) 4 (0.9) 203 (45.8) 30 (6.8) 7 (1.6) 33 (7.4) 1.39 (1.94) 0.9 (1.4) 129.54 (108.83)
60.53 2678 41 1222 8 49 8 19 69 30 186 220 89 145 0.44 0.3 38.33
NS NS NS NS NS NS NS NS 0.017 NS
