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Drug-Induced Connective Tissue Disorders
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167
this form of drug-triggered LE develop an inammatory dermatosis, often with photosensitivity
but rarely with systemic involvement (Lowe etal.
2011).
1.3 Pathophysiology
The pathophysiology of drug-induced LE is complex and incompletely understood but is likely to
involve the interplay between genetic factors,
drug metabolism and immunogenicity. Ultimately
there is enhanced auto-immunity causing
immune-mediated effects on target organs and
thus clinical manifestations (Rubin 2005).
Studies into the pathophysiology of drug-induced
LE have focused on the archetype causative
agents: procainamide and hydralazine. Potential
mechanisms have been suggested, including a
direct action of drugs or metabolites on the innate
or adaptive immune system. Downstream there
appears to be an immunostimulatory effect or
disruption to central immune tolerance.
Genetic Susceptibility
Procainamide and hydralazine contain aromatic
amines or aromatic hydrazines and undergo acetylation during drug metabolism. Drug-induced
lupus by these agents has been shown to occur
more frequently and more rapidly in patients who
have a genetically determined reduction of
hepatic n-acetyltransferase synthesis and are consequently slow at acetylating drugs (Hess 1988).
Conversely, the development of autoantibodies in
patients who are slow acetylators can be avoided
by the administration of N-acetylprocainamide,
the acetylated metabolite of procainamide (Stec
etal. 1979). Similarly, patients who have developed procainamide-induced lupus can experience
remission if administered N-acetylprocainamide,
rather than procainamide (Stec et al. 1979).
Variations in acetylator state are unlikely to be
implicated in the development of all drug-induced
LE, for example isoniazid-induced lupus occurs
with equal frequency in both fast and slow acetylators (Reidenberg etal. 1993). Other implicated
genetic variations in drug metabolism include
alterations in cytochrome P450 enzymes result-
ing in the production of toxic metabolites which,
in turn, can induce auto-immunity (McKinnon
and Nebert 1994).
It has also been suggested that there is an association between certain HLA alleles and the
development of drug-induced LE (Batchelor
et al. 1980). This relationship varies between
agents. HLA-DR4 is aligned to an increased risk
of hydralazine- (Batchelor et al. 1980) and
minocycline- induced LE (Dunphy et al. 2000),
whereas the presence of HLA-DR6Y increases
the risk of procainamide-induced LE (Adams and
Mongey 1994). HLA-DQB1 and HLA-DR2 have
also been associated with minocycline-induced
lupus (Batchelor etal. 1980). The presence of the
C4 null allele, which would prevent the activation
of C3 and clearance of immune complexes, has
also been shown to increase susceptibility to
hydralazine-induced LE (Speirs etal. 1989).
Eects onAdaptive Immunity
Certain drugs, including procainamide, hydralazine, quinidine and phenytoin, have been shown
to act as substrates for myeloperoxidase in activated neutrophils with the subsequent production
of a drug metabolite which directly affects lymphocyte function and induces auto-immunity
(Jiang et al. 1994). Small molecule drugs can
undergo haptenization with proteins and can
directly stimulate immune responses (Chang and
Gershwin 2011).
Procainamide and hydralazine can also inhibit
T cell methylation, similar to the effect seen with
ultraviolet radiation (Cornacchia etal. 1988). T
cell DNA hypomethylation causes increased
lymphocyte function associated antigen-1 (LFA-
1) with subsequent induction of autoreactivity
(Deng etal. 2003). Other studies have shown that
certain drug metabolites can interfere with T cell
tolerance, resulting in the development of autoreactive T cells (Rubin 2015).
Eects onInnate Immunity
Recent discovery of neutrophil extracellular traps
(NETs) has afforded additional insights into
other potential mechanisms of drug-induced LE.
Neutrophils can undergo a specic form of cell
death, termed NETosis, in which there is a
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S. J. Mounsey and E. Benton
removal of intracellular granular proteins which
are bound to chromatin as a defence mechanism
against pathogens. Studies have shown that some
drugs, such as procainamide and hydralazine, can
trigger NET formation via the stimulation of neutrophil muscarinic receptors and intracellular calcium inux, although this is not seen with all
medications (Vaglio et al. 2018; Irizarry-Caro
et al. 2018). Increased NET formation and
decreased clearance have been associated with
auto-immunity (Vaglio etal. 2018).
Clinical Features
Due to the large variety of symptoms and signs,
many of which overlap with idiopathic LE, the
diagnosis drug-induced lupus can be challenging.
