Lichen Planus-Like Drug Eruptions Due to B-Blockers

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Lichen Planus-Like Drug Eruptions Due to b-BlockersA Case Report and Literature Review

Chris Fessa,1 Penny Lim,2 Steve Kossard,2 Shawn Richards3 and Pablo Fernandez Pen as1,3,4

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

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 100mg daily, labetalol

800mg 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 separateoccasions for a month withoutimprovement 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 striaewere noted on some lesions on his limbs.Several

small erosions were seen on inspection of the oral mucosa.

With the clinical diagnosisof lichen planus-like drug eruption

(LDE) or idiopathic lichen planus (ILP), two punch biopsies

were taken from the right arm and left thigh. Histopathologic

evaluation revealed a prominent lichenoid reaction with a few

eosinophils. Hyperkeratosis, focal parakeratosis, basal vacuola

degeneration, acanthosis, and interface inflammation were presen

(figure 2). No loss of the granular layer was seen. The lymphocyte

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 alternativeb-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 condition

such as hypertension, heart failure, cardiac arrhythmias, hyper

thyroidism, migraines, and glaucoma. There are many docu

CASE REPORTS Am J Clin Dermatol 2012; 13 (6): 417-42

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

Adis ª 2012 Springer International Publishing AG. All rights reserved



mented adverse cutaneous drug eruptions associated with

b-blockers (table I). b-Blockers are noted to have the highest

occurrence of adverse cutaneous reactions compared with

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

b-blocker practolol was one of the UK’s worst drug catas

trophes resulting in 40 deaths and 1250 cutaneous reaction

including practolol-induced oculomucocutaneous syndrom

(toxic epidermal necrolysis) and drug-induced systemic lupu

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 identifiedwith atenolol being the most common.

The diagnosis of LDE is supported by the resolution of lesion

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 undu

distress. There are number of other factors that need to be noted

when considering a cutaneous drug reaction including recen

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

latent and resolution time frames. Other clinical concerns include

deducing the offending medication in cases of polypharmacy and

a

b

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

phocyteinfiltration, vacuolar basalcell layer degeneration, saw-tooth-likeret

ridges, acanthosis, focal para and hyperkeratosis, and a deep and per

vascular inflammatory infiltrative mainly consisting of lymphocytes with a

scattering of eosinophils (hematoxylin and eosin stain, magnification ·10).

418 Fessa et a

Adis ª 2012 Springer International Publishing AG. All rights reserved. Am J Clin Dermatol 2012; 13 (6



replacing the medication with an effective substitute. In our case,the patient was taking four agents that could have been respon-

sible for the development of a LDE.[10,11,20-22]

In many of the case reports, it was difficult to definitively

conclude that the lichenoid eruption was due to a b-blocker

medication. In three case reports, other medications were

ceased at the same time.[5,8,19] In a further case, the patienthad a

past history of ILP, making a final diagnosis difficult.[14]

In 26 cases, the medication was administered orally. The re-

maining three were topical ophthalmic preparations.[13,17] The age

of the patients was between 45 and 79 years (mean age 53 years),

and five were female and nine were male. The time period from the

commencement of the medication to onset of drug eruption

ranged from 4 days[17] to 7 years[16] with a median of 3 months.

Cross-reactivity among b-blocker agents has not been dem-

onstrated. After ceasing labetalol, our patient was commenced on

metoprolol to control his labile hypertension without further

eruptions occurring. Similarly, in four case reports of b-blocker-

induced LDE, no reaction was noted with an alternative

b-blocker.[11-13,15] Cross-reactivity with other medications has

only been noted between ocular timolol and dorzolamide.[17]

2.2 Clinical Features

Classic lichenoidpapules, described as small, flat-topped, scaly,

pruritic, and violaceous, was the most common finding, and the

presence of Wickham striae was noted in 9 of the 15 cases. In the

earlier stagesof development, the lesions mayappear as tiny, pink-

colored macules, while with resolution, there is a greater chance of

developing residual hyperpigmentation.[23] Other variants, such as

erosive and bullous, have been described in LDE. Erosions were

reported in 8 of the 15cases with 6 involving the oralmucosa and 2

affecting the genital region. Bullous lesions were seen in two cases

both associated with labetalol.[11,12]

