Key Points
Question
What is the background rate of venous thromboembolism (VTE) in patients with bullous pemphigoid in the US?
Findings
In this cohort study including 2654 patients with bullous pemphigoid and 26 814 comparator patients, a large-scale analysis of US claims data found a 2-fold increased risk of clinical VTE events in patients with bullous pemphigoid compared with similar patients without the disease.
Meaning
Clinicians should remain mindful of an increased risk of VTE when treating patients with bullous pemphigoid.
This cohort study using US claims data examines the incidence of venous thromboembolism in patients with bullous pemphigoid compared with similar controls.
Abstract
Importance
Studies have linked bullous pemphigoid (BP) with venous thromboembolism (VTE) across several data sources finding 6-fold to 15-fold increased incidence rates.
Objective
To determine the incidence of VTE in patients with BP compared with similar controls.
Design, Setting, and Participants
This cohort study used insurance claims data from a nationwide US health care database from January 1, 2004, through January 1, 2020. Patients with dermatologist-recorded BP were identified (≥2 diagnoses of BP [International Classification of Diseases, Ninth Revision (ICD-9) 694.5 and ICD-10 L12.0] recorded by dermatologists within 1 year). Risk-set sampling identified comparator patients without BP and free of other chronic inflammatory skin diseases. Patients were followed-up until the first of the following events occurred: VTE, death, disenrollment, or end of data stream.
Exposures
Patients with BP compared with those without BP and free of other chronic inflammatory skin diseases (CISD).
Main outcome
Venous thromboembolism events were identified and incidence rates were computed before and after propensity-score (PS) matching to account for VTE risk factors. Hazard ratios (HRs) compared the incidence of VTE in BP vs non-CISD.
Results
Overall, 2654 patients with BP and 26 814 comparator patients without BP or another CISD were identified. The mean (SD) age in the BP group was 73.0 (12.6) years and 55.0 (18.9) years in the non-CSID group. With a median follow-up time was 2 years, the unadjusted incidence rate (per 1000 person-years) of outpatient or inpatient VTE was 8.5 in the BP group compared with 1.8 in patients without a CISD. Adjusted rates were 6.7 in the BP group compared with 3.0 in the non-CISD group. Age-specific adjusted incidence rates (per 1000 person-years) in patients aged 50 to 74 years was 6.0 (vs 2.9 in the non-CISD group) and in those aged 75 years or older was 7.1 (vs 4.53 in the non-CISD group). After 1:1 propensity-score matching including 60 VTE risk factors and severity markers, BP was associated with a 2-fold increased risk of VTE (2.24 [1.26-3.98]) vs those in the non-CISD group. When restricting to patients aged 50 years or older, the adjusted relative risk of VTE was 1.82 (1.05-3.16) for the BP vs non-CISD groups.
Conclusions
In this nationwide US cohort study, BP was associated with a 2-fold increased incidence of VTE after controlling for VTE risk factors in a dermatology patient population.
Introduction
Prior studies have observed no meaningfully elevated risk of venous thromboembolism (VTE) for patients with several chronic inflammatory skin diseases, including psoriasis, atopic dermatitis, vitiligo, alopecia areata, and hidradenitis suppurativa1; however, the association with bullous pemphigoid (BP) and VTE is less clear.2 One study3 observed a 6-fold increased risk of VTE in patients with BP during acute phases of the disease, and in age- and sex-standardized analyses against published background risks they extrapolated an up to 15-fold increased risk. Although that study provided detailed characterization of the BP acuity in patients from Italy, they compared against published VTE background rates reported from Norway and only adjusted for age and sex, leaving room for considerable confounding by known risk factors for VTE.4 In this study, we used commercial claims data to evaluate the rate of VTE among patients with BP in the US.
