What drugs cause ANCA vasculitis? An overview of medication-induced autoimmune reactions

Drug-induced ANCA-associated vasculitis (AAV) is a recognized adverse effect of certain medications, with some case series highlighting its association with specific drugs like propylthiouracil and hydralazine. This condition involves inflammation of small blood vessels and is clinically and serologically similar to primary AAV.

Quick Summary

Several medications and illicit substances, including hydralazine, propylthiouracil, and cocaine adulterated with levamisole, are known to trigger ANCA vasculitis. This rare autoimmune reaction presents symptoms similar to the idiopathic form but often resolves with discontinuation of the causative agent.

Key Points

• Causative Agents: Key drugs that cause ANCA vasculitis include propylthiouracil, hydralazine, minocycline, and levamisole-adulterated cocaine.

• Diagnostic Clues: Overlapping serologies (ANCA, ANA) and dual ANCA positivity (anti-MPO and anti-PR3) are common in drug-induced cases.

• Critical Treatment: Discontinuing the causative drug is the most important step for resolution.

• Management for Severe Cases: Immunosuppressive therapy with corticosteroids or other agents may be needed for severe organ involvement.

• Watchful Surveillance: High clinical suspicion is needed for patients on chronic medications who develop unusual symptoms, as diagnosis can be challenging.

Understanding Drug-Induced ANCA Vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare and severe autoimmune disease characterized by inflammation of small blood vessels. While AAV can occur without a known trigger (idiopathic), it can also be induced by exposure to certain drugs, a condition known as drug-induced AAV (DIV). Understanding what drugs cause ANCA vasculitis is critical for both patient safety and effective treatment, which primarily involves removing the offending agent.

Major Drug Culprits and Associated Risks

Several classes of drugs have been repeatedly linked to the development of ANCA vasculitis. The presentation can vary from mild skin manifestations to life-threatening multiorgan involvement, including severe damage to the kidneys and lungs.

Antithyroid Medications (Thionamides):

• Propylthiouracil (PTU): One of the most frequently reported causes of DIV, particularly in young females receiving treatment for hyperthyroidism like Graves' disease. PTU-induced AAV often presents with the development of anti-myeloperoxidase (MPO) ANCA and can cause skin vasculitis, joint pain, and kidney damage.
• Methimazole: Another thionamide used for hyperthyroidism, it also has a documented association with ANCA vasculitis, though potentially less so than PTU.

Cardiovascular Drugs:

• Hydralazine: A vasodilator used to treat hypertension and heart failure, hydralazine has been increasingly reported as a cause of DIV. It can cause a lupus-like syndrome that overlaps with ANCA vasculitis, with some cases progressing to severe, life-threatening complications like pulmonary-renal syndrome.

Antibiotics:

• Minocycline: A tetracycline antibiotic commonly used for treating acne and other infections. Long-term use has been associated with various autoimmune conditions, including a polyarteritis nodosa-like vasculitis that is often ANCA-positive. Discontinuation of the drug typically leads to improvement, but severe cases with organ involvement, including stroke, have been reported.

Illicit Substances:

• Levamisole-Adulterated Cocaine: Cocaine is frequently cut with levamisole, an anti-helminthic agent that was withdrawn from the human market due to its toxicity. Use of this contaminated substance is a potent cause of ANCA vasculitis, often resulting in characteristic purpuric skin lesions, severe neutropenia, and systemic disease affecting the ears, kidneys, and lungs. A classic feature is dual ANCA positivity (anti-MPO and anti-PR3).

Other Notable Drugs:

• Allopurinol: This gout medication can induce vasculitis, with some cases involving ANCA positivity.
• Tumor Necrosis Factor (TNF)-α Inhibitors: Paradoxically, these agents, used to treat autoimmune diseases, have been reported to trigger new autoimmune phenomena, including ANCA vasculitis. Examples include Infliximab and Adalimumab.

The Mechanisms Behind Drug-Induced Autoimmunity

The exact pathophysiology of how these drugs trigger ANCA vasculitis is still being studied, but several mechanisms have been proposed:

• Haptenation: Some drugs, like hydralazine, may bind to immune system proteins like myeloperoxidase (MPO). This binding changes the protein's structure, causing the body's immune system to recognize it as foreign and mount an autoimmune response.
• Neutrophil Extracellular Traps (NETs): In the case of levamisole-tainted cocaine, the drug can cause neutrophils to release NETs, which are webs of DNA and granular proteins (including MPO and PR3) designed to trap pathogens. This can trigger a cascade of inflammation and lead to the formation of ANCAs.

