Adverse Reactions

Cutaneous and Systemic Manifestations

of Drug-Induced Vasculitis

Sandra M ten Holder, Melanie S Joy, and Ronald J Falk

OBJECTIVE: To evaluate the literature for published cases of drug-induced vasculitis with cutaneous and/or systemic manifestations.

DATA SOURCES: The MEDLINE database was searched from 1965 to December 1999 for articles focusing on drugs and vasculitis,
using various search terminologies (e.g., Churg-Strauss syndrome, Goodpasture’s syndrome, Henoch-Schönlein purpura, various
drugs suspected to induce vasculitis). Cases were included when they met the established criteria as described in the methodology.
DATA SYNTHESIS: Drugs found to be most frequently associated with vasculitis were propylthiouracil, hydralazine, colony-stimulating
factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, and methotrexate. The interval between the first
exposure and appearance of symptoms was reported to be extremely variable (hours to years). Vasculitis has occurred after drug
dosage increases and after rechallenge with the suspected drug. In the majority of cases, vasculitis has resolved after discontinuing
the drug. Patients with more severe, often life-threatening, manifestations have required treatment with corticosteroids,
plasmapheresis, hemodialysis, or cyclophosphamide. Death was the result in 10% of all published cases, with a predominance in
patients in whom multiple organ systems were involved.
CONCLUSIONS: Clinicians need to be suspect of drug-induced vasculitis to enable prompt diagnosis and treatment. This should
improve patient outcomes based on the data referenced for this article.
KEY WORDS: allopurinol, cefaclor, colony-stimulating factors, drug-induced vasculitis, hydralazine, isotretinoin, methotrexate,
minocycline, D-penicillamine, phenytoin, propylthiouracil, vasculitis.
Ann Pharmacother 2002;36:130-47.
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT. ACPE UNIVERSAL PROGRAM NUMBER 407-000-02-003-H01.

asculitis can affect small, medium, and large blood-
V vessel walls of cutaneous, renal, pulmonary, muscu-
loskeletal, neurologic, gastrointestinal, and ear, nose, and
throat tissues.1 Symptoms include purpura, abdominal
pain, hearing loss, nasal congestion and epistaxis, weak-
ness, numbness, and dyspnea.1,2 Other findings include
nephritis, hepatitis, and pneumonitis.1,2 The disease entity
ranges from relatively benign symptoms requiring support-
ive care to life-threatening episodes requiring intensive
care. The etiologies of vasculitis include autoimmune syn-
dromes, infectious agents, and medications.1,2 The focus of
this article is drug-induced vasculitis.
Author information provided at the end of the text.
The association of drug therapy with development of
cutaneous vasculitis is recognized with numerous thera-
peutic agents. In fact, it has been estimated2,3 that 10–20%
of dermal reactions to drugs are vasculitic reactions. Sys-
temic manifestations have been less well reported, even
though patients have commonly described nonspecific
symptoms such as fever, arthralgias, malaise, and lym-
phadenopathy. The identification of damage to organs re-
sulting in even temporary dysfunction has also not been
well reported. This issue may be reflective of the lack of
appropriate medical evaluation to identify concomitant
laboratory abnormalities that coincide with a vasculitic
skin rash. The interval between the first administration of a
drug and the development of vasculitis is extremely vari-
able between drugs, as well as the individuals receiving

130 ■ The Annals of Pharmacotherapy ■ 2002 January, Volume 36 www.theannals.com

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these agents. A dose-dependent reaction has been suggest-
ed in some case reports,4 although this is not consistent
across the spectrum of drugs. Due to the potential severity
of these reactions, there is a paucity of data to show recur-
rence of symptoms on rechallenge with the suspected drug.
The nomenclature of drug-induced vasculitis is complex
and has included several terms: leukocytoclastic vasculitis,
cutaneous vasculitis, serum sickness–like reactions, aller-
gic vasculitis, hypersensitivity syndrome, necrotizing vas-
culitis, Syndrome de Lyell, Stevens–Johnson syndrome,
Henoch–Schönlein purpura, polyarteritis nodosa, Good-
pasture’s-like syndrome, and Churg–Strauss syndrome.1,5-10
The Chapel Hill Consensus Conference on the Nomencla-
ture of Systemic Vasculitis1 standardized terminology as
follows: large-vessel vasculitides (giant-cell arteritis, Takaya-
su arteritis), medium-sized vessel vasculitides (polyarteritis
nodosa, Kawasaki disease), and small-vessel vasculitides
(Wegener’s granulomatosus, Churg–Strauss syndrome, mi-
croscopic polyangiitis, Henoch–Schönlein purpura, essen-
tial cryoglobulinemic vasculitis, cutaneous leukocytoclas-
tic angiitis). The names and definitions of vasculitides
from this conference were compared with the data in the
published case reports in order to obtain a consensus on
the diagnosis of vasculitis. This comparison was particu-
larly necessary for ambiguous terms in the literature such
as serum sickness–like reactions. The classification of
drug-induced vasculitides for cases published has been
confounded by the paucity of diagnostic data to confirm
diagnosis, such as biopsy and antineutrophilic cytoplasmic
autoantibodies (ANCA).
The histopathologic acute lesions in vasculitis are fibri-
noid necrosis of vessels with leukocyte infiltration. These
lesions can be present in arteries, arterioles, venules, and
capillaries. In the kidney glomerulus, segmental necrosis
and crescent formation are often the results of these pro-
cesses. Chronic sclerotic lesions with leukocyte infiltrates
evolve from the acute lesions.11 The necrotic and sclerotic
lesions often result in organ damage. Reviews of vasculitis
and its histopathologic findings have been published.11,12
We reviewed the literature for articles, most of which
are single case reports, that show a relationship between
drugs and vasculitic reactions. The concurrent role of au-
toimmune syndromes and infectious diseases complicate
the diagnosis and cannot be ruled out with certainty. The
data we have tabulated should provide clinicians caring for
individuals with suspected drug-induced vasculitis with
some information in order to provide a judgment as to the
likelihood of a relationship between a specific drug and
vasculitic syndrome. We methodically evaluated each arti-
cle to summarize the suspected drugs and specific vas-
culitic manifestations that ensued. The spectrum of disease
for each drug class and agents within that class were re-
viewed to determine the severity of the vasculitic reaction.
Methods
The MEDLINE database was searched for all articles from 1965 to
December 1999 focusing on drugs and vasculitic reactions. Search ter-
www.theannals.com
Downloaded from aop.sagepub.com at Bobst Library, New York University on June 1, 2015
minology included drug-induced vasculitis, Churg–Strauss syndrome,
Goodpasture’s syndrome, Henoch–Schönlein purpura, polyarteritis no-
dosa, Wegener’s granulomatosus, hypersensitivity vasculitis, microscop-
ic polyangiitis, serum sickness–like reaction, and cryoglobulinemia, as
well as the names of medications known to be suspects in drug-induced
vasculitis. Identified articles were evaluated to determine whether any of
their references contained additional relevant publications.
All articles in the English-language literature were reviewed to deter-
mine the probability of drug-induced vasculitis. The articles were re-
viewed by drug class, and pertinent data were abstracted. The key data
points that we believed were important included specific agent, daily
dose, patient demographics, site of vasculitis, therapy duration prior to
the disease manifestation, abnormal laboratory or histologic data, symp-
toms, treatment, and patient outcome. It was difficult to ascertain the
specific vasculitic classifications (as defined by the Chapel Hill Consen-
sus Conference1) from most of the articles we reviewed since a variety of
terminology was employed in publications dated prior to 1994. In gener-
al, cutaneous reactions are best described as examples of a leukocyto-
clastic angiitis. Most systemic vasculitides described appeared to be exam-
ples of lupus-like syndromes, microscopic polyangiitis, or Churg–Strauss
syndrome. Rarely could a diagnosis of Wegener’s granulomatosus be
made with certainty.
Although we could not review the published cases for accuracy of
vasculitic nomenclature, we did evaluate the cases for a generic diagno-
sis of vasculitis. Cases that did not exhibit any of the manifestations as
described by the Chapel Hill Consensus Conference1 were included in
our evaluation only if laboratory abnormalities and the clinical picture
strongly suggested vasculitis. A discussion on proposed putative mecha-
nisms and treatment modalities is also included.
Putative Mechanisms
The pathogenesis of drug-induced vasculitis is not well
understood and numerous mechanisms have been hypoth-
esized. Formal testing has not been conducted to classify
the methods for individual drug-induced vasculitis reac-
tions. Most drugs are low-molecular-weight substances,
which are not able to function as complete antigens, but re-
quire the formation of a complex with a plasma or tissue
macromolecule to stimulate antibody formation.13,14 The
drug or metabolite suspected of causing the vasculitis acts
as a hapten and binds to a protein, forming a complex to
stimulate antibody formation. These reactions may be di-
rect antigen/antibody interactions or may require the for-
mation of haptens to elicit this response.13,15-23 Drugs may
bind to enzymes such as myeloperoxidase and cause the
enzyme to act as the antigen.17 Antigen/antibody reactions
between drugs and ANCA may also involve cross-reactivi-
ty between drug metabolites and/or other cytoplasmic anti-
gens.
Drugs can bind to complement components and impair
the role of the classical pathway of the complement cas-
cade to dispose of immune complexes in a timely manner,
thus predisposing to tissue deposition.18,24-31 Vasculitis has
been proposed16,18,29 to be a reaction involving circulating
immune complexes and tissue deposits of these complex-
es. Tissue deposits are likely responsible for end-organ in-
volvement (e.g., lungs, kidney).
Drugs can alter the response of protective antibodies
and cytotoxic T cells.13,15,18,32-38 Protective antibodies can be
prevented from being formed.15 Reactive drug intermedi-
ates or metabolites can also interact with T cells to stimu-
late the immune system. Activated T cells can cause the
release of cytokines and interleukins that can cause the re-
The Annals of Pharmacotherapy ■ 2002 January, Volume 36 ■ 131
SM ten Holder et al.

