Clinical review'

Lichenoid drug eruptionsSima Halevy, MD, and Avi Shai, MD Beer-Sheva, Israel

Lichen planus-like or lichenoid eruptions from certain drugs and compounds can closelymimic idiopathic lichen planus. Thepatient's history and physical examination, histopatho­logic criteria, and certain tests can assist inthedifferentiation between a lichenoid drugerup­tionandidiopathic lichen planus andintheidentification oftheoffending drug. (J AM ACADDERMATOL 1993;29:249-55.)

Skin eruptions causedbycertain drugs and com­pounds can be identical or similar to lichen planus(LP). The terms Ll'-like or lichenoid describethesereactions. The list of drugs that can produce alichenoiddrug eruption (LDE) is longand becomessteadily longer.

Because LDE can resemble idiopathic LP clini­cally and histopathologically, it is not always possi­ble to conclude that LP or a lichenoid eruption hasbeen induced by a drug. Furthermore, the identifi­cation of the offending drug can be complicated byfactors such as simultaneous exposure to severaldrugs, drug interactions, andvariabilityinthe latentperiod between intake of a drug and appearance ofthe eruption.

IDENTIFICATION OF LDE BY HISTORY: AFEW GUIDELINES

The occurrence rate of LDE for certain drugs

Inducers of LDE are presented in Tables11-75andII.76-86 Skin reactionsinducedby gold are commonand include cutaneousaswell as oral lichenoid reac­tions.I-5 Penneys et a1.2 reported on 37 patients inwhom an eruption developed duringgoldtreatmentfor rheumatoid arthritis. A lichenoid eruption wasobserved in 11 of these patients.

Antimalarial agents are inducers of an LDE.Many American troops in Southeast Asia duringWorld War II were affected by these drugs." Qui­nine and quinidine are alsocommoninducers of anLDE.IO-15

Fromthe DepartmentofDermatology, SorokaMedical Centerof Ku­pat Holim,FacultyofHealthSciences, Ben-Gurion University oftheNegev.

Reprint requests: S. Halevy, MD,Dept.ofDermatology, SorokaMed­ical Center,P.O. Box 151, Beer-Sheva 84101, Israel.

Copyright® 1993 by the American Academy of Dermatology, Inc.

0190-9622/93 $1.00 +.10 16/1/47018

A high incidenceof LDE from penicillaminehasbeen reported by Powellet a1. 18 Of 131 patients withprimary biliary cirrhosis who receivedthe drug, 17(12.9%) had typical LP lesions. Six other patientsfrom a group of 70 (8.6%) with primary biliary cir­rhosis, who were treated with penicillamine, werereported by Seehafer et a1. 19

Other drugs with a relativelyfrequent associationwith an LDE are the thiazide diuretics22-24 and,B-adrenergic blocking agents.26-30

Age of patients with LDE and idiopathic LP

The mean age of patients with LP was reportedby Fellner'? and by Halevy and Feuerman'f to be 47and 49 years, respectively. In a multicenter study of577 patients with LP, the mean age was 50 years.89

For LDE, the mean age of 13 patients reported byWest et a1.23 was 57 years.In our study of 17 patientswith LDE, the mean age was 66 years (S. Halevy,unpublished data).

Latent period

For most drug eruptions, the latent period be­tween the beginningof administration of a drug andthe appearance of the eruption is about 1 or 2weeks,90 or up to 1 month.?! For LDE, the latentperiod seems to be longer. In 17 patients with LDEinducedby a variety ofdrugs,the mean latent periodwas 12 months (S. Halevy, unpublished data). Thelatent period for LDE has been reported to bebetween2 months and 3 yearsfor penicillamine,18,19approximately 1 year for ,B-adrenergic blockingagents,26 and 3 to 6 months for angiotensin-convert­ing enzyme inhibitors.33 In LDE induced byquinacrine,a shorter latent periodof 4 to 6weekshasbeen reported.'

The latent period is dependent on the offendingdrug but other factors may alsoplaya role in deter­mining its duration, that is, the dosage of the drug,

249

250 Halevy and Shai

Table I. Inducers of LDE

• Gold salts1-5• Antimalarials

Quinacrineand chloroquine'e?Quinineand quinidine'P''>Pyrimetharnine'f-!?

