Dermatology Online Journal

Atypical response to treatment in linear IgA bullous dermatosis of childhood: Revision of literature
Susana Moleiro MD, Vera Santos MD, Manuela Calha MD, Graça Pessoa MD
Dermatology Online Journal 17 (6): 5

Hospital de Faro

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Abstract

A three-year-old boy presented with 2 months of worsening skin lesions characterized by multiple clear vesicles and bullae. The histopathological and immunohistochemical examinations revealed changes consistent with linear IgA bullous dermatosis of childhood. Treatment with dapsone and prednisolone resulted in gradual clinical improvement. However, within a week of therapy he presented with diabetic ketoacidosis, the onset of type I diabetes mellitus. Since then, keeping this child asymptomatic has been a challenge. This case emphasizes the importance of close monitoring of patients taking systemic corticosteroids; the coexistence of other immune mediated conditions may influence the success of treatment.

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Case report

A three-year-old boy developed skin vesicles and bullae on the lower trunk and legs two months prior to admission. The intensely pruritic lesions rapidly spread asymmetrically to other sites on the body surface including the face, scalp, and ano-genital areas, sparing the mucous membranes. Fever was not reported nor was the patient ingesting any medication prior to the onset of the disease. Several antibiotics (flucloxacicillin, amoxicillin, and clavulanic acid) were prescribed after the skin lesions erupted, but these were not beneficial.

Figure 1	Figure 2

On admission the physical exam was unremarkable except for the presence of tense, clear vesicles and bullae, some on an erythematous base and arranged in an annular or rosette-like form (Figure 1).

The histopathological examination revealed subepidermal blistering with neutrophilic infiltration (Figure 2). The direct immunofluorescence of perilesional skin disclosed intense linear deposition of IgA and weak deposition of IgM, IgG, and C3 along the basal membrane zone (BMZ).

Figure 3

The patient was started on dapsone (25 mg per day) and then oral corticosteroids were added, leading to slow regression of the lesions (Figure 3). Shortly thereafter, on day 5 of his corticosteroids (2 mg/kg/day), he was admitted to the hospital with polyuria, polydipsia, and dehydration and was diagnosed with diabetic ketoacidosis (HbA1C 10.1%, low C-Peptide, negative islet cell antibodies, positive glutamic acid decarboxylase antibodies).

He was later discharged on medications including dapsone (40 mg per day), prednisolone (dose varies for skin exacerbations from 0.5-1.0 mg/kg/day), and insulin. In the following two years, he was readmitted several times for exacerbation of skin lesions usually following a dosage reduction of corticosteroids and uncontrolled diabetes. Erythromycin was tried unsuccessfully as a corticoid sparing agent and dapsone was stopped because of significantly elevated methemoglobulinemia, although the child was asymptomatic. He was then started on immunoglobulin infusions (IVIg) of 1 mg/kg every four weeks associated with the lowest possible dose of prednisolone. This last treatment strategy has been used for over a year with episodic exacerbations, controlled as an outpatient with corticoid adjustment. No other alternative drugs have been tried.

The HLA typing showed that the haplotypes B8, Cw7, and DR3-DQ2 were all present in this patient.

Discussion

Linear IgA bullous dermatosis (LABD) is a rare, acquired, autoimmune subepidermal bullous disease. The annual incidence of LABD varies across the world. Studies in Europe [1] and Tunisia [2] found an annual incidence of 0.2-0.5 and 1.25, respectively, as well as a male predominance (male/female ratio of 1.7:1) [2]. The disease affects people of all ages, but two peaks can be observed: LABD of childhood appears before the age of five and the adult linear IgA disease appears after the age of sixty [3].

It is often clinically misdiagnosed as bullous impetigo, dermatitis herpetiformis, or classic erythema multiforme [1, 4], but it can have an atypical presentation and resemble toxic epidermal necrolysis, especially when there is a history of antibiotic administration [1]. Other immunobullous diseases, such as bullous pemphigoid, bullous systemic lupus erythematosus, and epidermolysis bullosa acquisita might also be considered [4, 5]. For these reasons, the correct diagnosis of LABD relies on the pattern of the skin lesions, clinical course, as well as histopathology and direct immunofluorescence findings.