cruitment of additional T cells, eventually resulting in cel- Drugs Involved

lular damage.17,34,38-40
Drug metabolites and/or their physical structures can al-
ter the immune response or cellular membranes.13,15,17,41-47
Drugs or their metabolites can cause changes in leukocyte
function.13 Certain drug structures (e.g., sulphydryl or mer-
capto groups) may have the capacity to induce autoanti-
bodies or alter cellular membranes.41-43 Additionally, it has
been proposed46 that some drugs are metabolized into reac-
tive oxides that facilitate binding to macromolecules or af-
fect macrophage or lymphocyte function.
Other mechanisms that have been proposed are less well
defined.27,41,48-50 Drug-induced autoimmune diseases may
be due to activation of an unidentified gene through mech-
anisms involving DNA methylation.48 The advent of gene-
chip analysis may provide more direct evidence for this
modality. Genetic alterations in enzymes may also play a
role. Environmental factors or medications may up- or
down-regulate enzymes and thus alter antigenicity. The
normal pharmacologic mechanism of action of the sus-
pected drug has been implicated in precipitating vasculitic
reactions. For example, nonsteroidal antiinflammatory
drugs (NSAIDs) can shunt the arachidonic acid precursor
into the lipooxygenase pathway to favor the production of
lymphokines.44,45 Angiotensin converting-enzyme inhibitors
have been shown to increase the concentration of brady-
kinin, which may potentiate cutaneous reactions.27
The 10 drugs resulting in the most publications of drug-
induced vasculitis are propylthiouracil, hydralazine, granu-
locyte-colony stimulating factor (G-CSF), cefaclor, minocy-
cline, allopurinol, D-penicillamine, phenytoin, isotretinoin,
and methotrexate. We do not imply that these agents are
the most frequently implicated drug causes. Unreported,
unpublished, and/or undiagnosed cases account for this
discrepancy. Available data on the range of daily doses and
patient ages, organ involvement, number of deaths and re-
coveries, and therapy duration before the occurrence of
vasculitis are listed in Table 1.4,8,9,17,23,26,29,33-35,42,50-140 Several
other drugs have been less frequently implicated (Table
2).4,7,10,15,16,18-22,24,27,28,31,36,38,43,45,53,70,137,141-260 The sum of male
and female cases does not necessarily equal the total num-
ber of cases, since several case reports failed to report pa-
tient gender. Additionally, the sum of number of deaths
and number of cases with complete resolution does not al-
ways equal the total number of patients, since several case
reports did not disclose information on outcome. Several
other cases reported improvement of manifestations, but
failed to document whether a complete recovery occurred.
These cases are not included in the category “Resolution,”
but are included in the total number of cases. Table 3 sum-
marizes the commonly reported laboratory abnormalities
in patients presenting with drug-induced vasculitis. The

Table 1. The Drugs Most Frequently Associated with Vasculitis

Manifestation
Drug Dosea Pt. Age Gender Death Resolution Therapy
(n cases) (mg/d) (y) (M/F) C R H P GI O ANCA (n) (n) Durationb References

Propylthiouracil 50–600 13–80 6/38 + + + + + 1 43 3d–7y 23, 51-79

(44)
Hydralazine 50–250 11–79 8/17 + + + + + 1 17 6 mo – 13 y 8, 17, 50, 80-86
(25)
G-CSF/GM-CSF various 44–60 2/3 + + + 21 1 d – “weeks” 33-35, 87-91
(21)
Allopurinol 100–300 17–76 12/3 + + + + + 5 10 2h–9y 29, 92-104
(16)
Cefaclor unknown 6 mo – 4.5 y 9/14 + + + 13 1–2 wk 105-107
(13)
Minocycline 100 15–35 3/10 + + + + + 11 9 d – 9 mo 108-113
(13)
Penicillamine 250–2500 16–70 4/8 + + + + + 4 6 2 mo – 18 y 9, 26, 42, 114-122
(12)
Phenytoin 300 14–75 10/2 + + + + + + 7 5 1 wk – 17 y 4, 123-132
(12)
Isotretinoin 10–80 15–21 9/1 + + + + + 3 6–16 wk 133-137
(10)
Methotrexate various 19–42 2/ + + 10 1–5 d 138-140
(10)

ANCA = antineutrophilic cytoplasmic autoantibodies; C = cutaneous; G-CSF = granulocyte-colony stimulating factor; GI = gastrointestinal; GM-CSF
= granulocyte macrophage–colony stimulating factor; H = hepatic; O = other organ systems; P = pulmonary; R = renal.
a
Total daily dose at time of vasculitis manifestations.
b
Duration of therapy before symptoms appear.

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 Table 2. Other Drugs Associated with Vasculitis
Manifestation
Dosea Pt. Age Gender Death Resolution Treatment Therapy
Drug (mg/d) (y) (M/F) C R H P GI ANCA O (n) (n) (n)b Durationc References

Antibiotics/antiinfectives
ofloxacin 400 67–81 3/1 + + + + + 1 2 4 1–3 d 141-145

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ciprofloxacin 500–1000 49–81 6/3 + + + + 7 9 90 min – 6 wk 36,146-151
lomefloxacin 51 /1 + + 1 1 10 d 152
tetracycline 2000 73 /1 + 1 1 3d 153
imipenem/cilastatin 2000 73 1/ + 1 1 5d 154
cefuroxime 41 /1 + + 1 1 24 h 155
vancomycin 500–2000 35–66 2/1 + + + 3 3 1–6 d after discontinuation 156-158
vancomycin/teicoplanin 54–60 2/ + 2 2 12–17 d 159
clarithromycin 1000 83 /1 + + 1 1 6d 160
azithromycin/roxithromycin 250 49 1/ + + 1 1 3d 161
rifampin 450–600 31–79 1/1 + + + 1 1 2 1.5 wk 162,163
TMP/SMX 1600/320 53–69 1/1 + + + + + + 1 1 2 3–4 d 164,165
nitrofurantoin 35–78 /5 + 5 5 1 wk – 4 y 166
mefloquine 250 mg/wk 44–62 1/1 + + 2 2 3–4 wk 167-169
piperazine 1000 56 1/ + + 1 1 5d 170
Skin/mucous membrane agents
etretinate 30–70 61–71 1/1 + 2 9–11 d 137
Antivirals
didanosine 500 26 1/ + 1 1 4d 171
zidovudine 33–34 2/ + + 2 2 <2 wk – 1 mo 172
Cardiovascular agents
acebutolol 100 60 /1 + 1 1 2 wk 173
atenolol 100 62 /1 + 1 1 1 mo 174
sotalol 160 66 1/ + 1 1 7d 175
propranolol 80 68 1/ + 1 1 2y 176
chlorothiazide 50 62 /1 + + 1 5d 177
furosemide 20–1000 16–78 3/2 + + + 1 3 5 5 mo 178-182

