Version May 2024
INTRODUCTION — Lichenoid drug eruption, also called drug-induced lichen planus, is an uncommon, cutaneous adverse effect of several drugs [1-4]. It is characterized by a symmetric eruption of flat-topped, erythematous or violaceous papules resembling lichen planus on the trunk and extremities. The time interval between the initiation of the offending drug and the appearance of the cutaneous lesions varies from several weeks to a year or more and depends upon the class of drug, dose, host reaction, and concurrent medications [3]. Histologic examination reveals lichenoid interface dermatitis [5].
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of lichenoid drug eruptions. Lichen planus and other types of cutaneous adverse reactions to drugs are discussed separately.
●(See "Lichen planus".)
●(See "Exanthematous (maculopapular) drug eruption".)
●(See "Fixed drug eruption".)
●(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●(See "Acute generalized exanthematous pustulosis (AGEP)".)
●(See "Cutaneous adverse effects of conventional chemotherapy agents".)
●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)
EPIDEMIOLOGY — The incidence of lichenoid drug eruption is not known. It occurs more frequently in older adults, most likely related to the increased drug exposure with advancing age, without sex predilection. In small case series, the average age at onset was 44 to 66 years [6-8]. Lichenoid drug eruptions are exceedingly rare in children, with only a few cases reported in the literature [9-11].
ETIOLOGY AND PATHOGENESIS
Immunologic mechanism — The pathogenetic mechanism of lichenoid drug reaction is incompletely understood. T cells, keratinocytes, dendritic cells, and endothelial cells, which express activation markers, costimulatory molecules, and adhesion molecules (eg, MHC-class-II molecules, lymphocyte function-associated antigen [LFA] 1, L-selectin, intercellular adhesion molecule [ICAM] 1) are thought to be involved in the inflammatory reaction that ultimately leads to the apoptosis of basal keratinocytes [12].
Both CD4 and CD8 T cells are found at the dermoepidermal junction and within the epidermis. As in lichen planus, a persistent activation of CD8 autocytotoxic T lymphocytes against epidermal cells may be the crucial pathophysiologic factor [13]. Activated CD8 T cells induce the apoptosis of basal epidermal keratinocytes mainly through the perforin/granzyme B pathway [14,15]. These cells also produce type I and type II cytokines, such as interferon (IFN)-gamma and interleukin (IL) 5 [14-16]. IFN-gamma induces the expression of MHC-class-II molecules on keratinocytes and facilitates drug binding and presentation to CD4 T cells [12]. The stereotypical appearance of lichenoid drug reaction during immune checkpoint inhibitor therapies may underline the importance of T cell-triggered cytotoxicity [17,18].
Plasmacytoid dendritic cells are also thought to be involved in the early phase of lichenoid tissue reaction. They produce large amounts of type I IFN, such as IFN-alpha, which mediate the activation of IFN-gamma-secreting cytotoxic T cells directly or through the maturation of myeloid dendritic cells [19]. Tumor necrosis factor (TNF)-alpha and other inflammatory cytokines and chemokines are responsible for the amplification of the inflammatory response [20-23].
Medications — Cutaneous lichenoid eruptions have been associated with a broad variety of drugs (table 1), most frequently [2-4,6,9,17,18,24-37]:
●Angiotensin-converting enzyme (ACE) inhibitors
●Thiazide diuretics
●Antimalarials
●Beta blockers
●Gold salts
●Immune checkpoint inhibitors
●Tyrosine kinase inhibitors (eg, imatinib mesylate)
●TNF-alpha antagonists (eg, infliximab, adalimumab, etanercept)
Lichenoid eruptions involving the oral mucosa have been associated with [6,9,17,18,33]:
●ACE inhibitors
●Gold salts
●Nonsteroidal anti-inflammatory drugs (NSAIDs)
●Anticonvulsants
●Antiretrovirals
●Immune checkpoint inhibitors
In a systematic review of 49 reports (67 patients) of lichenoid drug eruptions associated with the use of biologic therapy, the most frequently implicated biologics were TNF-alpha inhibitors (78 percent), IL-1 inhibitors (9 percent), and IL-17A inhibitors (4.5 percent) [38]. The median time between biologic administration and lichenoid eruption was three months. Dupilumab-induced lichenoid and/or granulomatous-lichenoid eruptions in patients with atopic dermatitis may be explained by T helper (Th) 2 inhibition by dupilumab upregulation of Th1 pathways, which enhances Th1/Th17-dominated responses [39-41].
