What medications can trigger bullous pemphigoid?

According to extensive pharmacovigilance data analysis, over 90 medications have been associated with inducing bullous pemphigoid (BP). Drug-associated bullous pemphigoid (DABP) is a rare but serious adverse effect where certain medications can trigger the characteristic blistering of this autoimmune skin condition.

Quick Summary

This article explores the major classes of medications that can trigger bullous pemphigoid, including DPP-4 inhibitors, diuretics, and immune checkpoint inhibitors. It discusses the mechanisms involved, contrasts the drug-induced form with the idiopathic version, and outlines important management steps.

Key Points

• Gliptins are a major trigger: The class of antidiabetic drugs known as gliptins, especially vildagliptin, is strongly associated with triggering bullous pemphigoid.

• Diuretics have a long history of association: Common medications like furosemide and spironolactone, used for heart conditions, have been linked to bullous pemphigoid for many years.

• Cancer immunotherapy is a recent culprit: Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, are a new class of medications known to cause this adverse reaction.

• Antibiotics and other drugs are also implicated: Various antibiotics, beta-blockers, ACE inhibitors, and NSAIDs can also trigger the condition.

• Onset can be delayed: The time from starting a medication to the appearance of blisters can range from weeks to over a year, making diagnosis challenging.

• Cessation often leads to improvement: The cornerstone of managing drug-induced bullous pemphigoid is discontinuing the suspected medication under medical supervision.

• Differentiating from the idiopathic form is key: Drug-associated BP can present differently than the spontaneous version, sometimes appearing in younger patients or with mucosal involvement.

Bullous pemphigoid (BP) is an autoimmune blistering disease most commonly affecting the elderly, but a significant number of cases are attributed to medications. This phenomenon, known as drug-associated bullous pemphigoid (DABP), presents a diagnostic and management challenge for clinicians. Understanding the specific drug classes involved and the characteristics of DABP is crucial for prompt recognition and effective patient care. While the underlying pathology of BP involves the production of autoantibodies targeting proteins in the skin's basement membrane, medications can disrupt this immune tolerance through several proposed mechanisms.

Key Drug Classes Associated with Bullous Pemphigoid

The list of medications implicated in triggering BP is extensive and growing. The strongest associations are seen in several common drug classes.

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

This class of oral antidiabetic drugs is used to treat type 2 diabetes mellitus and has one of the highest reported associations with BP.

• Vildagliptin has shown a particularly strong statistical correlation and is the most frequently implicated gliptin.
• Other gliptins, including sitagliptin, linagliptin, and saxagliptin, have also been linked to BP cases.
• The latency period can be significant, with some cases developing more than a year after starting treatment.

Diuretics

Used to manage cardiovascular conditions, various diuretics have been consistently associated with BP over many years.

• Loop Diuretics: Furosemide is a well-known trigger, and bumetanide is also implicated.
• Aldosterone Antagonists: Spironolactone has a documented association.
• Thiazide Diuretics: Medications like hydrochlorothiazide have been reported to trigger BP.

Immune Checkpoint Inhibitors (ICIs)

These advanced cancer therapies have introduced a new category of drug-induced autoimmune reactions, including BP.

• Examples: Nivolumab, pembrolizumab, and durvalumab are some of the anti-PD-1/PD-L1 therapies linked to BP development.
• Mechanism: ICIs can unleash a robust immune response by removing inhibitory checkpoints on T-cells, inadvertently leading to the production of autoantibodies that target the skin.

Antibiotics

A variety of antimicrobial agents have been reported to trigger BP, often showing a shorter latency period than other drug classes.

• Penicillin and Derivatives: Penicillin, amoxicillin, and ampicillin are commonly cited culprits.
• Fluoroquinolones: Ciprofloxacin and levofloxacin have been implicated in some cases.
• Other Antimicrobials: Dapsone, tetracyclines, and vancomycin have also been associated with drug-induced blistering diseases.

Other Notable Medications

Beyond the major categories, numerous other drugs have been linked to BP, though with varying levels of evidence.

• Beta-blockers: Medications like propranolol and atenolol are associated with BP.
• ACE Inhibitors: Captopril, enalapril, and lisinopril have been linked to BP.
• Neuroleptics: Certain antipsychotic medications, such as risperidone, show a correlation with BP.
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Ibuprofen and piroxicam are included in the list of potential triggers.

Clinical Differences: Drug-Induced vs. Idiopathic Bullous Pemphigoid

While drug-induced BP can mimic the classic form, subtle differences can aid in diagnosis.

Feature	Drug-Associated Bullous Pemphigoid (DABP)	Idiopathic Bullous Pemphigoid (IBP)
Patient Age	Tends to occur in younger patients	Predominantly affects older age groups
Lesion Base	Often appears on normal-appearing skin	Commonly arises on an erythematous or urticarial (hive-like) base
Mucosal Involvement	Can be present, sometimes more common with gliptins	Usually rare
Response to Treatment	May respond quickly to cessation of the offending drug	May exhibit a more protracted course despite corticosteroid therapy
Nikolsky Sign	May be positive	Typically negative
Onset	Often more abrupt	Gradual onset, starting with pruritus

Proposed Mechanisms of Action

The exact way in which drugs induce BP is not fully understood and may vary depending on the medication. Several hypotheses have been proposed.

