What non‑tetracycline medications can cause drug‑induced lupus in a patient taking minocycline who has a negative antinuclear antibody, isolated anti‑histone positivity, and a painful cervical swelling?

Drug-Induced Lupus: Non-Tetracycline Causative Medications

Yes, numerous medications outside the tetracycline class can cause drug-induced lupus, with hydralazine, procainamide, and isoniazid being the highest-risk agents, followed by TNF-α inhibitors, which present with a distinct clinical pattern that may include renal involvement.

High-Risk Non-Tetracycline Medications

Traditional High-Risk Agents

• Hydralazine is one of the most common causes of drug-induced lupus, particularly at higher doses and in slow acetylators, and can produce a lupus-like syndrome that may include glomerulonephritis requiring immediate discontinuation 1, 2
• Procainamide is the other most frequently implicated agent in systemic drug-induced lupus, presenting with typical lupus-like symptoms and positive anti-histone antibodies 3, 4, 5
• Isoniazid causes drug-induced lupus as a rare adverse effect, with approximately 22% of patients developing antinuclear antibodies after a mean of 6 months of treatment 2, 3

Penicillamine (Wilson Disease Treatment)

• D-penicillamine causes a lupus-like syndrome marked by hematuria, proteinuria, and positive antinuclear antibodies as a late reaction, occurring in approximately 20-30% of patients requiring drug discontinuation 1
• This reaction typically develops after prolonged use and requires immediate discontinuation when nephrotoxicity is detected 1

Moderate-Risk Non-Tetracycline Medications

TNF-α Inhibitors (Distinct Presentation)

• Infliximab, adalimumab, and etanercept can cause drug-induced lupus with a clinical presentation that differs substantially from classic drug-induced lupus 2, 6, 3
• TNF-α inhibitor-induced lupus presents with higher incidence of cutaneous rashes, may involve renal complications (unlike classic drug-induced lupus), and can have low complement levels and anti-dsDNA antibodies present in approximately half of cases 2, 3, 4
• Anti-histone antibodies are less common with TNF-α inhibitors compared to classic drug-induced lupus agents 3, 4
• Approximately half of infliximab-treated patients who were ANA-negative at baseline develop positive ANA, and one-fifth develop anti-dsDNA antibodies 6

Antihypertensive Agents

• Calcium channel blockers and angiotensin-converting enzyme inhibitors are associated with drug-induced subacute cutaneous lupus erythematosus (SCLE), which is the most common form of drug-induced lupus 3, 4
• Methyldopa is a less frequently implicated antihypertensive agent causing systemic drug-induced lupus 5

Other Moderate-Risk Agents

• Quinidine is frequently implicated in systemic drug-induced lupus 4, 5
• Sulfasalazine can cause drug-induced lupus syndrome 5
• Chlorpromazine is associated with drug-induced lupus 5

Lower-Risk But Documented Agents

Drug Classes

• Anticonvulsants as a class have been implicated in drug-induced lupus 5
• Beta-blockers as a group can cause drug-induced lupus 5
• Sulfonamides have been associated with lupus-like syndromes 5
• Thiazide diuretics are linked to drug-induced SCLE 3

Specific Agents

• Terbinafine is commonly implicated in drug-induced SCLE 3, 4
• Proton pump inhibitors (including pantoprazole) have been associated with drug-induced SCLE and rarely CCLE 4
• Interferons can cause drug-induced SCLE, likely through disruption of the cytokine network 3, 5
• Fluorouracil agents and NSAIDs are associated with drug-induced chronic cutaneous lupus erythematosus (CCLE), though this is very rare 3, 4

Clinical Distinctions by Drug Class

Classic Systemic Drug-Induced Lupus Pattern

• Presents with constitutional symptoms, arthralgia/arthritis, myalgias, fever, and weight loss developing over weeks to months 7, 5
• Renal and central nervous system involvement are rare 7, 5
• Anti-histone antibodies are typically positive, while anti-dsDNA antibodies are rare 3, 7

TNF-α Inhibitor Pattern

• Higher incidence of cutaneous manifestations 3, 4
• Renal involvement occurs more frequently than in classic drug-induced lupus 2, 3
• Anti-dsDNA and anti-extractable nuclear antigen antibodies present in approximately 50% of cases 3
• Low complement levels may be present 3

Drug-Induced SCLE Pattern

• Most common form of drug-induced lupus overall 4
• Clinically and serologically very similar to idiopathic SCLE 3, 4
• Associated primarily with antihypertensives, terbinafine, and proton pump inhibitors 3, 4

Critical Clinical Considerations for Your Patient

Given the context of minocycline use with negative ANA but isolated anti-histone positivity and cervical swelling:

• Minocycline-induced lupus has a unique presentation affecting primarily young women, often with anti-dsDNA and p-ANCA antibodies positive but negative anti-histone antibodies, which differs from your patient's presentation 7
• The isolated anti-histone positivity with negative ANA is unusual and may suggest early drug-induced lupus or a different etiology for the cervical swelling 7
• If considering alternative antibiotics, avoid other tetracyclines and be aware that switching to any of the high-risk agents listed above could compound the lupus risk 1

Management Principles

• Resolution or marked improvement generally occurs within 2-5 weeks of drug withdrawal 7, 5
• Most patients require only NSAIDs or low-dose steroids after drug discontinuation 7
• Immunosuppressive drugs may be needed only in severe cases with renal or neurological involvement 7
• Some patients remain ANA-positive for prolonged periods after drug discontinuation, but no treatment is necessary in the absence of clinical features 7