• Penicillaminel8-2lDiuretics

Thiazidediureticszz-z4Furosemidel-PSpironolactonee

Antihypertensive agents• ~-Adrenergic blocking agents26-30

Angiotensin-converting enzymeinhibitorsCaptopril and enalapril3l-35

Methyldopa36-38Diazoxide'?

Calcium channelblockersNifedipine'?Cinnarizine"Flunarizinef

Phenothiazine derivatesMetopromazine and levomepromazine43Chlorpromazine'f

Sulfonylurea hypoglycemic agentsChlorpropamide and tolazamide45-47

Nonsteroidal antiinflammatory drugs48-5lSulfasalazine and Mesalazine-?Antituberculardrugs

Ethambutol-'p-Amino salicylic acid1,54, 55

Isoniazide1•55Streptomycin's

Antifungal drugsKetoconazole'?

Chemotherapeutic agentsHydroxyurea'?5-Fluorouracil58

Heavy metalsMercurials'?Arsenicals'"Bismuth''!

Miscellaneous drugsTetracycIines62•63

Carbamezepinesv'sProcainamide'fAllopurinol''?Pyritinol68

Iodides and radiocontrast media6.69Tiopronin (mercaptopropionylglycine)70,71Lithium carbonate"CyanamidefDapsonel-?"Amiphenazole/>

• Common inducers of LDE.

the patient's individual reaction to the drug, andtreatment with other drugs. The latent period maybe shortened significantly if the patient has beenpreviously exposed to the offending drug."

Journal of the American Academy of DermatologyAugust 1993

Table II. Inducers of LDE by contact

Colorfilm developers's 22. 76-78PPDA (p-phenylenediamine)IPPD (p-isopropylaminodiphenylamine)CD2CD3TTS (4-amino-N-diethyl-aniline sulfate)Antimony trioxide

Dental restorative materials79-82Musk ambrettefNickel84Aminoglycoside antibiotics'fGold86

Resolution of LDE

Variable lengths of resolution have been reportedfor LDE. As with the latent period, the resolutiontime may depend on the offending drug, but otherfactors may also be significant. Moreover, there is nouniform terminology in the literature to denote thestage of resolution. Different stages of resolution(initial stage, complete resolution) can be found insome articles under the general title of "resolution,"without a specific description. Inducers of LDE andthe reported resolution period are presented in Ta­ble III.

Penneys et al.? concluded that in dermatitisattributed to gold salts, the resolution time dependslargely on the severity and extent of the eruption.Most gold-induced eruptions, including the 11 pa­tients with LD E in that study, cleared within 3 to 24months.

Certain lichenoid eruptions tend to disappear or toappear intermittently, if the offending drug is notdiscontinued. Seehafer et al.'? described two pa­tients who continued the administration of penicil­lamine and had lichenoid lesions intermittently.Anderson10 described the slow disappearance of li­chenoid eruptions caused by quinidine, which lasteda few months despite continuing administration ofthe drug. Therefore it is likely that in some cases ofLDE, withdrawal of the drug is not always neces­sary, especially if its abrupt withdrawal mightendanger the patient.

LDE induced by contact with drugs andchemicals

Inducers of LDE by contact are presented in Ta­ble II.

Two types of reactions are observed after contactwith color film developers: (1) lesions of classic LPinduced by continuous exposure to small amounts of

Journal of the American Academy of DermatologyVolume 29, Number 2, Part I

Table III. Inducers of LDE: Resolution periodafter discontinuation of the offending drug

Halevy and Shai 251

Table IV. Drugs that induce photodistributedLDE

Drug

Short durationLabetalol-?Tolazamide"?Cyanamide-'Long durationPenicillamine'< !9Hydrochlorothiazide24Spironolactone"Propranolol-?Captopril32,35Flunarizinet­QuinidineI3-15,*Gold2

