Drug-induced cutaneous vasculitides

Abstract

Cutaneous vasculitides (CV) can be idiopathic or secondary to several triggers, including drugs, that account for up to 30% of all the cases of CV. Several drugs can induce CV, including some medications commonly used in dermatology, including minocycline, and several new drugs, such as anti--TNF agents. Different pathomecanisms are involved in the development of drug--induced CV, including the formation and deposition of immune complexes, the induction of neutrophil apoptosis, the formation of neoantigens between the drugs and proteins from the host, the shift of the immune response, and others. Although the diagnosis is difficult, because the clinical picture of drug--induced CV is in general indistinguishable from that of other forms of CV, it is important to recognize such entities in order to correctly manage the patient. Anamnesis, diagnostic algorithms to assess the likelihood of the association between a drug and a cutaneous reaction, skin biopsy and laboratory testing (including the search for anti--neutrophil cytoplasmic antibodies) are useful tools to make a diagnosis of drug--induced CV. About the therapy, while in idiopathic vasculitides the treatment is usually more aggressive and long--lasting, very often requiring a maintenance therapy with immunosuppressive drugs, in drug--induced CV the discontinuation of the suspected drug alone is usually enough to achieve complete remission, making the prognosis usually very good.

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VOLUME 150 - No. 2 - APRIL 2015
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Vol. 150 - No. 2 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 203
variant of a systemic vasculitis; or 3) cutaneous man-
ifestation of a systemic vasculitis.
CV may be primary or secondary. Secondary CV
recognize a wide range of causative agents, includ-
ing drugs and medications, that account from 10 to
30% of all the forms of CV,1-6 although the estimated
incidence of drug-induced CV is very low, probably
less than 1/100 000 people per year, and vasculitis
is one of the rarer patterns that occur as a drug reac-
tion (accounting for about 1-3% of reactions to any
individual drug).7, 8
In the 2012 Revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides
(CHCC2012),9 drug-induced vasculitides were in-
cluded for the rs time within the group of vasculi-
tis, while, for example, they were not included in the
previous CHCC1994.10
In fact, in CHCC2012, they are reported within the
group of vasculitis associated with probable etiology,
and are reported as drug-associated immune com-
plex vasculitis and drug-associated anti-neutrophil
cytoplasmic antibodies (ANCA)-associated vasculi-
tis.9 However, the cutaneous forms of drug-induced
vasculitides do not have a proper category in such a
nomenclature system.
Theoretically, all the forms of CV, including pol-
yarteritis nodosa (PAN), immune complex vasculitis,
ANCA-associated vasculitis, microscopic polyangi-
itis, eosinophilic granulomatosis with polyangiitis
SectionofDermatology,
DepartmentofSurgeryandTranslationalMedicine,
UniversityofFlorence, Florence, Italy
G ITAL DERMATOL VENEREOL 2015;150:203-10
E. ANTIGA, A. VERDELLI, D. BONCIANI, V. BONCIOLINI
L. QUINTARELLI, W. VOLPI, P. FABBRI, M. CAPRONI
Drug-induced cutaneous vasculitides
Cutaneous vasculitides (CV) can be idiopathic or secondary to
several triggers, including drugs, which account for up to 30%
of all the cases of CV. Several drugs can induce CV, including
some medications commonly used in dermatology, including
minocycline, and several new drugs, such as anti-TNF agents.
Different pathomecanisms are involved in the development
of drug-induced CV, including the formation and deposition
of immune complexes, the induction of neutrophil apoptosis,
the formation of neoantigens between the drugs and proteins
from the host, the shift of the immune response, and others. Al-
though the diagnosis is difcult, because the clinical picture of
drug-induced CV is in general indistinguishable from that of
other forms of CV, it is important to recognize such entities in
order to correctly manage the patient. Anamnesis, diagnostic
algorithms to assess the likelihood of the association between
a drug and a cutaneous reaction, skin biopsy and laboratory
testing (including the search for antineutrophil cytoplasmic
antibodies) are useful tools to make a diagnosis of drug-in-
duced CV. About the therapy, while in idiopathic vasculitides
the treatment is usually more aggressive and long-lasting,
very often requiring a maintenance therapy with immunosup-
pressive drugs, in drug-induced CV the discontinuation of the
suspected drug alone is usually enough to achieve complete
remission, making the prognosis usually very good.
