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.

Table I.
Medical treatment Physical modalities
Withdraw offending drug Ultraviolet therapy
Mid- or high-potency topical steroids
Oral retinoids
Oral LDE
Withdraw offending drug
Maintain good oral hygiene
Mucosal protectants (eg, milk of magnesia)
Topical anesthetic agents (eg, viscous lidocaine)
Mid- or high-potency topical steroids
Tacrolimus ointment
Systemic corticosteroids

Optimal Therapeutic Approach for this Disease

Of prime importance is to look for and discontinue the inciting drug. Because of the potential lag time between drug initiation and onset of eruption, the identification of the offending agent may not be straightforward in patients with multi-drug regimens. Consultation of drug reference lists can assist with this decision. In cases of uncertainty, more than one medication may need to be discontinued.

Resolution may occur over weeks to months and may take up to a year. Potent topical steroids may help to ameliorate the condition. Mid- or high-potency steroids (triamcinolone 0.1%; bethamethasone diproprionate 0.05% or clobetasol proprionate 0.05%) are used. For widespread cases, creams are recommended over ointments for ease of use. Lower potency topical steroids can be recommended for the folds (hydrocortisone 2.5% or desonide 0.05%).

For oral LDE, topical steroids (topical fluocinonide 0.05% or triamcinolone 0.1% in an adhesive base; topical clobetasol 0.05% ointment or aqueous solution) and topical tacrolimus have been employed with success. Topical mucosal protectants such as milk of magnesia, and topical anesthestics, such as viscous lidocaine, or magic mouthwash (usually a combination of diphenhydramine, viscous lidocaine and aluminum hydroxide) may be beneficial for symptom control. Good oral hygiene may lessen severity of disease. It may be prudent to add topical anti-candidal therapy when topical steroid use is planned for any length of time, given the high rate of candidal superinfection that may occur in these patients.

Patient Management

A thorough history is needed in some cases to assist in identifying the drug culprit. The patient should be made aware that avoidance of this medication (and similar medications in the drug class, for example, ACE inhibitors) is imperative.

A discussion of the prognosis and the possibility of a prolonged abatement time should be held with the patient and a treatment course planned accordingly. Potent topical steroids may suffice for symptom control and may hasten resolution.

For eruptions that are partially- or unresponsive to topical steroids, a short course of oral steroids may be tried. A discussion of alternative therapies for severe disease such as ultraviolet light or retinoids may be undertaken in cases that are refractory.

Unusual Clinical Scenarios to Consider in Patient Management

In patients with widespread LDE that is slow to resolve, narrow-band ultraviolet B light or oral PUVA therapy, as is given for LP, may be considered. A short course of oral corticosteroids may be beneficial in severe cases. Acitretin may also be tried in refractory cases. Immunosuppressive treatments, such as cyclosporine, mycophenolate mofetil or methotrexate, are usually not needed in LDE.

For oral LDE, systemic corticosteroids can be used in acute exacerbations, for multiple or widespread lesions and in patients whose condition is unresponsive to topical steroids. Levamisole in a dose of 50mg 3 times daily for 3 days has also been recently tried as monotherapy for oral LP, with success, and can be considered in refractory cases of oral LDE.

What is the Evidence?

Brauer, J, Votava, HJ, Meehan, S, Soter, NA. “Lichenoid drug eruption”. Dermatol Online J.. 2009. pp. 15-13. (A recent case and review of the literature.)

Ellgehausen, P, Elsner, P, Burg, G. “Drug-induced lichen planus”. Clin Dermatol. vol. 16. 1998. pp. 325-32. (A comprehensive review of the older culprit drugs causing DLE.)

Joseph, RW, Cappel, M, Goedjen, B, Gordon, M, Kirsch, B, Gilstrap, C, Bagaria, S. “Jambusaria-Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy”.

Pahlajani, A. “Cancer Immunol Res”. vol. 3. 2015 Jan. pp. 18-22. (Report detailing cases of DLE from anti-PD1 therapy).

Meller, S, Gilliet, M, Homey, B. “Chemokines in the pathogenesis of lichenoid tissue reactions”. J Invest Dermatol. vol. 129. 2009. pp. 315-9. (A comprehensive review of the role of chemokines in the pathophysiology of lichenoid tissue reactions.)

Thongprasom, K, Dhanuthai, K. “Steroids in the treatment of lichen planus: a review”. J Oral Sci. vol. 50. 2008. pp. 377-85. (A comprehensive review of the treatment of oral lichen planus with topical steroids.)

Wackernagel, A, Legat, FJ, Hofer, A, Quehenberger, F, Kerl, H, Wolf, P. “Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus”. Photodermatol Photoimmunol Photomed. vol. 23. 2007. pp. 15-9. (An excellent clinical study comparing the response of patients with LP to these two forms of ultraviolet light; statistically significant difference between the 2 treatment groups in terms of sustained overall clinical response rate.)

Weedon, D. “The lichenoid reaction pattern (“interface dermatitis”)”. Weedon’s Skin Pathology. 2010. pp. 35-70. (An excellent text on the histopathologic findings of the lichenoid dermatitides.)

Woo, V, Bonks, J, Borukhova, L, Zegarelli, D. “Oral lichenoid drug eruption: a report of a pediatric case and review of the literature”. Pediatr Dermatol. vol. 264. 2009. pp. 58-64. (An outstanding review of drug-induced oral LP.)