IntroductionImmune-mediated diseases (IMDs) are a heterogeneous group that comprise >100 chronic and often debilitating conditions that result from abnormal activation of the immune system.1Adapa D.S.Y. Anand S.Y. Mehaboobi S. Aramalla E.R. A Brief Review on Immune Mediated Diseases.,2Visser O. Trama A. Maynadie M. Incidence, survival and prevalence of myeloid malignancies in Europe. Current estimates suggest that approximately 5% to 8% of the population (roughly 23.5 million individuals) have IMDs in the United States; however, this estimate is based only on a limited number of IMDs of the >100 conditions, which underestimates the magnitude of this disease category.2Visser O. Trama A. Maynadie M. Incidence, survival and prevalence of myeloid malignancies in Europe.,3El-Gabalawy H. Guenther L.C. Bernstein C.N. Epidemiology of immune-mediated inflammatory diseases: incidence, prevalence, natural history, and comorbidities. Common examples of IMDs include inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and scleroderma.4Immune-mediated disease genetics: the shared basis of pathogenesis. Despite the diversity of organ systems affected, most IMDs result from the interplay of genetic and environmental factors and include alternating periods of disease flares and remission.4Immune-mediated disease genetics: the shared basis of pathogenesis.,5Virtanen A.T. Haikarainen T. Raivola J. Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases.Although no curative therapies exist for IMDs, achieving disease remission is a realistic therapeutic goal for several IMDs (eg, IBD and RA).6Kuek A. Hazleman B.L. Ostor A.J. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. However, an important consideration in the clinical management of patients with IMD is the increased risk of cardiovascular complications, particularly thromboembolic events (TEs).7England B.R. Thiele G.M. Anderson D.R. Mikuls T.R. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. The heightened risk of TEs among patients with IMDs typically results from an increase in coagulation and a decrease in anticoagulation mechanisms because of the intrinsic nature of IMDs.8The interactions between inflammation and coagulation. One prevalent and potentially life-threatening category of TEs among patients with IMDs is venous thromboembolic events (VTEs), which include deep vein thrombosis (DVT) and pulmonary embolism (PE).9Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. Although these are 2 distinct VTEs, development of a DVT may progress to a PE when the thrombus that forms in a deep vein is displaced to the lung, resulting in PE. Although the precise number of individuals affected by VTEs is unknown, 1 study estimated an annual incidence of 300,000 to 600,000 (1 to 2 per 1000) cases in the United States. VTEs typically require immediate medical attention because 10% to 30% of all patients presenting with VTE have been estimated to die within 30 days.11Beckman M.G. Hooper W.C. Critchley S.E. Ortel T.L. Venous thromboembolism: a public health concern. Another potentially life-threatening category of TEs among patients with IMDs is arterial thromboembolic events (ATEs), which include myocardial infarction (MI) and ischemic stroke (IS). In the United States, the incidence of stroke is 795,000 cases per year, with 87% of all strokes classified as IS.12Virani S.S. Alonso A. Benjamin E.J. Bittencourt M.S. Callaway C.W. Carson A.P. et al.Heart Disease and Stroke Statistics-2020 Update: A Report From the. The annual incidence of MI is thought to be roughly 525,000 new attacks and 210,000 recurrent attacks in the United States. Nearly 15% of patients hospitalized for MI or stroke die within 30 days. Specific IMDs associated with TEs include SLE and IBD, both of which have been linked to an increased risk of VTEs14Zoller B. Li X. Sundquist J. Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature.; similarly, RA and IBD have been associated with an increased risk of stroke.15Baena-Diez J.M. Garcia-Gil M. Comas-Cufi M. Ramos R. Prieto-Alhambra D. Salvador-Gonzalez B. et al.Association between chronic immune-mediated inflammatory diseases and cardiovascular risk.,16Yarur A.J. Deshpande A.R. Pechman D.M. Tamariz L. Abreu M.T. Sussman D.A. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events.Given the detrimental impact of TEs among individuals with IMDs, there is an increasing impetus among health care stakeholders to better understand and quantify the risk of TEs in this patient population. To the best of our knowledge, no previous study has systematically assessed the association between IMDs and risk of various TEs. In addition, although prior literature has found that risk factors for TEs among the general population include a history of TE, obesity, diabetes, and cardiovascular disease (CVD),17Tsai A.W. Cushman M. Rosamond W.D. Heckbert S.R. Polak J.F. Folsom A.R. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology., 18Wattanakit K. Lutsey P.L. Bell E.J. Gornik H. Cushman M. Heckbert S.R. et al.Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis., 19Deep venous thrombosis in peripheral vascular disease. an understanding of the risk factors in patients with IMD is lacking (ie, risk factors that may further impact the risk of TEs in the IMD patient population). This is of special interest, particularly after the introduction of novel targeted agents for the treatment of IMDs, such as Janus kinase (JAK) inhibitors, which have been associated with an increased risk of TEs.5Virtanen A.T. Haikarainen T. Raivola J. Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases.,20Scott I.C. Hider S.L. Scott D.L. Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk?. To better understand the real-world risk of TEs in patients with IMDs since the introduction of novel treatments for IMDs, the present study assessed the association between TEs and IMDs and characterized the risk factor profile of TEs among patients with IMDs in the United States.Participants and Methods Data Source