K : Vasculitis - Drug-related side effects and adverse
reactions - Antibodies, Antineutrophil Cytoplasmic
Vasculitides are a heterogeneous group of diseas-
es characterized by inammation and necrosis
of blood vessels. Vasculitides presenting with skin
involvement, namely cutaneous vasculitides (CV),
may be: 1) skin-limited vasculitis; 2) skin-dominant
Corresponding author: E. Antiga, Section of Dermatology, Depart-
ment of Surgery and Translational Medicine, University of Florence,
Viale Michelangelo 41, 50125 Florence, Italy.
E-mail: emiliano.antiga@uni.it
Anno: 2015
Mese: April
Volume: 150
No: 2
Rivista: GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Cod Rivista: G ITAL DERMATOL VENEREOL
Lavoro:
titolo breve: DRUG-INDUCED CUTANEOUS VASCULITIDES
primo autore: ANTIGA
pagine: 203-10

ANTIGA DRUG-INDUCED CUTANEOUS VASCULITIDES
204 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA April 2015
(Churg-Strauss), urticarial vasculitis and others, can
be triggered by drugs.
In this review, the causative drugs, the pathogen-
esis, the clinical features as well as the diagnosis and
treatment of drug-induced CV will be described and
discussed, in order to improve the knowledge of this
often unrecognised clinical entity with the aim of a
better care of the patients.
Causative drugs
Many drugs may cause CV, as reported in several
papers.11-13 The importance of various drugs as a
trigger is questionable, since in most of the reported
cases in the Literature the diagnosis was not con-
rmed neither by histopathological examination nor
by re-challenge with the offending drug. However,
among the medications that can cause vasculitis
(Table I), some of them seem to be more frequently
implicated, including penicillins, cephalosporins,
clindamycin, erythromycin, quinolones, propylth-
iouracil, hydralazine, thiazides, phenytoin, allopuri-
nol, and non steroideal anti-inammatory drugs. Al-
though less frequently than the medications reported
above, some of very commonly used drugs in derma-
tology, such as minocycline,14 tumor necrosis factor
(TNF)-inhibitors,15 retinoids,16 methotrexate,17 and
rituximab 18 can cause CV.
Minocycline
Minocycline is a tetracycline antibiotic widely
used for the treatment of acne vulgaris and has been
implicated in the development of drug-induced lu-
pus erythematosus. Several cases of minocycline-
induced CV have been reported in the Literature.14
Most of the patients had lesions resembling PAN (ei-
ther the systemic or the cutaneous variants), showing
subcutaneous nodules associated with livedo retic-
ularis. Histopathological examination showed in-
volvement of small vessels, medium vessels or both.
Systemic involvement was not uncommon, including
fever, weight loss, malaise, arthritis, myalgias and
neuritis; moreover, anti-nuclear antibodies (ANA)
and ANCA were often detected. Most cases of vas-
culitis due to minocycline have been reported after
long-term use (>2 years), mainly in patients treated
for acne. Therefore, in CV affecting young people
exhibiting autoimmune clinical manifestations, a po-
tential role for minocycline should be ruled out.19
TNF-α inhibitors
The group of TNF-inhibitors encompasses differ-
ent types of drugs that are able to block the TNF-α
pathway. In dermatology, they are mainly used for the
treatment of psoriasis and psoriatic arthritis, although
they are effective even in other inammatory skin
diseases. Along with increasing use of these agents
in clinical practice, secondary autoimmune condi-
tions paradoxically induced by anti–TNF-α therapy
have developed,20, 21 including vasculitis, that is the
most common autoimmune disease associated with
TNF-inhibitors.22 According to a recently published
paper by Sokumbi et al.,15 more than 200 cases of
anti-TNF-induced vasculitis have been reported in
the literature. Among the anti-TNF agents involved,
T I.—Drugs associated to the development of cutaneous vasculitis (modied from Kim MJ et al.).18
Common Uncommon Rare
Pennicillins ACE inhibitors Amiodarone
Cephalosporins Beta-blockers Aspirin
Minocycline Clindamycin Antipsychotics
Quinolones Cocaine+levamisole Gabapentin
D-pennicillamine COX-2 inhibitors Insulin
Propylthiouracil Furosemide Leunomide
TNF-α inhibitors Interferons Metformin
Hydralazine Isoniazide Meoquine
Methotrexate Leukotriene inhibitors Methamfetamine
NSAIDs Macrolides Phenotiazines
Allopurinol Retinoids Contrast media
Thiazides Sulfonylureas Rituximab