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torsemide 5–10 70–84 2/ + + + 2 2 1–2 d 183

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■
diltiazem 120 48–70 1/4 + + + 5 5 8 d – 3 mo 184,185
nifedipine 30–40 75–80 1/1 + 2 2 several months 186-188
methyldopa 500 39–71 4/1 + + 5 2 d – several months 189
guanethidine 15–60 56–68 1/2 + + + 1 2 3 1.5–2 y 190
captopril 75–450 43–63 3/2 + + + 2 3 5 2 wk – 8 mo 7, 191-194
enalapril 10–20 29–68 2/1 + + + 3 3 10 d – 5 wk 43,195,196
lisinopril 20 52–86 3/ + + + + 1 2 3 3 wk – 9 mo 27,197,198
losartan 50 62 1/ + + 1 1 2 wk 199
procainamide 2–4 g 53–74 4/ + 4 4 1 mo – 3 y 15,16,200
quinidine 800 18–78 5/1 + + 5 6 2–3 wk 31,201,202

2002 January, Volume 36

ANCA = antineutrophilic cytoplasmic autoantibodies; C = cutaneous; GI = gastrointestinal; H = hepatic; O = other; P = pulmonary; R = renal; TMP/SMX = trimethoprim/sulfamethoxazole.
a
Total daily dose at time of vasculitic manifestations.

■
b
Total number of patients reported with adverse events where the drug was implicated.
c
Duration of therapy before symptoms appear.

133
Manifestations of Drug-Induced Vasculitis

(continued on page 134)

 Table 2. Other Drugs Associated with Vasculitis (continued)

134
Manifestation

■
Doseb Pt. Age Gender Death Resolution Treatment Therapy
Drug (mg/d) (y) (M/F) C R H P GI ANCA O (n) (n) (n) Durationb References

Antithyroid medications
SM ten Holder et al.

thiamazole 5–45 49 /1 + + 1 1 6y 203

carbimazole 10–60 18–40 1/4 + + 5 5 4 wk 53,204,205
methimazole various 22–60 1/2 + + + + 3 3 3–5 y 70,206
methylthiouracil 21 /1 + 1 1 4y 207
Analgesics/antipyretics
naproxen 500–1000 43–79 4/2 + + + 6 6 3 d – 8 mo 20-22,208
diflunisal 21 /1 + 1 1 2d 19
ibuprofen 1200 77 1/ + 1 1 4d 45
etodolac 200 48 1/ 1 1 1d 209
aceclofenac 100–200 50–74 2/7 + + + 9 9 1–50 d 210,211

The Annals of Pharmacotherapy

indomethacin 22 1/ + 1 1 1 wk 212

■
flurbiprofen 200 59 /1 + 1 1 1 wk 213
acetaminophen 500 15 mo – 67 3/1c + + + + 5 5 30 min – 2 d 214-217
phenylbutazone 300–400 59–79 5/2 + + + + 2 3 7 hours – 4–5 wk 218-220
Antineoplastics
cytosine arabinoside various NR + + 4 6 3 d after reintroduction – 11 d from start 24,221-223
tamoxifen 20 56 /1 + 1 1 6 mo 224
interferon 4.5 × 106 IU 42 1/ + 1 1 1 wk 18
interleukin-2 16 or 24 × 106IU/m2 + 2 2 38
levamisole various 11.5–65 /3 + + 3 3 3 mo – 5 y 28,225,226
Rheumatologic agents

2002 January, Volume 36

sulfasalazine 2–3 g 41–58 1/1 + + 2 2 2 y–20 mo 227
gold 20 mg – 3.6 g 51 + ? 228
etanercept 50 mg/wk 58 /2 + 2 1 2 wk 229,230
Anticonvulsants
vigabatrin 2000 30 1/ + 1 1 6 mo 231
carbamazepine 600 66 2/ + + + + 1 1 2 3–4 wk 4,232

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Antidepressants/anxiolytics
trazodone 350 62 1/ + 1 1 several days 233
amitriptyline 50–59 1/1 + + 2 2 several days 234
nomifensine 150 50–64 /2 + + + + 2 2 1.5 y 235
maprotiline 125 83 /1 + 1 1 1 wk 236
diazepam 40 50 /1 + 1 1 2d 237
fluoxetine 20 49 1/1 + + 2 2 2 mo – 1 mo after discontinuation 238,239
Respiratory drugs
zafirlukast 40 45–67 2/3 + + + 3 5 2–9 mo 10,240-242
cromolyn 80 45 /1 + + + 1 1 10 mo 243

ANCA = antineutrophilic cytoplasmic autoantibodies; C = cutaneous; GI = gastrointestinal; H = hepatic; NR = not reported; O = other; P = pulmonary; R = renal.
a
Total daily dose at time of vasculitic manifestations.
b
Duration of therapy before symptoms appear.
c
Gender not reported in 1 patient.

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(continued on page 135)
 Manifestations of Drug-Induced Vasculitis

suspected drugs, vasculitic syndromes and labo-

References
ratory abnormalities are described in the follow-

247-249
250-252
244,245

253,254
ing sections for several commonly implicated

246

255
256

257

258
259

260
agents.

3 wk – 5 mo and 3 mo after discontinuation

ANTITHYROID THERAPY

Propylthiouracil has been the most common-

ly implicated drug reported to cause vasculitic
reactions. This reaction can involve the skin,
Durationb
Therapy

6 d after discontinuation
lungs, kidneys, muscles, and ears. The gender
distribution is difficult to ascertain since hyper-
thyroidism is more common in women (higher
few hours – 2 d

numbers of women receive this drug); thus, more

drug-induced vasculitis has been demonstrated in

3.5 mo
4–8 d

this population. Many cases appear to involve

4 wk
3d

7d

younger subjects, often children. The drugs im-

plicated, propylthiouracil, methimazole, thiama-
Treatment

zole/methylthiouracil, and carbimazole, are het-

(n)

2
1
4
6

2
1
1

1
3

ANCA = antineutrophilic cytoplasmic autoantibodies; C = cutaneous; GI = gastrointestinal; H = hepatic; O = other; P = pulmonary; R = renal.
erocyclic compounds containing a thioamide
Table 2. Other Drugs Associated with Vasculitis (continued)

group. Although similar chemically, vasculitis

Resolution

cross-reactivity between agents has not been

shown when 1 medication is substituted for an-
(n)

2
1
4
5

2
1
1

1
1

other. However, in cases in which patients were

rechallenged with the same agent, the vasculitic
symptoms reappeared.
Death
(n)

The diagnosis of vasculitis in patients receiv-

ing antithyroid agents has been established
based on the results of tissue biopsy specimens
GI ANCA O

showing infiltrates of neutrophils and leuko-

+

cytes. The variable and often prolonged time

course between commencement of therapy and
Manifestation

initial vasculitic symptoms (3 d–7 y) often

P

+
+

makes the absolute diagnosis difficult. In fact,

this diagnosis has often been ignored when ini-
H

tial symptoms appear. Also, the relationship be-

R

tween thyroid disease and drug-induced vasculi-

tis is confounding due to the immune mecha-
C

+
+

+
+
+

nisms involved in both entities. There have been

Gender

no definitive data to suggest a relationship be-

(M/F)

1/3
1/5

/1

/1

/1
2/
1/

2/

1/

1/

tween drug dosage and the occurrence of vas-

culitis (most reports did not show response to
Pt. Age

dose titration).
63–72

48–70
35–72

65–67
(y)

Total daily dose at time of vasculitic manifestations.