In this particular case, the lesions were typical of LABD, which are characterized by tense bullae arising abruptly on an erythematous base, and these may form a pattern known as “cluster of jewels” [1, 2, 3, 4]. Commonly there are excoriations and crusted papules, especially in cases of intense itching [3]. The perineum, face, scalp, and trunk [2] are the areas mainly affected, but the lesions can become widespread. Patients may have mucosal involvement, which can range from mild to severe, affecting oral, conjunctival [1, 3], nasal, or genital areas [1]. The clinical course is also helpful in guiding the diagnosis. The skin lesions persist after antibiotic therapy and may become chronic and widespread.

The histopathology examination is not specific for LABD [1]. The blisters are subepidermal with an inflammatory infiltrate of neutrophils and sometimes eosinophils in the superficial dermis [1]. Papillary microabcesses can occasionally be seen in the dermal papillary tips [3]. These findings, however, can also be encountered in other bullous diseases [1]. The diagnosis is confirmed by direct immunofluorescence on a perilesional skin biopsy, displaying linear deposits of IgA along the BMZ [1-6, 8, 10-13]. Sometimes patchy deposition of IgG [1], IgM, and C3 may also be detected [5]. Using indirect immunofluorescence, circulating BMZ IgA antibodies can be found in the sera of approximately half of the patients [1]. Biochemical investigation can reveal hypereosinophilia in some patients, but the remaining laboratory tests are usually normal [2].

The etiopathogenesis of LABD is still not entirely understood [1]. It is known to be mediated by IgA antibodies that target proteins of the epithelial adhesion complex [8]. The HLA system, which plays a determining role in immunity and in self-recognition in virtually all cells and tissues, might have an important role. Interestingly, the autoimmune haplotypes found in this patient (HLA-B8, CW7, and DR3) are not only associated with LABD [2, 3], but one of them (DR3-Q2) is considered to be a high risk for type I diabetes mellitus (DM) [7]. Probably this genetic predisposition combined with environmental triggers could explain the onset of these diseases.

The primary treatment of LABD is dapsone (1 to 2.5 mg/kg/day) [1-6, 8, 10-13] and most cases respond quickly. Because treatment with dapsone can have adverse effects such as hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient patients, methemoglobulinemia, agranulocytosis, and peripheral neuropathy, the enzyme G6PD must be assessed before beginning treatment and levels of methemoglobulin as well as the blood count with reticulocytes must be monitored regularly. However, this patient showed a slow response with multiple flares may be related to the coexistence of type I DM or to the presence of both linear and patchy deposition of antibodies at the BMZ.

For better disease control, the patient required concomitant treatment with corticosteroids, suggested in the literature as prednisolone in a dosage of 0.5 mg/kg/day [1, 2]. These drugs are known to cause, among other adverse effects, insulin resistance and hyperglycemia. These metabolic changes are noticed in nearly half the patients treated with glucocorticoids over a long period of time. If they cannot compensate for the additional insulin need, overt glucocorticoid-induced diabetes develops [9]. In this particular case, the high levels of glycosylated hemoglobin, low C peptide, and positive glutamic acid decarboxylase antibodies denoted an unknown preexistent diabetes mellitus of immune origin. The prednisolone prescribed was considered an aggravating factor that culminated in ketoacidosis, a life-threatening situation.

Immunoglobulin infusions and erythromycin were tried as corticoid sparing agents; there are some references in the literature that support their usage [11, 12]. Other options for treatment are sulfapyridine [1, 10], flucloxacillin [13], and immunossupressive drugs (azathioprine [1] or mycophenolate mofetil [10]).

Although the natural course of LABD is not completely characterized, in most cases resolution occurs approximately 2 years after the onset [2]. This case is an exception because keeping this child asymptomatic is an ongoing challenge. The resistance to treatment could be explained by the coexistence of immune-mediated diabetes mellitus and poor metabolic control. This case also highlights the need for careful drug monitoring, especially when glucocorticoids are used systemically and in high dosages, to quickly assess possible adverse effects.

References

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