• Immune Dysregulation: For drugs like ICIs, the mechanism is believed to involve a general activation of the immune system. By removing T-cell inhibition, these drugs can lead to an inappropriate autoimmune response and the production of anti-basement membrane antibodies.
• Direct Antigenic Modification: Some drugs, particularly those containing a sulfhydryl (-SH) group, like the ACE inhibitor captopril, may directly bind to basement membrane proteins, altering their structure and making them appear foreign to the immune system.
• Interference with Protein Function: The inhibition of the DPP-4 enzyme by gliptins could cause an accumulation of immune-related substrates, altering the immune environment and leading to a helper T cell (Th2)-skewed response that fosters autoantibody production.
• Molecular Mimicry: A drug's structure may resemble a microbial antigen, causing the immune system to misidentify the medication, leading to an autoimmune response.

What to Do If a Drug is Suspected

If blistering lesions appear after starting a new medication, it is crucial to consult a healthcare provider, ideally a dermatologist, for a proper diagnosis.

1. Review your medication history with your doctor, paying close attention to any recently started drugs.
2. Do not stop taking any prescribed medication on your own. Sudden cessation can be dangerous, and the medication may not be the cause. Your doctor will determine the safest course of action.
3. Diagnosis Confirmation: A doctor may order a skin biopsy and immunofluorescence studies to confirm the presence of BP and differentiate it from other blistering disorders.
4. Discontinuation of Offending Agent: If a specific drug is identified, discontinuing it under medical supervision is the cornerstone of management. In many DABP cases, this leads to rapid improvement.

Conclusion

The association between certain drugs and the development of bullous pemphigoid is well-documented, with gliptins, diuretics, and immune checkpoint inhibitors being among the most frequent triggers. The clinical presentation can vary, making a thorough medication review essential for any patient presenting with new blistering lesions. While the mechanisms are complex, prompt identification of drug-induced BP and discontinuation of the causative agent can significantly improve outcomes. Prescribing physicians should maintain a high index of suspicion, especially in high-risk patients who are elderly or have pre-existing neurological disorders, to facilitate early diagnosis and appropriate management.

Drug-Induced Bullous Pemphigoid: The Role of Medication Discontinuation

The definitive diagnosis of drug-induced bullous pemphigoid relies heavily on the temporal relationship between a new medication and the onset of symptoms, followed by improvement upon drug cessation. However, the decision to stop a necessary medication requires careful consideration of the risks and benefits. It is imperative that patients do not alter their regimen without expert medical guidance.

What happens after stopping the drug?

• Acute Course: For some patients, cessation of the offending agent leads to rapid resolution of the symptoms within weeks, suggesting a true drug-induced hypersensitivity.
• Chronic Course: Other cases resemble the classic idiopathic form and may require long-term treatment even after the drug is stopped. The medication in these instances may have simply been the initial trigger.

This distinction is vital for planning long-term management and determining the prognosis. A dermatologist with experience in drug-induced dermatoses is best equipped to navigate this complex process.

DermNet NZ offers an extensive database of skin conditions and their triggers.

Frequently Asked Questions

What are the most common medications that cause drug-induced bullous pemphigoid?

The most common medications that cause drug-induced bullous pemphigoid include dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), diuretics (especially furosemide), and immune checkpoint inhibitors used in cancer treatment.

How long does it take for bullous pemphigoid to appear after starting a new medication?

The latency period can vary significantly. For some drugs, like certain antibiotics, the reaction can occur within weeks. With other drugs, such as gliptins and immune checkpoint inhibitors, the onset can be months to over a year after starting the medication.

Is drug-induced bullous pemphigoid different from the regular kind?

Yes, drug-induced bullous pemphigoid often has different clinical features than the idiopathic (spontaneous) form. It can affect younger individuals, have lesions on normal-looking skin, and sometimes involve mucous membranes more frequently.

What is the primary treatment for drug-induced bullous pemphigoid?

The primary treatment is to discontinue the suspected offending medication under a doctor's supervision. This often leads to the resolution of symptoms. Systemic or topical corticosteroids may also be used to manage the blistering.

Can I stop taking my medication if I suspect it caused bullous pemphigoid?

No, you should never stop taking any prescribed medication without consulting your doctor. A healthcare professional, preferably a dermatologist, needs to evaluate your condition and determine the safest course of action, as sudden discontinuation can be dangerous.

What is the mechanism by which medications cause bullous pemphigoid?

The mechanism is complex and not fully understood, but it can involve immune system dysregulation, direct modification of skin basement membrane proteins by the drug, or other immune-related responses.

Can bullous pemphigoid return if I take the triggering medication again?

Yes. A key feature of drug-induced bullous pemphigoid is that a 'rechallenge' with the offending agent can result in a more severe reaction with a shorter onset time. For ethical and safety reasons, this is not a recommended test.