I. What every physician needs to know.
Drug-induced lupus (DIL) is an under-recognized disorder. It results from medications that induce production of autoantibodies and a lupus-like syndrome that can be systemic, cutaneous, or vasculitic in nature. Symptoms may include fatigue, fever, joint pains, arthritis, rash, muscle aches, and serositis. Diagnosis of DIL requires careful physical examination, history, and review of medicines taken by the patient.
Many medications have been linked to drug-induced lupus including hydralazine, procainamide, minocycline, carbamazepine, phenytoin, sulfasalazine, isoniazid, penicillamine, terbinafine, anti-tumor necrosis factor (anti-TNF) alpha inhibitors, and interferons. The risk of developing DIL is different for each medication. For example, for procainamide patients have a 20% per year risk of developing DIL, while patients on hydralazine have a 5-8% risk per year. Most other drugs linked to DIL show a relative incidence of DIL of less than 1%.
Proton pump inhibitors and statins, two of the most commonly prescribed medications in the United States, have been associated with drug induced lupus. In 2015, DIL was seen in patients on donepezil for Alzheimer’s dementia.
II. Diagnostic Confirmation: Are you sure your patient has drug-induced lupus?
There is no criteria to diagnose DIL. Diagnosis of drug-induced lupus is based on the presence of symptoms in a patient on a medication associated with causing the disease. There is resolution of symptoms once the offending agent is removed and recurrence of symptoms when patients are re-challenged with the medication. Laboratory studies should show positive ANA (anti-nuclear antibodies) in a diffuse-homogeneous pattern. This is due to autoantibodies binding to chromatin. Thus they are called anti-histone antibodies. Anti-histone antibodies may be seen in both systemic lupus erythematosus and drug-induced lupus. Anti-neutrophil cytoplasmic antibodies (ANCAs), especially perineuclear anti-neutrophil antibodies (pANCAs) have been positive in DIL due to hydralazine, propylthiouracil, and minocycline. Anti-phospholipid antibodies (APAs), such as lupus anticoagulant and anti-cardiolipin antibodies, have been seen in DIL associated with chlorpromazine, procainamide, and quinidine/quinine. Chlorpromazine-induced APAs are not associated with thrombosis while those APAs associated with procainamide and quinidine/quinine have been associated with thrombosis.
A. History Part I: Pattern Recognition:
Patients with drug-induced lupus often experience myalgias, arthralgias, fever, serositis, and cutaneous manifestations such as purpura, erythema nodosum, photosensitivity, urticarial vasculitis, and necrotizing vasculitis. Patients may have been on suspected medications from 2 weeks to up to 3 years before symptoms develop. The most frequently involved medication in causing DIL is procainamide.
Drugs commonly associated with DIL include:
Drugs less often associated with DIL include:
Drugs suggested to cause DIL include:
Calcium channel blockers
Drugs recently discovered to induce DIL include:
(List adapted from Katz and Zandman-Goddard 2010.)
B. History Part 2: Prevalence:
There are 15,000 to 30,000 new cases of DIL every year. DIL occurs mostly in the elderly, in men and women at equal rates, while systemic lupus erythematosus (SLE) occurs mostly in women of childbearing age. It is more common in Caucasians than African Americans, the opposite of what is seen in SLE. DIL due to minocycline is usually seen in young patients who are using the medication to treat acne.
C. History Part 3: Competing diagnoses that can mimic disease drug-induced lupus
DIL may be confused with systemic lupus erythematosus (SLE) but will lack certain features such as oral or nasal ulcers, alopecia and malar rash. SLE patients may have positive antibodies to double-stranded deoxyribonucleic acid (dsDNA) and anti-Smith, but these are rarely seen in DIL. DIL patients may have single-stranded DNA (ssDNA). Lupus-like syndrome associated with TNF-alpha antagonist use may be more difficult to distinguish from SLE due to the presence of malar rash, discoid rash, low complement levels, and additional positive antibodies such as anti-dsDNA, anti-histone antibodies, and anti-cardiolipin antibodies. Positive dsDNA antibodies have also been seen in DIL due to interferon-alfa.
D. Physical Examination Findings.
On examination, a patient may have low-grade fever, rash, joint swelling, hepatomegaly, and signs of pleuropericarditis.
Drug-induced cutaneous lupus can present as subacute cutaneous lupus (seen with hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme inhibitors, statins, TNF inhibitors, and proton pump inhibitors) or discoid cutaneous lupus (seen with TNF inhibitors).
E. What diagnostic tests should be performed?
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Laboratory testing should include ANA with antibody profile to help rule out systemic lupus erythematosus and other connective tissue diseases. Anti-Smith antibodies and dsDNA are usually negative in DIL. Complement levels decrease in SLE but are usually normal in DIL. TNF-alpha inhibitors may cause a lupus-like syndrome that has low complements and anti-dsDNA.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Imaging studies are not usually warranted. However, if the patient has symptoms of serositis, then it may be helpful to image the involved area (i.e. chest x-ray, computed tomography (CT) scan of chest or abdomen).
