Clinical Profile of Patients with Lichenoid Drug Eruption: A Observational Study

Abstract

Background:

Lichenoid drug eruption (LDE) is an uncommon cutaneous adverse drug reaction, where a variety of drugs used in day-to-day clinical practice have been implicated.

Objective:

To describe the clinico-demographic characteristics of patients with LDE and to identify the most likely drugs involved.

Methods:

In this prospective, observational study, consecutive patients with LDE presenting to the dermatology department of a tertiary teaching hospital were included. The clinico-demographic profile of patients with LDE and implicated drugs was noted. Treatment of drug reaction along with outcome was also documented. Naranjo adverse drug reaction probability scale was used for causality assessment of the drug reactions. A thorough literature review on LDE was also undertaken due to the paucity of existing literature.

Results:

A total of 15 patients (11 males and 4 females) with LDE were evaluated. Their age ranged from 37 to 61 years, with a mean of 51.53 ± 7.59 years. Anti-hypertensive medications (40%) were the most common culprit agent, followed by antitubercular drugs (33.4%), anti-diabetic agents (13.3%), and others (13.3%). The latent period (time from drug initiation to the appearance of a cutaneous eruption) varied from 15 days to 6 months (mean 2.2 months). Cutaneous involvement was generalized in 73.4% and photo-distributed lesions in 26.6%. Drug provocation test was done to identify the culprit drug. According to the Naranjo adverse drug reaction probability scale, one-third of LDEs were “definite,” whereas two-thirds were designated as “probable.”

Conclusion:

LDE is more common in the elderly population. The latent period is comparatively longer in LDE than in other common drug reactions. Prompt recognition and withdrawal of suspected drug are essential to minimize disease morbidity.

Introduction

Cutaneous adverse drug reactions (CADR) are commonly encountered in day-to-day clinical practice, with an incidence of 2–3% among all adverse drug reactions.[1] Physicians, spanning different specialities, come across many instances of suspected CADR in different clinical forms. Lichenoid drug eruption (LDE) is one such uncommon presentation of CADR. This accounts for 0.38–2.83% of all reported CADR.[2,3] There exists a dearth of studies on LDE, with only a few case series and scattered case reports documented in the literature till date,[4,5] which prompted the present undertaking. The present study aimed to evaluate the clinico-epidemiological characteristics and causative drugs in patients with LDE.

Methods

This observational study was carried out over a period of 3 years (December 2018–2021) in a tertiary care hospital in eastern India after approval from the institutional ethics committee was obtained. Written informed consent was obtained from all participating individuals, and the study was conducted in accordance with the principles of the Helsinki Declaration. Consecutive patients with clinical and corroborative histopathological features consistent with LDE were included in this study. A detailed history including current and/or prior medication and clinical examination was carried out in all subjects. Routine laboratory investigations including complete hemogram, liver function test, fasting blood sugar, urea, creatinine, viral markers for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and skin punch biopsy from the active lesional site for histopathological analysis were done in all clinically diagnosed cases. Suspected cases that showed histopathological features other than LDE were eventually excluded. In histologically confirmed cases of LDE, a drug provocation test (DPT) was done after symptom resolution in an inpatient setting to identify the culprit drug. Casualty assessment was done using Naranjo probability scale.

Data on clinico-demographic characteristics, relevant medical and drug histories, histopathological findings, treatment, outcome, result of DPT, and implicated culprit drug was recorded in a pre-tested, semi-structured schedule. Statistical analysis was done using GraphPad Prism version 5 (GraphPad Software Inc., San Diego, CA, USA; 2007) software and Microsoft Excel.

Results

During the study period, 21 patients presented with suspected LDE. Among them, histopathology was suggestive of lichen planus (2), lichen planus pigmentosus (1), and pityriasis rosea (1), while another patient refused consent for a biopsy. These patients were subsequently excluded from further analysis.

Demographic features

A total of 15 patients with LDE (age range 37–61 years; mean 51.53 years; SD7.59) were evaluated. Eleven were male and the rest were female, with a male-to-female ratio of 2.8:1 [Table 1].

Table 1.

