Lichenoid Drug Eruptions

Are You Confident of the Diagnosis?

• What you should be alert for in the history

Lichenoid drug eruptions (LDE) are usually pruritic. The onset may be within weeks of drug initiation, but LDE is atypical in that it can take up to 12 months to evolve. A latent period of 3 years has been reported with penicillamine. LDE from ACE inhibitors typically takes 3 to 6 months to appear. A comprehensive list of inciting agents is detailed under Etiology below.

• Characteristic findings on physical examination

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LDE usually presents with an eruptive onset of violaceous flat-topped papules and plaques. These are generally symmetrical, and widespread or generalized. A photodistributed form (photo-LDE) is well recognized. Certain features that may differentiate LDE from idiopathic LP have been described: larger and less monomorphic plaques, the lack of Wickham’s striae and the tendency toward eczematization and greater residual hyperpigmentation. The classic sites of involvement in LP (flexor aspects of extremities, sacral area) may be spared in LDE. Resolution of LDE is not immediate and it may take months to a year after drug discontinuation to abate completely.

Scalp involvement from drugs is rare and is described predominantly with antimalarials or gold. Genital involvement is reported with β-blockers. Oral LDE occur less frequently than LDE. They may occur without cutaneous lesions. Oral LDE is frequently asymptomatic, but burning or stinging, especially with hot or spicy foods or a change in texture in the mouth may be noted. The clinical appearance of oral LDE resembles that of idiopathic LP. Some forms are predominantly reticular and others mainly erosive. Commonly involved intraoral sites include the posterior buccal mucosa, the tongue, floor of mouth, palate, and the alveolar ridges.

• Expected results of diagnostic studies

The diagnosis of LDE may be made clinically, when a high index of suspicion is present, in the setting of the right drug history and when the typical features of the eruptive, widespread lichenoid rash are present. However, skin biopsy and histopathologic evaluation may be necessary to differentiate LDE from idiopathic LP and other papulosquamous disease in some cases.

Histopathological changes similar to idiopathic LP, such as Civatte bodies, vacuolar degeneration of the basal layer and a lymphocytic infiltrate are seen. Features that distinguish drug-induced LP from the idiopathic variety are the presence of focal parakeratosis instead of the usual hyperkeratosis and the presence of eosinophils and sometimes plasma cells in the inflammatory infiltrate. Further, the hypergranulosis and basal vacuolar change of usual LP may be less pronounced in the drug-induced form. The lymphocytic infiltrate may also be diminished and less band-like when compared with LP.

Photo-lichenoid drug-induced eruptions may have all the features of LP, and few if any of the features of drug-induced LP. Oral LDE may be indistinguishable from LP histopathologically.

• Diagnosis confirmation

In the differential diagnosis of LDE, the following conditions need to be borne in mind:

-Idiopathic LP. The clinical and histopathologic features of each are described above.

-Other papulosquamous diseases:

• Subacute eczema, or drug-induced eczematous eruptions, may manifest a violaceous appearance in darker skin types;

• Secondary syphilis is a great mimicker of disease and needs to be considered in atypical cases and in cases with palm and sole involvement.

• “Oid-oid” disease (Sulzberger-Garbe disease) is an itchy eruption with eczematous and lichenoid features that typically occurs in elderly men.

-Erythema dyschromicum perstans (ashy dermatosis) typically presents with gray to violaceous macules, as opposed to the papules and plaques of LP and LDE.

-The rash of dermatomyositis may be photo-exacerbated. The violaceous color may mimic photo-LDE. History and other physical findings may assist in narrowing the diagnosis.

-Chronic graft-versus-host disease may be lichenoid or sclerodermoid and may manifest oral reticular and atrophic plaques. This diagnosis should be considered in those with a history of a bone marrow or stem cell transplant.

Furthermore, the following conditions may resemble oral LDE:

– Lichenoid amalgam reaction: This is usually localized to the ventral and lateral aspects of the tongue near the site of dental amalgam. Whitish plaques are seen.

-Lupus erythematosus: There may be DLE-like lesions and tiny oral ulcers in LE. Reticular and atrophic plaques are also reported.

Who is at Risk for Developing this Disease?

The overall incidence of LDE is unknown. LDE from gold has been seen in 12.5% to 30% of patients in different series. Erosive oral LDE was seen in 30% of patients taking NSAIDS as opposed to 9% of controls. Of 60 patients on penicillamine, 12.5% developed LDE. Males and females are equally affected. LDE tends to affect an older age group than LP.

Although LP has been associated with the presence of HLA-B27, HLA-B51, HLA-Bw57, HLA-DR1and HLA-DR9 in various populations, no studies have addressed this question specifically for LDE.

What is the Cause of the Disease?

• Etiology

While nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, antimalarials, β-blockers, gold, lithium, methyldopa, penicillamine, ethambutol and sulfonylurea agents are time-honored offenders, LDE from many newer drugs has been described. Imatinib mesylate, statins, the tumor necrosis factor-α antagonists, sildenafil, the proton pump inhibitors and interferon are among these. A lichenoid eruption has developed at sites of granulocyte stimulating factor (GCSF) injection. Lichenoid eruptions are reported in association with anti-PDI (programmed death 1) therapy for various cancers.

Drugs that commonly cause photo-LDE are thiazide diuretics, tetracycline, quinine and quinidine. Furosemide, sparfloxacin, ethambutol and clopidogrel have also been implicated. Of historical value now is the association of color film developer with a photo-lichenoid eruption.

Common offending agents in oral LDE include NSAIDS, antihypertensive medication (β-blockers, thiazides, ACE inhibitors) and antirheumatics (antimalarials, gold salts, penicillamine) and antiretroviral therapies. Typically the eruption occurs 2 to 3 months after medication initiation, although onset may be as short as a few weeks or as long as 2 years. Oral LDE occurs predominantly in adults, although pediatric cases have been reported.

• Pathophysiology

The pathophysiologic events in LDE are not completely defined. In LP, CD8+ T cells invade the epidermis. Fas expression by keratinocytes is upregulated by interferon-g, which is produced by CD8 cells. Plasmacytoid dendritic cells also produce interferon-g. FasL is expressed on the surface of these CD8+ cells, and Fas/Fas ligand-mediated apoptosis occurs. It is likely that in LDE, drug haptens presented by Langerhans cells in the epidermis are responsible for the initial immunologic stimulus.

Systemic Implications and Complications

Although LDE may be widespread, pruritic and uncomfortable, thus affecting quality of life, no systemic complications occur.

Treatment Options

Treatment options for LDE are summarized in the Table I.