Cancer is not a risk factor for bullous pemphigoid Cancer is not a risk factor for bullous pemphigoid. A ten-year population-based cohort study CT Chen, MD,1,2 HY Hu, PhD,3,4 YT Chang, MD, PhD,1,2 CP Li, MD, PhD 2,5 and CY Wu, MD, PhD1,2,3* 1 Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan 2 National Yang-Ming University School of Medicine, Taipei, Taiwan 3 Institute of Public Health and Department of Public Health, National Yang-Ming University, Taipei, Taiwan 4 Department of Education and Research, Taipei City Hospital, Taipei, Taiwan 5 Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan British Journal of Dermatology. DOI: 10.111/bjd.17197

Lead researcher Chen-Yi Wu M.D., Ph.D. Attending Physician Department of Dermatology, Taipei Veterans General Hospital No. 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan   Associate Professor National Yang-Ming University School of Medicine No. 155, Sec.2, Li-Nong Street, Taipei, 11221, Taiwan

Introduction What’s already known about this subject ? Patients with cerebrovascular or neurologic diseases (e.g. dementia, Parkinson’s disease) have a higher risk of developing bullous pemphigoid (BP) Whether cancer is also a risk factor for BP remains unclear

Objective Is cancer associated with an increased risk of subsequently developing BP? Which types of cancer are most strongly associated with developing BP?

Methods (I) Design Retrospective cohort study Data sources Longitudinal Health Insurance Database 2000, a subset of Taiwan’s National Health Insurance Research Database containing medical records from 1 million randomly sampled beneficiaries Defining incident cases of cancer Subjects required a diagnosis of cancer (ICD-9 codes 140–239) + Catastrophic Illness Card (issued for pathology proven cancers), from 2002-2011 Patients with cancer diagnosis before 2002 were excluded Index date was the date of the first diagnosis of cancer Analysis included 36,838 cancer patients

Methods (II) Control group Each cancer patient was matched to 4 age-, sex- and index date-matched controls without cancer Subjects with BP diagnosed before the index date were excluded Defining incident cases of bullous pemphigoid ICD-9 code 694.5 At least three diagnosis codes in outpatient clinic records or at least one in admission records Covariates Socioeconomic status, urbanity, and comorbidities (hypertension, diabetes mellitus, hyperlipidaemia, renal disease, chronic liver diseases and cirrhosis, cerebrovascular disease, dementia, and coronary artery disease)

Methods (III) Statistical analyses Incidence rate ratio Hazard ratio Fine-Gray competing risk regression model (with mortality as the competing event) to eliminate the influence of higher mortality rates in the cancer group P-value <0.05 considered statistically significant

Results (I) Risk of BP stratified by age Age (years) Patients with cancer Controls IR ratio No. No. of BP IR (95% CI) Total 36,838 22 17.2 147,352 171 19.8 0.87 (0.53-1.36) <40 2,864 1 6.9 11,456 1.3 5.54 (0.07-435.24) 40-49 5,463 4.1 21,852 N/A 50-59 8,116 32,464 7 3.7 60-69 8,033 2 7.3 32,132 21 10.7 0.68 (0.08-2.77) 70-79 8,381 11 46.3 33,524 76 40.1 1.16 (0.55-2.19) ≥80 3,981 83.7 15,924 66 93.6 0.89 (0.35-1.95) BP: bullous pemphigoid; py: person-years; CI: confidence interval; Incidence rate (IR); No. of BP/100,000 py The average observation time was 3.48 years for the cancer group and 5.87 years for the control group.

Fine-Gray competing risk regression model Results (II) Multivariate analysis for prediction of bullous pemphigoid development Variable Fine-Gray competing risk regression model HR 95% CI P Cancer 0.47 0.23-0.94 0.03 Age, year 1.05 1.03-1.07 < 0.001 Sex (male/female) 1.28 0.83-1.97 0.27 Hypertension 1.33 0.81-2.18 0.26 Diabetes mellitus 1.69 1.10-2.59 0.02 Hyperlipidaemia 1.31 0.81-2.10 Renal disease 1.24 0.69-2.23 0.48 Chronic liver disease and cirrhosis 1.00 0.60-1.70 0.99 Cerebrovascular disease 2.14 1.36-3.34 0.001 Dementia 3.78 0.95-15.1 0.06 Coronary artery disease 1.01 0.44-2.32 0.98 HR: hazard ratio; CI: confidence interval

Results (III) Incidence for BP stratified by cancer type Cancer type Number Mean age (year) Number of BP No. of BP/100,000 py Stomach cancer 1,722 67.3 3 61.6 Colon and rectum cancer 5,067 65.5 15.9 Prostate cancer 1,678 72.6 6 80.5 Bladder cancer 1,125 67.9 2 38.7 Brain and other nervous system 430 49.8 128.3 Liver and intrahepatic bile ducts 4,642 62.8 1 8.9 Lung cancer 4,195 67.7 14 Other skin tumour 521 68.6 39.8 Cervix cancer 995 56.9 18.2 Kidney cancer 961 64.4 25.8 Others 2,094 58.7 14.4 BP: bullous pemphigoid; py: person-years

Discussion (I) No increased risk for BP among cancer patients (HR 0.47) The average observation time of BP development in cancer group was shorter than for the control group (likely due to the high mortality rate in cancer patients) Analysed by Fine-Gray competing risk regression model, which describes the direction of the effect, but not the magnitude of the effect The interpretation should be that cancer is not a risk factor for BP (rather than that cancer is a protective factor for BP)

Discussion (II) The authors observed a high risk for subsequent BP in patients with brain or other nervous system tumours The main target antigen in BP is BpAg1, with three major forms in the nervous system, epidermis and muscles A damaged blood brain barrier due to the presence of a brain tumour, or associated treatment e.g. surgery or radiation, could result in the exposure and cross-reactivity of the nervous system antigen to the epidermal antigen Age, diabetes mellitus, and cerebrovascular disease were independent risk factors for BP, similar to findings from other studies

Conclusions What does this study add? In this population-based study, there was no increased risk of BP seen in cancer patients Age, diabetes mellitus, and cerebrovascular disease were independent risk factors for BP

Research team HY Hu CY Wu YT Chang CP Li CT Chen

Call for correspondence Why not join the debate on this article through our correspondence section? Rapid responses should not exceed 350 words, four references and one figure. Further details can be found here.