There are no clinical features which are pathognomic of drug-induced lupus, however some
occur more commonly in the medicationtriggered group (Table 3). Unlike idiopathic
lupus, there are no universal criteria for the diagnosis of drug-induced LE.The disorder is divided
into drug-induced systemic lupus erythematosus
(SLE) and drug-induced subacute cutaneous
lupus erythematosus (SCLE).
Drug-Induced Systemic Lupus
Erythematosus
Drug-induced SLE is the most frequently
reported form of drug-induced lupus. Patients
with drug-induced SLE typically have fewer and
less severe symptoms than those with idiopathic
SLE (Antonov etal. 2004). After the initiation of
Table 3 Demographics and features associated with
drug-induced lupus and idiopathic lupus. Adapted from
Rubin (2015), Vaglio etal. (2018), Batchelor etal. (1980)
Drug-induced
lupus
Age of onset >50 20–40
M:F 1:1 1:9
Fever 40–50% 40–85%
Arthralgia/
myalgia
Rash 10–30% 50–70%
Malar rash <5% 40%
Renal
involvement
CNS involvement <5% 20–70%
80–95% 75–95%
<5% 30–50%
Idiopathic
lupus
the causative agent symptom onset is usually
delayed for 1–3 months; sometimes there is a
latency of 1–3 years. Symptoms vary greatly
between individuals and causative agents, and
can develop gradually or abruptly (Rubin 2015;
Vaglio etal. 2018). Arthralgia is one of the more
common presenting features, indeed often the
only symptom, and occurs in up to 90% of
patients (Borchers et al. 2007; Antonov et al.
2004). Myalgia is present in approximately 50%
of patients (Antonov et al. 2004); other symptoms include fever, pleurisy and pericarditis
(Rubin 2015; Vaglio et al. 2018; Borchers etal.
2007).
Drug-induced lupus SLE rarely causes major
internal organ involvement (Borchers etal. 2007;
Hess 1988). Exceptions to this include glomerulonephritis caused by hydralazine, quinidinerelated central nervous system toxicity, pleuritis
in up to 40% of cases of procainamide-induced
LE, and auto-immune hepatitis which occurs in
approximately 50% of patients with minocyclineinduced LE (Borchers et al. 2007; Cemil et al.
2013).
Skin rashes are less common in drug-induced
LE than in idiopathic SLE and often present with
different characteristics with a low incidence of
malar rash, discoid lesions, alopecia and photosensitivity (Chang and Gershwin 2011; Vaglio
etal. 2018; Cemil etal. 2013).
Drug-Induced Subacute Cutaneous
Lupus Erythematosus
Drug-induced SCLE is a distinct form of iatrogenic lupus which occurs following exposure to a
specic group of drugs, including the calciumchannel antagonists and proton pump inhibitors
(Table 2). Drug-induced SCLE has similarities
with the idiopathic form of SCLE including the
female predominance and the clinical presentation. Patients typically present with an annular or
polycyclic eruption on the torso and proximal
arms, although it can become generalized
(Fig.1). The dermatosis can be psoriasiform in
morphology and may occur in a photo-exposed
distribution. Erythema multiforme-like lesions
and bullous lesions have been reported
(Laurinaviciene et al. 2017). The majority of
Drug-Induced Connective Tissue Disorders
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Fig. 1 This patient developed an extensive, inammatory
eruption of annular and polycyclic lesions, consistent with
sub-acute cutaneous lupus erythematosus (SCLE), whilst
taking omeprazole
patients with drug-induced SCLE carry anti-Ro/
La antibodies in conjunction with antinuclear
antibodies (ANA), specically anti-histone antibodies. The lack of factors which discriminate
drug-induced SCLE from other entities often
leads to a misdiagnosis or a delay in diagnosis
(Gronhagen etal. 2012).
1.4 Diagnosis
Patients in whom there is a suspicion of druginduced lupus should have a complete medical
history and examination undertaken to exclude
other possible diagnoses. Biochemical, haematological and immunological laboratory testing
should include a full blood count, renal and liver
proling, urinalysis, antinuclear antibody (ANA)
anti-double stranded DNA, anti-Sm and antiRNP, anti-Ro/SSA and anti-La/SSB and antihistone antibodies. ANCA should be assayed in
patients who have been treated with minocycline,
hydralazine, propylthiouracil or methimazole.
