19
DRUG REACTIONS AND INTERACTIONS
Early diagnosis and discontinuation of the offending agent is
critical in drug-induced lupus erythematosus
The risk of inducing lupus erythematosus is considered to
be low or very low for most pharmacological agents, with
the exception of some cardiovascular drugs (e.g. procaina-
mide, hydralazine and quinidine). Concerns about drug-
induced lupus are also emerging for newer biological
modulators. Early diagnosis of drug-induced lupus is vital
and requires symptom onset to be temporally related to drug
initiation. Discontinuation of the causative agent is required
in all cases of drug-induced lupus.
Autoimmune diseases induced by
many drugs
More than 100 drugs from across a variety of classes have
been implicated in the induction of autoimmune diseases.[1]
The autoimmunity they induce is idiosyncratic and, there-
fore, considered to be a ‘type B’ adverse reaction (i.e. un-
predictable and potentially dependent on various factors, such
as overall health, genetic susceptibility, concurrent illness,
drug interactions and food or environmental factors, such as
physical activity/inactivity or exposure to sunlight).[1]
Drug-induced lupus is rare
Systemic lupus erythematosus (SLE), one of the most
common autoimmune diseases, has an incidence of
15 000–30 000 cases annually.[1] Drugs are thought to
induce »10% of all cases of SLE, and the number of drugs
associated with the disease increases each year. The pre-
sentation of drug-induced SLE varies depending on the drug
involved, and exceptions to the general patterns of in-
volvement are frequent. Of the American College of
Rheumatology criteria used in the diagnosis of idiopathic
SLE (i.e. malar rash, discoid rash, photosensitivity, oral ul-
cers, arthritis, serositis, renal disorder, haematological dis-
order, neurological disorder, immunological disorder and
antinuclear antibodies), the features that are commonly seen
in drug-induced lupus are arthritis, serositis, haematological
disorder, immunological disorder and antinuclear anti-
bodies). Symptoms in patients with drug-induced lupus may
be milder than those with idiopathic lupus, and there is
rarely any serious major organ system involvement.[1]
Drugs have also been associated with cutaneous lupus
erythematosus (CLE), including both subacute (SCLE) and
chronic (CCLE) cases.[1] SCLE is induced by drugs mainly
in older patients (mean age 59 years) and may occur weeks
or even years after the drug is initiated. Scalar annular
plaques and photodistributed erythema are the most frequent
dermatological symptoms.[1]
Exactly how each drug induces lupus appears to differ
between pharmacological agents. Predicting who may de-
velop the disease is difficult, with no data to indicate that
serological profiling prior to drug initiation provides any
benefit.[1] This article summarizes a review by Chang and
Gershwin[1] of the drugs that are most commonly associated
with drug-induced lupus.
High risk with some cardiovascular drugs
Cardiovascular drugs, especially antiarrhythmics, are
the agents most commonly associated with drug-induced
lupus.[1] However, only procainamide and hydralazine are
considered to carry a high risk of inducing the disease, with
quinidine being associated with a moderate risk (table I).[1]
Over the years there has been a drastic reduction in pro-
cainamide and quinidine use due to safer and more effective
drugs being developed.[1] This, together with the fact that doses
of these drugs are now kept lower than previously, may help to
explain the observed reduction in the incidence of procaina-
mide- and quinidine-induced lupus. Use of hydralazine has also
declined for similar reasons, although its use may be expected
to increase now that it is available as a fixed combination with
isosorbide dinitrite for congestive heart failure.[1]
Antihypertensives, specifically calcium channel antago-
nists (diltiazem, verapamil, nifedipine), thiazide diuretics
(hydrochlorothiazide), ACE inhibitors (cilazapril) and
b-adrenergic receptor inhibitors (acebutolol), are the drugs
most frequently associated with SCLE.[1]
But most drugs are low risk