A papular, lichenoid eruption with histopathologic features of lichenoid interface dermatitis is one of the most common skin reactions reported in patients with cancer treated with antagonist antibodies to immunologic checkpoints (eg, nivolumab and pembrolizumab), programmed cell death ligand 1 (PD-L1; eg, atezolizumab, avelumab), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; ipilimumab) [17,24,33,42-46]. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)
It is assumed that programmed cell death protein 1 (PD-1), PD-L1, or CTLA-4 inhibition leads to impaired T cell homeostasis in the skin, thus facilitating such cytotoxic inflammatory reactions. In a study comparing the RNA expression profile in affected skin from five patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and five individuals with skin reactions while on anti-PD-1 treatment, both SJS/TEN and anti-PD-1-induced eruptions were associated with expression of PI3 (elafin), GZMB (granzyme B), and CXCL9-11 (a group of chemokines involved in T cell activation) [42]. Unlike SJS/TEN, however, skin reactions from anti-PD-1 therapy showed increased expression of CCL27, granulysin, FAS ligand, and perforin. These findings were unusual and contradicted previously published data.
Moreover, a lichen planus-like eruption has been reported following BNT162b2 (Pfizer-BioNTech) [47-51], mRNA-1273 (Moderna) [49], and ChAdOx1 nCoV-19/AZD1222 (University of Oxford-AstraZeneca) [49,52,53] coronavirus disease 2019 (COVID-19) vaccine administration. (See "COVID-19: Vaccines".)
Because lichen planus can be associated with several viral infections (eg, hepatitis B and C virus or varicella-zoster virus) and has also been reported following other vaccinations (especially hepatitis B virus, influenza, and herpes zoster vaccines), the differentiation from a lichenoid drug eruption is rather impossible [54].
There are several reports of lichenoid eruption associated with leflunomide and teriflunomide [10,55-58].
Contribution of ultraviolet irradiation — Photosensitive lichenoid eruptions have been reported in patients taking a variety of drugs, in particular [6,59-61]:
●Thiazide diuretics
●Tetracyclines
The action spectrum for these drugs appears to be in the ultraviolet B (UVB) wavelength range (290 to 320 nm) [61,62].
CLINICAL MANIFESTATIONS
Latency — The latency period between drug initiation and appearance of the eruption varies from months to a year or more and depends upon the type of drug, dose, host reaction, previous exposure to the drug, and concurrent medications [3]. A latency period of two months to three years has been reported for penicillamine, three to six months for angiotensin-converting enzyme (ACE) inhibitors, and four to six weeks for quinacrine [30-32].
Skin lesions — Lichenoid drug eruption is characterized by a symmetric eruption of flat-topped, erythematous or violaceous papules, often grouped and confluent, on the trunk and extremities (picture 1A-C). Lesions closely resemble those seen in lichen planus (picture 2A-B), although in lichenoid drug eruption the individual lesions are less monomorphic and may have eczematous or psoriasiform morphology with marked desquamation [63]. In patients with darkly pigmented skin, lesions may be rather brown or hyperpigmented [64]. Wickham striae (picture 3), consisting of fine, white lacelike patterns highly characteristic of lichen planus, are usually absent, but their presence does not exclude a drug-related etiology [63].
The eruption can be localized or generalized, with a fairly symmetrical distribution. In some patients, the lesions are localized to the photoexposed areas and exhibit photoaggravation. In contrast to lichen planus, the lesions of lichenoid drug eruption are distributed on the extensor aspects of the extremities and dorsal aspects of the hands (picture 2A, 2C-D and picture 1A) [26]. Nails are usually spared. (See 'Lichen planus' below.)
