What Drugs Are Associated with Bullous Pemphigoid?

While the majority of bullous pemphigoid (BP) cases occur without an identifiable cause, up to 15% of cases may be linked to a distinguishable precipitant, such as a medication. This phenomenon, known as drug-associated bullous pemphigoid (DABP), has been linked to a growing list of pharmacological agents.

Quick Summary

This article explores the wide range of medications, from antidiabetics to immunotherapies and diuretics, that are associated with inducing bullous pemphigoid. It highlights key drug classes and diagnostic considerations for managing this autoimmune blistering disease.

Key Points

• Drug-Associated vs. Idiopathic BP: Drug-associated bullous pemphigoid (DABP) accounts for a minority of cases, typically triggered by a medication in genetically predisposed individuals.

• Gliptins are Major Culprits: A strong association exists between DPP-4 inhibitors (gliptins) like vildagliptin, used for diabetes, and the development of DABP, often with a delayed onset.

• Immunotherapy Risks: Immune checkpoint inhibitors, such as pembrolizumab and nivolumab used in cancer treatment, can trigger DABP, sometimes months after starting therapy.

• Medication Withdrawal is Key: Discontinuing the suspect drug is the primary management strategy and frequently leads to rapid resolution of the blistering.

• Diverse Drug Classes Implicated: Beyond gliptins and immunotherapies, a variety of medications, including certain diuretics, antibiotics (penicillins), and neuropsychiatric drugs, have been linked to DABP.

• Detailed Patient History is Critical: Clinicians must take a thorough medication history to identify potential drug-related causes, especially in elderly patients presenting with new-onset bullous pemphigoid.

Understanding Drug-Associated Bullous Pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder, characterized by the formation of tense, fluid-filled blisters on the skin. In most cases, the cause is unknown (idiopathic), but a subset is triggered by medication, a condition termed drug-associated bullous pemphigoid (DABP). Recognizing potential drug-induced causes is crucial for proper diagnosis and management, as discontinuing the offending agent is often the first and most critical step in treatment. Since first reported in 1970, over 90 medications have been implicated in inducing BP, and that number continues to grow as new therapies are introduced.

Key Drug Classes Associated with Bullous Pemphigoid

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors (Gliptins)

This class of oral antidiabetic drugs has emerged as one of the most significant risk factors for developing DABP, especially in elderly patients with diabetes.

• Vildagliptin: Has the strongest association and highest risk within this class.
• Sitagliptin, Linagliptin, and Alogliptin: Also have established associations with DABP.
• Mechanism: The exact mechanism is not fully understood, but it is believed that these drugs can trigger an immune response against the basement membrane proteins in the skin, leading to blister formation. The time to onset is typically around 11 months after starting the medication, though it can vary.

Immunotherapy Agents

Immune checkpoint inhibitors, a type of immunotherapy used to treat metastatic cancer, are a significant cause of DABP.

• PD-1 Inhibitors: Medications such as pembrolizumab and nivolumab are frequently cited.
• Delayed Onset: DABP from these agents can have a delayed onset, sometimes appearing 12 months into therapy or even after discontinuation.
• Severity: This form of DABP can be more severe and often requires drug withdrawal and specific medical treatment.

Diuretics

Certain diuretics, commonly prescribed for hypertension and heart failure, have a long-standing association with DABP.

• Loop Diuretics: Furosemide is a well-documented example.
• Aldosterone Antagonists: Spironolactone has shown a significant association.
• Thiazide Diuretics: Hydrochlorothiazide has also been implicated in some case reports.

Antibiotics

Multiple antibiotic classes have been linked to DABP, with varying strengths of evidence.

• Penicillins: Penicillin, amoxicillin, and ampicillin are among those with reported associations.
• Tetracyclines: Doxycycline is notable, though paradoxical as it is also used to treat BP.
• Fluoroquinolones: Levofloxacin has shown association.

Neuropsychiatric Medications

Several drugs used to treat neurological and psychiatric conditions have been associated with DABP, particularly in elderly patients.

• Antipsychotics: Risperidone is a specific example, and the class as a whole has been linked in studies.
• Antidepressants: Escitalopram and venlafaxine have been implicated in some cases.
• Dopaminergic Drugs: Used for Parkinson's disease, this class has shown association in meta-analyses.

Other Drug Classes

This is not an exhaustive list, as many other types of medications have been linked to DABP.

• NSAIDs: Non-steroidal anti-inflammatory drugs like ibuprofen.
• ACE Inhibitors: Captopril and enalapril.
• Beta-Blockers: Have been reported in case reports.
• TNF-alpha inhibitors: Etanercept and adalimumab.