Phenytoin Vancomycin Antidepressants
Cimetidine Warfarin Bortezomib

DRUG-INDUCED CUTANEOUS VASCULITIDES ANTIGA
Vol. 150 - No. 2 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 205
vasculitis,17,28,29 a case of a patient with exacerbation
of a pre-existing urticarial vasculitis,30 and a case of
systemic vasculitis with diffuse skin involvement.31
Rituximab
Rituximab is a genetically engineered chimeric
murine/human monoclonal antibody against the
CD20 antigen expressed on the surface of normal
and malignant B lymphocytes. In dermatology, it is
mainly used for the treatment of patients with au-
toimmune bullous diseases, connective tissue dis-
eases and vasculitis. According to a review by Kim
et al.,18 three cases have been reported yet of biopsy-
proven rituximab-induced vasculitis involving the
skin. Two of them developed purpuric lesions on the
lower limbs and the abdomen,32 while the third pa-
tient presented with generalized hemorrhagic vesi-
cles and blisters.33
Interestingly, the pathophysiology of vasculitis in
patients treated with rituximab, although controver-
sial, could be related with the deposition of ritux-
imab-antirituximab antibody immune complexes in
the vessel walls. Another possible explanation, as for
anti-TNF-α agents, is linked to the immunomodula-
tory effect of the drug with a shift of the immune
response.
Some increasingly used drugs, including leukot-
riene inhibitors, interferons, and several monoclonal
antibodies can cause CV. In these cases, it may be
difcult to distinguish drug-induced CV from CV
due to the underlying disease.34
Finally, illicit drugs, excipients, drug and food ad-
ditives, nicotine patches, pigment used in tattoos, in-
travenous drugs and vaccines can cause CV. Among
them, cases of CV induced by the intake of cocaine
adultered with levamisole are increasingly reported.
Levamisole is a drug used both for human and ani-
mals for its anti-helminthic and immunomodulatory
effects. Levamisole is also able to potentiate the phar-
macologic effects of cocaine, so its addition allows
for the adulteration of cocaine with minimal impact
on its perceived potency.35 Levamisole-induced CV
is characterized by the occurrence of purpuric le-
sions on the face and the extremities; ANCA specic
for human neutrophil elastase (HNE) are frequently
detected.36 The differential diagnosis includes We-
gener granulomatosis and cocaine-induced midline
destructive lesions, due to the localization and the
association with cocaine intake. Since levamisole is
etanercept, iniximab and adalimumab were the
most frequently implicated, but also golimumab was
reported to be the trigger in some cases.23, 24
Cutaneous involvement has been described in
about 60-80% of the patients, and includes palpa-
ble purpura, ulcerated lesions, blisters, erythema-
tosus macules and other manifestations. About half
of the cases show systemic disease, including neu-
ropathy as well as renal and lung involvement. His-
topathological examination showed the presence of
leukocytoclastic vasculitis of the small vessels in
the majority of the patients with skin involvement;
direct immunouorescence of the skin revealed im-
munoglobulin A (IgA) deposits in the skin and/or in
the kidneys in some cases, supporting a diagnosis of
IgA vasculitis.15
The discontinuation of the drug alone causes an
improvement of the manifestations in the majority of
the cases; moreover, although the subsequent use of
alternative anti– TNF-α agents may be possible, this
decision should be approached with caution.15
Retinoids
Retinoids are synthetic derivatives of vitamin A
that are able to modulate cell proliferation and dif-
ferentiation, as well as humoral and cellular immune
response. Retinoids are used for several skin condi-
tions, including acne and psoriasis. Some cases of
drug-induced CV due to isotretinoin and etretinate
have been reported in the Literature, together with
the so called “retinoic acid syndrome”, that is associ-
ated with the use of all trans retinoic acid in patients
acute promyelocitic leukemia and is characterized
by systemic involvement generally without skin le-
sions.16 By contrast, both isotretinoin and etretinate
have been implicated in cases of ANCA-positive CV,
granulomatosis with polyangiitis (Wegener’s), PAN,
and others.16, 25-27
Methotrexate
Methotrexate is one of the more commonly im-
munosuppressant drugs used for numerous im-
mune-mediated skin diseases, including psoriasis.