Checkpoint inhibitors may induce severe bullous forms of lichenoid drug eruption with frequent mucosal involvement (picture 4). Some patients present with isolated lichenoid mucositis [8]. These severe forms of lichenoid drug eruption need to be differentiated from other severe cutaneous adverse eruptions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Compared with SJS/TEN, the clinical course of these bullous lichenoid reactions is more protracted, the mucosal involvement is mild or absent, and the overall clinical outcome is better than for SJS/TEN. (See 'Stevens-Johnson syndrome/toxic epidermal necrolysis' below and "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)
Pruritus is frequent, although some patients are completely asymptomatic.
Oral lesions — Oral lichenoid drug eruptions are rare. The lesions are identical to those of oral lichen planus and may have an erosive or reticular morphology (picture 5). Erosive lesions are associated with pain, burning, and irritation. Reticular forms are usually asymptomatic. Oral lichenoid drug eruptions have been associated with several drugs, including allopurinol, ACE inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and antiretrovirals [6,9]. (See 'Medications' above.)
CLINICAL COURSE — The eruption resolves in weeks to months after the discontinuation of the offending drug, leaving postinflammatory hyperpigmentation (picture 6). Occasionally, the eruption disappears or recurs intermittently despite continuation of treatment [65,66].
PATHOLOGY
Histopathologic findings — Histologically, lichenoid drug eruption is an interface dermatitis. Lichenoid interface dermatitis is a nonspecific reaction pattern occurring in idiopathic lichen planus and other lichenoid eruptions (eg, lichenoid purpura, cutaneous graft-versus-host disease, pityriasis lichenoides chronica, discoid lupus erythematosus, fixed drug eruption) [5]. Lichenoid interface dermatitis also may be found in some cases of maculopapular drug reactions.
Major pathologic findings seen in both lichenoid drug eruption and lichen planus include:
●Damage of basal epidermal keratinocytes with multiple apoptotic cells (colloid or Civatte bodies)
●A band-like, lymphocytic infiltrate in the papillary dermis that obscures the dermoepidermal junction
●Pigmentary incontinence with dermal melanophages
Findings that are more typical of lichenoid drug eruption than lichen planus include (table 2 and picture 7) [8,26]:
●Focal parakeratosis
●Focal interruption of the granular layer
●Cytoid bodies in the cornified and granular layers
●Presence of eosinophils
●A higher number of necrotic keratinocytes, sometimes in clusters, as well as plasma cells and eosinophils
●Exocytosis of lymphoid cells into the upper epidermis
●Deeper, perivascular infiltrate
These features are seen more often in non-photodistributed lesions. Photodistributed lesions are usually indistinguishable from idiopathic lichen planus.
Direct immunofluorescence — Direct immunofluorescence shows globular deposits of immunoglobulin M (IgM), and occasionally immunoglobulin G (IgG) and immunoglobulin A (IgA), at the dermoepidermal junction and in the lower epidermis. Shaggy deposition of fibrinogen at the dermoepidermal junction is also seen. As in lichen planus, marked cytoid body staining may be present in most cases [67].
Immunohistochemical studies — Immunohistochemical studies show that the majority of the cells in the infiltrate at the dermoepidermal interface are CD4 and autoreactive CD8 effector T cells. In contrast to idiopathic lichen planus, in lichenoid drug reaction a correlation has been found between the number of T cells and CD8+ cells and between the number of granzyme B+ cells and necrotic keratinocytes [8]. Immunohistochemical staining is not routinely performed for the diagnosis of lichenoid skin eruption.
DIAGNOSIS — The diagnosis of lichenoid drug eruption is based upon a combination of the following findings:
●Clinical features – Symmetric eruption of flat-topped, erythematous or violaceous papules, often grouped and confluent, resembling lichen planus on the trunk and extremities (picture 1B-C, 2C). (See 'Skin lesions' above.)