The diagnosis of drug-induced LE should be
considered in all patients who have developed at
least one characteristic symptom of LE after taking a novel agent for at least a month. Suspicions
can be strengthened by a strongly positive ANA,
particularly anti-histone, and in patients in whom
symptoms and antibodies improve on withdrawal
of the causative agent, although recovery can
often take months (Hess 1988; Vedove et al.
169
2009). The differential diagnosis of drug-induced
LE following clinical examination includes dermatoses with annular, psoriasiform and photodistributed morphologies. Skin biopsy in
drug-induced LE provides little discriminating
benet since the histopathology in drug-induced
LE is similar to that in idiopathic LE (Antonov
etal. 2004).
Serological Prole
As with all auto-immune related conditions,
drug-induced lupus is associated with autoantibodies. The presence of these antibodies varies
between patients and causative agents. There are
also variations between drug-induced LE and
idiopathic LE which can help identify the underlying diagnosis (Table4).
Antinuclear antibodies are present in over
90% of patients with drug-induced LE, typically
in a homogenous pattern. 75–95% of patients
with drug-induced LE have anti-histone antibodies, which is strongly discriminatory since these
antibodies occur in only 20% of patients with
idiopathic SLE (Antonov etal. 2004; Yung etal.
1995). Drug-related anti-histone antibodies are
typically formed against the histone dimer H2AH2B and DNA, which is in contrast to the
H1-H2B dimer complex which is seen in idiopathic lupus (Yung et al. 1995). Other ANA,
including those targeted towards Sm, RNP and
SS-B/La, are rarely seen in drug induced lupus,
whereas they are more common in idiopathic
lupus. The exception to this is anti-SS-A/Ro,
which is observed in 70–90% of patients with
drug-induced SCLE (Rubin 2015). Anti-dsDNA
is the antibody associated with active SLE but is
much less common in drug-induced lupus.
Conversely, anti-ssDNA is more frequently seen
in drug-induced LE than idiopathic LE. The
exception to this occurs with patients receiving
biologic agents, such as tumour necrosis factor-α
(TNF-α) antagonists and interferon-α, who commonly develop anti-dsDNA antibodies although
their presence correlates poorly with clinical
symptoms (De Bandt 2006).
Other immunological tests which can be helpful include the hypocomplementemia induced by
quinidine; the circulating immune complexes
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Table 4 Autoantibodies associated with drug induced lupus and idiopathic lupus. Adapted from Rubin (2015), Vaglio
etal. (2018), Batchelor etal. (1980)
Drug-induced lupus Idiopathic lupus
ANA >90% >90%
ANA pattern Homogenous Heterogenous
Anti dsDNA 0–1%
Anti Sm <5% 20–30%
Anti-Ro (SSA) In drug-induced SCLE 30–40%
Anti-histone 90–95% 60–70%
Hypocomplementaemia <5% 40–65%
SCLE subacute cutaneous lupus erythematosus
a
Much more common in TNFa inhibitors
a
S. J. Mounsey and E. Benton
50–80%
induced by hydralazine, propothiouracil, minocycline and sulfasalazine; and the positive
Coombs test which can occur with methyldopa,
chlorpromazine and procainamide (Rubin 2015).
1.5 Management
The cardinal feature of drug-induced LE is the
improvement of symptoms on withdrawal of the
causative agent. Many patients improve within a
month, however in some patients symptoms can
persist for several months. Positive autoantibodies are slower to improve and may be present for
years.
There are no randomised controlled trials
examining the optimal treatment for druginduced lupus. Management is traditionally orientated around the use of anti-inammatory
agents, such as non-steroidal anti-inammatory
agents, and for the associated dermatosis to be
treated with an appropriate topical corticosteroid
preparation (Rubin 2015; Borchers etal. 2007).
In cases which are resistant to symptomatic treatment antimalarials, such as hydroxychloroquine,
may be considered. Occasionally patients require
a course of systemic corticosteroids.