This study used the IBM MarketScan Commercial and Medicare Supplemental Databases (2014–2018), which include both employer-paid (eg, active employees, early retirees, Consolidated Omnibus Budget Reconciliation Act continuees, and dependents) and employer-sponsored Medicare supplemental health care encounters. The databases contain information on patient enrollment history, dates of service, and claims for medical (eg, professional and institutional services) and pharmacy services, as well as demographic variables (eg, age, sex, and geographic region). All data are deidentified and comply with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act. Therefore, neither institutional review board approval nor informed consent were required for this study.

 Study Design and Sample Selection

In this retrospective study, patients with ≥1 of the following types of TEs were assessed: venous (ie, DVT and PE) and arterial (ie, MI and IS) (see Supplemental Table I for the diagnostic codes used to identify TEs). The study population comprised 2 cohorts of patients: those with IMDs (IMD cohort) and those without IMDs (non-IMD cohort). IMDs encompassed the common immune-mediated diseases, including ankylosing spondylitis, atopic dermatitis, IBD, MS, psoriasis, psoriatic arthritis, RA, and SLE. Both the IMD and non-IMD cohorts were used to assess the incremental risk of venous and arterial TEs associated with IMDs, whereas only the IMD cohort was used to assess the risk factor profile for venous and arterial TEs among patients with IMDs.

To be included in the IMD cohort, patients were required to meet the following criteria: ≥2 diagnoses (on different dates) for ≥1 IMD, identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes at any time (see Supplemental Table II for the diagnostic codes used to identify IMDs). For patients in the IMD cohort, the index date was defined as the day after a randomly selected date of a medical claim with an IMD diagnosis. The rationale for randomly selecting the date of IMD diagnosis was to obtain a diverse patient population rather than predominately capturing only patients who were newly diagnosed or only those with severe disease profiles. To be included in the non-IMD cohort, patients were required to have no evidence of an IMD diagnosis at any time. For patients in the non-IMD cohort, the index date was defined as the day after a randomly selected date of a medical claim.

All patients were required to have ≥1 year of continuous eligibility before the index date (baseline period). The study period was defined as the time from the index date until the earliest of patient death, end of continuous eligibility, or end of data availability. During the study period, patients were required to be ≥18 years old on the index date and to have ≥30 days of continuous eligibility after the index date. Patients in the IMD cohort were matched 1:1 with patients in the non-IMD cohort based on age (±1 year), sex, and index year. Data processing and statistical analyses were performed using SAS Enterprise Guide version 7.15 (SAS Institute Inc, Cary, North Carolina).

 Study Measures and Outcomes Patient Characteristics

Patient characteristics assessed during the baseline period included demographic characteristics, type of IMD, IMD and non-IMD treatments, select comorbidities and conditions of interest (see Supplemental Table III for full list of diagnostic codes), and age at index date. The comorbidities and conditions of interest selected for this analysis included risk factors for TEs and potential confounders for the association between IMDs and TEs based on the literature and clinical guidance. Characteristics were described using means (SDs) for continuous variables and numbers (percentages) for categorical variables. Statistical comparisons for matched samples were conducted using Wilcoxon signed-rank tests for continuous variables and McNemar tests for categorical variables.

 Unadjusted and Adjusted Incremental Risk of TEs

Patients with venous and arterial TEs were identified as those with ≥1 ICD-9-CM and/or ICD-10-CM code for DVT, PE, MI, or IS (Supplemental Table I) during the study period. Incidence rates (IRs) of TEs (overall and separately for DVT, PE, MI, and IS) were calculated as the total number of TEs divided by the total patient-years during the study period. For both cohorts, IRs for each TEs were also stratified by type of IMD.