Moreover, it is widely used in rheumatology, gastro-
enterology and in oncoemathology. In the Literature,
some cases of methotrexate-induced CV have been
reported, including cases of skin-restricted vasculitis
with a histopathological pattern of leukocytoclastic

ANTIGA DRUG-INDUCED CUTANEOUS VASCULITIDES
206 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA April 2015
then induce the production of ANCA. ANCA, in
turn, are able to bind the membrane-bound antigens,
causing a self-perpetuating constitutive activation by
cross-linking proteinase-3 (PR3), myeloperoxidase
(MPO) or other antigens and Fcγ receptors.41
Shift of the immune response
Some of the culprit drugs may act as modula-
tors of the immune system, facilitating the develop-
ment of an autoimmune response. As an example,
anti-TNF-α agents, via the inhibition of TNF-α, can
promote the expression of type 1 interferon by alter-
ing the balance between Th1 and Th2, leading to the
upregulation of antibody production and thus to the
development of vasculitis. Similar mechanism af-
fecting the immune response can be caused by the
therapeutic use of cytokines, such as interferon, that
is reported to cause drug-induced CV.42-44
Clinical features
The clinical manifestations of drug-induced CV
are similar to those of primary CV, and may include
both cutaneous signs and systemic involvement.
Skin involvement encompasses a wide range of
manifestations, from palpable purpura to livedo re-
ticularis, petechiae, urticarial lesions, papules, nod-
ules, necrotizing vasculitis, ulcerations, or polyar-
teritis-like appearance (Figure 1).
found as an adulterant in about 80% of cocaine,37
clinicians need to be aware of this entity.
Pathogenesis
The pathogenesis of drug-induced CV is not fully
understood. In some cases, different drugs may pro-
duce a similar clinical picture together with a similar
autoimmune prole, suggesting a common mecha-
nism. In other situations, the inammatory response
leading to the vascular damage directly depends
on the nature of the causative agent. Therefore, the
pathogenesis of drug-induced CV can be considered
multifactorial.34
Among the potential mechanisms underling the
development of drug-induced CV, the most com-
monly implicated are the formation and deposition
of immune complexes (IC), the direct activation of
the complement by the culprit drug, the direct dam-
age to the neutrophils with consequent liberation of
autoantigens, the induction of neutrophil apoptosis,
the formation of neoantigens between the drugs and
proteins from the host, the shift of the immune re-
sponse, and others.12 Some of the main mechanisms
responsible for the development of drug-induced CV
are described in detail below.
IC deposition
Most of the drug-induced CV are caused by the
formation of IC that form in the presence of antigen
excess. Accordingly, after drug intake, antidrug an-
tibodies develop and bind the culprit drug that acts
as autoantigen with the eventual formation of IC.
IC deposition in postcapillary venules activates the
complement which, in turn, induces mast cell de-
granulation and neutrophil chemotaxis. Neutrophils
release proteolytic enzymes and free oxygen radi-
cals, leading to damage of the vessel wall.38 This
mechanism probably accounts for 10-20% of small
vessel CV39 and is associated with several drugs in-
cluding antibiotics, diuretics, anticonvulsivants and
also by TNF-inhibitors.40
Neutrophil apoptosis
Some drugs, including sulfasalazine, can induce
neutrophil apoptosis that is associated with translo-
cation of ANCA antigens to the cell surface, which Figure 1.—Allopurinol-induced cutaneous vasculitis presenting
as purpuric and necrotic lesions of the legs.