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
Anti-histone antibodies are often ordered to diagnosis DIL. However, they are positive in systemic lupus erythematosus at the same rates (75%). Anti-histone antibodies may also be positive rheumatoid arthritis, Felty syndrome, and undifferentiated connective tissue disease.
III. Default Management.
A. Immediate management.
Hold any medications associated with drug-induced lupus. Symptomatic management for fever, myalgias, and arthralgias with aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). If symptoms persist, consider use of low dose prednisone. If resistant to treatment or symptomatic pericardial effusion, consider higher doses of prednisone.
B. Physical Examination Tips to Guide Management.
Thorough physical examination of skin, hair, and oral mucosa may help to distinguish DIL from SLE.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
D. Long-term management.
Patients should avoid the medication that caused drug-induced lupus. Symptoms should resolve within weeks of stopping the offending agent. Some patients may experience symptoms for up to 1 year. Antinuclear antibodies may resolve with symptoms or be present for long period.
E. Common Pitfalls and Side-Effects of Management
IV. Management with Co-Morbidities
No change in standard management with any comorbidity.
A. Renal Insufficiency.
Unlike systemic lupus erythematosus, drug-induced lupus is not associated with renal insufficiency.
B. Liver Insufficiency.
Drug-induced lupus is not associated with liver insufficiency.
C. Systolic and Diastolic Heart Failure
Drug-induced lupus is not associated with systolic and diastolic heart failure.
D. Coronary Artery Disease or Peripheral Vascular Disease
Drug-induced lupus is not associated with coronary artery disease or peripheral vascular disease, however patients can develop pericarditis.
E. Diabetes or other Endocrine issues
Drug-induced lupus is not associated with diabetes or other endocrine issues.
Drug-induced lupus is not related to development of malignancy.
G. Immunosuppression (HIV, chronic steroids, etc).
Drug-induced lupus is not associated with immunosuppression.
H. Primary Lung Disease (COPD, Asthma, ILD)
Patients with DIL may develop pleuritis.
I. Gastrointestinal or Nutrition Issues
J. Hematologic or Coagulation Issues
Hematologic findings in DIL are usually mild and may include leukopenia, thrombocytopenia, anemia, and elevated erythrocyte sedimentation rate (ESR).
K. Dementia or Psychiatric Illness/Treatment
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
B. Anticipated Length of Stay.
No need for hospitalization. If DIL occurs during hospitalization, stop possible offending agents and evaluate for evidence of systemic lupus erythematosus (SLE). If no evidence of SLE, then patient can be discharged with outpatient follow-up to ensure resolution of DIL.
C. When is the Patient Ready for Discharge.
No need for hospitalization. Discharge determined by other comorbidities.
D. Arranging for Clinic Follow-up
1. When should clinic follow up be arranged and with whom.
Clinic follow-up should be arranged within 2-4 weeks of discharge.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
E. Placement Considerations.
F. Prognosis and Patient Counseling.
Prognosis for drug-induced lupus is good. Symptoms usually will resolve with days or weeks of discontinuation of the medication. Antibodies may persist for longer periods.
VI. Patient Safety and Quality Measures
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Avoid the medication that caused onset of drug-induced lupus.
VII. What's the evidence?
Hochberg, MC. “Rheumatology”. 2014.
Katz, U, Zandman-Goddard, G. “Drug-induced lupus: An update”. Autoimmunity Reviews. vol. 10. 2010. pp. 46-50.
Callen, JP. “Drug-induced subacute cutaneous lupus erythematous”. Lupus. vol. 19. 2010. pp. 1107-1111.
Mor, A, Pillinger, MH, Wortmann, RL, Mitnick, HJ. “Drug-induced arthritic and connective tissue disorders”. Semin Arthritis Rheum. vol. 38. 2008. pp. 249-264.
Borchers, AT, Keen, CL, Gershwin, ME. “Drug-induced lupus”. Ann. N.Y. Acad. Sci.. vol. 1108. 2007. pp. 166-182.
Vasoo, S. “Drug-induced lupus: an update”. Lupus.. vol. 15. 2006. pp. 757-761.
Olsen, NJ. “Drug-induced autoimmunity”. Best Practice & Research Clinical Rheumatology. vol. 18. 2004. pp. 677
Shakoor, N, Michalska, M, Harris, CA, Block, JA. “Drug-induced systemic lupus erythematosus associated with etanercept therapy”. Lancet. vol. 359. 2002. pp. 579
Chang, RS, Cole, AJ. “Lamotrigine-induced lupus-like syndrome: a case report and literature review”. Am J Ther. vol. 21. 2014. pp. e85
Manzo, C, Putignano, S. “Drug-induced lupus erythematosus associated with donepezil: a case report”. Age and ageing. vol. 44. 2015. pp. 1062-1063.
Araujo-Fernandez, S, Ahijón-Lana, M, Isenberg, DA. “Drug-induced lupus: including anti-tumor necrosis factor and interferon induced”. Lupus. vol. 23. 2014. pp. 545-553.
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- Drug-induced lupus
- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has drug-induced lupus?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic disease drug-induced lupus
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes or other Endocrine issues
- F. Malignancy
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.