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Drug-Induced Rheumatic Syndromes

Raymond Yung, MD
Departments of Internal Medicine
University of Michigan
Ann Arbor, Mich.

Bruce Richardson, MD, PhD
Departments of Internal Medicine
Ann Arbor Veterans Affairs Medical Center

Ann Arbor, MI

Summary Points

  • A variety of drugs can be associated with rheumatic syndromes.

  • Drugs like minocycline, interferon, and anti-TNF agents can induce ANAs and anti-DNAs and, less commonly, clinical lupus syndromes.

  • A number of drugs, including G-CSF and GM-CSF, vaccinations, and leukotriene inhibitors are associated with ANCA-positive vasculitis.

 

Introduction
The intriguing possibility of iatrogenic autoimmunity was first raised in 1945 with a report of possible sulfadiazine-induced lupus (1).  This was followed by a number of anecdotal reports implicating sulfonamides and penicillin as the inciting agents for lupus or lupus-like illnesses. While the link between antibiotics and lupus was subsequently found to be relatively weak, these early reports highlighted the potential role of drugs in the induction of clinical rheumatic syndromes.

The drug-induced rheumatic diseases can be broadly divided into three main categories: drug-induced lupus (DIL), drug-induced myopathy/myositis (DIM), and drug-induced vasculitis (DIV).  Recent reports in two of these areas are emphasized in this review. (Read “Inflammatory Myopathies,” Vol. 51, No. 3, for more information about DIM.)  However, it is important to note that a majority of the publications regarding drug-induced rheumatic syndromes are case reports or case series and have not been examined by careful epidemiological studies.  Thus, the term “drug-induced” may be misleading and may be more appropriately referred to as “possibly associated.”

Drug-induced Lupus (DIL)
The incidence of DIL has been estimated to be ~15,000 to 20,000 per year with ~30,000 to 50,000 patients being affected in the United States at any given time (2). More than 100 drugs have now been implicated in DIL.

The drugs that have been most studied in DIL are procainamide and hydralazine (2). However, these drugs are not commonly prescribed today and the lupus-like illness they produce is often different from those implicated in DIL in recent years. Unlike patients with idiopathic lupus, patients with hydralazine-induced lupus (HIL) and procainamide-induced lupus (PIL) are usually older and more likely to be men, reflecting the age and sex of the patients receiving these drugs.   One-third of patients receiving procainamide for more than a year will develop symptoms, and almost all will become ANA-positive after 2 years. In contrast, less than 20% of hydralazine-treated patient will develop DIL. The patients at the greatest risk for developing HIL are those taking doses greater than 200 mg/day and those who have received more than 100 grams cumulative dose. 

Compared to idiopathic lupus patients, DIL patients have less renal, neuropsychiatric, and skin manifestations. Pleuropulmonary complaints are particularly common in PIL. More than 90% of PIL and HIL patients have antihistone antibodies, and 20% to 40% have rheumatoid factors. By definition, patients with DIL are ANA-positive. The pattern of the ANA is usually homogenous, reflecting reactivity again histone or histone-DNA complexes.  Accordingly, a speckled pattern ANA in a patient with suspected HIL or PIL makes a drug-induced etiology less likely.

A number of drugs have been reported to induce antiphospholipid antibodies. The strongest associations are with the use of chlorpromazine and procainamide. Although there are occasional reports of thrombosis, the risk of an associated clinical event appears to be low. For example, 56% to 87% of patients on chronic chlorpromazine therapy develop antiphospholipid antibodies but less than 6% of the antibody-positive patients have a thrombotic episode in up to 5 years follow-up (3,4). The reason for the low incidence of thrombosis is unclear, but most of the drug-induced anticardiolipin antibodies belong to the IgM subtype and probably have lower pathogenic potential.

Minocycline is a popular acne treatment and is also used in the treatment of rheumatoid arthritis.  Over the past decade, numerous reports of immune and autoimmune phenomena associated with its use have appeared in the literature, including serum sickness, lupus, autoimmune hepatitis, and vasculitis (5,6).  Women are more likely to be affected.  Symptoms also tend to be milder than idiopathic lupus, and include fever, arthralgia/myalgias and arthritis.  Renal and central nervous system involvement again are rare. Pneumonitis (included in the first reported case of minocycline-induced lupus) and hepatitis (in isolation or as part of the lupus syndrome) have been described in a number of cases, although the true incidence is unknown.   In addition, there are rare reports of skin disorders, including livido reticularis and cutaneous vasculitis. Serological changes in minocycline-induced lupus are also different from classical DIL with a higher incidence of anti-dsDNA antibodies (up to 30%), a positive p-ANCA (70%), and a lower incidence of antihistone (20%) antibodies.

