Am J Clin Dermatol 2012; 13 (6): 417-421

CASE REPORTS 1175-0561/12/0006-0417/$49.95/0

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Lichen Planus-Like Drug Eruptions Due to b-Blockers

A Case Report and Literature Review
Chris Fessa,1 Penny Lim,2 Steve Kossard,2 Shawn Richards3 and Pablo Fernandez Peñas1,3,4
1 Department of Dermatology, Westmead Hospital, Westmead, NSW, Australia
2 The Skin and Cancer Foundation Australia, Darlinghurst, NSW, Australia
3 The Skin and Cancer Foundation Australia, Westmead, NSW, Australia
4 Western Clinical School, Sydney Medical School, The University of Sydney, Westmead, NSW, Australia

Abstract Lichen planus-like drug eruptions (LDE) can appear similar or identical to idiopathic lichen planus. We
present a 45-year-old man with a widespread, violaceous, papular, generalized exanthema with histologic
features of a lichenoid reaction, which subsequently resolved with the cessation of labetatol. We found 29
cases of previously reported b-adrenoceptor antagonist (b-blocker)-associated LDE. This is a relatively rare
complication that may present as classic lichenoid papules indistinguishable from lichen planus and has a
predilection for the limbs, chest, back, and oral mucosa. Histologically, there is a lichenoid infiltrate often
with eosinophils. LDE may be due to drug cross-reactivity or as a result of a suppressed skin adrenergic
system. Multiple potential medications in case studies and the inability to differentiate LDE from idiopathic
lichen planus in cross-sectional association studies make any conclusive analysis difficult.

1. Case Report evaluation revealed a prominent lichenoid reaction with a few

A 45-year-old man presented to our clinic with a 1-month
history of a pruritic, papular, violaceous rash that commenced on
his thighs and progressively spread to his back, upper limbs, and
lower legs. Four months prior, the patient had suffered a type A
aortic dissection that was managed surgically. He had labile hy-
pertension and was managed with aspirin 100 mg daily, labetalol
800 mg three times per day, perindopril 10 mg daily, amlodipine
10 mg daily, and prazosin 4 mg twice daily. All medications were
commenced soon after the patient underwent surgery. Prior to
being reviewed at our clinic, his cardiologist was concerned he was
experiencing a drug-induced cutaneous reaction. Aspirin and
perindopril were ceased on separate occasions for a month without
improvement in symptoms. Both medications were reinstated and
no other alteration was made. He had no other medical history.
On physical examination, there were multiple, small
(2–5 mm), violaceous, flat-topped, shiny surface papules over
his limbs, lower back, and lateral abdominal wall (figure 1).
Wickham striae were noted on some lesions on his limbs. Several
small erosions were seen on inspection of the oral mucosa.
With the clinical diagnosis of lichen planus-like drug eruption
(LDE) or idiopathic lichen planus (ILP), two punch biopsies
were taken from the right arm and left thigh. Histopathologic
eosinophils. Hyperkeratosis, focal parakeratosis, basal vacuolar
degeneration, acanthosis, and interface inflammation were present
(figure 2). No loss of the granular layer was seen. The lymphocytes
extended into the deep dermis, involving the follicles and peri-
vascular regions. These findings favored LDE rather than ILP.
The patient was prescribed triamcinolone for the oral lesions,
nightly promethazine for the associated pruritus, and given
instructions on general skin care measures.
The patient was gradually weaned off labetalol in order to
reduce the risk of b-adrenoceptor antagonist (b-blocker)
withdrawal syndrome and to monitor his blood pressure. The
diagnosis of LDE was supported by a review 1 month later with
resolution of the lesions. The patient was given an alternative
b-blocker, metoprolol. On a subsequent review at 3 months, no
cutaneous lesions were present.
2. Discussion
b-Blockers are a class of drugs that bind to b-adreno-
receptors, which in turn antagonize sympathetic activity. They
play a role in the treatment of a number of medical conditions
such as hypertension, heart failure, cardiac arrhythmias, hyper-
thyroidism, migraines, and glaucoma. There are many docu-
418 Fessa et al.