Antithyroid drug–induced vasculitis initially

67

68
47

41

59

43

presents as general symptoms of fever, nausea,

Duration of therapy before symptoms appear.
10 000 units

sore throat, polyarthralgias, synovitis, and joint

500–3000

300–600

200–400
(mg/d)
Dosea

various

swelling at some time after initiating drug thera-

2.55 g
1200
300

py. Skin lesions usually present as purpuric le-

sions, which often progress to necrotic ulceration.
Anticoagulants/thrombolytics

Vasculitic skin rashes, without further progres-

sion to the kidney or other organs have been re-
Gastrointestinal agents

Radiocontrast agents

ported in several series.54-56,58,59,66,68,71,72,79,206,207 In a

diphenhydramine
Drug

chlorpromazine

few cases, a more localized skin rash developing

Antihistamines
streptokinase
Antipsychotics
L-Tryptophan

on the buttocks, face, arms, and legs after 7 days

Antidiabetics

pimagedine
cimetidine

metformin
nizatidine

coumarin

to 4 years of propylthiouracil therapy has been

heparin

described.54,55,59,207 Two cases56 describe an inter-

esting presentation of a generalized skin rash.
The patients reported received propylthiouracil
b
a

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 Table 3. Laboratory Abnormalities Described in Cases of Drug-Induced Vasculitis

136
Parameter
Clcr  BUN  SCr Proteinuria Hematuria PR3 ANCA MPO ANCA p-ANCA c-ANCA Anti-HNE ANA Anti-dsDNA  CRP
C3/C4  ALT  AST  ESR  WBC

■
Propylthiouracil + + + + + + + + + + +
Methimazole + + + +
Thiamazole + + + + + +
SM ten Holder et al.

Hydralazine + + + +
Cefaclor + +
G-CSF + + +
Tetracycline + + + + + +
Minocycline +
Allopurinol + + + + + + + +
Penicillamine + + +

The Annals of Pharmacotherapy

Phenytoin + + + +

■
Isotretinoin + + + + +
Fluoroquinolones + + + + + +
ACE inhibitors + + + +
Procainamide/quinidine + +
Diltiazem/nifedipine + + + + +
Methyldopa + + + + + +
Acetaminophen + + +
GI medications + + + +

2002 January, Volume 36

Cimetidine
Omeprazole
β-Blockers + +
Levamisole + + +
Rifampin +

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Carbamazepine + + + + + + +
Nomifensine +
Chlorpromazine + +
Losartan + + + +
Thiazide + +
Guanethidine + + +
Vigabatrin + +
Cromolyn + +

ACE = angiotensin-converting enzyme; ALT = alanine aminotransferase; ANA = antineutrophilic antibodies; ANCA = antineutrophilic cytoplasmic autoantibodies; AST = aspartate aminotransferase; BUN = blood
urea nitrogen; c-ANCA = cytoplasmic antineutrophilic cytoplasmic autoantibodies; C3/C4 = complement; Clcr = creatinine clearance; CRP = c-reactive protein; ds-DNA = double-stranded DNA; ESR = erythro-
cyte sedimentation rate; G-CSF = granulocyte-colony stimulating factor; GI = gastrointestinal; HNE = human neutrophil elastase; MPO = antimyeloperoxidase; p-ANCA = perinuclear antineutrophilic cytoplasmic

www.theannals.com
autoantibody; PR3 = antiproteinase 3; SCr = serum creatinine; WBC = white blood cell count.