Resolution PEriod

Up to 1 mo2wk3 wk

1-4mo2.5 mo3 mo4mo1-2mo2moUp to 5 mo3-24 mo

Quinine, quinidine'Pf>Thiazide diuretics and furosemide!,22-24Diazoxide'?Tetracyclines62,63Ethambutol'!Chlorpromazine' ?Carbamazepine'"5-Fluorouracil'sPyritinol68

Table V. Drugs that induce oral involvement inLDE

*For quinidine, resolution began within 2 weeksafter drugwithdrawal.Complete resolutionhas been reportedto occur within 2 to 5 monthsafter drug withdrawal.

the offending agent and (2) lichenoid lesions withtypical findings of contact dermatitis, inducedby asingle, but much larger, acute exposure." Patchtests performed with the offending compounds areusually positive.v 22

The topical use of dental restorative materialsmay alsogiverise to an oral LDE.79-82 This appearsto be related to the mercury content, althoughothercomponents (especially metals) cannot be excluded.Positive patch test reactions to dental restorativematerial were produced in 21 % of 24 patients withlichenoidoral lesions, compared with 8%of 12con­trols.82Similar observations have been reportedbyMobacken et al.8! and by Lundstrom.r? In the laststudy, replacement of amalgam fillings in eight pa­tients with lichenoidoral lesions and positive patchtests to dental restorativematerials werefollowed bymarked clinical improvement in six patients.

PHYSICAL EXAMINAnON

In general, there are no specific morphologic cri­teria for the diagnosis of a drug eruption. However,the morphology, location, and pattern of an LDEmay aid in its diagnosis.

Morphology of LDE

Lesions of LDE can be similar to those ofidiopathic LP or have an atypical appearance. AnLDE may have eczematous papules and a general­ized eczematousskin reactionwith marked desqua­mation.' Lesions of LDE are considered to be morepsoriasiform and larger than lesions of idiopathicLP.22 Wickham's striae are usually, but not always,

Nonsteroidal antiinflammatory drugs48,50

Gold salts"Penicillamine'f-19Sulfonylurea hypoglycemia agents45,47Angiotensin-converting enzyme inhibitors34Methyldopa"Allopurinol'"KetoconazolefCyanamide"Dental restorative materials79-82

absent in lesions of LDE.! A greater tendencytoward residualhyperpigmentation has been notedin LDE.! Severe alopecia can accompany LDE be­causeoffollicular involvement. In some patientsde­creasedsweatproduction can alsooccur; atrophyofthe dermal portion of the sweat duct has beenobserved in these cases," Sulzberger et a1.9 de­scribed two patients with an LDE caused byquinacrinethat was associated withhair loss and at­rophy of sweat glands.

Location of LDE

Idiopathic LP has a predilection for the flexor as­pect of the forearms and the legs. Moreover, a pho­todistributedpattern in idiopathic LP (with the ex­ception of LP actinicus'") is not likely. However,LDE usually appearsasasymmetric eruption onthetrunk and extremities.I A photodistributed patternis found in a highpercentage of cases.22Drugs thatproduce photodistributed LDE are listed in TableIV.

In idiopathic LP, the incidence of mucous mem­brane involvement approaches 70% in some series."Involvement of theoral mucosa in LDE isless com­mon than in idiopathic LP.l It may occur with orwithout cutaneous involvement. Drugs that induceoral LDE are listed in Table V.

252 Halevy and Shai

Special patterns of LDE

A few case reports have described unique LDEs.The occurrence of LP pemphigoides and LP pern­phigoides-like lesions after the administration ofcaptopril and cinnarizine, respectively,was reportedby Flageul et a1,31 and by Miyagawa et al.41 Grun­wald et al.69 reported bullous LDE related to the useof a radiographic contrast material. This form ofLDE has also been reported by Gange and Jones'?for labetalol and by Hsiao et al.70 for tiopronin (a­mercaptopropionylglycine). Gold therapy has beenassociated with LP pigmentosus." Nifedipine wasreported as the inducer of exfoliative dermatitis withlichenoid features .f Ulcerative LDE has been asso­ciated with the administration of hydroxyurea.Fmethyldopa.P propranolol.P and lithium carbon­ate. 72

HISTOPATHOLOGIC FEATURES

The histopathologic pattern ofLDE lesions can beindistinguishable from idiopathic LP. The "classi­cal" histopathologic findings that are indicative ofLDE are eosinophils and plasma cells in the cellularinfiltrate, focal parakeratosis, and an infiltratearound deep vessels."