Methods
Study Population
Using US insurance claims data from a single, nationally operating, commercial health insurer from 2004 through 2019 and the methodology described in our earlier study,1 we evaluated risk of VTE in patients with BP compared with those without BP and free of other chronic inflammatory skin diseases (CISD). Overall, BP was defined as 2 dermatologist encounters with a diagnosis of bullous pemphigoid at both visits (International Classification of Diseases, Ninth Revision (ICD-9) 694.5 and ICD-10 L12.0), and no diagnosis for another chronic inflammatory skin disease (psoriasis, atopic dermatitis, alopecia areata, vitiligo, and hidradenitis suppurativa) at any of those 2 visits. Cohort entry date was the second dermatologist visit. The comparator group (non-CISD) comprised of patients with no diagnosis of BP and no diagnosis of another CISD at any time. Risk-set sampling was used to identify 10 patients without CISD for every 1 with BP. As in our prior study, we sampled from all plan enrollees who had at least 2 visits to a dermatologist within a year but were not diagnosed with BP or another CISD at any time.1 Cohort entry date was the second dermatologist visit. The Brigham and Women’s Hospital’s institutional review board approved this study and written informed consent was waived because all data used were deidentified.
To reduce confounding, patients in the BP and non-CISD groups were excluded if they had any of the following conditions before their cohort entry: prior VTE, use of an anticoagulant, diagnosis of cancer excluding nonmelanoma skin cancer,5 prothrombotic condition, sickle cell disease, HIV/AIDS, or comorbid chronic inflammatory conditions associated with VTE (rheumatoid arthritis, inflammatory bowel disease, and lupus).1
Outcomes
Incident VTE events, ie, deep venous thrombosis or pulmonary embolism, were identified during all available follow-up times. For the primary outcome, VTE was defined as either an inpatient encounter with a VTE discharge diagnosis in the primary position, or an outpatient encounter with a diagnosis of VTE followed by initiation of an anticoagulant within 7 days or hospitalization for VTE within 7 days (positive predictive value [PPV] of 72%-90%).6,7,8 This broader, more sensitive but possibly less specific, primary definition was used to help capture a representative incidence rate (IR) estimate. The secondary outcome was a more specific but less sensitive definition limited to only inpatient events: hospitalization with a primary discharge diagnosis of VTE (PPV, 83%-90%).1,6 A highly specific end point definition helps to minimize biased hazard ratios of IRs for comparative analyses.9 For this reason our secondary outcome was restricted to inpatient VTE events recorded as the primary discharge diagnosis. Follow-up lasted until the first of the following: incident VTE, end of data, disenrollment from health plan, or death.
Statistical Analysis
To account for potential difference in VTE risk factors, we used propensity-score (PS) matching (1:1 nearest neighbor matching with a maximum caliper of 0.02 on the PS scale).10,11 We evaluated VTE risk factors, comorbidities, systemic glucocorticoid use, and other treatments in the 365 days before cohort entry (eTable 1 and 2 in Supplement 1 display the full list of risk factors evaluated). All patient characteristics were included in a PS model. Multivariable logistic regression was used to estimate the PS, ie, predicting the presence/absence of BP. Kaplan-Meier curves were plotted for BP after PS matching. Incidence rates and hazard ratios were calculated before and after 1:1 PS-matching to adjust for VTE risk factors (eTable 2 in Supplement 1). The previously validated Aetion Evidence Platform (version 4.12; Aetion, Inc) was used to conduct all analyses.12,13,14
Results
We identified 2991 patients with BP, and through 10:1 risk-set sampling, we found 29 910 comparator patients without BP or another CISD. The median follow-up time was 2 years. The mean (SD) age in the patients with BP group was 73.0 (12.6) years and in the non-CSID group was 55.0 (18.9) years (Table 1). The IR of VTE—inpatient or outpatient with evidence of treatment—was 8.5 per 1000 person-years in BP compared with 1.8 in patients without CISD, resulting in approximately a 5-fold increased risk in an unadjusted analysis (unadjusted hazard ratio, 4.85; 95% CI, 3.60-6.55). After 1:1 PS matching adjusting for 80 VTE risk factors and severity markers, BP was associated with a 2-fold increased risk of VTE (adjusted hazard ratio [aHR], 2.24; 95% CI, 1.26-3.98) vs those in the non-CISD group (Table 2; Figure). The substantial decrease in HRs from 4.85 to 2.24 after adjustment for VTE risk factors illustrates the importance of comparing against patients with equal VTE risk beyond age-sex standardization to identify the incremental risk associated with BP.