Unadjusted and adjusted incidence rate ratios (IRRs) were used to compare the IRs of TEs between the IMD cohort and the non-IMD cohort. The 95% confidence intervals (CIs) and P values were estimated using generalized linear models with a Poisson distribution and a sandwich (robust) variance estimator; an offset was used to account for varying lengths of follow-up time. The adjusted IRRs controlled for age at index date, sex (female), baseline type of IMD, baseline comorbidities and conditions of interest, baseline non-IMD treatments, and baseline TEs of interest.

 Risk Factor Profile Among Patients With IMDs

To evaluate risk factors for TEs among patients with IMDs, multivariable regressions were conducted separately for DVT, PE, MI, and IS. IRRs, 95% CIs, and P values were estimated using generalized linear models with a Poisson distribution and a sandwich (robust) variance estimator; an offset was used to account for varying lengths of follow-up time. The risk factors assessed included age at index date, sex (female), baseline type of IMD, baseline comorbidities and conditions of interest, baseline non-IMD treatments, baseline IMD treatments, and baseline TEs of interest.

Discussion

This real-world, retrospective claims–based study evaluated the association between various TEs among patients with and without IMDs and characterized the risk profile of TEs among patients with IMDs. Results from the present analysis indicate that patients with IMDs had increased rates of all TE types (ie, DVT, PE, MI, and IS) compared with patients without IMDs, and these rates varied with each IMD assessed. Importantly, the increase in rates of TEs remained statistically significant after adjusting for potential confounders. Furthermore, among patients with IMDs, several factors further affected the incidence of TEs. These factors included previous TEs (defined as evidence of TEs during the baseline period), the presence of comorbidities, and treatments for non-IMDs as well as IMDs. Although certain treatments were found to increase the risk of TEs (eg, glucocorticoids and JAK inhibitors), other treatments were associated with a lower risk of TEs (eg, hormone replacement therapy).