Most drugs are associated with a low incidence of drug-
induced lupus and are consequently considered to be low or
very low risk.[1] Drug-induced lupus or signs/symptoms con-
sistent with the disease have been seen with agents such as
penicillamine, sulfasalazine, chlorpromazine and ciclosporin,
although evidence is generally limited to case reports.[1]
SCLE has been associated with some antifungals (terbi-
nafine, griseofulvin), NSAIDs (piroxicam, naproxen), the
antidepressant bupropion, and several other drugs (e.g. ianso-
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20

Table I. Summary of key features of selected agents associated with drug-induced lupus erythematosus[1]
Procainamide Hydralazine Quinidine Minocycline TNFa inhibitors
Drug class
Antiarrhythmic Antihypertensive Antiarrhythmic Antibacterial Biological modulator
Risk of drug-induced lupus
High High Moderate Low No data
Year that drug-induced lupus was first reported
1962 1953 1988 1992 1993
Incidence of drug-induced lupus
»20% of pts during the »5–8% of pts Case reports (risk may be Calculated to be 14.2 »0.2% of pts
first year of therapy lower than previously cases per 100 000
believed) prescriptions
Major clinical features of lupus
Polyarthritis, Rash, fever, myalgias, Cutaneous and Arthritis, arthralgias, Skin manifestations,
polyarthralgias, myalgias, polyarthralgias, neurological myalgias, fever, weight glomerulonephritis
constitutional symptoms, polyarthritis, pleuritis; manifestations, pleuritis, loss, malaise, skin
pericarditis, pleuritis glomerulonephritis and peripheral and clotting manifestations (»25% of
vasculitis are rare abnormalities cases), hepatitis
Distinguishing laboratory features of drug-induced lupus
Anaemia Anaemia, leukopenia Thrombocytopenia, Elevated liver enzymes Thrombocytopenia
hypocomplementaemia
Autoantibodies associated with drug-induced lupusa
Anti-H2A-H2B-DNA, ANA, ANCA, anti-dsDNA, Anti-H2A-H2B-DNA ANA, pANCA, anti-dsDNA ANA, anti-dsDNA,
antihistone, anticardiolipin anti-H1 histone antinucleosome,
anticardiolipin
Possible mechanism(s) of inducing lupus
Central tolerance DNA hypomethylation, Apoptosis Antigen modification, Cytokine shift, apoptosis,
inhibition, apoptosis, DNA macrophage activation haptenization bacterial infection
hypomethylation
a Not all individuals with autoantibodies will necessarily develop clinical lupus.
ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ds = double-stranded; pANCA = protoplasmic-staining ANCA;
pts = patients; TNF = tumour necrosis factor.

prazole, leflunomide, docetaxel, tamoxifen),[1] and there have
been reports of lupus and SCLE occurring with HMG-CoA
reductase inhibitors (statins) [some cases resulting in death][2]
and the antiplatelet agent ticlopidine.[3,4] CCLE has occurred
rarely with NSAIDs and fluorouracil agents.[1]
Drug-induced autoimmunity has also been seen with anti-
thyroid drugs, and autoimmune diseases, such as Sjörgen’s
syndrome, have been linked to aromatase inhibitor therapy.[1]
Minocycline: low risk but symptoms can
be severe
The tetracycline antibacterial agent minocycline was first
reported to induce lupus in 1992, with the condition being
observed after long-term exposure (median 19 months).[1,5]
The risk of experiencing drug-induced lupus with minocy-
cline is considered to be low (table I).[1] The single use of
the drug is associated with a risk ratio of 8.5–16 versus non-
use, depending on the duration of treatment.[1,5] There ap-
pears to be a genetic element involved in minocycline-
induced lupus susceptibility,[1] with a small study finding
that all affected patients had a particular HLA-DQB1 allele
and were HLA-DR2 or -DR4 positive.[6]
Minocycline-induced lupus occurs in significantly more
women than men (32.7 vs 2.3 cases per 100 000 prescriptions)
and appears to affect younger patients (median age 21 years).[1]
Even children receiving minocycline were found to develop
autoimmunity in a small retrospective study.[7] Their symp-
toms (most commonly constitutional, polyarthralgias and ar-
thritis) generally resolved after drug discontinuation, although
7 of the 27 children developed chronic disease.[7]