for 1–1.5 years without incident, but after discontinuing
and restarting therapy, the symptoms appeared within 1–2
months. Skin biopsy data have shown vessel walls that
were infiltrated with red blood cells, leukocytic nuclei,
eosinophils, and neutrophils, deposits of immunoglobulin
(Ig) M and C3, and granulomatous structures with giant
cells.54,55,68,79,206 Treatment consisted of discontinuing the of-
fending agent in all cases. In some cases, therapy with glu-
cocorticoids and/or plasmapheresis was initiated.55,58,59,72,78,79
Renal vasculitis with or without skin involvement was
reported in 21 patients.23,53,56,57,60-63,67,69,70,73,75,78,79,203 Abnor-
malities in urinalysis or serum creatinine and blood urea
nitrogen have been seen 4 weeks to 7 years after com-
mencing therapy. These laboratory changes appeared after
skin involvement was noted in patients who exhibited vas-
culitis in both organ systems. In 1 case report,70 a patient
received methimazole for 23 years and developed renal
symptoms only after the drug was discontinued and then
restarted. Urine abnormalities have consisted of reduced
creatinine clearance, proteinuria, and presence of granular
casts and red blood cells. Renal biopsy specimens have
shown focal segmental glomerulosclerosis with crescents,
interstitial inflammation and fibrosis, mesangial prolifera-
tion, and in some cases, IgA, IgM, IgG, and C3 deposi-
tion.23,57,60,70,78,203 Treatment in all of these patients consisted
of discontinuing the offending agent.
In 1 study,53 where the patient had progressive, severe
renal disease, therapy consisted of plasmapheresis, pulse
corticosteroids, and cyclophosphamide. In other cas-
es,23,57,61-63,67,69,70,203,206 treatment with a single immune-mod-
ulating pharmacologic agent (e.g., glucocorticoids) or a
combination of glucocorticoids and/or plasmapheresis or
cyclophosphamide was initiated. Positive ANCA titers were
demonstrated in several cases, with antiproteinase 3 (PR3)
and c-ANCA positivity less common than antimyeloper-
oxidase (MPO) and p-ANCA.23,53,56,57,61-63,69,70,78,79,203,206
Vasculitis has also affected the lungs, nasal mucosa,
muscles, and ears. Pulmonary involvement has been de-
scribed as hemoptysis, wheezing, congestion, cough, fever,
dyspnea, pleuritic pain, and the presence of infiltrates on
chest X-ray.51,53,65,76,77,79 Propylthiouracil has been identified
in all pulmonary cases, with symptoms occurring 3 weeks
to 4 years after beginning therapy. Treatment consisted of
cyclophosphamide and/or prednisone in 4 patients and
drug withdrawal in all patients. One patient inadvertently
rechallenged herself with 1 dose of propylthiouracil, result-
ing in vasculitic symptoms appearing 5 days later.65 Vas-
culitis was diagnosed by nasal biopsy in another patient.56
Joint and muscle pain and generalized swelling have also
been described. Abnormal laboratory parameters included
elevated erythrocyte sedimentation rate (ESR), ANCA
positivity (anti-PR3 and anti-MPO), and positivity of anti-
bodies against human neutrophil elastase (HNE). Anti-
HNE antibodies have been reported56 in 1 series describing
3 patients suspected of having propylthiouracil-induced
vasculitis. Anti-HNE titers remained at a detectable, low
concentration in 2 of these patients for the duration of fol-
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Manifestations of Drug-Induced Vasculitis
low-up and disappeared in 1 patient. Treatment of nasal
vasculitis consisted of discontinuing propylthiouracil.
Bilateral deafness occurred in 1 patient 3 days after
switching to propylthiouracil from carbimazole,64 while
less-severe decreased hearing acuity and tinnitus occurred
in another patient also receiving propylthiouracil.64,74 The
laboratory abnormalities included anemia, leukocytosis,
positive antinuclear antibodies (ANA) and elevated ESR.
The 4 cases involving myositis occurred in patients receiving
carbimazole therapy.204,205 Signs and symptoms included
pruritus, proximal muscle pain, cramping and weakness,
and elevated creatine kinase. These occurred after patients
received therapy for 1 week to 3 months. Muscle biopsy
showed interstitial lymphocyte and histiocyte infiltrations
near the vascular structures.204
CARDIOVASCULAR AGENTS
Vasculitis has been reported in patients receiving various
antihypertensive agents (Tables 1 and 2). The drugs that
have been implicated include methyldopa, guanethidine, pe-
ripheral vasodilators (hydralazine), β-blockers (acebutolol,
atenolol, propranolol, sotalol), diuretics (furosemide,
torsemide, chlorothiazide), calcium-channel blockers (dilti-
azem, nifedipine), angiotensin-converting enzyme inhibitors
(enalapril, captopril, lisinopril), and the angiotensin II antag-
onist losartan.7,8,27,43,49,50,80-86,173-199 Other cardiovascular drugs,
such as the antiarrhythmic agents procainamide and quini-
dine, have also been associated with vasculitis (Table
2).3,7,15,16,31,200-202 Hydralazine has been the antihypertensive
agent most frequently associated with vasculitis (Table 1).
Hydralazine-induced cutaneous vasculitic manifestations
have included lower extremity palpable purpuric and macu-
lopapular eruptions, and hemorrhagic blisters on the lower
legs, arms, trunk, nasal septum, and uvula.84-86
Systemic manifestations can include arthralgias, myal-
gias, hoarseness, and retinal vascular inflammation, with
arthralgias and myalgias being the initial presenting symp-
toms.8,80,82-84,86 These symptoms have been reported to oc-
cur 6 months to 13 years after initiating treatment with hy-
dralazine. Laboratory abnormalities include a positive
ANA, p-ANCA, MPO -ANCA, and antidouble-stranded
DNA antibodies.8,50,80,81,84,85 Renal biopsy results showed
scant deposits of IgG, IgM, and C3, typical of those found
in ANCA-positive pauci-immune glomerulonephritis.50,81
Direct immunofluorescence of cutaneous lesions showed
deposits of IgM, fibrin, and C3.84,85 Although some studies
did not report ANCA positivity and biopsy data, but re-
ported only rapidly progressive glomerulonephritis, we
categorized this as vasculitis versus drug-induced lupus,
since drug-induced lupus usually does not cause signifi-
cant kidney damage. This scenario was applied consistent-
ly for procainamide and hydralazine, since both agents
have been associated with drug-induced lupus. Treatment
regimens consisted of discontinuing the suspected drug,
and in some cases prednisone was added. Vasculitic le-
sions resolved within 10 days to 8 months after hydrala-
zine was discontinued.80,85
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SM ten Holder et al.
Methyldopa has been associated with vasculitis of the
myocardium. One series of case reports189 describes fatali-
ties in all 5 patients with this diagnosis. The patients were
relatively healthy on initiation of methyldopa treatment.
After taking the medication for at least 2 days, the patients
complained of flu-like symptoms, fatigue, and lethargy. At
autopsy, cardiomegaly was found, as well as infiltrates of
lymphocytes, neutrophils and eosinophils, and focal necro-
sis of myocardial cells.
ANTIBIOTICS/ANTIINFECTIVES
Several antiinfective agents have been reported to in-
duce a vasculitic syndrome. Presumed vasculitis due to β-
lactam antibiotics (imipenem/cilastatin), fluoroquinolones
(ofloxacin, ciprofloxacin, lomefloxacin), tetracyclines
(minocycline, tetracycline), cephalosporins (cefuroxime,
cefaclor), glycopeptides (vancomycin, teicoplanin), azith-
romycin, clarithromycin, trimethoprim/sulfamethoxazole,
nitrofurantoin, piperazine, and rifampin have been de-
scribed (Tables 1 and 2)36,105-113,141-170 Mefloquine, didano-
sine, and zidovudine have also been associated with vas-
culitis (Table 2).167-169,171,172
The classification of vasculitic reactions due to cefaclor
was difficult to ascertain due to reports of a serum-sickness
versus serum sickness–like reaction. All articles that de-
scribed a classic serum-sickness reaction (urticaria, edema,
arthritis, arthralgias) were excluded. Articles that described
a serum sickness–like reaction were included since they re-
ported an atypical presentation that included renal or end-
organ involvement, fever, lymphadenopathy, and a non-
pruritic rash. Serum sickness–like reaction involving cefa-
clor appears to be confined primarily to skin manifestations
on the face and extremities, arthritis or arthralgias, with or
without fever.105,106 It also appears to occur more frequently
in children, although this might just reflect the extensive
use of the antibiotic in children.106,107 Serum sickness–like
reactions may occur during or following the second or sub-
sequent course of therapy with cefaclor.106,107 Symptoms
developed 1 to 2 weeks after the start of cefaclor therapy.
The clinical course consisted of improvement after discon-
tinuation of cefaclor; however, some cases also required
treatment with antihistamines, analgesics, or corticosteroids.
A case of drug-related Henoch–Schönlein purpura was de-
scribed in a patient taking cefuroxime.155
Cutaneous vasculitic manifestations induced by the
tetracyclines include skin rash, urticarial eruption, erythe-
ma nodosum, nonpalpable reticulated purpura, livedo
reticularis, and erythematous macular eruptions.108,109,111,112,153
These cutaneous reactions have begun 2 days to 9 months
after the start of tetracycline therapy. In 3 cases,109 vasculi-
tis occurred after minocycline therapy had been renewed
following an uneventful previous course of therapy. Sys-
temic vasculitic complications can include fever, lym-
phadenopathy, conjunctivitis, swelling in the eyes and
mouth, arthralgias, and symmetrical polyarthritis.108-110,112
Biopsy results showed perivascular inflammatory infil-
trates consisting of neutrophils, eosinophils, and histio-
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cytes, and necrotizing vasculitis with fibrinoid necrosis of
vessel walls and thrombosis.108,112,113 All 3 patients reported
by Elkayam et al.109 had a positive rechallenge test. Abnor-
mal laboratory findings included elevated hepatic transam-
inases, serum creatinine, positive p-ANCA, and anti-
MPO.108-111,153 A common serologic marker in patients with
minocycline-induced vasculitis was high titers of p-
ANCA.109 Treatment consisted of withdrawing the tetracy-
cline and, in some cases, administering a tapering course
of prednisone with resolution of symptoms within weeks
to months of treatment.108-112,153
HEMATOPOIETIC AGENTS
G-CSF and granulocyte macrophage–colony stimulat-
ing factor (GM-CSF) have been associated with the devel-
opment of vasculitis in several cases and exacerbation of
vasculitis in 1 case (Table 1).33-35,87-91 Cutaneous vasculitis
occurs as an adverse drug reaction in 6% of patients with
chronic benign neutropenias treated with G-CSF/GM-CSF,
but rarely in patients with neutropenia associated with ma-
lignancy and chemotherapy.34 Systemic involvement, al-
though less common, produces arthralgias, renal vasculitis,
and fever.34,35,87,89,91 Lesions generally occur days to weeks
after the first administration of G-CSF/GM-CSF. Because
some cases of vasculitis developed simultaneously with an
increase in circulating granulocytes, it has been pro-
posed34,35,87,90 that the onset of cutaneous vasculitis can be
prevented if the absolute neutrophil count is kept <800/mm3
by careful dose titration. Skin biopsy results have docu-
mented leukocytoclastic angiitis.34,35,87-90 Abnormal labora-
tory data have included increases in serum creatinine,
hematuria, and proteinuria.34,35,89,90 Resolution of symptoms
was reported either after discontinuing the suspected drug
or initiating adjunctive therapy with prednisone or topical
corticosteroids.
RHEUMATOLOGIC AGENTS
Allopurinol is a potent inhibitor of xanthine oxidase and
is prescribed for patients with hyperuricemia. Fifteen cases
describing vasculitic reactions to allopurinol have been
published (Table 1).29,92-104 Cutaneous vasculitic reactions
have not been reported to occur independent of systemic
symptoms. In fact, 1 systemic case never manifested any
type of cutaneous reaction.29 The first symptom to appear