Overall, the results of this study align with prior studies that documented the increased risk of TEs associated with IMDs.15Baena-Diez J.M. Garcia-Gil M. Comas-Cufi M. Ramos R. Prieto-Alhambra D. Salvador-Gonzalez B. et al.Association between chronic immune-mediated inflammatory diseases and cardiovascular risk.,21Ramagopalan S.V. Wotton C.J. Handel A.E. Yeates D. Goldacre M.J. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study.,22Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. However, the magnitude of the increase in the risk of TEs associated with IMDs (1.49 times higher in patients with IMDs vs patients without IMDs) is considerably lower in the current study compared with previous studies.21Ramagopalan S.V. Wotton C.J. Handel A.E. Yeates D. Goldacre M.J. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study.,22Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. For example, 1 study found the risk of PE to be 6.38 among patients with autoimmune disorder, with the risk ranging from 4.21 to 16.44 among patients with various autoimmune disorders.22Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Another study among patients with select IMDs found the risk of VTE to range from 3.61 to 4.60.21Ramagopalan S.V. Wotton C.J. Handel A.E. Yeates D. Goldacre M.J. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study. There are a few explanations to account for the difference in the magnitude of TE risk. First, some of the previously published studies21Ramagopalan S.V. Wotton C.J. Handel A.E. Yeates D. Goldacre M.J. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study.,22Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. included exclusively hospitalized patients, who are more likely to represent a sicker population compared with the patients in this study. Second, the present study adjusted for a larger set of covariates than previous studies; for example, few studies that assessed the association between IMDs and TEs also adjusted for treatments.21Ramagopalan S.V. Wotton C.J. Handel A.E. Yeates D. Goldacre M.J. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study.,22Zoller B. Li X. Sundquist J. Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Given that some treatments may further increase the risk of TEs, including them as covariates may reduce the estimated effect of IMDs on TE risk.In the present study, a previous TE (ie, TEs during the baseline period) was the biggest risk factor for reoccurring TEs. This finding aligns with several studies that have reported that a history of TEs is associated with an increase in the risk of subsequent TEs.23Anderson Jr., F.A. Spencer F.A. Risk factors for venous thromboembolism., 24An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study., 25Hansson P.O. Sorbo J. Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors., 26Kyrle P.A. Kammer M. Eischer L. Weltermann A. Minar E. Hirschl M. et al.The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study., 27Bergstrom L. Irewall A.L. Soderstrom L. Ogren J. Laurell K. Mooe T. One-Year Incidence, Time Trends, and Predictors of Recurrent Ischemic Stroke in Sweden From 1998 to 2010: An Observational Study. For example, results from an observational, prospective study found that patients who experienced an unprovoked VTE in the absence of a temporary risk factor, such as surgery, trauma, or pregnancy, faced an increased risk of subsequent TEs; the cumulative risk of TE recurrence increased by approximately 10% 1 year after unprovoked VTEs, 32% after 10 years, and 44% after 20 years.26Kyrle P.A. Kammer M. Eischer L. Weltermann A. Minar E. Hirschl M. et al.The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. Other clinical factors that have been proposed to account for the heightened risk of subsequent TEs include location of prior TEs and continued progression of cardiovascular events, such as atherosclerosis, residual thrombus, and/or impaired venous flow.28Carrier M. Rodger M.A. Wells P.S. Righini M. LEG G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis., 29Previtali E. Bucciarelli P. Passamonti S.M. Martinelli I. Risk factors for venous and arterial thrombosis., 30Fahrni J. Husmann M. Gretener S.B. Keo H.H. Assessing the risk of recurrent venous thromboembolism–a practical approach. It is also possible there are other risk factors associated with previous TEs that have yet to be identified.29Previtali E. Bucciarelli P. Passamonti S.M. Martinelli I. Risk factors for venous and arterial thrombosis. Among individuals with IMDs, the increased risk of TEs, both initial and recurrent, is believed to result from an interplay of systemic inflammation and cardiovascular factors (eg, hypercoagulable states).14Zoller B. Li X. Sundquist J. Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature.,15Baena-Diez J.M. Garcia-Gil M. Comas-Cufi M. Ramos R. Prieto-Alhambra D. Salvador-Gonzalez B. et al.Association between chronic immune-mediated inflammatory diseases and cardiovascular risk. In the present study, in addition to CVD, peripheral vascular disease and diabetes were associated with a significant increase in the risk of TEs. Moreover, the results of the present study align with previous studies that have identified all the aforementioned conditions as risk factors for TEs.17Tsai A.W. Cushman M. Rosamond W.D. Heckbert S.R. Polak J.F. Folsom A.R. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology., 18Wattanakit K. Lutsey P.L. Bell E.J. Gornik H. Cushman M. Heckbert S.R. et al.Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis., 19Deep venous thrombosis in peripheral vascular disease.In addition to previous TEs and the presence of comorbidities, medications, such as hormone replacement therapy and oral contraceptives, also affect the risk of TEs. In the present study, hormone replacement therapy was associated with a lower risk of TEs among women. This finding contrasts with some prior studies that have reported an increase in the risk of TEs among women receiving hormone therapy.31Where are we 10 years after the Women's Health Initiative?., 32Rossouw J.E. Manson J.E. Kaunitz A.M. Anderson G.L. Lessons learned from the Women's Health Initiative trials of menopausal hormone therapy., 33Canonico M. Plu-Bureau G. Lowe G.D. Scarabin P.Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis., 34Vinogradova Y. Coupland C. Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. However, inconsistencies can be found in the literature to date. For example, the route of hormone therapy administration affects findings; oral estrogen therapy has been associated with a 2-fold increase in the risk of TEs within the first 2 years of treatment, whereas transdermal administration of estrogen has not been associated with an increase in the risk of TEs.31Where are we 10 years after the Women's Health Initiative?.,33Canonico M. Plu-Bureau G. Lowe G.D. Scarabin P.Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. In addition, the impact of hormone therapy on TE risk has been reported to vary based on the presence of comorbidities, the addition of progesterone to the therapeutic regimen, duration of therapy (ie, short term vs long term), and age.31Where are we 10 years after the Women's Health Initiative?.,32Rossouw J.E. Manson J.E. Kaunitz A.M. Anderson G.L. Lessons learned from the Women's Health Initiative trials of menopausal hormone therapy. Furthermore, because physician and patient behaviors cannot be accounted for in administrative claims data, the observed decreased risk associated with hormone replacement therapy could be attributable to the physicians’ considerations. Specifically, it is possible that physicians may have avoided prescribing hormone replacement therapy in cases where patients had significant risk factors for TEs.Use of oral contraceptives has historically been associated with an increased risk of TEs in healthy women.35de Bastos M. Stegeman B.H. Rosendaal F.R. Van Hylckama Vlieg A. Helmerhorst F.M. Stijnen T. et al.Combined oral contraceptives: venous thrombosis.