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Drug-Induced Vasculitis
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patients with PTU-associated DIV had a positive
MPO-ANCA on serological testing. Renal manifestations were common with proteinuria and/or
microscopic haematuria in 57% of cases. Renal
involvement was an important cause of morbidity
and end-stage renal disease was reported in eight
patients, four of whom underwent kidney transplant. Extreme cases of PTU-associated cutaneous vasculitis have been reported causing
extensive skin involvement with progression to
widespread, full-thickness skin necrosis, septic
shock and death (Wall etal. 2017).
3.4 Cocaine/Levamisole
One of the more commonly reported and studied
forms of DIV relates to cocaine misuse. Cocaine
purchased for illicit use is frequently contaminated with the anti-helminth drug levamisole.
Powdered levamisole, which is normally used in
veterinary practice, resembles cocaine and has
been used as an additive (a “cutting agent”) in
cocaine and crack cocaine, bulking up the drug to
increase prot for the dealer. In addition, a
metabolite of levamisole potentiates the stimulatory effects of cocaine. However, levamisole is
highly immunogenic and is the source of cocaineinduced DIV. Patients present with clinical features resembling an ANCA-associated vasculitis,
which include fever, neutropenia, arthralgia, purpura and other signs of cutaneous vasculitis.
Some users will develop midline destructive
lesions characterized by localized granulomatous
inammation around the nasopharynx, destruction of the nasal septum and, in severe cases,
saddle nose deformity (Marquez etal. 2017). A
distinguishing feature is that these patients are
often positive for multiple autoantibodies
including ANCA, ANA, anti-phospholipid and
anti- dsDNA antibodies. ANCA antibodies tend
to be non-specic; patients can be MPO-ANCA
and PR3-ANCA positive (Marquez etal. 2017;
Carmona-Rivera etal. 2017).
Addiction counselling is of key importance
for these patients as cessation of cocaine misuse
will result in resolution of the vasculitis in most
cases (Marquez et al. 2017). Occasionally, the
vasculitis will perpetuate or will be severe enough
to warrant immune suppression with steroids and
immunomodulatory therapy (Marquez et al.
2017).
3.5 Cancer Immunotherapy
The development of immunotherapy in the treatment of cancer has dramatically improved the life
expectancy of patients with solid organ tumours,
haematological malignancies and melanoma.
The most commonly prescribed immunotherapeutic drugs are checkpoint inhibitors (CPIs)
which enhance the anti-tumour activity of T-cells
resulting in tumour suppression and regression,
even in patients with unresectable metastatic disease (Kostine et al. 2019). The use of CPIs is
associated with a wide variety of manifestations
resembling autoimmune disease, collectively
termed immune related adverse events irAEs
(Calabrese etal. 2018). The frequency of irAEs
has been reported to be high, up to 90% in some
studies (Calabrese etal. 2018). The majority of
irAEs are rheumatic in nature resembling rheumatoid arthritis or polymyalgia rheumatica; however, polymyositis, scleroderma, sicca syndrome
and vasculitis syndromes can also occur (Kostine
etal. 2019). In one systematic review of vasculitis associated with CPIs, the authors found 20
case reports that met their denition for inclusion
(Daxini etal. 2018). The majority of cases were
associated with melanoma and the most common
manifestations of vasculitis were giant cell arteritis and primary CNS vasculitis. Cases of digital
vasculitis, granulomatosis with polyangiitis and
cryoglobulinaemic vasculitis were also reported.
The Common Terminology Criteria for
Adverse Events (CTCAE) grades irAEs from
1-to-5 based on the severity (grades 1 and 2 are
mild, grade 5 is fatal) (Puzanov et al. 2017).
Grade 1 events do not typically require intervention while grade 3 or higher usually warrants
intervention with corticosteroids, immunomodulation and cessation of the CPI. An important
observation is that many irAEs can persist despite
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J. Stack
cessation of CPI (Calabrese etal. 2018). In these
cases, a close liaison between patient and oncologist is required to formulate a decision about the
continuation of CPI therapy.
4 Pathogenesis
Perhaps the most studied form of DIV is cocaine–
levamisole vasculitis. Our understanding of this
entity has helped to uncover pathogenetic principles which may underlie other DIV syndromes.