Clinical profile of patients with LDE

Age/sex	Comorbidities	Ongoing medication	Symptoms	Onset (months)	Site	Clinical morphology	DPT with	Culprit drug	Treatment	Time to resolution (weeks)
60/M	Hypertension Diabetes mellitus	Metformin Amlodipine Losartan	Pruritus	3	Generalized	Coalescing papule and plaques	Metformin Amlodipine Losartan	Losartan	Clobetasol propionate (0.05%) cream and oral antihistaminic. Losartan was replaced with atenolol	1
61/M	Hypertension Diabetes mellitus	Metformin Enalapril	Pruritus	3	Photo distributed over face and extensor forearms	Coalescing papule and plaques	Metformin Enalapril	Enalapril	Mometasone furoate (0.1%) cream, sunscreen lotion and oral antihistaminic Enalapril was replaced with amlodipine	2
52/M	Hypertension	Amlodipine	Pruritus	1	Photo distributed over dorsum of both hands and extensor forearms	Coalescing lichenoid and eczematous plaques	Amlodipine	Amlodipine	Clobetasol propionate (0.05%) cream, sunscreen lotion and oral antihistaminic Amlodipine was replaced with telmisartan	1
53/F	Hypertension	Hydro chlorothiazide Losartan	Pruritus	6	Photo distributed over back and extensor forearms	Coalescing lichenoid and eczematous plaques	Hydro chlorothiazide	Hydro chlorothiazide	Clobetasol propionate (0.05%) cream, sunscreen lotion and oral antihistaminic Hydrochlorothiazide was replaced with losartan	2
47/F	Hypertension	Amlodipine	Pruritus	5	Generalized	Coalescing papule and plaques	Amlodipine	Amlodipine	Clobetasol propionate (0.05%) cream and oral antihistaminic Amlodipine was replaced with losartan	2
43/M	Hypertension	Amlodipine Enalapril	Pruritus	1	Generalized	Coalescing papule and plaques	Amlodipine Enalapril	Enalapril	Clobetasol propionate (0.05%) cream and oral antihistaminic Enalapril was replaced with atenolol	2
55/F	Pulmonary tuberculosis	Isoniazid Rifampicin Pyrazinamide Ethambutol	Pruritus	3	Generalized	Coalescing papule and plaques	Isoniazid Rifampicin Pyrazinamide Ethambutol	Ethambutol	Clobetasol propionate (0.05%) cream and oral antihistaminic ATD stopped, later started sequentially And found Ethambutol culprit agent which was re-started at lower doses	3
59/M	Tuberculous pleural effusion	Isoniazid Rifampicin	Pruritus	1	Generalized	Lichenoid plaques over the trunk and Psoriasiform	Isoniazid Rifampicin	Rifampicin	Clobetasol propionate (0.05%) cream and oral antihistaminic ATD stopped and later started	4
		Pyrazinamide Ethambutol				plaques over the extremity			sequentially and rifampicin given at lower doses
58/M	Pulmonary tuberculosis	Isoniazid Rifampicin Pyrazinamide Ethambutol	Pruritus	1	Generalized	Lichenoid and eczematous plaques	Isoniazid	Isoniazid	Clobetasol propionate (0.05%) cream and oral antihistaminic ATD stopped and later started sequentially and isoniazid given at lower doses and later full dose	3
50/M	Pulmonary TB	Isoniazid Rifampicin Pyrazinamide Ethambutol	Pruritus	2	Generalized	Coalescing papule and plaques	Isoniazid Rifampicin Pyrazinamide	Pyrazinamide	Clobetasol propionate (0.05%) cream and oral antihistaminic ATD stopped and later started sequentially and pyrazinamide given at lower doses	2
56/M	Pulmonary TB	Isoniazid Rifampicin Pyrazinamide Ethambutol	Pruritus	1	Generalized	Coalescing papule and plaques	Isoniazid Rifampicin Pyrazinamide	Pyrazinamide	Clobetasol propionate (0.05%) cream and oral antihistaminic ATD stopped and later started sequentially and pyrazinamide given at lower doses	3
40/M	Diabetes mellitus	Metformin Glimepiride	Pruritus	1	Generalized including oral mucosa	Coalescing papule and plaques	Metformin Glimepiride	Glimepiride	Clobetasol propionate (0.05%) cream, triamcinolone acetonide oral paste (0.1%) and oral antihistaminic Glimepiride was replaced with vildagliptin	2
57/M	Diabetes mellitus Hypertension	Metformin Vildagliptin Losartan	Pruritus	2	Generalized	Coalescing papule and plaques	Metformin Vildagliptin	Vildagliptin	Clobetasol propionate (0.05%) cream and oral antihistaminic Vildagliptin was replaced with voglibose	3
37/M	HIV	Tenofovir Lamivudine Nevirapine	Pruritus	2	Generalized including oral mucosa	Coalescing papule and plaques	Tenofovir	Tenofovir	Clobetasol propionate (0.05%) cream, triamcinolone acetonide oral paste (0.1%) and oral antihistaminic ART stopped and later started sequentially; tenofovir was replaced with zidovudine	2
45/F	Nil	Naproxen	Pruritus	15 days	Photo distributed over face and extensor forearms	Coalescing papule and plaques	Naproxen	Naproxen	Mometasone furoate (0.1%) cream and oral antihistaminic Naproxen was withdrawn	2