was epididymitis that occurred 2 days after restarting al-
lopurinol therapy that had been inadvertently discontinued
for 3 days. Reported cutaneous manifestations include dif-
fuse macular rash more prominent on the back and ab-
domen, nonpruritic, nonfollicular, macular exanthema on
the trunk and proximal extremities, toxic epidermal rash,
and erythema multiforme.93,94,96,98 Skin biopsy revealed a
leukocytoclastic vasculitis with fibrinoid necrosis and lym-
phocytic infiltrate, and numerous eosinophils.97,98 Cutaneous
lesions occurred from 2 hours (after restarting therapy) to 9
years after initiating allopurinol therapy. Generalized vas-
culitic manifestations include fever, lymphadenopathy,
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glomerulonephritis and renal failure, hepatitis and compro-
mised liver function, myalgia, and seizures.95-104
Abnormal laboratory findings have included increased
serum creatinine, blood urea nitrogen, aspartate amino-
transferase (AST), alanine aminotransferase; proteinuria,
eosinophilia, leukocytosis, positive p-ANCA, and anti-
MPO antibodies.29,92-97,99,101-103 Kidney biopsy results
showed glomerulonephritis with necrotizing arteritis, tubu-
lointerstitial nephritis, and infiltrates of mononuclear cells
and eosinophils around dermal blood vessels. Liver biopsy
specimens showed granulomatous inflammation or pleomor-
phic periportal infiltrates with eosinophilia.94,95,104 Vasculitic
lesions were treated with discontinuation of the suspected
drug and, in some cases, therapy with diphenhydramine or
cortisone. Two rechallenge tests were positive. Skin le-
sions disappeared within days to weeks after discontinuing
allopurinol. One-third of the reported cases resulted in
death; all of the deaths were the result of acute renal fail-
ure. One patient also presented with hepatic involvement.
The autopsies revealed acute necrotizing arteritis involving
the small muscular arteries and perivascular spaces in the
myocardium, spleen, testes, and cerebral cortex, arterial
nephrosclerosis, and linear deposits of γ-globulin and com-
plement along the glomerular basement membrane.92,103
Pathologic findings at autopsy were similar in other cases:
extensive acute vasculitis involving small-and medium-
sized vessels of the heart, lungs, liver, testes, kidney, colon,
and the vasa vasorum of muscular arteries.29
Several case series describing penicillamine-induced vas-
culitis have been published (Table 1).9,26,42,114-122 The vasculi-
tis has resulted in glomerulonephritis, microscopic pol-
yarteritis, cutaneous ulcers on the hands and pinnae of both
ears, and purpuric rashes.26,42,114-117,119 These systemic vas-
culitic lesions occurred 2 months to 18 years after the onset
of penicillamine therapy. One report118 even suggested an
occurrence of vasculitis 3 years after discontinuation of D-
penicillamine. Indirect immunofluorescence of renal biop-
sies failed to show IgG, IgA, or C3 deposits in 1 trial116;
however, granular deposits of IgA and C3 in the
mesangium and along capillary walls were found in anoth-
er study.117 Scanty granular deposits and patchy interrupted
staining for IgG and C3 complement have been reported in
2 cases.114,115 Peces et al.42 reported the presence of circulat-
ing antibodies to the glomerular basement membrane.
Treatment consisted of discontinuing penicillamine and, in
most cases, administering prednisone and cyclophos-
phamide; some patients required hemodialysis.9,114,117 Most
lesions resolved within days to months after discontinuing
penicillamine, although several fatalities were report-
ed.114,117 The fatalities during penicillamine therapy oc-
curred in the setting of pulmonary involvement. The pa-
tients presented with coughing, hemoptysis, and lung infil-
trates. The onset of pulmonary involvement occurred 1–3
years after the initiation of penicillamine therapy.114
Etanercept has been associated with drug-induced vas-
culitis.229,230 The reaction began as a purpuric rash at the in-
jection site 2 weeks after initiating therapy. Progression of
the rash to noninjected sites soon followed. Discontinua-
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Manifestations of Drug-Induced Vasculitis
tion of therapy and addition of corticosteroids resulted in
resolution of the vasculitic skin rash.230
ANTICONVULSANTS
Anticonvulsant-induced vasculitis has been reported in
several case series, implicating phenytoin, carbamazepine,
and vigabatrin (Tables 1 and 2).4,14,123-132,231,232
Phenytoin has been the most frequently reported anti-
convulsant linked to drug-induced vasculitis. Although this
syndrome has been reported in only 12 patients receiving
anticonvulsants, there appears to be a predilection for the
reaction in older patients and in African American
men.4,123,124,127-129 Dose–response relationships have not
been determined since all the patients received a daily dose
of 300 mg.
The initial presentation of the vasculitic reaction has
been reported3,124,126,129 to consist of a fever and the forma-
tion of a generalized, often pruritic, maculopapular rash re-
sembling erythema multiforme. The systemic involvement
of the reaction was often not realized until autopsy. Thus,
in only a few cases where skin or kidney biopsies were
performed, did treatment consist of systemic cortico-
steroids.125,126,130 Several of the patients received preemp-
tive antibiotics due to the initial presentation of fever. The
high mortality rate of 64% associated with phenytoin-in-
duced vasculitis is confounding. It may be due to the ag-
gressive multiorgan presentation of the disorder in some
patients or misdiagnosis and failure to start systemic corti-
costeroid therapy. Thus, increased rates of survival were
seen in patients who were initiated on systemic glucocorti-
coids and continued to receive them until resolution of all
symptoms. Autopsy reports clearly indicate the diffuse,
systemic vasculitis involvement: necrotizing or granuloma-
tous vasculitis of the kidney, spleen, and liver involving
small to medium arteries, veins, arterioles, and venules;
fibrin deposition; and extensive eosinophilia. The lungs
were affected in 4 patients in whom interstitial pneumoni-
tis with involvement of pulmonary blood vessels and
eosinophilic infiltration were demonstrated.123,125,127 Report-
ed laboratory abnormalities included leukocytosis, periph-
eral eosinophilia, elevated ESR and hepatic transaminases,
anemia, complement deficiency, and positive c-ANCA.
Carbamazepine-associated vasculitis appears to be less
common based on the number of publications.4,232 Both re-
actions presented as a pruritic rash and occurred 3– 4
weeks after initiating carbamazepine therapy. Both patients
had multiorgan involvement of the kidneys, skin, and/or
spleen. The outcomes in the 2 cases were significantly dif-
ferent. This may have been due to early232 versus late4 initi-
ation of glucocorticoids. Laboratory abnormalities includ-
ed elevated ESR, proteinuria, active urinary sediment,
leukocytosis, eosinophilia, and reduced creatinine clear-
ance. Skin biopsy showed complement and immunoglobu-
lin deposits in the small blood vessels.232
One case of vigabatrin-associated vasculitis has been re-
ported.231 Systemic manifestations included neuropathy
with impairment of vision. Laboratory results showed
The Annals of Pharmacotherapy ■ 2002 January, Volume 36 ■ 139
SM ten Holder et al.
leukocytosis, increased IgA, increased acute phase proteins
α-2 and β-globulin, and slightly positive double-stranded
DNA antibodies. The diagnosis of allergic vasculitis was
based on information obtained from a lymphocyte trans-
formation test, as well as the clinical course. After discon-
tinuing the vigabatrin and adding cortisone therapy, mani-
festations resolved.
SKIN AND MUCOUS MEMBRANE AGENTS
Isotretinoin is a synthetic analog of vitamin A pre-
scribed for the treatment of severe acne. Several cases of
isotretinoin-induced vasculitis have been described (Table
1).133-137 The complications were systemic and occurred
6–16 weeks after starting therapy and even 6 weeks after
completion of isotretinoin therapy in 1 case.134 Symptoms in-
cluded fever, renal insufficiency, myalgias, arthralgias, epis-
taxis, purpuric papules, and glomerulonephritis.133,134,136,137
The arthralgias were the initial symptoms to appear in sev-
eral patients. Laboratory testing showed positive ANA.133
Three cases of Wegener’s granulomatosus induced by
isotretinoin were reported.136,137 Lung, skin, and synovial
biopsies showed vascular and interstitial granulomas, neu-
trophil infiltration in vessel walls, and perivascular infil-
trates of plasma cells and lymphocytes, respectively.133,136,137
Treatment consisted of discontinuation of retinoids in all
cases. Additional therapies included steroid injections,
NSAIDs, oral prednisolone, cyclophosphamide, and D-
penicillamine.133,134,136,137
The causal relationship between vasculitis and isotretinoin
therapy in the cases described by Epstein et al.136 is uncer-
tain, since both patients were suffering from otitis media
and episodes of epistaxis prior to beginning isotretinoin
treatment. In the second patient, worsening of ongoing
arthralgias and the onset of cutaneous papules started 3
weeks after isotretinoin therapy was discontinued. Further-
more, nasal and otic symptoms are often initial symptoms
of vasculitis, thus raising the question as to whether the
vasculitis actually predated the use of isotretinoin. Both pa-
tients required treatment with cyclophosphamide and pred-
nisolone. Drug rechallenge was not performed in either pa-
tient with isotretinoin-associated vasculitis.
ANTINEOPLASTICS
Several chemotherapeutic agents have been associated
with vasculitis. Cytosine arabinoside, methotrexate, ta-
moxifen, interleukin-2, interferon, and levamisole have
been implicated (Tables 1 and 2).18,24,28,38,138-140,221-226 Cuta-
neous lesions associated with cytosine arabinoside oc-
curred 3–5 days after therapy reintroduction and 10 –11
days after initiation of therapy.221,222 Systemic manifesta-
tions included fever, edema and erythema, hypotension, and
diarrhea.222,223 Two patients with cytosine arabinoside–as-
sociated vasculitis were concomitantly receiving leukocyte
transfusions and other chemotherapies.222 Skin biopsy re-
sults showed leukocytoclastic angiitis, leukocytoclastic
vasculitis with eosinophilic infiltration, pronounced en-
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dothelial swelling in association with complement C3b ag-
gregation in all capillaries, dermal necrotizing vasculitis
with vascular disruption, fibrinoid degeneration, neu-
trophilic inflammation, and leukocytoclasia.24,221-223 Al-
though details about treatment and outcome were not pro-
vided in all cases, 2 patients with cytosine arabinoside–in-
duced vasculitis were treated with hydrocortisone therapy.222
Patients recovered after the drug was discontinued or treat-
ment was completed.221,222
Cutaneous lesions associated with methotrexate oc-
curred 24 hours to 5 days after the start of therapy. Several
cases reported138,140 a vasculitis syndrome that occurred
during the second treatment course; systemic manifesta-
tions were confined to fever. Skin biopsy results showed
leukocytoclastic angiitis, monoclonal immunoglobulin de-
position, and mononuclear vasculitis.
One case of tamoxifen-induced cutaneous vasculitis oc-
curred 6 months after the start of therapy.224 Laboratory ab-
normalities included elevated AST and decreased C4. Skin
biopsy results were compatible with leukocytoclastic vas-
culitis. Withdrawal of tamoxifen resulted in clearing of the
symptoms. In reports38 of cutaneous reactions to inter-
leukin-2, biopsy specimens from 2 patients showed severe
epidermal necrosis and microvasculitis. One case report18
of vasculitis associated with interferon was found. The cu-
taneous manifestation began on the tip of the finger 1 week
after the start of therapy. Lesions regressed after interferon
therapy was discontinued.
Three cases of vasculitis induced by levamisole, an im-
munostimulant drug used for the treatment of rheumatoid
