Lloyd-Lavery A, Chi C, Wojnarowska F, Taghipour K. The Associations Between Bullous Pemphigoid and Drug UseA UK Case-Control Study. JAMA Dermatol. 2013;149(1):58-62. doi:10.1001/2013.jamadermatol.376
Author Affiliations: Department of Dermatology, Oxford University Hospitals (Dr Lloyd-Lavery), and Nuffield Department of Clinical Medicine, University of Oxford (Dr Wojnarowska), Oxford, England; Department of Dermatology and Centre for Evidence-Based Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Chiayi, Taiwan (Dr Chi); and Department of Dermatology, Whittington Hospital and King's College London, London, England (Dr Taghipour).
Objective To explore associations between bullous pemphigoid (BP) and previous drug use in the United Kingdom.
Design A case-control study comparing the drug history of consecutive patients with BP and control subjects.
Setting Tertiary care center for immunobullous diseases and skin tumor clinics at Oxford University Hospitals.
Patients or Other Participants Eighty-six consecutive BP patients and 134 consecutive controls from the same region and similar in age and sex who presented with other dermatological diagnoses.
Main Outcome Measures Crude and adjusted odds ratios and 95% confidence interval of BP in relation to each drug.
Results Loop diuretics were used significantly more frequently by the BP patients (crude odds ratio, 2.4 [95% CI, 1.2-5.0; P = .02]; adjusted odds ratio, 3.8 [1.5-9.7; P = .006]). No significant differences were found between groups for use of other diuretics, aspirin, antidepressants, antiepileptics, antihypertensives, or central nervous system agents (eg, antipsychotics). Patients with BP used calcium or vitamin D supplements, antibiotics, antihistamines, and prednisolone significantly more often on multivariate analysis.
Conclusions The findings of our study demonstrate increased use of loop diuretics in patients with BP before the development of BP. The mechanism behind such an association clearly warrants further investigation.
Bullous pemphigoid (BP) is an autoimmune bullous dermatosis in which autoantibodies directed against BP230 and BP180 proteins of the dermoepidermal junction lead to the formation of subepidermal blisters. Drug-induced BP has been documented in anecdotal case reports. Such an association has been suggested for multiple drugs, including furosemide,1- 8 angiotensin-converting enzyme inhibitors (ACEIs),9 β-blockers,10 penicillins,11 and more recently anti–tumor necrosis factor agents used for psoriasis.12
Two French multicenter case-control studies more than 10 years apart found that significantly more patients with BP were taking diuretics (specifically spironolactone) and neuroleptics (antipsychotics) compared with control subjects.13,14 No other published studies have investigated associations between BP and medications, and no such studies have been performed in the United Kingdom. The objective of this study was to explore associations between BP and previous drug use in the United Kingdom.
We conducted a case-control study comparing the drug history of BP patients and controls. Because we performed an exploratory study and lacked pilot data, we did not perform a sample size calculation and thus collected as much data as possible. We included the medical notes of 86 consecutive local BP patients (excluding tertiary referrals) in this study from the Department of Dermatology, Oxford University Hospitals, from January 1, 2004, through December 31, 2008. We analyzed the medical notes and the complete drug history as supplied by the patient's general practitioner (responsible for all regular prescriptions) at the time the diagnosis was recorded. The data we collected from each patient were retrospective because we were interested in the medications they were taking before the diagnosis of BP. Most study subjects were outpatients. The diagnosis of BP was based on a characteristic clinical picture and positive results of direct and/or indirect immunofluorescence studies. A total of 134 consecutive controls from the same region and similar in age (±5 years) and sex who presented to the department with other dermatological diagnoses (chiefly benign and malignant skin tumors but not inflammatory skin disease) underwent similar investigation with regard to drug history.
All drugs were analyzed individually and in groups, including antihypertensives (ACEIs, β-blockers, calcium channel antagonists, diuretics, and centrally active antihypertensives), cardiovascular drugs (antiplatelet agents, warfarin sodium, statins, antiarrhythmics, and antianginals), immunosuppressants, and agents acting on the central nervous system (antidepressants, antiepileptics, antipsychotics, antiparkinsonians, dementia drugs, and hypnotics), to examine their associations with BP. We calculated the odds ratio (OR) and 95% confidence interval of BP in relation to each drug. A 95% confidence interval not containing 1.00 is statistically significant at P = .05. In addition, we performed a multivariate logistic regression analysis after adjustment for age, sex, cerebrovascular disease and dementia (which are associated with BP as previously shown by our group15), and patient comorbidities for drugs that were significantly associated with BP in the univariate analysis. Because some drugs may be indicated for certain comorbidities, we adjusted for such confounding comorbidities in the multivariate model to examine whether the drugs were truly associated with BP. For example, we adjusted for hypertension and ischemic heart disease in the multivariate model to examine whether loop diuretics were associated with BP.
We obtained ethical approval from the Oxfordshire Clinical Research Ethics Committee (C02.177).
The characteristics of cases and controls are summarized in Table 1. Our results showed that loop diuretics were used significantly more frequently by the BP patients (crude OR, 2.4 [95% CI, 1.2-5.0; P = .02]; adjusted OR, 3.8 [95% CI, 1.5-9.7; P = .006] when adjusted for age, sex, cerebrovascular disease, dementia, hypertension, and ischemic heart disease). We found no associations of BP with the use of other diuretics, namely, thiazide diuretics and spironolactone (Table 2).
Although in the crude univariate analysis aspirin appeared to be used more frequently by the BP patients, this difference was not significant when adjustments were made for age, sex, cerebrovascular disease, dementia, ischemic heart disease, and atrial fibrillation. Similarly, on multivariate analysis, we found no significant differences between the 2 groups in the use of antidepressants when we adjusted for age, sex, cerebrovascular disease, dementia, and depression or in the use of antiepileptics when we adjusted for age, sex, cerebrovascular disease, and dementia.
