Case Report: Erythema Multiforme Induced by Lithium Contact

Abstract

Erythema multiforme (EM) is an acute, self-limited mucocutaneous disease with diverse triggering factors, and the recurrences are quite common. A 24-year old male presented with multiple erythematous, itchy papules and plaques on multiple sites. He has worked in a lithium battery factory and experienced the chemical burn 2 weeks ago. A histopathologic examination on right wrist showed a scattered lymphocytic infiltration, vacuolar degeneration, and necrotic keratinocyte. The final diagnosis was EM after occupational lithium exposure. He was treated by oral methylprednisolone and experienced recurrences after returning to the same workplace after remission. Although the precise pathogenesis is unknown, the pathogenesis of EM by lithium is related to the effect of lithium on immune system, different from other etiologies. To our knowledge, our case is the first report of EM following the chemical burn and occupational lithium exposure. We report this as an interesting case of EM.

INTRODUCTION

Erythema multiforme (EM) is an acute self-limited mucocutaneous disease triggered by various causes such as infections and drugs. We experienced a case of EM triggered by lithium and whose course is influenced by additional lithium exposures. Even though lithium has been reported to induce cutaneous side effects after oral intake for the treatment of bipolar disorder, there were no case reports of EM after lithium contact. We report the rare case of EM induced by occupational lithium contact. To our knowledge, our case is the first report of EM following the chemical burn and occupational lithium contact.

CASE REPORT

A 24-year-old male presented with multiple erythematous, itchy papules and plaques on multiple sites. He has worked in a lithium battery factory and experienced the chemical burn by lithium 2 weeks ago. A week after burn, a solitary, erythematous papule was found in the right wrist where he was injured by the chemical burn, and this lesion extended to both arms and thighs within a day. The physical examination revealed multiple erythematous to purple-red papules and plaques with a central dark zone on wrists (Fig. 1A, B), arms (Fig. 1C), and thighs (Fig. 1D). Oral and genital mucosal areas were preserved without invasion. There was no nonspecific history including herpes simplex infection and abnormal laboratory findings except the white blood cell count of 11,750/µl. A punch biopsy was performed on the right wrist which showed a scattered lymphocytic infiltration, vacuolar degeneration, and necrotic keratinocyte (Fig. 2). Based on the clinical features and histologic findings, the final diagnosis was EM. He was treated by methylprednisolone (30 mg/day) and the dose has been reduced gradually for 3 weeks. After the full remission of skin lesions, he has experienced recurrences after returning to the lithium battery factory. The recurrence occurred on the previous skin lesion as rapidly as 12 hours and resolved after avoiding the workplace. The patient gave us written consent for publishing all photographic materials.

Fig. 1. Multiple erythematous to purple-red papules and plaques with a central dark zone on wrists (A, B), arms (C), and thigh (D).

Fig. 2. The biopsy specimen on right wrist shows a scattered lymphocytic infiltration and vacuolar degeneration (A: H&E, ×100). High-power view showing lymphocytic infiltration, vacuolar degeneration, and necrotic keratinocyte (B: H&E, ×200).

DISCUSSION

EM is an acute, self-limited mucocutaneous disease with the target lesions. EM lesions usually distribute peripherally, sometimes accompanied by oral or genital mucosal erosion. There are numerous causes of EM including infections, drugs, malignancy and cases of diverse etiologies such as immunotherapy, vaccination, topical agent have also been reported recently¹,²,³. Among these factors, infection accounts for approximately 90% of cases, and the most common agent is herpes simplex virus (HSV) and mycoplasma pneumoniae. Drug-associated EM also accounts for less than 10% of cases triggered by nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics²,³. Though EM usually subsides within 1 to 4 weeks without complication except for transient skin discoloration, the recurrences are quite common⁴. Because most etiologies of recurrence were not found, finding etiologies of EM could be an important determinant for preventions by avoiding triggers⁴.

There have been several studies to find out the pathogenesis according to each etiology. Although the precise pathogenesis of EM is unknown, the association with HSV infection and EM has long been evaluated⁵. The mainstay pathogenesis of herpes associated EM is delay type hypersensitivity. The virus is phagocytosed by circulating mononuclear cells, particularly CD34+ Langerhans cell precursors which travel to the epidermis by upregulation of adhesion molecules⁶. HSV genes in the skin lead to the recruitment of helper T cell and production of interferon-gamma (IFN-γ) which induces the inflammation, resulting in EM. Also, there is a hypothesis that drug-induced EM is related to metabolic idiosyncrasy which produces the reactive metabolite inducing hypersensitivity as haptens. The drug-induced EM is distinct from herpes associated EM in that tumor necrosis factor-alpha (TNF-α) is involved rather than IFN-γ⁷.

Although EM is usually induced by generalized exposure, there is a suggested term “contact erythema multiforme (CEM)” to describe the case of EM triggered by contacting antigen through skin⁸,⁹. CEM is a noneczematous disease with allergic contact sensitivity. The contact EM is similar to usual EM in the view of pathogenesis by checking the epidermal expression of ICAM-1, HLA-DR molecules on keratinocytes, and immunophenotype of lymphocytes¹⁰. Specific CD8+ T cell can attack the keratinocytes resulting in the keratinocyte apoptosis and cytokine (TNF-α) production. Since lithium has been reported to increase the TNF-α secretion with an increase in TNF-α mRNA by stimulating monocytes, it could be the potential pathogenesis to induce EM⁷,¹¹. It suggests that lithium itself can induce immune responses, resulting in EM in skin.

Allergic contact dermatitis was another differential diagnosis considering exposure history. However, this case shows the target like lesions on the acral lesions and the lesions extended suddenly and simultaneously. In addition, the histology shows more specific to EM. Vacuolar degeneration of basal cells and epidermal necrosis were shown in histopathology, but there were no evident histopathologic characteristics of allergic contact dermatitis such as eosinophil infiltration and spongiosis in this case.

Similar to our case, there have been 3 case reports of EM after the lithium treatment as a mood-stabilizing agent¹²,¹³,¹⁴. Lithium is chemical element and white alkali metal which has been used in industry including glass, ceramics and lithium batteries and medicines for treating bipolar disorder¹⁵. Considering the history of preceding chemical burn and the first manifesting lesions, lithium can be exposed by the contact on the impaired barrier lesion or inhalation. After absorption, lithium is not bound to plasma proteins and does not undergo hepatic metabolism¹⁶. It means that the metabolic pathway is not related to pathogenesis. The characteristic of lithium suggests that lithium itself can induce immune responses in skin not through allergen.

This case characterized that the skin lesion and symptoms recurred after re-exposure to lithium during the administration period of methylprednisolone. Unfortunately, we did not take clinical close-up photos and did not execute the patch test including lithium. However, our case is the first report of EM following the chemical burn and occupational lithium exposure to our knowledge. Through this case, clinicians should be aware of the possible occurrence of EM after lithium exposure. We report this as an interesting case of EM and further studies for understanding the pathogenesis of EM will be needed.