●Evaluation of a skin biopsy – Histologic findings of interface dermatitis with a band-like lymphocytic infiltrate and other histopathologic features more characteristic of lichenoid drug eruption (picture 7). (See 'Histopathologic findings' above.)
●Medication history – Evidence of temporal relationship between drug intake and development of skin lesions. The assessment of a temporal relationship between drug intake and onset of the eruption may be difficult because of the wide variability in the latency time, particularly in patients on multiple medications. (See 'Latency' above.)
●Clinical course – Resolution upon drug withdrawal and recurrence upon rechallenge.
Patch testing with the patient's drugs has been used to try to determine the offending agent in patients with various types of cutaneous drug reactions and in patients with oral lichen planus [68-70]. However, patch testing is not routinely performed in patients with suspected lichenoid drug eruptions because false negative results are frequent. In small observational studies only 30 to 50 percent of patients with cutaneous drug reactions had positive or clinically relevant patch tests [68-70].
DIFFERENTIAL DIAGNOSIS
Lichen planus — The cutaneous lesions of lichen planus are shiny, flat, polygonal, violaceous papules (picture 2B, 2E-F); the morphology is similar to that of lichenoid drug eruption. However, in lichen planus, fine, white lacelike patterns known as Wickham striae are present over the surface of many papules (picture 3). Moreover, the lesions of idiopathic lichen planus are typically distributed symmetrically over the extremities and tend to involve the flexural areas of wrists, arms, and legs (picture 2A), whereas in lichenoid drug eruption the lesions typically occur on the trunk and extensor surfaces. Oral involvement is common in lichen planus and less so in lichenoid drug eruption. The histopathologic differential diagnosis of lichen planus and lichenoid drug eruption is summarized in the table (table 2). (See "Lichen planus".)
Stevens-Johnson syndrome/toxic epidermal necrolysis — Severe bullous lichenoid drug eruption associated with checkpoint inhibitors is rare and needs to be differentiated from Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Key clinical aspects that distinguish a lichenoid eruption from SJS/TEN include:
●A shorter latency between drug intake and onset of skin lesions (four days to up to four weeks) in SJS/TEN compared with lichenoid eruption.
●Protracted, rather than acute, clinical course of lichenoid eruptions, with slow development of bullous lesions (picture 4) over time in some patients.
●Mild or absent mucosal involvement in lichenoid eruptions compared with the almost universal mucosal involvement in SJS/TEN.
●The clinical outcome of lichenoid drug eruption is generally favorable.
The histology of both lichenoid drug eruptions and SJS/TEN is characterized by necrotic keratinocytes and subepidermal cleft formation. However, the more prominent lymphocytic infiltrate, along with jagged acanthosis (often with parakeratosis), is suggestive of lichenoid drug eruption.
A 2019 critical analysis of published cases of SJS/TEN and TEN-like reactions associated with immune checkpoint inhibitor therapy (n = 14) showed that many likely represented bullous lichenoid drug eruptions; isolated, erosive lichenoid mucositis; or bullous dermatitis in previously irradiated skin (radiation recall dermatitis), with only a few of these cases being genuine SJS/TEN [18]. An analysis of 4150 severe, cutaneous adverse reactions reported to the German registry between January 2003 and February 2019 in the context of immuno-oncologic medication confirmed only one case of TEN induced by pembrolizumab. Several reported bullous cases represented bullous lichenoid drug reactions to pembrolizumab, obinutuzumab, and nivolumab [45]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Lupus erythematosus — The macular-papular exanthema in lichenoid drug eruption, especially if accentuated in photoexposed areas, has similarities with lupus erythematosus. On histology, a lichenoid interface dermatitis may be seen in some cases of chronic cutaneous lupus erythematosus. In contrast to lichenoid drug eruption, lesions of lupus erythematosus show a moderately dense perivascular and periappendageal lymphocytic infiltrate in the papillary and reticular dermis, with abundant mucin deposits in the latter. There is focal or continuous epidermal thinning, smudged appearance of the dermoepidermal junction with vacuolar degeneration of basal cells, individual necrotic keratinocytes, and a thickened basal membrane zone. Direct immunofluorescence reveals a band-like deposition of IgG and IgM along the basement membrane zone in most cases. (See "Overview of cutaneous lupus erythematosus".)