a any other antihypertensive medication.[3] Of special note, the

b-blocker practolol was one of the UK’s worst drug catas-
trophes resulting in 40 deaths and 1250 cutaneous reactions
including practolol-induced oculomucocutaneous syndrome
(toxic epidermal necrolysis) and drug-induced systemic lupus
erythematosus-like syndrome in the 1970s.[4]

2.1 b-Blocker-Induced Lichen Planus-Like Drug Eruption

b-Blocker-induced LDE is a well described but rare adverse

reaction. A PubMed literature search revealed 16 English
language articles with cases of b-blocker-associated LDE
(table II). This included 12 case reports, one case series of two
patients, two histologic reviews, and one observational study.
In total, 29 cases of b-blocker-induced LDE were identified,
with atenolol being the most common.
The diagnosis of LDE is supported by the resolution of lesions
following withdrawal of medication. Many older studies have also
re-challenged subjects with the offending agent to confirm the
diagnosis. However, this practice has largely been ceased due to
obvious safety issues and to avoid subjecting patients to undue
distress. There are number of other factors that need to be noted
when considering a cutaneous drug reaction including recent
medication changes, pre-existing skin conditions, drug concen-
trations, and literature on adverse reactions of the suspected
agent.[2] Clinical suspicion may be hampered by unpredictable
b
latent and resolution time frames. Other clinical concerns include
deducing the offending medication in cases of polypharmacy and

Fig. 1. (a) Extensive violaceous rash over lower back, anterior aspect of
forearm, and medial arm. (b) Close-up view of forearm. Small (2–5 mm),
multiple papules can be seen.
Fig. 2. Histologic image demonstrating band-like, upper dermal, T-lym-
phocyte infiltration, vacuolar basal cell layer degeneration, saw-tooth-like rete
mented adverse cutaneous drug eruptions associated with
ridges, acanthosis, focal para and hyperkeratosis, and a deep and peri-
b-blockers (table I). b-Blockers are noted to have the highest vascular inflammatory infiltrative mainly consisting of lymphocytes with a
occurrence of adverse cutaneous reactions compared with scattering of eosinophils (hematoxylin and eosin stain, magnification ·10).

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Lichen Planus-Like Drug Eruptions Due to b-Blockers 419