Table 1. Selected Baseline Patient Characteristics, Before and After Adjustment With 1:1 PS-matchinga.
| Patient characteristic, within 365 d before cohort entry | Unmatched patients | After 1:1 propensity-score matching | ||
|---|---|---|---|---|
| BP | Non-CISD | BP | Non-CISD | |
| Patients, No. | 2654 | 26 814 | 1863 | 1863 |
| Age, mean (SD), y | 73.86 (12.58) | 55.28 (18.90) | 72.41 (13.14) | 72.81 (12.29) |
| Sex, No. (%) | ||||
| Female | 1479 (55.7) | 15 186 (56.6) | 996 (53.5) | 1032 (55.4) |
| Male | 1175 (44.3) | 11 628 (43.4) | 867 (46.5) | 831 (44.6) |
| Race, No. (%)b | ||||
| Asian | 118 (4.4) | 759 (2.8) | 63 (3.4) | 62 (3.3) |
| Black | 275 (10.4) | 1552 (5.8) | 172 (9.2) | 176 (9.4) |
| Hispanic | 200 (7.5) | 1647 (6.1) | 121 (6.5) | 128 (6.9) |
| White | 2061 (77.7) | 22 856 (85.2) | 1507 (80.9) | 1497 (80.4) |
| Comorbid conditions, No. (%) | ||||
| Obesity or weight gain | 323 (12.2) | 2534 (9.5) | 228 (12.2) | 229 (12.3) |
| Tobacco use | 308 (11.6) | 1517 (5.7) | 208 (11.2) | 204 (11.0) |
| Pregnancy | 28 (1.1) | 423 (1.6) | 18 (1.0) | 17 (0.9) |
| Miscarriage | 4 (0.2) | 48 (0.2) | 2 (0.1) | 4 (0.2) |
| Stroke (excluding TIA) | 6 (0.2) | 16 (0.1) | 3 (0.2) | 2 (0.1) |
| TIA | 50 (1.9) | 206 (0.8) | 33 (1.8) | 31 (1.7) |
| Nephrotic syndrome | 3 (0.1) | 12 (0.0) | 2 (0.1) | 1 (0.1) |
| Varicose veins | 112 (4.2) | 547 (2.0) | 71 (3.8) | 79 (4.2) |
| Dyslipidemia | 1468 (55.3) | 10 230 (38.2) | 1042 (55.9) | 1048 (56.3) |
| Endocarditis | 149 (5.6) | 343 (1.3) | 80 (4.3) | 75 (4.0) |
| Atrial fibrillation | 28 (1.1) | 40 (0.1) | 13 (0.7) | 13 (0.7) |
| Syncope | 119 (4.5) | 519 (1.9) | 77 (4.1) | 87 (4.7) |
| Peripheral vascular disease | 458 (17.3) | 1352 (5.0) | 261 (14.0) | 275 (14.8) |
| Hypertension | 1305 (49.2) | 5494 (20.5) | 826 (44.3) | 830 (44.6) |
| Liver disease | 57 (2.1) | 478 (1.8) | 41 (2.2) | 45 (2.4) |
| Dementia or other neurological disorders | 331 (12.5) | 405 (1.5) | 159 (8.5) | 155 (8.3) |
| Diabetes, severe or complicated | 444 (16.7) | 1271 (4.7) | 263 (14.1) | 272 (14.6) |
| Congestive heart failure | 345 (13.0) | 714 (2.7) | 196 (10.5) | 209 (11.2) |
| Chronic obstructive pulmonary disease | 398 (15.0) | 1704 (6.4) | 249 (13.4) | 269 (14.4) |
| Alcohol abuse | 37 (1.4) | 257 (1.0) | 25 (1.3) | 22 (1.2) |
| Renal disease or failure | 452 (17.0) | 1256 (4.7) | 255 (13.7) | 272 (14.6) |
| Hemiplegia or paraplegia | 68 (2.6) | 63 (0.2) | 30 (1.6) | 24 (1.3) |
| Gagne chronic comorbidity score, mean (SD) | 1.19 (1.99) | 0.27 (0.99) | 0.91 (1.75) | 0.98 (1.80) |
| Fracture, No. (%) | ||||
| Fracture of upper and lower extremities (excluding hip fractures) | 118 (4.4) | 689 (2.6) | 74 (4.0) | 82 (4.4) |