Lichenoid granulomatous dermatitis — Lichenoid granulomatous dermatitis is a histopathologic reaction pattern with vacuolar alteration of the basal layer with necrotic keratinocytes and a chronic, inflammatory infiltrate consisting of lymphocytes, eosinophils, plasma cells, and macrophages forming variable types of granulomas. In more than one-third of the cases, the most common clinical correlates are drug eruptions [71].
Other specific diagnoses that share this histopathologic pattern are lichenoid keratosis, tattoo reactions, postherpetic dermatitis, scabies or postscabietic dermatitis, pigmented purpuric dermatosis, and lichen striatus. Dermal eosinophils and psoriasiform epidermal changes are more often associated with drug eruptions, perineural and perifollicular inflammation are more often associated with tattoo reaction and postherpetic dermatitis, and red blood cell extravasation is more often associated with pigmented purpuric dermatosis [71].
A special and rare subtype is giant cell lichenoid dermatitis, a rare condition considered an unusual variant of lichenoid drug eruption or a manifestation of sarcoidosis [72]. Histopathologic findings include multinucleated giant cells.
Keratosis lichenoides chronica — Keratosis lichenoides chronica, also called Nekam's disease, is a rare disorder characterized by violaceous, tiny papules centered on hair infundibula and sweat ducts and arranged in a linear and reticulate pattern (picture 8) [73,74]. Histologically, there is a lichenoid infiltrate with focal epidermal acanthosis and atrophy.
TREATMENT
Indications — Lichenoid drug eruptions generally resolve spontaneously a few weeks to a few months after the discontinuation of the offending drug [6,75]. However, treatment may be warranted in the following situations:
●Patients who cannot discontinue the offending drug
●Prolonged disease (ie, persistent lesions several months after discontinuation of the drug)
●Extensive disease (eg, involving the trunk and extremities)
●Symptoms (eg, pruritus)
Cutaneous eruption — Treatment options include topical or systemic corticosteroids and oral retinoids.
●For patients with symptomatic disease involving a limited skin area (eg, the extremities), we suggest topical corticosteroids rather than oral corticosteroids. We generally use a superpotent topical corticosteroid (eg, clobetasol propionate 0.05% (table 3)) ointment or cream twice daily for two to four weeks. Mid-potency corticosteroids, such as mometasone furoate 0.1% ointment or cream, can be used for facial lesions.
●For patients with extensive, symptomatic disease, we suggest oral corticosteroids rather than oral retinoids. In adult patients, we generally use prednisone 30 to 60 mg per day for two to six weeks. Prednisone is then tapered over the next two to six weeks. Acitretin 25 to 35 mg per day for 6 to 12 weeks is an alternative for patients in whom systemic corticosteroids are contraindicated.
The efficacy of topical corticosteroids, systemic corticosteroids, and acitretin for lichenoid drug eruption has not been evaluated in randomized trials. Their use is based upon clinical experience and limited evidence of efficacy from a few small clinical studies in patients with idiopathic lichen planus [76-78]. (See "Lichen planus", section on 'Treatment'.)
Oral eruption — The reticular form of oral lichenoid drug eruption is generally asymptomatic and does not require treatment. Topical or oral corticosteroids are used for the treatment of the erosive form to reduce pain and discomfort and hasten healing.
●For patients with oral, erosive lichenoid drug eruption, we suggest topical corticosteroids as first-line treatment. We typically use a superpotent topical corticosteroid (eg, clobetasol propionate 0.05% ointment) two or three times per day for four to eight weeks.
●For patients with oral, erosive lichenoid drug eruption that does not respond to topical corticosteroids, we suggest oral corticosteroids. In adult patients, we generally use prednisone at a dose of 30 to 60 mg per day for two to six weeks. Prednisone is then tapered over the next two to six weeks.