Van den Haute et al.28analyzed 15 patients withidiopathic LP and 15 patients with LDE. No histo­pathologic feature was found to be a statisticallysignificant criterion to differentiate LDE from idio­pathic LP. However, although all the histologic fea­tures of idiopathic LP could be seen in LD E, certainfindings that were present in more than 50% of LD Enever occurred in idiopathic LP . These are (1) focalparakeratosis, (2) focal interruption of the granularlayer, and (3) cytoid bodies in the cornified andgranular layers. In addition, eosinophils were notobserved in idiopathic LP but were found in 2 of 15patients with LDE. Other features that were morecharacteristic of LDE than of idiopathic LP wereatrophy of the epidermis, exocytosis of lymphoidcells into the upper epidermal layers, and an infil­trate around deep vessels.28

A recent histopathologic study conducted byWest et a1.23 revealed that photodistributed LDEtends to bear more resemblance to idiopathic LPthan to nonphotodistributed LDE. No significantdifferences in immunofluorescence staining pat­terns were found between LDE and idiopathic LP,which suggests that common mechanisms are in­volved.t"

Journal of the Amer ican Academy of DermatologyAugust 1993

IN VIVO AND IN VITRO TESTS FOR LDE

In vivo tests: Withdrawal and challenge tests

In LDE, similar to other forms of drug eruptions,withdrawal of a suspected drug followed by disap­pearance of the lichenoid eruption may confirm thediagnosis . However, as mentioned before, disap­pearance of certain LDEs has been documented ina few cases when the offending drug was not discon­tinued. l'' 19

Reexposure of a patient with a drug eruption toa suspected drug can be dangerous. Therefore chal­lenge tests are not generally recommended." How­ever, a challenge test can be confined only to the skinas a patch test, in cases of LDE caused by contactwith color film developers. v 22, 76 dental restorativematerials,80-82 nickel salts,84 and aminoglycosideantibiotics.P

Attempts have been made to use patch tests notonly for contact LDE, but also for the usual LDE.Kurumaji and Miyazaki" described a patient inwhom LDE developed after 2 years' treatment withtiopronin. Patch testing revealed positive reactionsnot only to tiopronin but also to captopril andn-penicillarnine, neither of which had ever beentaken by the patient. It has been suggested that thesulfhydryl groups these drugs contain playa role inthe pathogenesis of LDE. Negative patch test resultswere obtained in patients with LDE from ethamb­utol,53 chlorpromazine.f and carbamazepine.v' Forthe last two drugs, photopatch test results were pos­itive.44, 64

In vitro tests

Haim et al. 15 reported the case of a patient withphotodistributed LD E caused by quinidine, in whomboth leukocyte migration inhibition factor (LIF)and lymphocyte transformation tests, in the pres­ence of the offending drug, were negative.

Halevy et a1.24 used the macrophage migrationinhibition factor (MIF) test to identify hydrochlo­rothiazide as an inducer of a photodistributed LDE.Grunwald et al.69 described a patient with bullousLP after intravenous pyelography in whom an MIFtest to the radiocontrast medium was positive. Wolfet a1. 14 reported the cases of four patients with qui­nidine-induced LDE. In three the MIF test waspositive to quinidine, and a false-negative reactionwas found in the other. A recent controlled studyconducted by Halevy et al.95 indicated that the MIFtest for drugs can assist in the evaluation of various

Journal of the American Academyof DermatologyVolume 29, Number 2, Part I

types of drug eruptions (including LDE) and in theidentificationof the offending drug(s). MIF, a lym­phokinereleasedfrom sensitized lymphocytes by anappropriate antigen, correlated well with cellularimmunity in animal models and in humans.96-98 Itmay be that a drug-specific cellular immune re­sponse possibly plays a role in the pathogenesis ofLDE. However, it is possible that positive MIF re­sponses in drug eruptions (including LDE) reflectsecondary immunologic hypersensitivity"

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