The release of neutrophil extracellular traps
(NETs) has been shown to be an important mechanism through which cocaine–levamisole can initiate autoimmunity leading to vasculitis
(Carmona-Rivera etal. 2017; Lood and Hughes
2017; Pieterse and van der Vlag 2017). The pro-
cess of NET release is known as NETosis, a type
of neutrophil programmed cell death in which
chromatin bres (the breakdown product of
DNA, histones and granule-derived antimicrobial proteins) are expelled from cells
(Brinkmann and Zychlinsky 2012). It is a powerful defence mechanism used by the body to ght
pathogens that are too large to be phagocytosed.
Aberrant NETosis has been identied as a feature
of autoimmune disease, thrombosis and malignancy (Kaplan and Radic 2012). Lemavisole has
been shown to generate NETs enriched in neutrophil elastase (NE), a neutrophil-derived protein
which is highly immunogenic and capable of
stimulating expression of ANCA (Lood and
Hughes 2017). Continuous generation of NETs is
hypothesized to lead to a breakdown in immune
tolerance. NETs become pathogenic and lead to a
perpetuation of the immune response with resulting inammation and vasculitis (Pieterse and van
der Vlag 2017). In addition, cocaine and/or
levamisole are both capable of upregulating
expression of B cell activating factor (BAFF), a
key stimulant of B cell replication and differentiation, which may increase ANCA production
and explain why ANCA titres can persist long
after cocaine cessation (Lood and Hughes 2017).
These above mechanisms may shed light on
other forms of drug-induced vasculitis. For
example, DIV associated with PTU has also been
associated with NETosis and MPO-ANCA gen-
eration in rats, which has been shown to cause
pauci-immune glomerulonephritis and pulmonary capillaritis (Nakazawa etal. 2012).
Vasculitis and other irAEs associated with
CPIs are not associated with auto-antibody formation and tend not to regress once the CPI has
been discontinued (Calabrese et al. 2018). The
mechanism by which irAEs occur remains
unknown however a number of mechanisms are
proposed. One hypothesis suggests that CPIs,
acting on the host immune system, impair
immune tolerance leading to autoimmunity.
Another proposes that CPIs result in the unmasking of pre-existing autoimmunity. T-cell epitope
spreading has also been suggested, whereby
T-cells start to recognize and react to healthy host
tissue antigen in addition to tumour antigen
(Calabrese etal. 2018).
5 Conclusion
There are a wide variety of drugs associated with
DIV, and a drug aetiology needs to be considered
in all patients presenting with vasculitis.
Clinicians should be aware of the potential for
systemic disease involvement in patients with
DIV and to examine the patient and investigate
appropriately. Ultimately, however, DIV is a
diagnosis of exclusion.
As the use of new cancer immunotherapeutic
drugs increases there will be a growing burden of
irAEs, which include vasculitis. In this emerging
eld of oncological therapeutics it is the check
point inhibitors which are especially liable to
induce vasculitis. Powerful efcacy is coupled to
the potential for serious side effects and therefore
the ability to recognize autoimmune adverse
reactions is an important principle in the use of
these drugs.
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Drug-Induced Autoimmune
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Bullous Diseases
MichaelBenzaquen, MichaelHertl,
andLucaBorradori
Abbreviations
BP Bullous pemphigoid
DIBP Drug-induced BP
DPP4i Dipeptidyl peptidase-IV inhibitors
EBA Epidermolysis bullosa acquisita
IF Immunouorescence
LABD Linear IgA bullous dermatosis
NSAIDs Nonsteroidal anti-inammatory
drugs
PD1i Programmed cell death protein-1
inhibitors
TNFα Tumor necrosis factor alpha
Autoimmune bullous diseases comprise two
major types: intraepidermal blistering diseases
such as the pemphigus group of diseases and the
subepidermal blistering diseases comprising
pemphigoid group of diseases [bullous pemphi-
M. Benzaquen (*) · L. Borradori
Department of Dermatology, Inselspital—University
Hospital of Bern, Bern, Switzerland
e-mail: michael.benzaquen@insel.ch;
luca.borradori@insel.ch
M. Hertl
Department of Dermatology, University Hospitals
Marburg, Marburg, Germany
e-mail: michael.hertl@uni-marburg.de
goid (BP), linear IgA bullous dermatosis
(LABD), gestational pemphigoid], the group of
mucous membrane pemphigoids and epidermolysis bullosa acquisita (EBA) (Amber etal. 2018;
Di Zenzo etal. 2016; Kim etal. 2016). Besides
the immunological process, a variety of medications have been reported as potential triggers in
the pathogenesis. The diagnosis of drug-induced
autoimmune bullous diseases is challenging;
patients are often exposed to several drugs with
prolonged latency periods between exposure and
onset of the disease. In addition, the epidemiological risk of many drugs remains unclear.
