Raymond Yung, MD
Departments of Internal Medicine
University of Michigan
Ann Arbor, Mich.
Richardson, MD, PhD
Departments of Internal Medicine
Ann Arbor Veterans Affairs Medical Center
Ann Arbor, MI
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
A number of drugs,
including G-CSF and GM-CSF, vaccinations, and leukotriene inhibitors are associated with
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
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
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
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.
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.
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,
Takayasus 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).
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.
Hoffman BJ. Sensitivity of sulfadiazine
resembling acute disseminated lupus erythematosus. Arch Dermatol Syph 1945;51:190-2.
Yung RL, Richardson BC. Drug-induced lupus.
Rheum Dis Clin North Am 1994; 20:61-86.
Zarrabi MH, Zucker S, Miller F, et al.
Immunologic and coagulation disorders in chlorpromazine-trested patients. Ann Intern Med
Canoso RT, de Oliviera RM. Chlorpromazine-induced
anticardiolipin antibodies and lupus anticoagulant: ansebce of thrombosis. Am J Hematol
Schlienger RG, Bircher AJ, Meier CR.
Minocycline-induced lupus. A systemic review. Dermatol 2000;200:223-31.
Elkayam O, Yaron M, Caspi D. Minocycline-induced
autoimmune syndromes: an overview. Semin Arthritis Rheum 1999;28:392-7
Ioannou Y, Isenberg DA. Review: Current evidence
for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis
Rheum 2000, 43:1431-41.
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.
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
Ronnblom LE, Alm GV, Oberg KE. Autoimmunity after
alpha-interferon therapy for malignant carcinoid tunors. Ann Intern Med 1991;115:178-83.
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.
Calabrese LH, Duna GF. Drug-induced vasculitis.
Curr Opin Rheumatol. 1996;8:34-40.
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.
Jain KK. Cutaneous vasculitis associated with
granulocyte colony-stimulating factor. J Am Acad Dermatol. 1994;31:213-5.
Brown MA, Bertouch JV. Rheumatic complications of
influenza vaccination. Aust N Z J Med. 1994;24:572-3.
Zaas A, Scheel P, Venbrux A, Hellmann DB. Large
artery vasculitis following recombinant hepatitis B vaccination: 2 cases. J Rheumatol
Courtney PA, Patterson RN, Lee RJ.
Henoch-Schonlein purpura following meningitis C vaccination. Rheumatology 2001;40:345-6.
Jamaleddine G, Diab K, Tabbarah Z, Tawil A,
Arayssi T. Leukotriene antagonists and the Churg-Strauss Syndrome. Semin Arthritis Rheum
Masi A, Hamilos DL. Leukotriene antagonists:
bystanders or causes of Churg-Strauss Syndrome. Semin Arthritis Rheum 2002;31:211-7.
Galaria NA, Werth VP, Schumacher HR.
Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000;27(8):2041-4.
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.
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
Miller FW, Hess EV, Clauw DJ, Hertzman PA, et al. Approaches
for identifying and defining environmentally associated rheumatic disorders. Arthritis