Table I. Adverse cutaneous reactions associated with b-blockers[1,2] An extensive and symmetric distribution involving the trunk
Psoriasiform eruption and limbs is typical of a LDE, while involvement of the flexor
Eczematous eruption surfaces of the wrist, the ankles, the lumbar region, and mucosal
Lichenoid eruption surfaces is associated with ILP. Reviewing the b-blocker-induced
Xerosis
LDE literature, the most common sites affected were the limbs,
back, trunk, and oral mucosa (table III). Cases involving the hands
Lupus erythematous
and feet had mixed dorsal and palmar/plantar involvement.[10,14,15]
Alopecia
Although mucosal involvement in LDE is reported as rare in
Hyperpigmentation
dermatology textbooks, oral lesions were noted in our case as
Raynaud phenomenon
well as in five other case reports. Also, a further two reports
Toxic epidermal necrolysis
cited penile lesions.[9,11] In total, half of the b-blocker-induced
Peyronie disease
LDE literature with anatomic location descriptions had mu-
Scalp tingling
cosal involvement. This is in line with a retrospective review that
demonstrated an association of b-blocker use with mucosal li-
replacing the medication with an effective substitute. In our case, chen planus.[24] In a further study of the 19 patients attending
the patient was taking four agents that could have been respon- a cardiology clinic with oral lichenoid lesions, 14 were taking a
sible for the development of a LDE.[10,11,20-22] b-blocker medication.[25] In both studies it is difficult to ascertain
In many of the case reports, it was difficult to definitively whether the lesions were drug induced or idiopathic in nature as
conclude that the lichenoid eruption was due to a b-blocker no data about response to medication cessation were described.
medication. In three case reports, other medications were
ceased at the same time.[5,8,19] In a further case, the patient had a
2.3 Histology
past history of ILP, making a final diagnosis difficult.[14]
In 26 cases, the medication was administered orally. The re- Both LDE and ILP share many histologic findings such as
maining three were topical ophthalmic preparations.[13,17] The age band-like, upper dermal T-lymphocyte infiltration, vacuolar
of the patients was between 45 and 79 years (mean age 53 years), basal cell layer degeneration, and saw-tooth-like rete ridges.[26]
and five were female and nine were male. The time period from the Although there is not a feature that is pathognomonic, a number
commencement of the medication to onset of drug eruption of features are associated with LDE. A small comparative his-
ranged from 4 days[17] to 7 years[16] with a median of 3 months. tology analysis of 15 cases of ILP and LDE (eight of which were
Cross-reactivity among b-blocker agents has not been dem- due to a b-blocker) found that focal parakeratosis, interruption of
onstrated. After ceasing labetalol, our patient was commenced on the granular layer, and cytoid bodies in cornified and granular
metoprolol to control his labile hypertension without further layers occurred in >50% of LDE cases while never occurring in
eruptions occurring. Similarly, in four case reports of b-blocker-
induced LDE, no reaction was noted with an alternative Table II. Number of lichenoid eruptions associated with specific b-blocker
b-blocker.[11-13,15] Cross-reactivity with other medications has medications
only been noted between ocular timolol and dorzolamide.[17] b-Blocker Number of lichenoid eruptions
[3,5-7]
Atenolol 9
2.2 Clinical Features Propanolol[3,6,8,9] 4
[10-12] a
Labetalol 4
Classic lichenoid papules, described as small, flat-topped, scaly, Pindolol[7] 3
pruritic, and violaceous, was the most common finding, and the [13]
Levobunolol 2
presence of Wickham striae was noted in 9 of the 15 cases. In the
Metoprolol[7,14] 2
earlier stages of development, the lesions may appear as tiny, pink- [15]
Sotalol 1
colored macules, while with resolution, there is a greater chance of
Acebutolol[16] 1
developing residual hyperpigmentation.[23] Other variants, such as
[17]
Timolol 1
erosive and bullous, have been described in LDE. Erosions were
Nebivolol[18] 1
reported in 8 of the 15 cases with 6 involving the oral mucosa and 2
[19]
affecting the genital region. Bullous lesions were seen in two cases Oxprenolol 1

both associated with labetalol.[11,12] a Our case report has been included.