Nevertheless, recognition and cessation of any
suspected drug trigger is essential for the management disease.
1 Drug-Induced Pemphigus
Pemphigus is an autoimmune acquired bullous
disease affecting the skin and/or mucous membranes, characterised by intraepidermal blistering. This condition is associated with Nikolsky’s
sign; the direct Nikolsky is when the application
of slight pressure on a blister results in extension
of the blistering to adjacent skin and the indirect
Nikolsky is when rubbing on clinically normal
skin causes shearing. This group of diseases is
associated with autoantibodies predominantly
© 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_15
181
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M. Benzaquen et al.
directed against two desmosomal components:
desmoglein 1 and/or desmoglein 3 (Amber etal.
2018).
Despite the identication of genetic and envi-
ronmental predisposing factors, various drugs
have been repeatedly implicated as potential triggers of pemphigus (Kim etal. 2016). The clinical
presentation of drug-induced pemphigus is similar to the idiopathic disease. An increasing
number of drugs (Brenner and Goldberg 2011)
have been reported to induce pemphigus, highlighting the importance of a detailed clinical history and evaluation in order to identify the
potential culprit medication.
1.1 Clinical Features
Drug-induced pemphigus presents with mucocutaneous erosions and accid vesicles and blisters.
It is clinically, histologically and immunologically indistinguishable from the classical disease
(Korman etal. 1991; Landau 1997).
1.2 Drug Causality
andPathophysiology
It is postulated that the binding of drugs to cellular proteins induces a structural change or uncovers hidden epitopes, thereby stimulating an
autoimmune response (Ruocco et al. 1993).
Other postulated mechanisms include direct disruption of cell–cell adhesions, cytokine activation and derangements in intracellular calcium
(Brenner etal. 1998; Marsden etal. 1976; Newby
etal. 2000; Feliciani etal. 2000).
The four main groups of chemical structures
in drugs that have been involved in triggering
pemphigus are (1) sulfhydryl radical (thiol drugs
or SH drugs), (2) phenolic drugs, (3) drugs with
an active amide group and (4) others (Korman
etal. 1991).
• Thiol drugs (e.g. penicillamine, captopril or
gold sodium thiomalate). Penicillamine was
the rst drug reported in 1976 to induce pemphigus foliaceus. Up to 7% of patients taking
penicillamine for at least 6 months would
develop pemphigus (Marsden etal. 1976).
Thiol drugs are postulated to induce acantholytic changes in skin through the inhibition
of enzymes involved in the aggregation of
keratinocytes as well as activating enzymes
such as plasminogen activator involved in cell
adhesion homeostasis. The activation of plasminogen activator may contribute to the loss
of cell–cell adhesion, as well as to the formation of thiol-cysteine bonds instead of cysteine–cysteine bonds, resulting in the formation
of neo-antigens with its downstream immunological effects (Ruocco etal. 1993).
• Phenolic drugs, including aspirin, levodopa,
rifampicin or heroin, have also been linked to
anecdotal cases of drug-triggered pemphigus
by the release of cytokines such as tumor
necrosis factor alpha (TNFα) and
interleukin-1α from keratinocytes (Newby
etal. 2000). These cytokines are involved in
the regulation and synthesis of complement
and proteases like plasminogen activator,
which are mediators of acantholysis (Feliciani
etal. 2000).
• Amide drugs such as acetazolamide was rst
identied in 2009, as potential trigger of druginduced pemphigus (Lo Schiavo etal. 2009).
• Others: Calcium channel blockers,
angiotensin- converting enzyme inhibitors,
antibiotics, nonsteroidal anti-inammatory
drugs (NSAIDs), or pyrazolone derivatives
are some examples of non-thiol non-amide
non-phenol drugs that have also been related
to some cases of pemphigus. Intracellular calcium is essential for keratinocyte homeostasis,
cell differentiation, cell–cell adhesion and the
proper conformation of the pemphigus antigens. It is therefore plausible that calcium
channel blockers may under certain circumstances act as a trigger or aggravating factor
(Brenner etal. 1998).