| Fracture of neck or femur, hip | 32 (1.2) | 59 (0.2) | 13 (0.7) | 19 (1.0) |
| Surgery, No. (%) | ||||
| Gynecologic | 1 (0.0) | 56 (0.2) | 1 (0.1) | 0 |
| Abdominal | 45 (1.7) | 160 (0.6) | 25 (1.3) | 22 (1.2) |
| Cardiovascular | 66 (2.5) | 203 (0.8) | 39 (2.1) | 46 (2.5) |
| Musculoskeletal | 51 (1.9) | 309 (1.2) | 29 (1.6) | 28 (1.5) |
| Systemic glucocorticoid use, No. (%) | ||||
| Prior use of systemic glucocorticoids, past 180 d | 1558 (58.7) | 4058 (15.1) | 790 (42.4) | 812 (43.6) |
| Recent use of systemic glucocorticoids, past 60 d | 1233 (46.5) | 1262 (4.7) | 513 (27.5) | 498 (26.7) |
| Sum of daily dose of systemic glucocorticoids, in prednisone mg equivalencies, mean (SD) | 858.72 (1526.19) | 62.56 (355.72) | 454.27 (1062.39) | 376.42 (1167.87) |
| Use of systemic immunomodulators, No. (%) | ||||
| Nonbiologic immunomodulatorsc | 374 (14.1) | 429 (1.6) | 170 (9.1) | 172 (9.2) |
| Biologic immunomodulatorsd | 14 (0.5) | 26 (0.1) | 6 (0.3) | 7 (0.4) |
| Tumor necrosis factor inhibitors (TNFi)e | 3 (0.1) | 10 (0.0) | 1 (0.1) | 1 (0.1) |
| Non-TNFif | 11 (0.4) | 17 (0.1) | 5 (0.3) | 6 (0.3) |
| Infliximab | 0 | 3 (0.0) | 0 | 0 |
| Targeted synthetic immunomodulatorsg | 0 | 0 | 0 | 0 |
| Other medication use, No. (%) | ||||
| Antiarrhythmics | 291 (11.0) | 1318 (4.9) | 169 (9.1) | 166 (8.9) |
| Isotretinoin | 1 (0.0) | 800 (3.0) | 1 (0.1) | 0 |
| Antiplatelets | 156 (5.9) | 704 (2.6) | 95 (5.1) | 89 (4.8) |
| Statins | 980 (36.9) | 6463 (24.1) | 629 (33.8) | 625 (33.5) |
| Tamoxifen | 1 (0.0) | 15 (0.1) | 0 | 0 |
| Nonoral contraceptives | 4 (0.2) | 201 (0.7) | 2 (0.1) | 4 (0.2) |
| Oral contraceptives | 79 (3.0) | 3371 (12.6) | 72 (3.9) | 65 (3.5) |
| Hormone replacement therapy | 135 (5.1) | 3196 (11.9) | 109 (5.9) | 108 (5.8) |
| Healthcare utilization, No. (%) | ||||
| Rheumatology visit | 68 (2.6) | 482 (1.8) | 44 (2.4) | 80 (4.3) |
| Internal medicine or general physician visit | 1486 (56.0) | 9735 (36.3) | 991 (53.2) | 1055 (56.6) |
| Hospitalization | 366 (13.8) | 775 (2.9) | 184 (9.9) | 185 (9.9) |
| Emergency department visit | 379 (14.3) | 1314 (4.9) | 217 (11.6) | 211 (11.3) |
| No. of prescription medications, mean (SD) | 10.47 (7.79) | 6.00 (5.24) | 8.70 (7.47) | 8.73 (6.83) |
| No. of office visits, mean (SD) | 7.24 (5.13) | 4.37 (3.37) | 6.75 (4.19) | 6.96 (4.96) |
| ESR test ordered | 143 (5.4) | 641 (2.4) | 88 (4.7) | 91 (4.9) |
Abbreviations: BP, bullous pemphigoid; CISD, chronic inflammatory skin disease; ESR, erythrocyte sedimentation rate; TIA, transient ischemic attack; TNFi, tumor necrosis factor inhibitor.