M=Male; F=Female; HIV=Human immunodeficiency virus; ATD=Anti-tubercular drug; DPT=Drug provocation test; TB=Tuberculosis; ART= Antiretroviral therapy

Latency and clinical characteristics

The latent period from ingestion of the culprit drug to the appearance of LDE ranged from 15 days to 6 months (mean 2.2 months, SD 1.59).

Pruritus was the most common complaint (100%). The drug eruption was generalized involving the trunk, face, and extremities in 11 patients (73.4%) [Figure 1]. Photo-distributed lesions involving the extensor forearms, dorsal hands, and upper back were present in four patients (26.6%) [Figure 2]. On cutaneous examination, coalescing lichenoid papules and plaques were present in all patients (100%) [Figures 3-6]. Lichenoid and eczematous lesions were noted in three (20%) patients, and one (6.7%) patient had lichenoid and psoriasiform lesions. Two patients (13.3%) had oral mucosal involvement. Hair, nails, and genital mucosa were not involved in any of these patients. Systemic affliction was not documented in any individual.

Figure 1.

Hydrochlorothiazide induced LDE. Coalescing violaceus papules and plaques photo distributed over extensor forearm (a) and upper back (b). Enalapril induced LDE. Coalescing violaceus papules and plaques distributed over face (c)

Figure 2.

Losartan induced generalized lichenoid eruption involving trunk and extremity (a, b, and c). Amlodipine induced photo distributed LDE dispersed over the dorsum of both hands and extensor forearms (d)

Figure 3.

Rifampicin induced generalized LDE presenting as coalescing lichenoid plaques with koebnerization over trunk and extremity (a and b). Psoriasiform plaques were present in both legs of the same patient (c)

Figure 6.

Glimepiride induced LDE. Multiple discrete and coalescing violaceus papules, plaques, and hyperpigmented patches distributed over the trunk and extremity

Figure 4.

Pyrazinamide induced generalized LDE presenting as coalescing violaceus papules and plaques distributed over trunk and extremity (a and b) generalized LDE due to isoniazid. Coalescing violaceus and eczematous plaques distributed over trunk and extremity (c)

Figure 5.

Tenofovir induced generalized LDE presenting as coalescing violaceus patches and plaques over trunk and extremity (a and b)

Hypertension was the most common concomitant ailment present in seven patients (46.7%), followed by tuberculosis (5, 33.3%), diabetes mellitus (4, 26.7%), and HIV infection (1, 6.7%).

Evaluation

No significant alteration in biochemical parameters was noted on routine laboratory evaluation. A transient elevation of hepatic enzymes was observed in two patients, which reverted to the normal limit in a fortnight. On histopathological examination, parakeratosis, vacuolar interface dermatitis with dense band-like lymphocytic dermal infiltration obscuring the dermoepidermal junction, and a variable presence of eosinophils were noted [Figure 7].

Figure 7.

Histopathological examination from lesion showing hyperkeratosis, focal parakeratosis basal cell degeneration with upper dermal band-like infiltrate comprising mononuclear cells, multiple colloid bodies in the upper epidermis, melanin incontinence, and sparse deep dermal perivascular infiltration

Treatment and symptoms resolution

Suspected drug/drugs were withdrawn after consulting with the treating physician. Cutaneous lesions over the trunk and extremities were treated with potent topical corticosteroids cream (clobetasol propionate 0.05% cream), over the face with midpotent topical corticosteroid (mometasone furoate 0.1% cream), in the oral mucosa with triamcinolone acetonide (0.1%) oral paste, along with emollient, sunscreen lotion, and oral antihistaminic. The median time to complete symptoms resolution was 2.2 weeks overall (range: 1–4 weeks).

