Topical imiquimod-induced linear IgA bullous dermatosis

Abstract

A 68-year-old woman was referred to the unit of dermatology for a large basal cell carcinoma on the chin. She was treated with imiquimod cream 5%, and 4 weeks after she developed isolated and grouped tense serum-filled vesicles and bullae on lips, nose, scalp, ankles and lumbar area, and then expanded to the whole body. Histological examination was consistent with a subepidermal bullous dermatosis. Moreover, direct immunofluorescence showed linear deposition of IgA at the basement membrane zone supporting the diagnosis of linear IgA bullous dermatosis (LABD). Dapsone 50 mg/day was administered, and the lesions gradually improved within some weeks, and no new lesions appeared. The temporal relationship between the application of the drug and the development of the disease indicates a role of this topical agent in triggering LABD.

Background

Imiquimod is an imidazoquinoline amine, inducer and modifier of both innate and adaptive immune responses which acts through the production of interferon alpha and other cytokines. Topical imiquimod 5% is used to treat a variety of skin conditions, for example, basal cell carcinomas.¹ Topical imiquimod is known to induce the production of interferon alpha, tumour necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-1 receptor antagonists, IL-6, IL-8, IL-10, IL-12 and several other cytokines.² Linear IgA bullous dermatosis (LABD) is a rare autoimmune disease caused by IgA autoantibodies against the epidermal basement membrane zone which promotes the formation of subepidermal bullae.³ Here, we report the first case of LABD induced by imiquimod utilised for the topical treatment of basal cell carcinoma.

Case presentation

A 68-year-old woman was referred to our dermatology unit for the presence of an expansive lesion located on the chin. Histological examination of a biopsy specimen confirmed it as superficial basal cell carcinoma. Because of the patient’s refusal to remove the lesion surgically, we decided to use topical imiquimod 5% 5 days a week for 6 weeks.

After 4 weeks from the beginning of the treatment, the patient developed isolated and grouped tense serum-filled vesicles and bullae. Particularly some lesions had a rosette pattern (string of pearls sign) surrounded by healthy skin. The lesions initially appeared on lips, nose, scalp, ankles and lumbar area and then expanded so as to involve large areas of skin (figures 1 and 2).

Figure 1.

Polycyclic, grouped blisters with rosette configuration on the lower limbs.

Figure 2.

Polycyclic, grouped blisters with rosette configuration on the back.

Her medical record revealed no family history for autoimmune diseases, and the patient denied the use of other drugs besides imiquimod. Moreover, she denied applying imiquimod cream to other sites besides the chin.

Investigations

A skin biopsy was taken at the edge of a blister for the histological examination and from normal-appearing perilesional skin for direct immunofluorescence. Histological examination showed subepidermal bullae with an underlying neutrophil-predominant dermal infiltrate (figure 3). Moreover, the direct immunofluorescence demonstrated linear deposition of IgA at the basement membrane zone supporting the diagnosis of LABD (figure 4).

Figure 3.

A subepidermal bulla with an underlying neutrophil-predominant dermal infiltrate.

Figure 4.

Direct immunofluorescence demonstrated linear deposition of IgA at the basement membrane zone.

Treatment

Topical imiquimod was immediately stopped, and the patient was treated with oral prednisone (25 mg/day). Subsequently, dapsone 50 mg/day was associated and prednisone gradually discontinued.

Outcome and follow-up

Four weeks after the start of dapsone, the blistering lesions had almost entirely healed with only a few residual lesions.

Discussion

LABD is a rare autoimmune disease characterised by subepidermal bullae induced by the presence of IgA autoantibodies against the epidermal basement membrane zone.

This pathology occurs in both adults and children. Clinical presentations are heterogeneous and are characterised by different manifestations on both skin and mucous membranes ranging from target like to erythematous papules, urticarial plaques or vesiculobullous eruptions.⁴

The most characteristic clinical features of LABD are polycyclic, grouped blisters with rosette configuration.⁵ Both humoral and cellular immune responses are probably involved in the pathogenesis of this disease. In particular, antibody-induced local inflammatory response and release of proteolytic enzymes by neutrophils and other inflammatory cells may contribute to the development of skin and mucosal lesions.

Different forms of LABD have been described: idiopathic, systemic disorder related and drug induced.^{6 7}

The drugs most often described in association with LABD are antibiotics (ie, vancomicin, penicillin, metronidazole), but also non-steroidal anti-inflammatory agents and antiepileptic have been indicated as triggering factors for the disease.⁶ LABD induced by imiquimod has not been previously described, although pemphigus-like lesions induced by imiquimod have been reported.⁸ The disease typically occurs 3–4 weeks after the causative drug is initiated and generally resolves within several weeks after drug cessation, although in some cases, it can persist for years. In our case, the temporal relationship between the application of the drug and the development of the disease is consistent with a role of this topical agent in triggering LABD.^{9 10}

In pharmacokinetic studies of topical imiquimod use, it has been observed that serum concentrations of the drug is very low, reflecting minimal dermal absorption. Therefore, it has been hypothesised that systemic effects related to imiquimod could result from the locally produced cytokines spreading into the systemic circulation.¹ To this regard, topical imiquimod is known to induce the production of several cytokines which may be responsible for the onset of the disorder, notably interferon alpha, TNF-α, IL-1, IL-6, IL-8, IL-10 and IL-12.² In particular, it has been hypothesised that the pathophysiological mechanism responsible for drug-induced LAD could involve IL-6 and IL-10 which play a role in the regulation of IgA isotype switching and B cell differentiation.⁴

Learning points.

• Imiquimod is an imidazoquinoline amine inducer and modifier of both innate and adaptive immune responses which acts through the production of interferon alpha and other proinflammatory cytokines.

• Liner IgA bullous dermatosis (LABD) is a rare autoimmune disease caused by IgA autoantibodies against the epidermal basement membrane zone which promotes the formation of subepidermal bullae.

• Different forms of LABD have been described: idiopathic, systemic disorder related and drug induced.

• The drugs most often described in association with LABD are antibiotics, but also non-steroidal anti-inflammatory agents and antiepileptic agents have been described in association with this condition.

• This is the first case of LABD induced by imiquimod, although pemphigus-like lesions induced by imiquimod have already been reported.