A number of the new recombinant biologics have been implicated in DIL including interferon a (IFNa), interferon g (IFNg), and anti-TNF therapies (7).  Between 4% and 19% of IFNa-treated patients develop some forms of autoimmunity (7,8,9,10).  Approximately 12% of patients receiving this drug develop an ANA, and between 0.15% and 0.7% will develop a lupus-like illness.  Anti-dsDNA antibodies occur in 8%, and almost all with IFNa-induced lupus have elevated anti-dsDNA antibodies. Although female gender appears to be a risk factor for the development of anti-dsDNA antibodies, approximately equal numbers of cases of male and female IFNa-induced lupus are reported in the literature.  The duration of treatment to onset of lupus ranges from 1 month to 7 years; the dose and duration may be important determinants. Because autoimmune thyroid diseases are common following IFNa treatment (especially in those with pre-existing thyroid antibodies), patients may also present to the clinician with soft-tissue rheumatic complaints secondary to thyroid dysfunction.

Anti-TNF therapy represents a significant advance in the treatment of rheumatoid arthritis. It has also become apparent that patients receiving either anti-TNF monoclonal antibodies or TNF receptor antagonists can develop serological evidence of autoimmunity (11).  In one study, new ANA and anti-dsDNA antibodies were found in 33% and 9% of infliximab recipients, respectively.  However, there is clear discordance between the development of autoantibodies and clinical autoimmunity, with less than 20 symptomatic patients reported in the literature and in abstract form.

At present, it is not possible to predict who will develop DIL.  If necessary, patients with idiopathic lupus should be allowed to take potentially lupus-inducing drugs, including procainamide and hydralazine, but with careful monitoring.A number of the new recombinant biologics have been implicated in DIL including interferon a (IFNa), interferon g (IFNg), and anti-TNF therapies (7).  Between 4% and 19% of IFNa-treated patients develop some forms of autoimmunity (7,8,9,10).  Approximately 12% of patients receiving this drug develop an ANA, and between 0.15% and 0.7% will develop a lupus-like illness.  Anti-dsDNA antibodies occur in 8%, and almost all with IFNa-induced lupus have elevated anti-dsDNA antibodies. Although female gender appears to be a risk factor for the development of anti-dsDNA antibodies, approximately equal numbers of cases of male and female IFNa-induced lupus are reported in the literature.  The duration of treatment to onset of lupus ranges from 1 month to 7 years; the dose and duration may be important determinants. Because autoimmune thyroid diseases are common following IFNa treatment (especially in those with pre-existing thyroid antibodies), patients may also present to the clinician with soft-tissue rheumatic complaints secondary to thyroid dysfunction.

Drug-Induced Vasculitis (DIV)
Ingestion of a number of drugs has been associated with the development of ANCA-positive vasculitis (12,13). Renal involvement with glomerulonephritis is common. The antibodies often lack specificity and may show direct activity against MPO, elastase, and PR-3. Discontinuation of the offending drug results in resolution of the clinical disease and a fall in the ANCA titer. DIV should be differentiated from drug-induced ANCA production, which is much more common, and DIL.

Hematopoietic growth factors including G-CSF and GM-CSF are used for conditions such as chronic benign neutropenia, chemotherapy-related neutropenia, and Feltys syndrome. Administration of these growth factors has been associated with the development of cutaneous leukocytoclastic and, rarely, systemic vasculitis (7,12,13,14). Interestingly, there is a particularly high prevalence of vasculitis among patients with chronic benign neutropenia receiving these growth factors. In this population there appears to be a close temporal relationship between exposure and the onset of vasculitis. The risk of vasculitis increases when the absolute neutrophil count (ANC) rises above 800/mm3, and the problem almost always subsides with decreasing ANC.  Cessation of therapy is usually associated with prompt resolution of the vasculitis as well. A number of vasculitis mimics may also develop in association with hematopoietic growth factors, including Sweets syndrome and pyoderma gangrenosum. 

Vaccination against a number of pathogens including hepatitis B, influenza, and others have been associated with the development of localized or systemic vasculitis.   The associations reported include cryoglobulinemia, polyarteritis nodosa, Takayasu'ss arteritis, Churg-Strauss syndrome, giant cell arteritis, cutaneous leukocytoclastic vasculitis, Henoch-Schonlein purpura, Kawasaki disease, and microscopic polyangiitis (15,16,17). The onset of vasculitis varies from 2 to 50 days. Most cases resolve spontaneously or with steroid therapy. Rare incidents of relapsing or fatal illness have been reported, although some of these cases may be related to an infectious agent or co-incidental primary/idiopathic disease. Vaccination may trigger the onset of an underlying autoimmune process. The overall incidence of vaccination-induced vasculitis appears to be low. The authors recommend that clinicians should not withhold the appropriate vaccination from patients with pre-existing autoimmune diseases or vasculitis based on these case reports. 