2 Drug-Induced
Dermatomyositis
Dermatomyositis (DM) is classied alongside
polymyositis (PM) in the idiopathic inammatory myopathies. The clinical manifestations of
DM are heterogenous with varying degrees of
myositis and skin involvement. Some patients
with DM suffer the additional pathological complexity of interstitial lung disease and/or internal
malignancy. Across the spectrum of clinical presentations skin involvement is a prominent part
of the syndrome; in a subset of patients cutaneous
disease occurs in isolation, the so-called clinically amyopathic DM (CADM). Although predominantly a disorder of auto-immunity
characterized by myositis specic antibodies
(MSAs), a DM-like syndrome can be induced by
drugs. Patients affected by drug-induced DM are
typically over 50years of age; there is no sex predilection (Seidler and Gottlieb 2008). Drugs
which have been documented as a cause of DM
include hydroxycarbamide (hydroxyurea),
statins, penicillamine, quinidine and phenylbutazone. Reports have also suggested that the following may be involved in drug-induced DM:
caritcaine, niumic acid, etoposide, imatinib,
interferon alpha, omeprazole, phenytoin, alfuzosin, gembrozil and etanercept, and the BCG
vaccine (Dourmishev and Dourmishev 1999;
Seidler and Gottlieb 2008).
Unlike idiopathic dermatomyositis, patients
with drug-induced DM dermatomyositis do not
carry one of the MSAs, ANA, anti-Ro or antiJo- 1 (Seidler and Gottlieb 2008). Clinically there
may be the typical features of heliotrope eyelid
erythema, Gottron’s papules and an upper torso
dermatosis, along with a proximal myopathy.
Hydroxycarbamide-induced DM is associated
with a lichenoid dermatosis on the ngers.
Patients with drug-induced DM may also have a
pre-existing malignancy or auto-immune condition and tend to report a higher incidence of previous adverse drug events (Seidler and Gottlieb
2008).
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171
3 Drug-Induced Scleroderma
In scleroderma, or systemic sclerosis, patients
present with thickening and tightening of the skin,
typically in acral areas, along with involvement of
the renal, pulmonary, cardiac, gastro- intestinal,
nervous and hepatic systems (Sahoo etal. 2020;
Brogan and Olsen 2003). The idiopathic form is
characterized by the presence of autoantibodies,
including anti-Scl70 or anti- centromere, which
are involved in a multifactorial combination of
genetic and environmental pathogenetic events.
The resulting disruption of blood vessels, broblast dysregulation and aberrant deposition of
matrix proteins results in sclerosis (Haustein and
Haupt 1998). Drugs have been suggested to contribute towards the development of scleroderma in
a few case series. The implicated drugs include
bleomycin and docetaxel, morphine, tryptophan,
ethosuximide, amphetamines, penicillamine, fosinopril, triamcinolone and cocaine (Haustein and
Haupt 1998). Unlike idiopathic scleroderma,
drug-induced scleroderma usually does not have
positive autoantibodies (Haustein and Haupt
1998). Upon withdrawal of the causative agent a
large proportion of patients have either resolution
of cessation of disease progression. For the
remaining patients with symptomology treatment
is orientated towards specic systems, with the
use of topical and oral corticosteroids, PUVA or
UVA1 therapy.
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Drug-Induced Vasculitis
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JohnStack
Abbreviations
AAV ANCA associated vasculitis
ANA Anti-nuclear antibody
ANCA Anti neutrophil cytoplasmic
antibody
BAFF B-cell activating factor
bDMARD Biologic disease modifying anti
rheumatic drug
BVAS Birmingham vasculitis activity score
CPI Checkpoint inhibitor
CTCAE Common Terminology Criteria for
Adverse Events
DIV Drug induced vasculitis
DMARD Disease-modifying anti-rheumatic
drug
EULAR European league against
rheumatism
IBD Inammatory bowel disease
irAE Immune-related adverse event
MPO Myeloperoxidase
NE Neutrophil elastase
NETs Neutrophil extracellular traps
PR3 Proteinase 3
PTU Propylthiouracil
RA Rheumatoid arthritis
J. Stack (*)
Department of Rheumatology, Mater Misericordiae
University Hospital, Dublin, Ireland
School of Medicine, University College Dublin,
Dublin, Ireland
e-mail: john.stack1@ucd.ie
TNF Tumour necrosis factor
1 Introduction
Drug-induced vasculitis (DIV) is recognized as a
distinct entity within the revised 2012 Chapel
Hill vasculitis consensus criteria, under the category “vasculitis with known aetiology”
(Sunderkötter etal. 2018). An increasing number
of drugs can provoke necrotizing inammation of
the small, medium and sometimes large vessels
resulting in tissue ischaemia and inammation.
In the skin this can give rise to petechiae, purpura
and skin necrosis. When DIV arises in internal
organs life-threatening complications can occur.