These are selected patient characteristics, see eTable 1 in Supplement 1 for the complete patient characteristics evaluated and adjusted for in the study. All of the patient characteristics (ie, VTE risk factors) in this table and in eTable 1 in Supplement 1 were included in the propensity-score model for adjustment.
This US database uses proprietary algorithms to define race. Race is a derived ethnicity. The member’s ethnicity is derived by using the member’s name and geography. Once the ethnicity is determined, the member is mapped to 1 of 4 race categories (A-Asian, B-Black, H-Hispanic, W-White).
Nonbiologic immunomodulators were defined as methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, sulfasalazine, and leflunomide.
Biologic immunomodulators were defined as adalimumab, etanercept, golimumab, certolizumab, infliximab, dupilumab, risankizumab-rzaa, tildrakizumab, ixekizumab, secukinumab, guselkumab, ustekinumab, abatacept, rituximab, anakinra, and tocilizumab.
Tumor necrosis factor inhibitor biologic immunomodulators were defined as adalimumab, etanercept, golimumab, certolizumab, and infliximab.
Non-TNFi biologic immunomodulators were defined as dupilumab, risankizumab-rzaa, tildrakizumab, ixekizumab, secukinumab, guselkumab, ustekinumab, abatacept, rituximab, anakinra, and tocilizumab.
Targeted synthetic immunomodulators were defined as tofacitinib or baricitinib.
Table 2. Incidence of Inpatient or Outpatient Venous Thromboembolism in Patients With Bullous Pemphigoid (BP) vs Those Without BP.
| Variable | BP | Non-CISD | BP vs non-CISD, hazard ratio (95% CI) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Patients, No. | Person-time in 1000 person-years | Events, No. | Incidence rate per 1000 person-years | Patients, No. | Person-time in 1000 person-years | Events, No. | Incidence rate per 1000 person-years | ||
| VTE, inpatient or outpatient with treatment (primary analysis) a | |||||||||
| Unmatched | |||||||||
| Total patients with BPb | 2654 | 7417 | 63 | 8.49 | 26 814 | 76 010 | 133 | 1.75 | 4.85 (3.60-6.55) |
| Age 18-49 y | 140 | 437 | 1 | 2.29 | 9802 | 25 986 | 18 | 0.69 | 3.17 (0.42-23.73) |
| Age ≥50 y | 2514 | 6980 | 62 | 8.88 | 17 011 | 50 022 | 115 | 2.30 | 3.84 (2.82-5.23) |
| Age 50-74 yc | 1023 | 3150 | 25 | 7.94 | 12 436 | 36 518 | 73 | 2.00 | 3.96 (2.51-6.24) |
| Age ≥75 yc | 1491 | 3831 | 37 | 9.66 | 4575 | 13 504 | 42 | 3.11 | 3.04 (1.95-4.73) |
| Without immunomodulator use | 2272 | 6291 | 54 | 8.58 | 26 365 | 74 825 | 132 | 1.76 | 4.85 (3.54-6.66) |
| 1:1 PS matchedd | |||||||||
| Total patients with BP | 1863 | 5356 | 36 | 6.72 | 1863 | 5661 | 17 | 3.00 | 2.24 (1.26-3.98) |
| Age 18-49 y | 111 | 349 | 0 | 0.00 | 111 | 327 | 0 | 0.00 | NA |
| Age ≥50 yc | 1742 | 5006 | 34 | 6.79 | 1742 | 5385 | 20 | 3.71 | 1.82 (1.05-3.16) |
| Age 50-74 yc | 768 | 2378 | 14 | 5.89 | 768 | 2357 | 7 | 2.97 | 2.00 (0.81-4.96) |
| Age ≥75c | 935 | 2525 | 18 | 7.13 | 935 | 2650 | 12 | 4.53 | 1.55 (0.75-3.23) |
| Without immunomodulator usee | 1663 | 4761 | 34 | 7.14 | 1663 | 5106 | 18 | 3.53 | 2.01 (1.13-3.56) |