To date, there are 22 case reports of asthma patients developing Churg-Strauss syndrome (CSS) while receiving leukotriene inhibitors (18,19). The duration of exposure varies from 2 days to 10 months. All the patients have received inhaled or systemic corticosteroid for their asthma. Onset of CSS is often associated with exposure to the offending drug during a steroid taper.  It is therefore possible that these cases represent unmasking of undiagnosed CSS with tapering of the steroids rather than a drug-induced disease (18,19). Nevertheless, in the absence of further information, it remains possible that some cases of CCS are an idiosyncratic eosinophil-based response to leukotriene inhibitors. Whether the association between leukotriene inhibitors and CCS is real will only be answered by large epidemiologic studies. In the meantime, clinicians caring for asthma patients on leukotriene inhibitors need to be aware of this potential problem. Symptoms and decline in pulmonary functions disproportionate to the patients prior clinical course, the appearance of new pulmonary infiltrate in the absence of infection and rising eosinophil count should prompt the clinicians to evaluate for possible CCS (19).

Conclusions
The list of drugs capable of inducing rheumatic syndromes is growing. A major problem for clinicians and scientists is to evaluate the likelihood and the importance of the association in case reports or small case series.  Primary elements in the assessment of a possible association between exposure and the development of a rheumatic disorder include temporal association, lack of likely alternative explanations, rechallenge, and biological plausibility (23). It is also important for the medical and research community to further define such an association with rigorous epidemiologic and laboratory studies. It is currently not possible to identify a specific person who is at risk for developing a drug-induced rheumatic syndromes (except if the patient has a history of the drug reaction). 

In most instances, concern about the possibility of drug-induced rheumatic syndrome should not deter the clinician from prescribing a drug. Drug-induced rheumatic syndromes represent a unique situation whereby the specific inciting agent for a rheumatic disorder is known. Better understanding of the underlying mechanisms for these diseases will likely provide valuable clues to the cause of many idiopathic rheumatic syndromes as well.  

References

  1. Hoffman BJ. Sensitivity of sulfadiazine resembling acute disseminated lupus erythematosus. Arch Dermatol Syph 1945;51:190-2.

  2. Yung RL, Richardson BC.  Drug-induced lupus.  Rheum Dis Clin North Am 1994; 20:61-86.

  3. Zarrabi MH, Zucker S, Miller F, et al. Immunologic and coagulation disorders in chlorpromazine-trested patients. Ann Intern Med 1979;91:194-9. 

  4. Canoso RT, de Oliviera RM. Chlorpromazine-induced anticardiolipin antibodies and lupus anticoagulant: ansebce of thrombosis. Am J Hematol 1988;27:272-5.

  5. Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systemic review. Dermatol 2000;200:223-31.

  6. Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum 1999;28:392-7

  7. Ioannou Y, Isenberg DA. Review: Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 2000, 43:1431-41.

  8. Ronnblom LE, Alm GV, Oberg KE. Possible induction of systemic lupus eryhtematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med 1990;227:207-10.

  9. Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M et al: Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996;25:283-91.

  10. Ronnblom LE, Alm GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tunors. Ann Intern Med 1991;115:178-83.

  11. Charles PJ, Smeenk RJT, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor a. Arthritis Rheum 2000;43:2383-90.

  12. Calabrese LH, Duna GF. Drug-induced vasculitis. Curr Opin Rheumatol. 1996;8:34-40.

  13. Choi HK, Slot MC, Pan G, Weissbach CA, Niles JL, Merkel PA. Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine. Arthritis Rheum 2000;43:2488-92.

  14. Jain KK. Cutaneous vasculitis associated with granulocyte colony-stimulating factor. J Am Acad Dermatol. 1994;31:213-5.

  15. Brown MA, Bertouch JV. Rheumatic complications of influenza vaccination. Aust N Z J Med. 1994;24:572-3.

  16. Zaas A, Scheel P, Venbrux A, Hellmann DB. Large artery vasculitis following recombinant hepatitis B vaccination: 2 cases. J Rheumatol 2001;28:1116-20.

  17. Courtney PA, Patterson RN, Lee RJ. Henoch-Schonlein purpura following meningitis C vaccination. Rheumatology 2001;40:345-6.

  18. Jamaleddine G, Diab K, Tabbarah Z, Tawil A, Arayssi T. Leukotriene antagonists and the Churg-Strauss Syndrome. Semin Arthritis Rheum 2002;31:218-27.

  19. Masi A, Hamilos DL. Leukotriene antagonists: bystanders or causes of Churg-Strauss Syndrome. Semin Arthritis Rheum 2002;31:211-7.

  20. Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000;27(8):2041-4.

  21. Cunnane G, Warnock M, Rehman Q, Fye K, Gaikh San DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2001;44(3):S373.

  22. Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS. Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001;44(5):1149-54.

  23. Miller FW, Hess EV, Clauw DJ, Hertzman PA, et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000;43:243-9.

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