DRUG-INDUCED CUTANEOUS VASCULITIDES ANTIGA
Vol. 150 - No. 2 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 207
tion, from the direct immunouorescence of the
skin, and from the laboratory; moreover, all the tests
that are useful to exclude CV secondary to infec-
tions, neoplasms or other known causes should be
performed (the detailed discussion of these points
do not fall within the scopes of the present review
and is reported in other papers in this issue).
After the conrmation of the diagnosis of CV, the
main tool to be used to suspect a drug as a causative
agent is the anamnesis, that should investigate the
timing of the eruption in relation to the introduction
of new drugs (although sometimes the onset may be
delayed for several months or even years from drug
administration) and may be helpful to exclude other
potential causes of vasculitis. Together with the an-
amnesis, several questionnaires have been designed
for determining the likelihood of whether an adverse
drug reaction is actually due to the drug rather than
the result of other factors and can be helpful as ad-
ditional tools for the diagnosis of drug-induced CV.
Among them, the most commonly used are prob-
ably the Naranjo algorythm 46 and the Korean algo-
rithm score.47
One of the main points of these algorithms is
the implementation of a challenge-dechallenge-re-
challenge test, that is one of the standard means of
assessing adverse drug reaction, but is not always
easy to be performed. Positive dechallenge reac-
tions with the resolution of CV on withdrawal of
the medication associated with the recurrence of the
manifestations after the reintroduction of the drug
can be considered diagnostic of a drug-induced CV.
As reported above, histopathological examination
it is not only crucial for the diagnosis of CV, but can
also suggest a potential drug etiology in case of a
high tissue eosinophilia ratio.11
Together with the anamnesis, the challenge-
dechallenge-rechallenge test, histopathology and
laboratory data, although not very specic, can be
helpful in diagnosing a drug-induced form of CV. In
particular, about 20% of patients with drug-induced
CV (and up to 80% of patients with drug-induced
systemic vasculitis) have blood eosinophilia.11, 48
Moreover, ANCA testing is another laboratory test
that should always be performed in the suspect of
drug-induced vasculitis. In particular, ANCA assays
using combined indirect immunouorescence (IIF)
and antigen-specic enzyme-linked immunosorb-
ent assays (ELISA) rather than relying on either test
alone are recommended.12, 48 In fact, IIF can be false
Systemic involvement is usually mild and non
specic and can occur with fever, malaise, arthral-
gia, myalgia and weight loss. By contrast, renal or
pulmonary involvement, that can complicate sys-
temic vasculitis and are associated with a worse
prognosis, are usually absent.45
Due to the fact that clinical manifestations, and
in particular the skin signs, are quite unspecic, the
differential diagnosis between drug-induced CV and
primary vasculitis or CV secondary to causes differ-
ent from drugs based only on clinical appearance
is not possible, and other diagnostic tests should be
performed.
Pathology
As in other forms of CV, skin biopsy for his-
topathological examination and direct immunouo-
rescence is mandatory to achieve the diagnosis and
should be performed in the right site and at the right
time, in order to avoid unspecic or false negative
results (see the paper by Filosa et al. in this issue).
In general, ndings from histopathological exam-
ination usually do not differ between idiopathic and
drug-induced CV, being leukocytoclastic vasculitis
of the small vessels the most common nding in case
of CV. However, in some cases, histopathological
examination can also suggest a potential drug etiol-
ogy. In fact, as demonstrated by Barhami et al.,11 a
high tissue eosinophilia ratio in biopsy samples is
a quite specic nding related to drug-induced CV.
Direct immunouorescence of the skin can show
immune deposits around blood vessels. This may be
important for the diagnosis of IgA vasculitis (for-
merly Henoch-Schoenlein purpura), where IgA de-
posits can be found both in the skin and in the me-
sangial areas.
Diagnosis
As reported above, in general drug-induced CV
are clinically indistinguishable from primary CV or
CV due to other causes. Therefore, the differential
diagnosis from other forms of CV is difcult and
several issues should be considered.