| VTE, inpatient (secondary analysis) f | |||||||||
| Unmatched | |||||||||
| Total patients with BP | 2654 | 7499 | 35 | 4.67 | 26 814 | 76 209 | 65 | 0.85 | 5.48 (3.63-8.26) |
| Age 18-49 y | 140 | 444 | 0 | 0.00 | 9802 | 26 026 | 7 | 0.27 | NA |
| Age ≥50 y | 2514 | 7055 | 35 | 4.96 | 17 011 | 50 180 | 58 | 1.16 | 4.28 (2.81-6.51) |
| Age 50-74 y | 1023 | 3187 | 16 | 5.02 | 12 436 | 36 611 | 34 | 0.93 | 5.44 (3.00-9.87) |
| Age ≥75 y | 1491 | 3868 | 19 | 4.91 | 4575 | 13 569 | 24 | 1.77 | 2.74 (1.50-5.00) |
| Without immunomodulator use | 2272 | 6357 | 32 | 5.03 | 26 365 | 75 022 | 65 | 0.87 | 5.80 (3.80-8.86) |
| 1:1 PS matched | |||||||||
| Total patients with BP | 1863 | 5389 | 22 | 4.08 | 1863 | 5671 | 13 | 2.29 | 1.77 (0.89-3.51) |
| Age 18-49 y | 111 | 349 | 0 | 0.00 | 111 | 327 | 0 | 0.00 | NA |
| Age ≥50 y | 1742 | 5038 | 22 | 4.37 | 1742 | 5417 | 10 | 1.85 | 2.33 (1.10-4.93) |
| Age 50-74 y | 768 | 2387 | 11 | 4.61 | 768 | 2366 | 4 | 1.69 | 2.74 (0.87-8.60) |
| Age ≥75 y | 935 | 2551 | 10 | 3.92 | 935 | 2672 | 6 | 2.25 | 1.67 (0.61-4.62) |
| Without immunomodulator use | 1663 | 4795 | 24 | 5.00 | 1663 | 5127 | 12 | 2.34 | 2.11 (1.06-4.23) |
Abbreviations: CISD, chronic inflammatory skin disease; IMD, immune-modulating drug; NA, not applicable; PS, propensity-score; VTE, venous thromboembolism.
We identify incident VTE, deep venous thrombosis or pulmonary embolism, events during all available follow-up time. We defined VTE as either a hospitalization with a primary discharge diagnosis of VTE, or an outpatient visit with a diagnosis of VTE followed by initiation of an anticoagulant within 7 days or hospitalization for VTE within 7 days.
Although the risk-set-sampling identified 2991 and 29 910 patients, respectively, further exclusions and censoring on day 0 resulted in 2654 patients with BP and 26 814 comparators.
These are not mutually exclusive age categories, in that the patients in the age 75 years or older subgroup are also included in the age 50 years or older subgroup. PS matching is then conducted in each subgroup of age separately, as such the numbers may not add up to the age 50 years or older group.
Patients were 1:1 propensity-score matched (0.02 caliper) on more than 60 VTE risk factors, severity markers, systemic corticosteroid use, treatments, and other patient characteristics. See eTables 1 and 2 in Supplement 1 for a detailed list of all adjustment variables.
In a subgroup analysis we excluded patients using systemic immunomodulating agents defined as patients receiving treatment with nonbiologic immunomodulatory agents (methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, sulfasalazine, or leflunomide), biologic immunomodulatory agents (dupilumab, risankizumab-rzaa, tildrakizumab, ixekizumab, secukinumab, guselkumab, ustekinumab, abatacept, adalimumab, etanercept, golimumab, certolizumab, infliximab, rituximab, anakinra, or tocilizumab), and targeted synthetic immunomodulatory agents (tofacitinib or baricitinib), not including systemic corticosteroids.