An extensive and symmetric distribution involving the trunk

and limbs is typical of a LDE, while involvement of the flexo

surfaces of the wrist, the ankles, the lumbar region, and mucosa

surfaces is associated with ILP. Reviewing the b-blocker-induced

LDE literature, the most common sites affected were the limbs

back,trunk, and oral mucosa (table III). Cases involving the hand

and feet had mixed dorsal and palmar/ plantar involvement.[10,14,15

Although mucosal involvement in LDE is reported as rare in

dermatology textbooks, oral lesions were noted in our case a

well as in five other case reports. Also, a further two report

cited penile lesions.[9,11] In total, half of the b-blocker-induced

LDE literature with anatomic location descriptions had mu

cosal involvement. This is in line with a retrospective review tha

demonstrated an association of b-blocker use with mucosal li

chen planus.[24]

In a further study of the 19 patients attendinga cardiology clinic with oral lichenoid lesions, 14 were taking a

b-blocker medication.[25] In both studies it is difficult to ascertain

whether the lesions were drug induced or idiopathic in nature a

no data about response to medication cessation were described

2.3 Histology

Both LDE and ILP share many histologic findings such a

band-like, upper dermal T-lymphocyte infiltration, vacuola

basal cell layer degeneration, and saw-tooth-like rete ridges. [26

Although there is not a feature that is pathognomonic, a number

of features are associated with LDE. A small comparative his

tology analysis of 15 cases of ILP and LDE (eight of which wer

duetoa b-blocker) found that focal parakeratosis, interruption o

the granular layer, and cytoid bodies in cornified and granula

layers occurred in >50% of LDE cases while never occurring in

Table I. Adverse cutaneous reactions associated with b-blockers[1,2]

Psoriasiform eruption

Eczematous eruption

Lichenoid eruption

Xerosis

Lupus erythematous

Alopecia

Hyperpigmentation

Raynaud phenomenon

Toxic epidermal necrolysis

Peyronie disease

Scalp tingling

Table II. Number of lichenoid eruptions associated with specific b-blocke

medications

b-Blocker Number of lichenoid eruption

Atenolol[3,5-7] 9

Propanolol[3,6,8,9] 4

Labetalol[10-12] a 4

Pindolol[7] 3

Levobunolol[13] 2

Metoprolol[7,14] 2

Sotalol[15] 1

Acebutolol[16] 1

Timolol[17] 1

Nebivolol[18] 1

Oxprenolol[19] 1

a Our case report has been included.

Lichen Planus-Like Drug Eruptions Due to b-Blockers 41




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-

travasationof 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). Onlytwo 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]

The pathogenesis of b-blocker-induced LDE is unclear but i

may involve the blockade of b-adrenoreceptors. The b2 sub

class of receptors is present on epidermal keratinocytes, Lang

erhans cells, and dendritic cells.[34] These cells also posses

pattern recognition receptors (PRR), whose role is to detec

pathogen-associated molecular patterns (PAMP). Rises in in

flammatory cytokines and antigen-specific plasmacytoid den

dritic cells necessary for the pathologic cascade of lichenoid

tissue reactions occur when skin is exposed to a non-selective

b-blocker and a peptidogylcan (a PAMP).[35] This suggests tha

the dermal adrenergic system may have a role in controlling the

T helper-1 response of pathogens that is recognized by th

PRRs and thus its blockade with a b-blocker may potentiall

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

cutaneous homeostasis and in the pathogenesis of a number o

inflammatory dermatoses.[36] In wound healing, the b-adre

nergic system influences extracellular signal regulated kinases

which in turn affect keratinocyte migration.[34] b-Adrenergi

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] Th

involvement of the cutaneous b-adrenergic system in multipl

dermal processes may also suggest a more complex pathogenesi

cascade in b-blocker-induced lichen planus.

3. Conclusion

LDE is a relatively rare complication associated with the us

of b-blocker medication. It may present as classic lichenoid

papules that are indistinguishable from lichen planus and has a

Table III. Anatomic location of b-blocker-induced lichenoid drug eruption

cases

Anat omic loca tion of lesions Number of ca sesa

Arms 9

Legs 9

Trunk 6

Mouth 6

Back 4

Hands 3

Generalizedb 2

Feet 2

Face 2

Genital region 2

Nail involvement 1

Scalp 1

Neck 1

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 hasbeen included in thetable.On subsequentreview,

the distribution was described as generalized.

Table IV. Histologic features of b-blocker-induced lichenoid drug eruptions

Histologic feature Number of cases

Extension of infi ltrate 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. Th

histologic studies were excluded, as it was not possible to clearly defin

the findings of the b-blocker case. The Mullins et al. [17] paper was als

excluded as the histology findings related to the initial dorzolamide

induced lichen planus-like drug eruption.

420 Fessa et a




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, deepperivascular 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 aredirectly 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: [email protected]

Lichen Planus-Like Drug Eruptions Due to b-Blockers 42


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Lichen Planus-Like Drug Eruptions Due to B-Blockers