Clinical and immunopathological spectrum of immunoglobulin M pemphigoid: a multicenter case series

Abstract

Background and objectives: Pemphigoid diseases are primarily mediated by IgG or IgA autoantibodies against the cutaneous basement membrane zone (BMZ). Although recent observations suggest the existence of exclusively IgM-mediated pemphigoid disease, a larger study is lacking.

Patients and methods: This prospective multicenter study included ten patients with exclusive IgM deposition along the BMZ by direct immunofluorescence (IF). Circulating IgM was detected by indirect IF and immunoblotting with recombinant BP180.

Results: The cohort, four females and six males with a median age of 77 years, presented predominantly with prurigo-like lesions without blisters and mucosal involvement. Sera from nine patients demonstrated linear IgM labeling the blister roof of human salt-split skin by indirect IF. Four patients yielded IgM reactivity against BP180, but none against BP230. In none of the controls (n = 100), anti-BMZ IgM was seen by direct IF. 1/30 and 3/60 controls with or without pruritic non-pemphigoid diseases revealed serum IgM reactivity against the BMZ, respectively.

Conclusions: IgM pemphigoid is characterized by exclusive tissue-bound anti-BMZ IgM, serum anti-BMZ IgM reactivity with BP180 as main target antigen, a predominantly non-bullous clinical phenotype, absence of mucosal involvement, and a rather mild disease course. Our findings indicate that IgM pemphigoid may represent a distinct entity.

Keywords: IgM; autoimmune bullous diseases; immunobullous diseases; pemphigoid.

FIGURE 1

Clinical manifestations of IgM pemphigoid. (a) Confluent, erythematous, well‐defined urticarial plaques along with multiple excoriated papules on the buttocks and lower back in patient 6. (b) Multiple grouped pinhead‐sized excoriated papules with an erythematous base on the breast in patient 6. (c) Disseminated discoid erythematous plaques on the upper back and left arm in patient 5. (d) Erythematous papules and plaques on the dorsum of the left foot in patient 6. (e) Erythematous macules and plaques with few excoriated papules on the left hip in patient 8. (f) Erythematous macules on the antecubital fossa in patient 10.

FIGURE 2

Histopathological spectrum of IgM pemphigoid. (a) Superficial perivascular dermatitis with mild dermal edema and mild lymphohistiocytic infiltrates with scattered eosinophils (asterix) in patient 3 (hematoxylin‐eosin staining [HE], scale bar: 100 µm). (b) Chronic nodular prurigo‐like parakeratosis, irregular acanthosis, and hypergranulosis in patient 6. In the upper dermis, fibrosis and patchy lymphohistiocytic infiltrates are present. Scale bar, 100 µm. (c) Mild spongiotic and psoriasiform dermatitis in patient 10 (HE, scale bar: 100 µm). (d) Perivascular lymphocytic infiltrates with admixed neutrophils (arrows) and few eosinophils (asterix) at higher magnification of (c) (scale bar: 20 µm).

FIGURE 3

Immunopathological features of IgM pemphigoid. (a–c) Direct immunofluorescence (IF) microscopy of a perilesional skin biopsy with sharply delineated, distinct, linear depositions of IgM at the cutaneous BMZ in (a) patient 9, (b) patient 10 and (c) in patient 3. (d) Thick, homogenous band of IgM deposits at the basement membrane zone in a patient with lupus erythematosus in comparison. (e) Indirect IF microscopy on human 1 M salt‐split skin with IgM deposits labeling the epidermal side of the artificial split in patient 6. (f) Linear IgM deposition along the blister roof of salt‐split skin by multiplex IF BIOCHIP^® mosaic (Euroimmun, Lübeck, Germany) in patient 4. (g) IgM autoantibodies against BP180 NC16A by BIOCHIP^® mosaic with recombinant BP180 in patient 3. (h) No IgM deposition by indirect IF microscopy on salt‐split skin was seen in a control patient with atopic dermatitis.

FIGURE 4

Immunoblot analyses of IgM pemphigoid. (a) Immunoblot analyses with recombinant BP180 NC16A. Serum IgM reactivity was detected in patient 3 (lanes 9 and 10), but not in patient 4 (lane 11). Sera of healthy blood donors served as negative controls (lanes 1–5). Sera of three previously reported patients with IgM pemphigoid were used as positive controls (lanes 6–8). (b) By immunoblotting with the recombinant BP180 ectodomain, patient 6 and patient 7 displayed serum IgM reactivity (lanes 8 and 9, respectively). Normal human sera are shown in lanes 1–5, and two previously reported patients with IgM pemphigoid in lanes 6 and 7. Migration positions of the recombinant proteins are indicated by arrows, molecular weight markers in kDa are shown at the right.