A list of common drug associations with pem-
phigus is summarised in Table 1 (Kaplan et al.
1992; Palleria etal. 2019).
The latency period from drug initiation to the
onset of pemphigus is variable. In cases associ-
Drug-Induced Autoimmune Bullous Diseases
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Table 1 Drugs commonly reported to induce pemphigus
Chemical structure Drug class Drug name
Thiol drugs Captopril
Fosinopril
Gold sodium thiomalate
Penicillamine
Thiopronine
Pyritinol
5-Thiopyridoxine
Mercaptopropionylglycine
Phenolic drugs Levodopa
Phenobarbital
Phenytoin
Heroin
Rifampicin
Lysine acetylsalicylate
Progesterone
Drug with an active amide
group
Non-thiol non-amide
non-phenolic drugs
Angiotensin-converting-enzyme
inhibitors
Pyrazalone derivatives Aminophenazone
Antibiotics Ampicillin
Nonsteroidal anti-inammatory
drugs
Others
Acetazolamide
Glibenclamide
Indapamide
Cilazapril
Enalapril
Fosinopril
Lisinopril
Benazepril
Quinapril
Ramipril
Noramidopyrine
Azapropazone
Oxyphenylbutazone
Phenylbutazone
Amoxicillin/clavulanic acid
Penicillin
Isoniazid and ethambutol
Cephalexin
Noroxacin
Ciprooxacin
Piroxicam
Diclofenac
Interleukin-2, interferon-α2a and β
Propranolol
Bisoprolol/hydrochlorothiazide
Nifedipine
Carbamazepine
Hydroxychloroquine
Tetanus, diphtheria, typhoid, anthrax, and
inuenza vaccinations
183
ated with antibiotics, it typically varies between
2weeks and 2months, whereas in ACE inhibitor/
ARB related and Penicillamine-related cases, the
latency is prolonged; occurring between 4 to
24months and 2 to 48months respectively (Saito
etal. 2018; Yung and Hambrick 1982).
2 Drug-Induced Bullous
Pemphigoid (DIBP)
BP is an acquired autoimmune disease that
affects mainly the elderly and is characterised by
subepidermal blistering (Amber et al. 2018).
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M. Benzaquen et al.
More than 50 different drugs have been associated with the onset of BP (Vassileva 1998) and
this number will increase with the emergence of
new therapies. Two forms of DIBP have been
described. The rst one, regarded as a true DIBP,
is an acute and self-limited condition with a
prompt response after withdrawal of the incriminated drug. The second form, considered as a
drug- triggered BP, is characterised by a more
chronic and severe course similar to classic BP,
in which the medication seems to have a role in
the initiation of the disease, which then follows
its spontaneous normal course (Lee and
Downham 2006).
2.1 Clinical Presentation/
Investigations
Drug-induced BP (DIBP) is characterised by a
younger age of onset. The trunk, the limbs (most
commonly the lower legs) and the face can be
involved and the rash is intensely pruritic. In contrast to classic BP, it has been observed that the
bullae in DIBP tends to occur on normalappearing skin rather than appearing on erythematous or urticarial base (Kawaguchi etal. 2019;
Stavropoulos etal. 2014). Erythema multiformelike target lesions on palms and soles as well as
mucosal lesions may be present (Alcalay et al.
1988). Post-bullous erosions heal spontaneously
without scarring. Nevertheless, in the absence of
prospective series specically addressing the
clinical features of drug-induced cases compared
with an adequate control population, there is little
evidence supporting the idea that drug-triggered
cases can be differentiated entirely on clinical
grounds.
Besides subepidermal blisters, histological
features often linked to DIBP include intraepidermal vesicles and necrotic keratinocytes. A
dense dermal inammatory inltrate containing
many eosinophils, neutrophils with lymphocytes
and histiocytes may be present, as well as thrombus formation. Similarly to classic BP, IgG antibodies and C3 along the linear basement
membrane zone are detected in 90% of cases by
direct immunouorescence (IF) microscopy,
whereas circulating IgG antibodies are detected
in 75% of cases with indirect IF (Stavropoulos
etal. 2014).