Lupus induced by minocycline can be very severe and the
frequency of minocycline use in the treatment of inflam-
matory acne vulgaris means that, overall, more patients are
affected.[1] The autoimmune adverse effects of the drug can
also be very severe, with autoimmune hepatitis occurring
frequently (table I) and showing no improvement 1 month
after ceasing the drug.[1] Physician-patient discussion of the
risks associated with minocycline and the alternative treat-
ment options available is encouraged.[1]

Drugs Ther Perspect 2011; Vol. 27, No. 12


Risk emerging with biological modulators
It is becoming apparent that there may also be a risk of
developing drug-induced lupus or SCLE with newer biolo-
gical modulators, such as tumour necrosis factor (TNF)-a
inhibitors (table I) and interferons.[1]
Concern with TNFa inhibitors y
TNFa inhibitors are indicated for the treatment of various
autoimmune diseases, including ulcerative colitis, Crohn’s
disease, ankylosing spondylitis, rheumatoid arthritis, psoriasis
and psoriatic arthritis, and are the most widely used biological
modulators.[1] Infliximab was the first to be made available
for clinical use, and has since been joined by etanercept,
adalimumab, certolizumab pegol and golimumab. Most are
antibodies to TNFa, although etanercept is a fusion protein
(TNFa receptor fragment plus human IgG1 Fc portion).[1]
Autoantibody production appears to be significant with
TNFa inhibitors (table I), with early infliximab trials in
patients with rheumatoid arthritis being the first to observe
the phenomenon.[1] However, this may not be a class effect,
as infliximab and etanercept have been found to have dif-
fering autoantibody profiles in some clinical studies.[1,8,9]
As with traditional drugs, not all patients with auto-
antibodies during TNFa inhibitor therapy will necessarily
develop clinical lupus (table I).[1] When 125 patients with
Crohn’s disease who were antinuclear antibody (ANA) ne-
gative received infliximab in a prospective cohort study,[10]
more than half (56.8%) tested ANA positive after 24 months,
although drug-induced lupus developed in only two patients
and autoimmune haemolytic anaemia in one patient. Symp-
toms may develop weeks or months after initiating TNFa
inhibitor therapy.[1]
A review of 56 cases of TNFa inhibitor-induced lupus
found most cases to be consistent with SLE, of which the
majority were attributable to infliximab and etanercept.[11]
Compared with nonTNFa inhibitor-induced lupus, TNFa
inhibitor-induced lupus appeared to be associated more
frequently with rash, anti-double-stranded-DNA antibodies,
hypocomplementaemia, leukopenia and thrombocytopenia,
and less frequently with antihistone antibodies.[11]
y and cytokines
Interferon-a is used to treat a variety of cancers,[1] and
although very few patients (<1%) appear to develop SLE, it
can be severe, with some patients experiencing life-threa-
tening multiorgan involvement (e.g. serositis, glomerulone-
phritis, discoid rash, vasculitis and myopericarditis).[12]
Interestingly, the development of autoimmunity with in-
terferon therapy may actually improve treatment outcomes
21
in some cancers. A substudy of a large randomized trial
found that patients with melanoma who developed autoanti-
bodies or clinical signs of autoimmunity with interferon-a-
2b had significant improvements in relapse-free and overall
survival.[13] However, another study found no correlation
between autoimmunity and objective tumour response among
135 patients receiving interferon-a therapy for malignant
midgut carcinoid tumours (25 of whom developed an auto-
immune disease, only one of which was SLE, after 9 months’
treatment).[14]
Autoimmune phenomena have also been observed with
interleukin-2 therapy, including autoimmune thyroiditis (in-
cidence »15%), fibromyalgia, vasculitis, anti-insulin anti-
bodies and chronic inflammatory arthritis.[1,15,16]
Diagnosis can be challenging
Early diagnosis of drug-induced lupus is vital.[1] How-
ever, no standard or universal criteria exist for its diagnosis
and, as presentation of the disease can vary with the drug,
standard criteria for idiopathic SLE are not always met.