arthritis, relapsing nephrotic syndrome, and some malig-
nancies have been reported.28,225,226 Cutaneous lesions con-
sisted of a purpuric rash with a livedo pattern on the arms,
legs, breasts, and/or face.225,226 Systemic symptoms includ-
ed fever and arthralgias, which began 3 months to 5 years
after initiating levamisole. Skin biopsy results revealed
leukocytoclastic vasculitis with predominant eosinophils
and IgM in the basement membrane and C3 around the
vessels, and neutrophil and eosinophil infiltration of the
vessel wall with obliteration of the lumen.28,225 Laboratory
data showed positive p-ANCA, ANA, and antihistone au-
toantibodies.226 Treatment consisted of withdrawing the
suspected drug and adding prednisone in 1 patient. Lesions
disappeared within 2 weeks after levamisole was discon-
tinued, although all antibodies were detectable 7 months
later in 1 patient.226
ANALGESICS/ANTIPYRETICS
Several case series have reported vasculitic-like reac-
tions to NSAIDs and acetaminophen (Table 2).19-22,45,208,209
Although the individual NSAIDs are slightly different
chemically and derivatives include proprionic acid (naprox-
en, oxaprozin, flurbiprofen, ketoprofen, fenoprofen),
pyrrolizine carboxylic acid (ketorolac, tolmetin, zomepirac),
indoleacetic acid (indomethacin, etodolac), anthranilic acid
(meclofenamate), naphthylalkanone (nabumetone), oxi-
cam (piroxicam), indeneacetic acid (sulindac), salicylic
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acid (diflunisal), phenylalkanoic acid (ibuprofen), pyra-
zolone (phenylbutazone), and phenylacetic acid (ace-
clofenac, diclofenac), several have been identified as sus-
pects in drug-induced vasculitis. The cross-reactivity be-
tween chemical groups for inducing drug-associated
vasculitis is possible since all NSAIDs have a similar basic
structure.
Similar to other implicated drug classes, the diagnosis of
vasculitis and causality to NSAIDs have not been defini-
tively made in the published cases due to failure to obtain
confirmatory biopsies (skin, kidneys, liver) and the ab-
sence of drug rechallenge in some cases. Treatment with
topical or systemic corticosteroid derivatives has generally
led to the resolution of symptoms. Isolated cutaneous reac-
tions have been the predominant manifestations.
Isolated cutaneous manifestations were reported20,22,45,211-213
in several case series with aceclofenac, indomethacin,
ibuprofen, flurbiprofen, and naproxen therapy. Vasculitic le-
sions initially consisted of palpable and erythematous pur-
pura, with progression to necrosis of the toes and fingers in
some cases. When skin biopsies were performed, results
showed endothelial cell damage, and neutrophil, eosinophil,
and lymphocyte infiltration, with more pronounced activity
around the capillaries.20,45,212,213 Elevated ESR was reported
in 1 patient.22 In some cases, fever and a migratory pol-
yarthritis were reported.20 The time course from initial in-
gestion of the suspected NSAID and cutaneous reaction
ranged from 3 to 50 days.20,22,45,211,212 The treatment consist-
ed of discontinuing the NSAID and adding corticosteroids
in some patients. Vasculitic reactions resolved in all patients
by 1 week to 3 months after treatment.
Systemic vasculitic reactions have been reported19,21,208-210
for naproxen, diflunisal, etodolac, and aceclofenac by sev-
eral authors. The implication that an NSAID caused the re-
action was confounded by the ingestion of concomitant as-
pirin therapy in 1 report.21 Systemic complications includ-
ed nephritis, paralytic ileus, hemoptysis, pneumonia, pedal
edema, facial swelling, arthralgias, myalgias, and giant-cell
temporal arteritis. Biopsy confirmed the presence of
nephritis, eosinophilic pneumonia, and temporal arteritis in
several cases.19,21,208,209 The time frame from appearance of
cutaneous reactions to systemic complications ranged from
2 to 18 days. Furthermore, the formation of a skin rash oc-
curred in most patients prior to the development of sys-
temic reactions.21,208,210 Laboratory findings showed elevat-
ed IgG, IgA, IgE, and immunoglobulin complexes; leuko-
cytosis; eosinophilia; increased ESRs, serum creatinine,
and blood urea nitrogen; proteinuria; and an active urinary
sediment. Therapy for the systemic vasculitic reactions
consisted of discontinuation of the NSAID in all cases.
Pharmacologic therapy included initiating high-dose oral
corticosteroids or antihistamines.19,208-210
Five cases of acetaminophen-induced vasculitis have
been reported.214-217 Within hours after the intake of the sus-
pected drug, dermatologic eruptions appeared.214,215 Isolat-
ed cutaneous manifestations were reported in 4 cases. Skin
biopsies confirmed leukocytoclastic vasculitis in 3 cas-
es.214-217 The fourth patient was believed to have Henoch–
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Manifestations of Drug-Induced Vasculitis
Schönlein purpura, although it was unclear whether a biop-
sy was performed.215 Laboratory findings included elevat-
ed liver enzymes and elevated serum concentrations of in-
terleukin-6, as well as an increase in interferon-γ.217 Sys-
temic manifestations included lung and liver involvement
in 1 patient.216 Lesions usually disappeared spontaneously
after acetaminophen was discontinued; however, therapy
with oral prednisone was required in 1 case.215
Treatment
Although there is no standard approach to the treatment
of drug-induced vasculitis, the suspected drug should be dis-
continued in most patients. In only a few of the reviewed
cases was the suspected drug continued (due to the paucity
of therapeutic alternatives).43,138,159,190 Other treatment modal-
ities have consisted of supportive care and/or topical or sys-
temic medications to treat the cutaneous or systemic vas-
culitic symptoms. In less severe cases, usually those limited
to cutaneous involvement or general systemic symptoms
(e.g., malaise, myalgias, arthralgias, fatigue, fever), therapy
has consisted of topical corticosteroid products, NSAIDs,
and antihistamines. These agents are prescribed since they
often lead to the prompt relief of symptoms. Therapy for pa-
tients with more severe, often life-threatening, manifesta-
tions (e.g., glomerulonephritis, pulmonary involvement,
hepatitis) has consisted of systemic approaches such as
hemodialysis, pulse corticosteroids, cyclophosphamide, and
plasmapheresis.53,55,58,59,72,78,79,207 Chronic low-dose oral corti-
costeroids have been initiated after initial aggressive sys-
temic therapy in order to prevent recurrence of vasculitic le-
sions.43,159,190 This treatment is often continued for several
months after the initial vasculitic event.
Complete resolution of vasculitic manifestations was re-
ported in most of the reviewed cases. About 3% of all case
reports failed to provide information regarding patient out-
come; approximately 10% reported patient death. There
has been significant variability in the cases regarding the
resolution of symptoms with each therapeutic intervention
and the time frame of appearance of symptoms after initi-
ating the offending drug. However, resolution of most
symptoms has generally occurred in 1– 4 weeks. Some pa-
tients have had persistent laboratory abnormalities (elevat-
ed serum creatinine, proteinuria, positive ANCA titers)
throughout their clinical follow-up.57,79,83,104,149,177 The suc-
cess of various treatment modalities appears to depend on
the early identification of a possible drug-induced disease
process and implementation of appropriate treatment. Fa-
talities were reported in cases where the systemic nature of
the vasculitic process was not realized; thus, aggressive ther-
apeutic approaches were not implemented.9,19,29,92,123,127,129,141
In addition, inaccurate diagnosis of the condition as an in-
fection due to symptoms such as fever, arthralgias, and
myalgias rather than vasculitis has led some clinicians to
initiate treatment with antibiotics instead of or prior to cor-
ticosteroids.125,129 Although not described in these reports,
delays caused by patients failing to seek early medical in-
tervention may also lead to worsened outcomes.
The Annals of Pharmacotherapy ■ 2002 January, Volume 36 ■ 141
SM ten Holder et al.
Summary
Drug-induced vasculitis has been reported to occur with
most classes of medications. These reactions can range
from cutaneous and mild systemic symptoms to invasive
involvement of several organs. The diagnosis of this condi-
tion is complicated for several reasons including: (1) re-
ports available in only single to multiple patient case se-
ries, and thus physicians often do not recognize the syn-
drome (inappropriate diagnosis); (2) variable time course
for agents and patients for vasculitis development after ini-
tiating drug therapy; (3) lack of confirmatory data regard-
ing drug rechallenge; (4) failure to evaluate appropriate
laboratory and invasive tests; and (5) failure to use stan-
dardized general terminology such as “vasculitis” to de-
scribe the entity and failure to classify the type of vasculitis
in the literature (as defined by the Chapel Hill Consensus
Conference). The use of standardized criteria, such as that
developed by Jennette et al.,1 enables one to feel confident
that a definition of vasculitis was made. Further identity of
the specific type of vasculitis may enhance our understand-
ing of this drug-induced disease entity and its treatment.
There is also confusion regarding this syndrome since
there are different proposed mechanisms for its develop-
ment between and among drugs/drug classes. The evalua-
tion of pertinent laboratory data and prompt histologic
confirmation of the disease may aid in the diagnosis. The
need for clinicians to be aware of drug-induced disease is
important so that prompt diagnosis and treatment of pa-
tients can occur to ensure favorable outcomes. Appropriate
therapy should be implemented promptly and continued
until resolution of vasculitic symptoms in order to prevent
relapse. Adequate documentation of this potentially seri-
ous drug-induced reaction in the patient medical record is
necessary to prevent inadvertent rechallenge. Finally, there
is a need for diligent reporting of suspected drug-induced
vasculitis in the literature and as MedWatch reports to the
Food and Drug Administration, especially for the newer
pharmacologic entities.
Sandra M ten Holder MS, Glomerular Disease Collaborative Net-
work (GDCN) Coordinator, Division of Nephrology and Hyperten-
sion, School of Medicine, The University of North Carolina at Chapel
Hill, Chapel Hill, NC
Melanie S Joy PharmD, Clinical Assistant Professor, Division of
Nephrology and Hypertension, School of Medicine, Division of Phar-
macotherapy, School of Pharmacy, The University of North Caroli-
na at Chapel Hill
Ronald J Falk MD, Professor and Chair, Division of Nephrology
and Hypertension, School of Medicine, The University of North Car-
olina at Chapel Hill
Reprints: Melanie S Joy PharmD, University of North Carolina at
Chapel Hill, CB #7155, 348 MacNider Bldg., Chapel Hill, NC 27599-
7155, FAX 919/966-4251, E-mail Melanie_Joy@med.unc.edu
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EXTRACTO
OBJETIVO: Evaluar los casos de vasculitis inducida por medicamentos
reportados en la literatura y sus manifestaciones cutáneas y/o sistémicas.
FUENTES DE DATOS: Se hizo una revisión de la literatura en MEDLINE
entre el 1965 a 1999 buscando artículos enfocados en medicamentos y
vasculitis. Los casos de vasculitis reportados fueron incluidos en la
evaluación si cumplían con los criterios previamente establecidos y
descritos en la sección de metodología.
SÍNTESIS DE DATOS: Los medicamentos más frecuentemente asociados a
vasculitis lo son propiltiouracilo, hidralacina, factores estimulantes de
colonias, alopurinol, cefaclor, minociclina, D -penicilinasa, fenitoína,
isotretinoína, y metotrexato. El tiempo entre la primera exposición y la
aparición de síntomas es altamente variable (horas a años). La vasculitis
puede ocurrir al aumentar la dosis o después de la reexposición al agente
www.theannals.com
 Manifestations of Drug-Induced Vasculitis