2.2 Pathophysiology
Several pathomechanisms have been proposed.
These include (a) change in T-regulatory cells
(CD4+, CD25+, Foxp) resulting in the stimulation
of B-cell clones and the release of autoantibodies
against the basement membrane zone (Bowman
and Delrieu 2009), (b) molecular mimicry arising
from structural similarity between drugs and autoantigens leading to the activation of CD4+ T cells
and the initiation of the autoimmune cascade in
susceptible individuals (Bowman and Delrieu
2009), (c) drugs acting as antigenic haptens, bind-
ing and modifying protein molecules in the basement membrane, resulting in the exposure of
hidden antigenic sites (Lee and Downham 2006).
In a retrospective study comprising 34
patients, Patsatsi et al. (2009) described an
increased detection rate with a signicant higher
level of anti-BP180 autoantibodies in a group of
patients with BP receiving systemic medications
prior to the disease, compared with a group of
patients who did not receive any medications.
2.3 Drug Causality
Since the rst report of salicylazosulphapyridineinduced BP in 1970 (Bean et al. 1970), many
other drugs have been reported to induce or trigger BP (detailed in Table2).
In a case–control study assessing the drugs
used on a long-term basis prior to onset of BP, it
was found that two classes of drugs, diuretics and
neuroleptics, were used more frequently by BP
patients than by control subjects. Among diuretics, the risk was linked to aldosterone antagonists
(Bastuji-Garin etal. 2011). In a UK case–control
study, loop diuretics were used signicantly more
frequently by the BP patients (Lloyd-Lavery
etal. 2013). Antibiotics, antiarrhythmics, antihypertensives, NSAIDs, and TNFα inhibitors have
also been incriminated (Vassileva 1998).
Drug-Induced Autoimmune Bullous Diseases
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Drugs commonly reported to induce bullous
Table 2
pemphigoid
Drug class Drug name
Antibiotics Actinomycin
Antiarrythmicsantihypertensives
Diuretics Furosemide
Neuroleptics Risperidone
Salicylates Aspirin
Nonsteroidal
anti-inammatory
drugs
DPP4 inhibitors Vildagliptin
Antirheumatics D-penicillamine
TNFα inhibitors
PD1 inhibitors Nivolumab
Vaccines Inuenza
Amoxicillin
Ampicillin
Cephalexin
Ciprooxacin
Chloroquine
Dactinomycin
Levooxacin
Penicillin
Rifampicin
Calcium channel-blockers:
Amlodipine; Nifedipine
Angiotensin-converting-enzyme
inhibitors: Captopril; Enalapril;
Lisinopril
Beta-blockers: Nadolol;
Practolol
Angiotensin II antagonists:
Losartan
Spironolactone
Flupentixol
Gabapentin
Levetiracetam
Sulfasalazine
Salicylazosulphapyridine
Azapropazone
Diclofenac (topical)
Ibuprofen
Mefenamic acid
Phenacetin
Sitagliptin
Linagliptin
Tiobutarit
Tiopronin
Adalimumab
Efalizumab
Etanercept
Pembrolizumab
Swine u
Tetanus toxoid
HZV
Hexavalent combined
Vaccines
Table 2 (continued)
Drug class Drug name
Others Arsenic
Clonidine
Erlotinib
Galantamine hydrobromide
Fluoxetine
Gold thiosulphate
Interleukin-2
Methyldopa
Terbinane
Tolbutamide
Omeprazole
Psoralens with UVA
Placental extracts
Potassium iodide
Sulphonamide
DPP4 dipeptidyl peptidase-IV, TNFα tumour necrosis
factor alpha, PD1 programmed cell death protein-1
Recently, two classes of drugs have been
shown to have increased epidemiological risk:
Dipeptidyl peptidase-IV inhibitors (DPP4i), and
programmed cell death protein-1 inhibitors
(PD1i).