The first step is to establish whether the symptoms/signs
are actually consistent with lupus, as drugs have been linked
to a variety of other autoimmune diseases with potentially
overlapping symptoms, or the illness may be due to hyper-
sensitivity not autoimmunity.[1] A careful assessment of the
patient’s medical history and symptoms should be made,
with identification of a temporal relationship between symp-
tom onset and drug initiation being critical (table II).[1] It is
also important to be aware of the drugs associated with
lupus and their corresponding degree of risk, although it
may not always be possible to unequivocally establish a
cause and effect relationship.[1]
Drug-induced lupus may be differentially diagnosed
via exclusion of drug hypersensitivity, exacerbation of pre-
existing lupus, unmasking of idiopathic SLE, serum sick-
ness, drug-induced autoimmune haemolytic anaemia, eosi-
nophilia-myalgia syndrome, toxic oil syndrome and heavy
metal- or environmentally-induced lupus.[1] However, di-
agnosis can be confounded by other illnesses or exposures
(e.g. food, toxins, other medications) and by host and ge-
netic susceptibilities. In 2007, criteria were proposed to help
diagnose drug-induced lupus. These included:[17]
 sufficient and continuous drug exposure;
 at least one SLE characteristic;
 no prior evidence of SLE or other autoimmune disease;
 disease resolution within weeks or months of drug
discontinuation.
Diagnosing lupus induced by biological modulators can
be particularly challenging, as patients are often receiving
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22
Table II. Factors to consider when diagnosing
drug-induced lupus erythematosus[1]
Patient history
Assess patient age, sex, ethnicity
Check for a history of drug reactions, other autoimmune disease,
family history of autoimmune disease, and exposure to other
environmental agents
Symptoms
Look for a temporal relationship between initiation of the drug and
symptom onseta
If the drug has been stopped, check for symptom resolution
Conduct a review of the system; look for signs of nephritis, vasculitis
and neuropsychiatric symptoms
Check for the following types of symptoms:
 constitutional (e.g. fever, weakness, fatigue, weight loss)
 dermatological (e.g. malar or other rashes,
photosensitivity, mucosal involvement)
 musculoskeletal (e.g. weakness, arthralgias, arthritis)
 respiratory (e.g. shortness of breath, chest pain,
wheezing)
 gastrointestinal (e.g. abdominal pain, abdominal masses,
nausea/vomiting)
 haematological (e.g. petechiae, bleeding, pallor)
a Dosage and duration of therapy before symptoms develop can
very considerably. However, unlike hypersensitivity reactions,
autoimmunity is generally induced by higher dosages of drug
and correlates positively with cumulative dose.
these agents for the treatment of autoimmune diseases,
making it hard to distinguish true drug-induced lupus from
the worsening of existing lupus or the unmasking of another
autoimmune disease.[1]
Discontinue the drug for fast
symptom relief
In patients with an established diagnosis of drug-induced
lupus, the inciting drug should be discontinued as this gen-
erally results in symptom resolution within 1–2 weeks.[1,18]
However, symptoms of TNFa inhibitor-induced lupus may
take 1–4 months to resolve, whilst those of drug-induced
SCLE may take 2–3 months.[1] The primary pharmacological
treatment option after drug cessation is corticosteroids, al-
though patients need to be informed of the adverse effects that
may occur with long-term use. Management is otherwise
supportive, with resolution of symptoms usually occurring
before autoantibodies have disappeared.[1]
Disclosure
This review was adapted from Drug Safety 2011; 34 (5): 357-74[1] by
Adis editors and medical writers. The preparation of this article was not
supported by any external funding; however, financial support for the
Drugs Ther Perspect 2011; Vol. 27, No. 12
preparation of the original review[1] was provided by the American
Autoimmune Related Diseases Association.
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