Drug provocation test and drug causality assessment

DPT was performed in all patients after informed written consent in an inpatient setting after a drug-free washout period of at least 5 elimination half-lives of the suspected drug or at least 4 weeks after the drug reaction, whichever is longer. DPT was performed with the reintroduction of the suspected drug initially at one-fourth of the recommended dose, with a doubling of the dose every 3 days, until the full therapeutic dose was reached or an adverse drug reaction occurred, whichever came first. In a patient with multiple concomitant medications, suspected drugs were challenged one by one, starting at one-fourth of the recommended dose, with a doubling of the dose every 3 days, until the full therapeutic dose was reached or an adverse drug reaction occurred, and subsequent drugs were reintroduced once a patient tolerated the full dose of the first drug with no adverse event. After identification of the culprit drug, depending on the patient’s severity of the drug reaction, it was re-started at lower doses very carefully or withdrawn completely as per the treating physician’s discretion.

Classification of LDE according to the Naranjo adverse drug reaction probability scale showed all 15 (100%) adverse drug reactions as “definite.”

Implicated pharmacological agent

Anti-hypertensive drugs were the most common (6, 40%) culprit drug causing LDE. The medications implicated under this category included calcium channel blockers—amlodipine (2, 13.3%), angiotensin converting enzyme inhibitors—enalapril (2, 13.3%), angiotensin II receptor antagonist—losartan (1, 6.7%), and hydrochlorothiazide (1, 6.7%).

Anti-tubercular drugs (ATDs) (33.3%) were the second most common group. Pyrazinamide was the causative agent in two (13.3%) patients. Rifampicin, isoniazid, and ethambutol were implicated in one (6.7%) patient each. The anti-diabetic medications glimepiride and vildagliptin resulted in LDE in one (6.7%) patient each. In one HIV-infected patient (6.7%), tenofovir was found to be the culprit agent.

Discussion

LDE is an infrequent CADR that was first reported to be caused by arsenic and was used for syphilis treatment dated in 1929.[5] Since then, ingestion, contact, or inhalation of numerous drugs have been implicated in causing this drug reaction. LDE has been frequently associated with gold, antimalarials, antihypertensives, NSAIDs, proton-pump inhibitors, anti-diabetics, anti-tuberculars, TNF-α inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, and biological agents.[6,7,8] Although the mechanism of LDE is not fully understood, it has been hypothesized that cross-reactivity between the drug and keratinocytes both acting as antigens, leading to T cell-mediated autoimmune damage of basal keratinocytes. A more vital role of CD8+ cells, plasmacytoid dendritic cells, and granzyme B-containing cells has been hypothesized in the pathogenesis of LDE.[4,5] Clinically most of the time, it is very difficult to differentiate LDE from idiopathic lichen planus. However, more generalized symmetric distribution, the tendency to involve photo-distributed sites sparing classic flexural sites of idiopathic LP, more eczematous or psoriasiform morphology, and absence of Wickham’s striae favor the diagnosis toward LDE.[9] Although idiopathic LP and LDE share many histopathological similarities, the presence of varying degree of eosinophilic infiltrates, focal parakeratosis and focal interruption of granular layer, cytoid bodies in cornified, granular and upper spinous layer, and deep perivascular infiltrate differentiate LDE from lichen planus.[10] Apart from corroborative clinical findings and histopathological features, temporal intake of drug history, regression of lesions after withdrawal of the offending drugs, and reappearance of similar lesions during drug provocation tests substantiate the diagnosis of LDE.

The demographic data of our patients showed that their age ranged between 37 and 61 years, with most patients (66.67%) being above 50 years old. Similar to the present study, Halevy et al.[5] and Akbas and Kilinc[11] also noted that LDE is more common in the fifth decade of life onwards. Age-related physiological decline of renal and hepatic functions, presence of concomitant disease, use of multiple drugs, and drug interaction may explain the increased rate of drug-related adverse events in the relatively more advanced age group. In contrast to a previous study by Akbas and Kilinc,[11] male preponderance was noted in our study. The relatively higher prevalence of tuberculosis, type 2 diabetes mellitus, and hypertension with the use of multiple drugs may facilitate more drug reactions in men.