sospechoso. En la mayoría de los casos, la vasculitis desaparece al
descontinuar el medicamento. Pacientes con manifestaciones más
severas y amenazantes a la vida pueden requerir tratamiento con
corticosteroides, plasmaféresis, hemodiálisis, o ciclofosfamida. La
muerte ocurrió en el 10% de los casos reportados, particularmente en
aquellos donde múltiples órganos fueron afectados.
CONCLUSIONES: El profesional de la salud debe estar en vigilancia por la
ocurrencia de vasculitis inducida por medicamentos para responder
prontamente con el diagnóstico y tratamiento de dichos pacientes. Esto
debe mejorar el pronóstico de los pacientes según se desprende de los
artículos revisados.
Mitchell Nazario
RÉSUMÉ
OBJECTIF: Evaluer la littérature relative aux publications de cas de
vascularites induites par des médicaments entraînant des manifestations
cutanées et/ou systémiques.
SOURCES DE DONNÉES: La base de données MEDLINE (1965 à 1999) a
été utilisée pour retrouver des articles relatifs aux médicaments et aux
vascularites, en recourant à diverses terminologies de recherche. Les cas
rapportés de vascularites ont été retenus dès lors qu’ils correspondaient
aux critères établis, décrits dans les méthodes.
SYNTHÈSE DE DONNÉES: Les médicaments se révélant être le plus souvent
associés à une vascularite sont: propylthiouracile, hydralazine, facteurs
de croissance cellulaire, allopurinol, cefaclor, minocycline, D -
penicillamine, phenytoïne, isotrétinoïne, et méthotrexate. Le délai entre
la première exposition et l’apparition des symptômes apparaît d’une
extrême variabilité (quelques heures à plusieurs années). Les
vascularites sont survenues après des augmentations de posologies et es
réintroductions des médicaments suspects. Dans la plupart des cas, la
vascularite a disparu après l’arrêt du médicament incriminé. Les patients
sujets aux manifestations les plus sévères, mettant souvent en jeu le
pronostic vital, ont dû être traités par corticoïdes, plasmaphérèse,
hémodialyse, et cyclophosphamide. Il y a eu décès dans 10% des cas
publiés, plus particulièrement en cas d’atteintes multiorganiques.
CONCLUSIONS: Les cliniciens doivent être attentifs au risque de
vascularite induite par des médicaments pour pouvoir effectuer un
diagnostic et un traitement précoces. Ceci devrait contribuer à améliorer
le sort des patients d’après les données référencées dans cet article.
Michel Le Duff

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• Be a Christian Servant in Your Daily Pharmacy Activities
by Richard L. Cramer and Stephen P McDonald
• The Practice of Pharmacy in China
by Rebecca L. Wood
• Serving God in Haiti
by Tonya Teague

For membership and subscription information, contact:

Christian Pharmacists Fellowship International • PO Box 1717 • Bristol, TN 37621
Phone 423/764-6000 • FAX 423/764-4490
Christian Pharmacists Fellowship International (CPFI) is a worldwide, nondenominational ministry of individuals working in all areas of pharmaceutical service and prac-
tice. CPFI’s mission is to help pharmacy professionals grow spiritually and to promote fellowship among pharmacists. In fulfillment of these goals, many members serve as
missionaries, demonstrating Jesus Christ’s love through medical care to the disadvantaged of the world.

www.theannals.com The Annals of Pharmacotherapy ■ 2002 January, Volume 36 ■ 147

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