The exact prevalence of DIV remains unknown
as no large population-based studies have been
performed. Much of our knowledge derives from
case reports and case series and is therefore likely
to be prone to reporting bias.
While most cases will be mild, presenting
with arthralgia, malaise and cutaneous leucocytoclastic vasculitis, some cases of DIV can be
severe and cause major organ involvement, critical illness and rarely death (Sunderkötter et al.
2018; Ortiz-Sanjuán et al. 2014). Clinicians
therefore need to be vigilant for systemic disease
involvement, stop the offending agent promptly
and initiate immunomodulatory therapy when
necessary.
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_14
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J. Stack
2 Clinical Approach
Although DIV commonly presents with skin
signs it is important for dermatologists to be
aware of the potential for systemic disease
involvement. A full vasculitis work-up is
required, including a screen for lung, renal, gastric and CNS involvement. The Birmingham
Vasculitis Activity Score (BVAS) is a freely
available tool used for scoring disease activity in
clinical trials but can also be used as a screening
device to identify clinical features of systemic
vasculitis (Luqmani etal. 1994).
It is important to remember that DIV is a diagnosis of exclusion. Since there are no established
DIV diagnostic criteria, the following questions
should help the clinician reach a diagnosis of
DIV.
1. Is there a temporal association between drug
initiation and vasculitis?
2. Is serum ANCA positive with
multi-antigenicity?
3. Have other diseases, including other forms of
vasculitis, been excluded?
4. Do symptoms resolve following cessation of
culprit drug?
Similarly, there are no established treatment
guidelines to help guide management of DIV.As
with all adverse drug reactions the critical intervention is stopping the offending drug.
Re-challenge with the culprit is not recommended
since a disease relapse is likely. Consideration
should also be given to the avoidance of medications in the same pharmacological class as the
offending drug (Radić etal. 2012). In mild cases
of DIV with low-grade arthralgia and a vasculitic
rash, simply stopping the causative agent may be
all that is required. Some patients will require a
short course of oral prednisolone (e.g. 0.5–1.0mg/
kg/day reducing over 6–12 weeks). Cases with
internal organ involvement or more severe cutaneous disease may require longer and higher doses
of steroid with additional immune suppression
using drugs such as mycophenolate mofetil,
methotrexate or azathioprine. In situations when
DIV is causing life-threatening manifestations
(e.g. proliferative glomerulonephritis or alveolar
haemorrhage) the treatment approach should be
the same as severe ANCA-associated vasculitis:
high dose pulsed methylprednisolone and rituximab or cyclophosphamide. In some instances,
plasma exchange can be used as induction therapy, followed by long-term maintenance immune
suppression and gradual steroid withdrawal. Such
cases will require specialist input from clinicians
with expertise in treating vasculitis. The EULAR
guidelines on the management of ANCA- associated vasculitis provide a helpful resource (Yates
et al. 2016). Ultimately management of DIV
should be tailored to the individual patient. A proposed algorithm outlining the diagnosis and management of DIV is outlined in Fig.1.
Suggested Diagnostic and Treatment Algorithm for DIV
Diagnosis and Initial
Management
Tr
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History supporting DIV:
1. Temporal association between drug initiation and
vasculitis?
2. Serum ANCA positive with multi-antigenicity?
3. Other diseases excluded?
4. Symptoms resolve following cessation of drug?
Initial management
• Stop culprit drug
• Avoid re-challenging with same drug
• Consider avoiding same classes of culprit
drug
Basic Investigations:
Labs: FBC, Renal, Liver, Bone profile, CRP, ESR, Coag
ANA, ENA, ANCA, APS screen, C3 C4, dsDNA,
Cryoglobulins, Hepatitis, screen, HIV screen
CXR, Urine dipstick, MSU, Urine protein: creatinine ratio
Skin biopsy
175
eatment
Fig. 1 Outline of the proposed algorithm for the diagnosis and management of DIV
3 Drugs Commonly Associated
Numerous classes of drugs have been reported to
be associated with DIV. The drugs commonly
reported to cause cutaneous vasculitis are listed
in Table1. The major drug classes are discussed
below.