In LDE, the time interval from the introduction of the offending drug to the appearance of a cutaneous eruption tends to be much longer than in other drug reactions. Similar to previous findings, the latent period in the present study ranged from 15 days to 6 months, with the most common latent period documented between 1 and 3 months. (80%) In the present study, a maximum latent period was noted with hydrochlorothiazide (6 months) and amlodipine (5 months). In contrast to the previous study by Akbas and Kilinc,[11] pruritus was present in all patients (100%). In the present study, LDE was noted to be generalized in 73.4% of patients. This is in discordance with the previous observation by Akbas and Kilinc,[11] where generalized LDE was present in 37.5% of patients.

Similar to previous study findings, no hair, nail, or genital mucosa involvement was noted in the present study. However, two patients (13.3%) had oral mucosa involvement, where rifampicin and isoniazid were found to be the culprit drugs. Apart from lichenoid papules and plaques, LDE may consist of eczematous, psoriasiform, or pityriasis rosea-like morphology. In the present study, lichenoid plaques with eczematous lesions were found in 20% of patients. Cessation of the offending drug along with topical steroids led to the resolution of lesions in all patients within 1–4 weeks. However, variable resolution time ranging from 2 weeks to 2 years has been reported for LDE. This variable resolution period depends on the offending drug, patient age, concomitant diseases, and other drug intake.

A drug provocation test was done very vigilantly in all patients of the present study to identify the culprit drug. After identification of the culprit drug, depending on the patient’s severity of the drug reaction, it was re-started at lower doses very carefully or replaced with another drug according to the treating physician’s advice. In the present study, anti-hypertensive drugs (40%) were the most common group of drugs causing LDE. Among them, enalapril and amlodipine were the most common offenders. This is similar to the previous case series by Akbas and Kilinc,[11] where amlodipine was the most common culprit drug among antihypertensive medications. Similar to the previous case report by Kanwar et al.,[12] an enalapril induced photosensitive lichenoid eruption was noted in one (6.7%) of our patients. In discordance with the previous case report by Ruiz et al. and Firth and Reade, no mucosal involvement was documented in patients with enalapril induced LDE in the present study.[13,14] Similar to the previous case report by Halevy et al.,[15] lichenoid photosensitive eruption induced by hydrochlorothiazide was documented in one (6.7%) patient. Among angiotensin receptor blocker, telmisartan has been reported to cause LDE.[16] However, losartan induced LDE as found in one of our patients (6.7%) has not been documented so far.

ATDs (33.3%) were the next common group of culprit drugs in the present study. This is in contrast to the previous study by Akbas and Kilinc,[11] where ATDs were not implicated in any of the patients. Among ATD, pyrazinamide was found to be the most common offender. This is in concordance with the previous study by Tan et al.,[17] where pyrazinamide was the most common cause of CADR among ATDs. In concordance with the previous case report by Feng et al.,[18] rifampicin was associated with mixed lichenoid and psoriasiform lesions in one patient. LDE presenting as erythroderma due to ATDs has been reported by Katare et al.[19] However, none of our patients on anti-tubercular treatment presented with erythroderma.

Oral hypoglycemic agents including glimepiride, metformin, and chlorpropamide have been reported to cause LDE.[20,21] However, LDE due to vildagliptin, a dipeptidyl peptidase-4 inhibitor, as noted in one of our patients (6.7%), has not been reported in the literature till date. Similar to the previous case report by Woolley et al. and Gupta et al., tenofovir was associated with LDE in an HIV-infected patient.[22,23]

According to the Naranjo adverse drug reaction probability scale, all LDEs were “definite” (100%). This is in contrast to the previous study by Jadhav et al., where most of the reported CADR had a “probable” association.[24]

Limitations

Single-centre study and small number of patients are some of the limitations of the present study.

Conclusion

LDE can be induced by a variety of drugs used in daily clinical practice. Nowadays, numerous emerging drugs have also been reported to cause LDE. Longer latent periods and varied clinical presentations of LDE often pose a diagnostic dilemma. The treating physician should be aware of this relatively uncommon adverse drug reaction and consult a dermatologist for the management of the drug reaction.

Patient consent

Informed written consent has been directly obtained from the patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.