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420
Table III. Anatomic location of b-blocker-induced lichenoid drug eruption
cases
Anatomic location of lesions Number of casesa
Arms 9 erhans cells, and dendritic cells.[34] These cells also possess
Legs 9 pattern recognition receptors (PRR), whose role is to detect
Trunk 6 pathogen-associated molecular patterns (PAMP). Rises in in-
Mouth 6 flammatory cytokines and antigen-specific plasmacytoid den-
Back 4
Hands 3
b b-blocker and a peptidogylcan (a PAMP).[35] This suggests that
Generalized 2
Feet 2
Face 2
Genital region 2
Nail involvement 1
Scalp 1
Neck 1 cutaneous homeostasis and in the pathogenesis of a number of
a Based on 15 cases with anatomic lesion distribution information including
our case.
b In both generalized cases, an anatomic description was given on initial
assessment, which has been included in the table. On subsequent review,
the distribution was described as generalized.
ILP cases. In addition, the presence of eosinophils was only noted
in LDE cases.[7] Other histologic features that are more often seen
in LDE cases include deep vessel inflammatory infiltrate, scat-
tered histiocytes and plasma cells, increased number of necrotic
keratinocytes, non-wedge-shaped hypergranulosis, and granular
layer atrophy.[27-29] On the other hand, histologic clues that are
more associated with ILP include focal hypergranulosis, epidermal
hyperplasia, melanophages in a thickened papillary dermis, ex-
travasation of erythrocytes, clefts at the dermo-epidermal junction,
and uneven acanthosis.[28] In addition, cases associated with a
photodistributed LDE may have histologic features more in line
with ILP.[30] Analyzing the histologic characteristics of the
b-blocker-induced LDE cases that have been published is difficult
due to incomplete pathologic descriptions. The most common
finding was a lichenoid infiltrate with eosinophils (table IV). Only
two papers reported the presence of cytoid bodies.[6,10] The his-
tology findings of eosinophils, deep vessel lymphoid infiltrate, and
focal parakeratosis supported a diagnosis of a LDE in our case.
2.4 Pathogenesis
Lichenoid tissue reactions are an autoimmune T-cell re-
sponse primarily targeting the epidermis. It is common for the
antigen to be unknown; however, cross-reactivity with viruses,
chemicals, drugs, and self-antigens may be the trigger.[31-33]
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Fessa et al.
The pathogenesis of b-blocker-induced LDE is unclear but it
may involve the blockade of b-adrenoreceptors. The b2 sub-
class of receptors is present on epidermal keratinocytes, Lang-
dritic cells necessary for the pathologic cascade of lichenoid
tissue reactions occur when skin is exposed to a non-selective
the dermal adrenergic system may have a role in controlling the
T helper-1 response of pathogens that is recognized by the
PRRs and thus its blockade with a b-blocker may potentially
lead to a T helper-1-sustained skin inflammatory process such
as a lichenoid tissue reaction.
The b-adrenergic system has been suggested to play a role in
inflammatory dermatoses.[36] In wound healing, the b-adre-
nergic system influences extracellular signal regulated kinases,
which in turn affect keratinocyte migration.[34] b-Adrenergic
dysfunction occurs in keratinocytes of both psoriatic and viti-
ligo affected lesions.[37,38] The use of b-blockers in patients with
psoriasis may lead to further lesion eruptions.[39] Interestingly,
corticosteroids, a mainstay therapy in inflammatory dermatosis,
lead to increased keratinocyte expression of b2-receptors.[40] The
involvement of the cutaneous b-adrenergic system in multiple
dermal processes may also suggest a more complex pathogenesis
cascade in b-blocker-induced lichen planus.
3. Conclusion
LDE is a relatively rare complication associated with the use
of b-blocker medication. It may present as classic lichenoid
papules that are indistinguishable from lichen planus and has a
Table IV. Histologic features of b-blocker-induced lichenoid drug eruptions
Histologic feature Number of casesa
Extension of infiltrate around deep vessels 6
Exocytosis of lymphocytes into upper epidermis 6
Eosinophils in the cellular infiltrate 5
Focal parakeratosis 5
Cytoid bodies 2
Epidermal atrophy 1
a Based on the histologic description of 13 case studies and our case. The
histologic studies were excluded, as it was not possible to clearly define
the findings of the b-blocker case. The Mullins et al.[17] paper was also
excluded as the histology findings related to the initial dorzolamide-
induced lichen planus-like drug eruption.
Am J Clin Dermatol 2012; 13 (6)
Lichen Planus-Like Drug Eruptions Due to b-Blockers
predilection for the limbs, chest, back, and oral mucosa. Certain
histologic features are commonly seen in b-blocker-induced LDE
including the presence of eosinophils, deep perivascular lymphoid
infiltration, focal parakeratosis, and exocytosis of lymphocytes in
the superficial epidermis. The triggering factor of b-blocker-
associated LDE may be due to drug cross-reactivity or as a result
of a suppressed skin adrenergic system.
Acknowledgments
No sources of funding were received to prepare this case report. The
authors have no conflicts of interest that are directly relevant to the content
of this case report.
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Correspondence: Dr Chris Fessa, Department of Dermatology, Westmead
Hospital, Corner of Hawkesbury and Darcy Roads, Westmead, NSW 2145,
Australia.
E-mail: cfessa@yahoo.com.au
Am J Clin Dermatol 2012; 13 (6)