For a more specific but less sensitive definition, we limited the secondary outcome to include only inpatient events, defined as hospitalization with a primary discharge diagnosis of deep venous thrombosis or pulmonary embolism.
Figure. Time to Venous Thromboembolism (VTE) in Patients With Bullous Pemphigoid vs Similar Patients Without a Chronic Inflammatory Skin Disease (CISD).
This Kaplan Meier curve shows results after adjustment with 1:1 propensity-score matching. The shaded area represents 95% confidence intervals.
When limiting to primary discharge diagnosis of VTE (positive predictive value, 90%), risk of VTE increased by 77% in patients with BP vs non-CISD (HR, 1.77; 95% CI, 0.89-3.51). However, almost all of the population was aged older than 50 years. Only 140 patients with BP were identified in the age range of 18 to 49 years, with no VTE events after PS matching. As such, we focused on an analysis restricted to patients aged 50 years or older, who had a relative risk of VTE of 1.82 (95% CI, 1.05-3.16). The effect remained elevated when limiting to inpatient VTE events only (HR, 2.33; 95% CI, 1.10-4.93).
When evaluating those aged 50 to 74 years and those older than 75 years, an increased IR of VTE was associated with older age (IR, 5.9 and 7.1, respectively). Few patients used systemic immunomodulatory agents (15%), aside from systemic glucocorticoids (58.7%). Among 2272 patients without prior immunomodulator use, the relative risk of VTE was minimally lower (2.01; 95% CI, 1.13-3.56) compared with the overall analysis.
Discussion
The association of 2-fold increased risk of VTE in patients with BP observed in this study after adjustment for multiple VTE risk factors and severity markers complements our earlier study1 in other, more common CISDs, which found no meaningfully increased risk of VTE in patients with psoriasis, atopic dermatitis, alopecia areata, vitiligo, and hidradenitis suppurativa, vs participants without CISDs.
The current study population captured patients who all sought specialty care (2 dermatologist visits in past year), of whom 58.7% had used systemic corticosteroids, suggesting that the study population was comprised of more patients with mostly moderate-to-severe disease, though granularity on disease severity is difficult to capture in claims data. A recent study15 using a Taiwanese database, similarly, found a 2-fold increased risk of VTE in patients with BP in Taiwan. The 6-fold increase in VTE risk found in earlier studies are likely a result of limited adjustment for VTE risk factors.
Limitations
Some limitations remain. Despite adjustment for 80 covariates with 1:1 PS matching, residual confounding cannot be completely ruled out. Although disease severity can be approximated by systemic medication use, claims data cannot provide more detailed granularity of severity. We used claims data that was collected from commercial insurance, including Medicare Advantage plans, but it does not cover Medicare Fee-For-Service plans.
Conclusions
The findings of this cohort study suggest that as new medications such as JAK inhibitors and biologics emerge as potential for new therapeutics for BP, physicians must be mindful of the potential for added VTE risk faced by these patients, especially as they become older. Future research should help identify the mechanism of coagulopathy and determine whether treatment of BP or therapeutics aimed at directly reducing VTE risk are appropriate interventions in this population.
eTable 1. All Baseline Patient Characteristics, Comparing Patients With a CISD vs Patients Without a CISD, Before and After 1:1 Propensity-Score Matching
eTable 2. List of All Baseline Patient Characteristics, Including, VTE Risk Factors, Comorbidities, Systemic Glucocorticoid Use, and Other Treatments Evaluated and Adjusted For in the Propensity-Score Model
eReference
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. All Baseline Patient Characteristics, Comparing Patients With a CISD vs Patients Without a CISD, Before and After 1:1 Propensity-Score Matching
eTable 2. List of All Baseline Patient Characteristics, Including, VTE Risk Factors, Comorbidities, Systemic Glucocorticoid Use, and Other Treatments Evaluated and Adjusted For in the Propensity-Score Model
eReference
Data Sharing Statement