The Three Causal Mechanisms of Drug-Associated Bullous Pemphigoid

Drug-associated BP can be triggered by different mechanisms, often classified by the drug's chemical structure.

1. Thiol-Drugs: These contain a sulfhydryl group and are known to potentially disrupt the structural integrity of the basement membrane zone. D-penicillamine is a classic example.
2. Phenol-Drugs: Containing a phenol group, these drugs can alter the antigenicity of the basement membrane, leading to autoantibody production. Aspirin is an example.
3. Non-thiol/Non-phenol Drugs: This expanding category includes numerous drugs from gliptins to immunotherapies that do not rely on a thiol or phenol group but trigger autoimmunity through other pathways.

Comparison of Drug Classes Associated with DABP

Drug Class	Examples	Strength of Association	Proposed Mechanism
DPP-4 Inhibitors (Gliptins)	Vildagliptin, sitagliptin	Strongest evidence, particularly vildagliptin	Immunological trigger; potential upregulation of inflammatory mediators
Immunotherapy (PD-1/PD-L1)	Pembrolizumab, nivolumab	Strong evidence; well-documented association	Modulation of the immune system leading to autoimmunity
Diuretics	Furosemide, spironolactone	Significant evidence, especially aldosterone antagonists	Alteration of basement membrane antigens; non-immune disruption
Antibiotics (Penicillins)	Penicillin, amoxicillin	Significant association found in large population studies	Formation of neoantigens; immunological trigger
Neuropsychiatric Drugs	Risperidone, dopaminergics	Significant evidence from case-control studies	Connection between nervous system and skin development; underlying neurologic disease involvement
NSAIDs	Ibuprofen	Commonly implicated in case reports	Alteration of basement membrane antigens

Diagnosis and Clinical Management

The diagnosis of DABP is challenging and requires careful patient history. Clinicians should be suspicious of DABP in elderly patients who develop classic bullous pemphigoid lesions after starting a new medication. Confirmation typically involves standard BP diagnostics, including skin biopsy for histopathology and direct immunofluorescence.

Management generally follows these steps:

1. Drug Discontinuation: The first step is to stop the suspected medication, which often leads to rapid resolution of symptoms.
2. Symptomatic Treatment: Corticosteroids (topical or systemic) and other immunosuppressive agents may be used in the short term to manage symptoms, especially if the disease is widespread or severe.
3. Refractory Cases: In some cases, the condition may become chronic and require standard BP treatments, such as doxycycline, dapsone, or other immunosuppressants.

Conclusion

Drug-associated bullous pemphigoid is a recognized adverse effect of a wide array of medications, ranging from common diuretics and antidiabetics to modern cancer immunotherapies. Due to the low prevalence of the disease, it is not recommended to avoid these medications preemptively. However, heightened awareness among healthcare professionals regarding what drugs are associated with bullous pemphigoid is vital for early recognition, prompt discontinuation of the offending agent, and effective patient management. Patients who develop new blistering rashes should consult their doctor, disclosing all current and recently started medications for a proper assessment.

For more information on the systemic review of DABP, see the article published in Acta Dermato-Venereologica.

Frequently Asked Questions

What is drug-associated bullous pemphigoid (DABP)?

DABP is a form of the autoimmune blistering skin disease, bullous pemphigoid, that is triggered by exposure to a specific medication. It exhibits clinical and immunopathological features identical to the idiopathic form.

Which diabetes medications are most commonly associated with bullous pemphigoid?

The class of oral antidiabetic drugs known as DPP-4 inhibitors, or gliptins, are strongly linked to DABP. Vildagliptin, sitagliptin, and linagliptin are specific examples with a significant association.

Can cancer immunotherapy drugs cause bullous pemphigoid?

Yes, immune checkpoint inhibitors used in cancer therapy, including PD-1 inhibitors like pembrolizumab and nivolumab, are well-documented triggers of DABP.

What happens if a drug is suspected of causing bullous pemphigoid?

If a medication is suspected, the first step is to discontinue it. In many cases, this action alone can resolve the blistering. Corticosteroids or other medications may be used to manage symptoms during the recovery period.

Are diuretics linked to bullous pemphigoid?

Yes, studies have found an association between diuretics and bullous pemphigoid, particularly with loop diuretics like furosemide and aldosterone antagonists like spironolactone.

Are antibiotics ever linked to bullous pemphigoid?

Yes, a significant association has been found with several antibiotic classes, including penicillins, although the evidence varies among different antibiotic types.

Is it possible for a medication to both cause and treat bullous pemphigoid?

Yes, in rare cases involving biologics, a drug from a class such as anti-TNF-alpha inhibitors has been reported to both cause and successfully treat bullous pemphigoid. Additionally, doxycycline is an antibiotic linked to DABP but is also used for milder cases of BP.