DPP4i are oral anti-hyperglycaemic drugs
administered to patients with type 2 diabetes. An
increasing number of reports have suggested that
DPP4i could trigger BP.García etal. (2016) identied 170 cases of BP in patients under DPP4i in
the EudraVigilance database, suggesting that the
intake of DPP4i was more frequently associated
with the development of BP when compared to
that of other drugs. In this latter report, a high
disproportionality for vildagliptin was found. A
French case–non-case study recording all spontaneous reports of DPP4i-related BP in the National
Pharmacovigilance Database also provided evidence for a strong signal for an increased risk of
BP associated to DPP4i exposure, especially
vildagliptin (Béné etal. 2016). Finally, Benzaquen
etal. (2018) conrmed for the rst time in a retrospective study that DPP4i were associated with
an increased risk of developing BP. Association
with vildagliptin was signicantly higher compared to that with other DPP4i with an adjusted
odds-ratio of 3.57.
186
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M. Benzaquen et al.
Immune check point inhibitors which are
increasingly used in the treatment of metastatic
melanoma and other metastatic cancers, represent another class of drugs increasingly incriminated as a trigger of immune-mediated dermatoses
such as vitiligo, lichenoid eruptions and autoimmune blistering diseases. Twenty-two cases of
BP associated with PD1i (nivolumab or pembrolizumab) have been reported so far in the literature (Lopez and Geskin 2018). Dysregulation of
PD1 pathway can impair peripheral tolerance and
alter the balance within the immune system, leading to the development of off-target effects and
autoimmunity. With the anticipated signicant
growth in the number of patients eligible to
receive checkpoint inhibitors, physicians should
be aware of these additional cutaneous autoimmune association with BP.
3 Drug-Induced Linear IgA
Bullous Dermatosis (LABD)
LABD comprises a heterogeneous group of autoimmune subepidermal blistering disorder characterised by the detection of linear deposits of IgA
(alone or as the predominant immunoreactant in
combination with other immunoglobulins) along
the basement membrane zone as detected by
direct IF microscopy studies. Immunologically,
the detected IgA autoantibodies may demonstrate
reactivity with various antigens, including specic antigenic regions of the extracellular domain
of BP180, as well as BP230 and type VII collagen (Amber et al. 2018). It is estimated that at
least 2% of all LABD is attributed to drug administration (Horiguchi etal. 2008).
3.1 Clinical Presentation
The lesions in LABD often exhibit annular and
polycyclic patterns with vesicles and bullae arising on the edge with central crusting or healing.
These so-called cluster of jewels or string of
pearls signs are characteristic for LABD, especially in the childhood form (Horiguchi et al.
2008). In contrast, drug-induced LABD may
present with more polymorphic and/or atypical
features mimicking other forms of bullous dermatosis, severe drug eruptions, vasculitis or even
neutrophilic dermatoses (Dietrich et al. 2012).
Chanal et al. (2013) performed a retrospective
single-centre cohort study of 28 patients diagnosed with LABD between 1995 and 2010: 16
patients with spontaneous LABD and 12 with
drug-induced LABD. Nikolsky sign and large
erosions were signicantly more frequent in
drug-induced than spontaneous LABD, with no
between-group differences for erythematous
plaques, target or target-like lesions, string of
pearls, location, mucosal involvement or histological features. Hence, drug-induced LABD
appear to be more severe than the spontaneous
form. Physicians should be aware of this diagnosis and perform a direct IF in case of lesions
mimicking toxic epidermal necrolysis.
3.2 Pathophysiology
The mechanism of drug-induced autoimmunity
in LABD is not clear. However, it has been shown
that in patients with vancomycin-induced LABD,
IgA reactivity to collagen VII is acquired in the
presence of vancomycin (Yamagami etal. 2018).
3.3 Drug Causality
The latency between drug initiation and onset of
disease ranges between 2days to 4weeks. A variety of medications have been implicated with
vancomycin being the most frequently cited
(Baden et al. 1988; Whitworth et al. 1996).
Vancomycin-associated LABD has also been
reported following exposure to vancomycinimpregnated cement spacers used in knee arthroplasty (Riemenschneider et al. 2018). Several
other drugs have also been associated with
LABD, including NSAIDs (piroxicam, naproxen,
diclofenac) (Bouldin etal. 2000; Plunkett etal.
2001), amiodarone (Primka etal. 1994), antibiot-
ics (ceftriaxone, penicillin) (Combemale et al.
1993; Yawalkar etal. 1999) and acetaminophen
(Avci etal. 2003). Recently, Garel etal. have collected, in a French retrospective study from 1985
to 2017, 69 cases of drug-induced LABD. 29
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