3.1 Antibiotics
In one large single-centre case series of 773
patients, antibiotics were reported to be the most
common trigger of DIV representing 62.3% of all
cases (Ortiz-Sanjuán etal. 2014). Among antibiotic class, ß-lactam antibiotics were the most
commonly reported. Causality is however often
difcult to prove in these cases, as patients will
Mild
No organ involvement
Observe
Consider short course
of oral steroids
(0.5mg/kg reducing
over 6-12 weeks)
withCutaneous Vasculitis
Moderate
(Organ involvementnon-life threatening)
Steroids
Immunosuppressive
drugs e.g.
methotrexate,
mycophenolate
azathioprine
Severe
(e.g. necrotizing
glomerulonephritis,
alveolar haemorrhage)
High dose steroid
Rituximab
Cyclophosphamide
typically have concurrent infections which are
also known to trigger cutaneous vasculitis.
3.2 Anti-TNF-α Agents
Since the mid-1990s numerous targeted biologic
therapies have been developed to treat a variety
of autoimmune diseases and many of these have
been associated with DIV.The most commonly
reported class of biologic drugs associated with
DIV are the anti-TNF-α monoclonal antibodies
(Sokumbi etal. 2012). Reported cutaneous manifestations of anti-TNF-α DIV include erythematous macules and bullous lesions as well as
palpable purpura. Skin biopsies of anti-TNF-α
DIV demonstrate leucocytoclastic vasculitis.
Withdrawal of the anti-TNF-α agent usually
leads to resolution of symptoms. In a small, retro-
176
https://t.me/medicina_free
Table 1 Prescribed drugs associated with cutaneous vasculitis
Speciality Drug class Drug References
Oncology-immunotherapy Checkpoint
inhibitors
EGFR inhibitors Panitumumab Kamo etal. (2019)
Proteosome
inhibitors
Oncology-Hormonal therapy Aromatase
inhibitors
Rheumatology/Gastroenterology/
Dermatology/
Microbiology Antibiotics Antibiotics Ortiz-Sanjuán etal. (2014)
Haematology Anti-coagulant Warfarin Hamada etal. (2017), Hsu etal. (2012)
Endocrinology Anti-thyroid
Biologics Anti-TNF Sokumbi etal. (2012), Sehgal etal.
Direct oral
anti-coagulant
medication
Dabrafenib Niro etal. (2018)
Trametinib Niro etal. (2018)
Nivolumab Tomelleri etal. (2018)
Pembrolizumab Tomelleri etal. (2018)
Lapitinib Peuvrel etal. (2013)
Erlotinib Fekete and Fekete (2019)
Ixazomib Alloo etal. (2018)
Anastrazole Bock etal. (2014)
Letrozole Digklia etal. (2014), Woodford etal.
(2019)
(2018)
Rituximab Abe etal. (2019)
Denosumab Sanchez etal. (2019)
Tocilizumab Sehgal etal. (2018), Sakaue etal. (2014)
Abatacept Shibata etal. (2013)
Minocycline Kermani etal. (2012), Lenert etal. (2013)
Rivaroxaban Sainz-Gaspar etal. (2018), Dean etal.
(2017), Chaaya etal. (2016)
Dabigatran An etal. (2017)
Propylthiouracil Wall etal. (2017)
J. Stack
spective, single-centre case series of 8 patients
with histologically proven DIV caused by antiTNF-α, 7/8 had evidence of systemic vasculitis
with conrmed mononeuritis in 6/8 patients and
IgA nephropathy in 1/8 patients. A majority of
the patients were treated with an immunosuppressant in addition to prednisolone; the mean
time to resolution was 6.9 months. In another
study of anti-TNF-α DIV, 6/9 of patients who
were rechallenged with the same anti-TNF agent
relapsed (Mohan etal. 2004).
Despite the studies cited above, determining
whether anti-TNF is responsible for causing vasculitis can be difcult. Anti-TNF-α agents are
used to treat diseases such as rheumatoid arthritis
(RA) and inammatory bowel disease (IBD)
which can in themselves be associated with vasculitis. A temporal association with commencement of anti-TNF, improvement upon cessation
of anti-TNF, and an otherwise quiescent underlying disease can help to support a diagnosis of
DIV.Although anti-TNF can induce anti-nuclear
antibodies, the association between drug-induced
antibodies and subsequent vasculitis has not been
well dened. It is hypothesized that development
of antibodies can lead to an immune complexmediated vasculitis (Moustou etal. 2009).
3.3 Propylthiouracil
Propylthiouracil (PTU) causing DIV is well
described. A review of 128 cases found that the
most common manifestations were rash, fever
and arthralgia (Wall etal. 2017). Rash was present in 51% of cases. The vast majority were found
to have positive ANCA on immunouorescence
(typically perinuclear, p-ANCA). Up to 84% of
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