The efficacy of topical and oral corticosteroids for the treatment of oral, erosive lichenoid drug eruption has not been evaluated in randomized trials. Their use is based upon clinical experience and limited evidence of efficacy from randomized trials in idiopathic oral lichen planus [79,80]. (See "Lichen planus" and "Oral lichen planus: Management and prognosis".)
RECHALLENGE — Re-exposure, in general, is contraindicated but possible in individual patients after thorough risk-benefit evaluation if the provoking drug is of irreplaceable importance [45,81].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)
SUMMARY AND RECOMMENDATIONS
●Definition – Lichenoid drug eruption, also called drug-induced lichen planus, is an uncommon, cutaneous adverse effect of several drugs, characterized by a symmetric, papular eruption resembling lichen planus on the trunk and extremities. (See 'Introduction' above.)
●Etiology – The drugs most frequently reported are angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, antimalarials, beta blockers, and checkpoint inhibitors (table 1). The latency period between drug initiation and the appearance of the eruption varies from several weeks to a year or more. (See 'Medications' above and 'Latency' above.)
●Clinical presentation – Lichenoid drug eruption manifests with a symmetric eruption of erythematous or violaceous, flat-topped, polygonal papules, often grouped and confluent. They have eczematous or psoriasiform morphology with marked desquamation. The eruption involves the trunk and predominantly extensor aspects of the extremities (picture 1B-C, 2C-D). Severe bullous lichenoid reactions that mimic Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been associated with checkpoint inhibitors (picture 4). (See 'Skin lesions' above and 'Stevens-Johnson syndrome/toxic epidermal necrolysis' above.)
●Diagnosis – The diagnosis of lichenoid drug eruption is based upon a combination of the following (see 'Diagnosis' above):
•Clinical findings of a symmetric eruption of flat-topped, erythematous or violaceous papules resembling lichen planus on the trunk and extremities (picture 1B-C, 2C)
•Histologic findings of interface dermatitis with a band-like, lymphocytic infiltrate and necrotic keratinocytes (picture 7) (see 'Histopathologic findings' above)
•Temporal relationship between drug intake and development of skin lesions
•Resolution upon drug withdrawal and recurrence upon rechallenge
●Clinical course – Lichenoid drug eruptions generally resolve spontaneously a few weeks to a few months after the discontinuation of the offending drug. Treatment may be warranted in patients who cannot discontinue the offending drug or have symptomatic or extensive disease. (See 'Indications' above.)
●Treatment
•Limited disease – For patients with symptomatic disease involving a limited skin area (eg, the extremities), we suggest topical corticosteroids rather than oral corticosteroids (Grade 2C). We generally use a superpotent topical corticosteroid (eg, clobetasol propionate 0.05% (table 3)) ointment or cream twice daily for two to four weeks. Less potent topical corticosteroids, such as mometasone furoate 0.1% ointment or cream, can be used for facial lesions. (See 'Cutaneous eruption' above.)
•Extensive/symptomatic disease – For patients with extensive, symptomatic disease, we suggest oral corticosteroids rather than oral retinoids (Grade 2C). We generally use prednisone 30 to 60 mg per day for two to six weeks. Prednisone is then tapered over the next two to six weeks. Acitretin 25 to 35 mg per day for 6 to 12 weeks is an alternative for patients in whom systemic corticosteroids are contraindicated. (See 'Cutaneous eruption' above.)
•Oral, erosive lesions – For patients with oral, erosive lichenoid drug eruption, we suggest topical corticosteroids rather than oral corticosteroids as first-line treatment (Grade 2C). We typically use clobetasol propionate 0.05% ointment two or three times per day for four to eight weeks. (See 'Oral eruption' above.)
•Refractory, oral lesions – For patients with oral, erosive lichenoid drug eruption that does not respond to topical corticosteroids, we suggest oral corticosteroids (Grade 2C). We generally use prednisone at a dose of 30 to 60 mg per day for two to six weeks. Prednisone is then tapered over the next two to six weeks. (See 'Oral eruption' above.)
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