We found no differences between the 2 groups in the use of antihypertensives, including ACEIs and β-blockers, or in the use of cardiovascular drugs in general and central nervous system agents, including antipsychotics. Our results also showed that calcium or vitamin D supplements, antibiotics, antihistamines, and prednisolone were used significantly more frequently by the BP patients on multivariate analysis (Table 2).
This study demonstrates significantly increased use of loop diuretics in patients with BP, an association independent of age, sex, cerebrovascular disease, dementia, hypertension, and ischemic heart disease. This finding is in contrast to previous French studies13,14 that found such an association with spironolactone rather than loop diuretics. Spironolactone appears to be used more frequently in France and was used by 7.4% of French controls in the most recent French study compared with 3.7% of our UK controls.14 In accordance with our findings, case reports suggesting an association between furosemide use and BP have been frequently reported.1- 8 Different theories have been proposed for the association of drugs, including furosemide, with the development of BP; these theories include the drug acting as an antigenic hapten or the occurrence of immune dysregulation with disruption in T–suppressor cell function.16
The association of BP with diuretics does not appear to be related to a higher risk for cardiovascular disease, and myocardial infarction does not occur more frequently in patients with BP compared with the controls.17 Furthermore, our results remained significant despite adjustment for ischemic heart disease and hypertension (Table 2). In keeping with these results, we found no differences between the 2 groups in the use of antihypertensives, including ACEIs and β-blockers, and in the use of cardiovascular drugs in general.
Our findings that prednisolone, antibiotics (but no particular antibiotic class on subanalysis), and antihistamines (H1 but not H2 antagonists) were more commonly prescribed to BP patients likely reflect medications prescribed in general practice to treat symptoms before referral to a specialist for diagnosis of BP, although we cannot comment on this specifically because information on the duration of use for each medication was not available. An increased use of calcium and vitamin D supplements may be associated with the prescription of oral prednisolone to treat BP. It has been suggested that the immunomodulatory effect of statins may protect patients against inflammatory diseases, including BP,18 but we found no difference in statin use between the BP patients and controls.
We also found no difference in antipsychotic use between the 2 groups, an association previously reported in French BP patients.13,14 Although the use of antidepressants and antiepileptics appeared to be greater in the BP group on initial univariate analysis, this finding was not significant on multivariate analysis when relevant comorbidities are taken into account (Table 2) and may reflect the known association of BP and neurological disease.15,19
Our group has previously shown that BP patients have significantly increased rates of neurological disease, specifically dementia and cerebrovascular disease.15 In most of these patients, BP developed after the neurological disease. More recently, a large population-based study has demonstrated that patients diagnosed as having BP are more likely to have been diagnosed as having various neurological disorders, including stroke and dementia, before the BP diagnosis.20 We adjusted our significant univariate results for cerebrovascular disease and dementia in the multivariate logistic regression analysis to check that the association was still significant.
The Oxford University Hospitals constitute a tertiary referral center for immunobullous disorders, ensuring that all patients diagnosed as having BP fulfilled the diagnostic criteria. However, only local patients were included to be representative of the local population, to ensure that patients and controls were exposed to similar local prescribing practices, and to avoid bias for severe BP. An accurate and complete drug history provided by the patient's general practitioner at the time of referral was available for all patients because patients with incomplete notes or an uncertain diagnosis were excluded from the study. The limitations of this study include its hospital-based setting, with the potential implications for referral bias; however, because most patients were seen in an outpatient setting, patients were not selected for severe BP and poor general health. The lack of information on the duration of use for each drug meant that relevance of duration could not be assessed, although all medication therapy was commenced before the hospital or clinicopathological diagnosis of BP. Therefore, we cannot specifically address a potential causal relationship between loop diuretics and the development of BP. In addition, we might have found no association with the use of supplements, including vitamins, because these products are frequently purchased over the counter without a physician's prescription and may not have been included in the patient's drug history as provided by his or her general practitioner or mentioned by the patient at the time of inclusion in the study. As a matter of routine, the treating physician inquires about all medications. Although inclusion of a greater number of controls might have increased the statistical power, we could identify only 134 similar in age and sex
In conclusion, although reports have implicated various drugs in the development of BP, a case-control study investigating this relationship after consideration of the indications for the drugs in the United Kingdom has not been published previously. The findings of our study demonstrate increased use of loop diuretics in BP patients. The mechanism behind such an association clearly warrants further investigation.
Correspondence: Antonia Lloyd-Lavery, BM BCh, MA, MRCP, Department of Dermatology, Oxford University Hospitals, Old Road, Headington, Oxford OX3 7LE, England (firstname.lastname@example.org).
Accepted for Publication: July 14, 2012.
Author Contributions: Drs Lloyd-Lavery and Taghipour had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wojnarowska and Taghipour. Acquisition of data: Lloyd-Lavery and Taghipour. Analysis and interpretation of data: Lloyd-Lavery, Chi, Wojnarowska, and Taghipour. Drafting of the manuscript: Lloyd-Lavery, Chi, and Taghipour. Critical revision of the manuscript for important intellectual content: Lloyd-Lavery, Chi, Wojnarowska, and Taghipour. Statistical analysis: Chi. Obtained funding: Taghipour. Administrative, technical, or material support: Lloyd-Lavery and Taghipour. Study supervision: Wojnarowska and Taghipour.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported in part by the Dunhill Medical Trust.
Role of the Sponsors: The Dunhill Medical Trust had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Additional Contributions: Richard Mayon-White, MBBS, FRCP, FFPH, of the Department of Primary Health Care Sciences, University of Oxford, provided epidemiological advice.