Clinical Comparison: Drug-Induced vs. Idiopathic AAV

Although drug-induced AAV can be clinically and serologically similar to its idiopathic counterpart, certain features can help distinguish the two.

Feature	Drug-Induced ANCA Vasculitis (DIV)	Idiopathic ANCA Vasculitis (AAV)
Causative Factor	Clear temporal relationship with drug exposure	Unknown; possibly a combination of genetics and environment
Autoantibody Profile	Often dual-positive ANCA (MPO + PR3); additional autoantibodies common (ANA, anti-histone)	Typically single-positive ANCA (either MPO or PR3)
Associated Features	Overlap with drug-induced lupus is possible; high incidence of neutropenia with levamisole	No overlap with drug-induced lupus; neutropenia is uncommon
Disease Severity	Generally milder, but severe organ-threatening disease can occur	Variable severity, can be life-threatening and more aggressive
Prognosis	Generally favorable upon discontinuation of the offending drug	Relapses are common and long-term immunosuppression is often needed
Relapse Risk	Re-exposure to the drug is a major cause of relapse	Relapses are more unpredictable

Diagnosis and Treatment Approach

Diagnosis begins with a high index of suspicion based on a patient's history, especially a recent change in medication. A detailed drug history is essential. Serological testing for ANCAs is a key step, along with evaluation of other autoantibodies like antinuclear antibodies (ANA). A biopsy of affected tissue, such as skin or kidney, may be required for confirmation.

The cornerstone of treatment for DIV is the immediate discontinuation of the suspected drug. In many milder cases, this action alone can lead to complete remission. For severe cases involving vital organ damage, particularly the kidneys or lungs, aggressive immunosuppressive therapy may be necessary. This often includes high-dose corticosteroids, sometimes combined with cyclophosphamide or rituximab, along with supportive care. Unlike idiopathic AAV, long-term maintenance immunosuppression may not be required once the drug is removed, but vigilant monitoring is essential.

Conclusion

While drug-induced ANCA vasculitis is a rare but serious adverse effect, prompt recognition and discontinuation of the triggering medication can lead to a favorable outcome. For clinicians, maintaining a high index of suspicion in patients presenting with vasculitic symptoms and a history of exposure to known culprits is paramount. For patients, open communication with healthcare providers about all medications and supplements is key to ensuring a timely diagnosis and effective treatment plan. Further research continues to shed light on the mechanisms of these complex autoimmune reactions.

For more information on the management of ANCA-associated vasculitis, refer to the Johns Hopkins Vasculitis Center.

Frequently Asked Questions

What is the most common drug to cause ANCA vasculitis?

Historically, propylthiouracil (PTU) is one of the most frequently cited causes of drug-associated ANCA vasculitis, especially in young women with hyperthyroidism.

Can cocaine cause ANCA vasculitis?

Yes, especially cocaine that has been adulterated with levamisole. This can cause a severe form of ANCA vasculitis with characteristic skin lesions and systemic involvement.

How is drug-induced ANCA vasculitis different from idiopathic vasculitis?

Drug-induced ANCA vasculitis typically has a clear temporal relationship with the start of a medication, often resolves after stopping the drug, and can present with overlapping autoantibodies, including dual ANCA positivity.

Does hydralazine always cause ANCA vasculitis?

No, it is a rare but serious side effect of hydralazine, a medication used for hypertension. While generally well-tolerated, it is important to be aware of the risk, especially with higher doses.

What are the first steps in treating drug-induced vasculitis?

The primary and most crucial step in treatment is the immediate discontinuation of the medication suspected of causing the vasculitis. For severe cases, additional immunosuppressive therapy might be necessary.

How is drug-induced ANCA vasculitis diagnosed?

Diagnosis involves clinical suspicion based on patient history, serological testing for ANCA and other autoantibodies, and sometimes a tissue biopsy to confirm vessel inflammation.

Can minocycline cause ANCA vasculitis?

Yes, long-term use of the antibiotic minocycline, often for acne, has been linked to ANCA vasculitis, and in rare cases, can cause severe complications like stroke.