The rst step is a correct diagnosis of CV, that
should be made combining data from the clinical
observation, from the histopathological examina-

ANTIGA DRUG-INDUCED CUTANEOUS VASCULITIDES
208 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA April 2015
Treatment
Since the pathogenesis of a conrmed drug-in-
duced CV is directly linked to the culprit drug, the
rst step for the treatment of the disease is the dis-
continuation of any suspect medication, that may be
all that is required to achieve the complete remission
of the clinical manifestations. This is particularly
important because the treatment for primary CV in-
cludes more aggressive procedures and might not be
suitable for patients with drug-induced CV, who in
general have a less severe course and usually do not
require maintenance therapy.50
Therefore, treatment should be based on indi-
vidualised assessment and, in patients with organ
involvement, it should depend on the severity of the
clinical manifestations. Accordingly,
in patients with exclusive skin involvement, a short
course of systemic or even topical corticosteroids, in
association with supportive therapy (including com-
pression and wound care in case of ulcerations) may
be enough to control the disease.34
By contrast, in cases with systemic disease, cor-
ticosteroids and other immunosuppressive agents
(such as mycophenolate, azathioprine or, in severe
cases, cyclophosphamide) may be necessary in order
to improve organ function and prevent progression
to severe, irreversible disease.
As general measures, it is important to avoid re-
challenge and to carefully consider the use of drugs
of the same class of the culprit one. Finally, the pa-
tient should be also followed-up (including ANCA
testing) in order to monitor the occurrence of a
chronic vasculitis even after the discontinuation of
the drug.12
Conclusions
CV can be secondary to drug intake in up to 30%
of all the cases of CV. Several drugs can induce CV,
including some medications commonly use in der-
matology and several new drugs, such as anti-TNF
negative in some cases and cannot detect ANCA
specicities, that can be important for the diagnosis
since drug-induced CV have usually multispecic
ANCA, while the other forms of ANCA-associat-
ed vasculitis usually show single ANCA specici-
ty. More in detail, the majority of ANCA-positive
drug-induced CV have been associated with P-
ANCA pattern, MPO being the most frequently re-
lated antigen, although cases associated with PR3
C-ANCA have also been described.19 Other anti-
bodies that can be found in drug-induced CV, of-
ten in combination with anti-MPO and/or anti-PR3,
are directed against lactoferrin, catepsin G, HNE,
bactericidal permeability increasing protein (BPI),
and azurocidin.49 Regarding the most frequent im-
plicated drugs, patients with hydralazine-induced
CV are almost always positive for high-titer MPO-
ANCA, that can be accompanied by HNE-ANCA
and lactoferrin-ANCA. Patients with minocycline-
induced CV are usually positive for MPO-ANCA,
with some cases positive also for HNE, cathepsin
G, BPI. Propylthiouracil is often associate to MPO-
ANCA and, in a minority of cases, to HNE, lactofer-
rin, BPI, azurocidin,
cathepsin G. The positivity for both MPO- and
PR3-ANCA is considered quite specic for patients
with CV induced by levamisole-adultered cocaine;
in such patients, ANCA directed against HNE,
cathepsin G, lactoferrin may also be found.
Other markers that are often positive in patients
with drug-induced CV are ANA (that are almost al-
ways positive in patients with hydralazine-induced
CV), anti-double strand DNA, and anti-histone anti-
bodies, with few patients positive also for antiphos-
pholipid antibodies.
Finally, although systemic involvement is usually
less frequent than in CV not induced by drugs, sev-
eral laboratory tests should be performed in order to
assess the involvement of different systems basing
on the clinical features (Table II). When necessary,
medical imaging and/or biopsies in potential in-
volved organs, including kidneys and lungs, should
be performed.
T II.—Suggested laboratory investigations in patients with drug-induced cutaneous vasculitis.
Complete blood count, ESR, C-reactive protein, electrolytes, protein electrophoresis
Liver function tests
Blood urea nitrogen, creatinin, urinalysis, urine cocaine and levamisole
C3, C4, ANCA, ANA, ENA, anti-dsDNA, anti-phospholipides

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a maintenance therapy with immunosuppressive
drugs, in drug-induced CV the discontinuation
of the suspected drug alone is usually enough to
achieve complete remission, making the prognosis
usually very good.
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