BJD
British Journal of Dermatology
CASE REPORT
The expanding spectrum of IgA pemphigus: a case report and review of the literature S. Geller,1 A. Gat,2 T. Zeeli,1 A. Hafner,1 R. Eming,3 M. Hertl3 and E. Sprecher1 1
Department of Dermatology, Tel Aviv Sourasky Medical Center 6, Weizmann Street, Tel Aviv 64239, Israel Department of Pathology, Tel Aviv Sourasky Medical Center 6, Weizmann Street, Tel Aviv 64239, Israel 3 Department of Dermatology and Allergology, Philipps University, Biegenstrasse 10, 35037 Marburg, Germany 2
Summary Correspondence Eli Sprecher. E-mail: [email protected]
Accepted for publication 26 February 2014
Funding sources Minerva Stiftung supports Dr Shamir Geller’s research fellowship at Philipps University, Marburg, Germany.
Conflicts of interest
IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term ‘IGAP spectrum’.
None declared. DOI 10.1111/bjd.12940
What’s already known about this topic?
• •
IgA pemphigus (IGAP) is a rare variant of pemphigus. Pemphigus is traditionally subdivided into subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis.
What does this study add?
• •
A case report and a review of previous reports pointing to the need to revise the current classification of IGAP. The possibility of the existence of a spectrum of IGAP-like diseases.
Within the group of autoimmune bullous diseases of the skin, IgA pemphigus (IGAP) and linear IgA bullous dermatosis (LABD) are two distinct disorders mediated by IgA autoantibodies directed against adhesion molecules located in the epidermis and in the dermoepidermal basement membrane zone (BMZ), respectively. IgA pemphigus is a rare, distinct variant of pemphigus, typically presenting with pustules, erosions or crusts found at the periphery of erythematous annular plaques, and favouring intertriginous regions. Skin biopsies show histological features of intraepidermal blisters with mild acantholysis and neutrophilic infiltration. Epidermal cell surface tissue-bound IgA and circulating IgA autoantibodies are found in most cases, and usually target desmocollin (Dsc) and desmoglein (Dsg) glycoproteins, which are members of the cadherin superfamily, cal650
British Journal of Dermatology (2014) 171, pp650–656
cium-dependent cell adhesion molecules.1 IgA antibodies against nondesmosomal antigens have also been described.2 Binding of IgA antibodies to keratinocyte cell surface antigens leads to accumulation of neutrophils in the epidermis, resulting in – for reasons that are still elusive – intraepidermal blistering. Currently, IGAP is subdivided based on histopathological and immunological criteria into two subtypes: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN). SPD is characterized by subcorneal pustules and is associated with IgA reactivity against Dsc1, a desmosomal cadherin that is most strongly expressed in the uppermost epidermal layers.3,4 In contrast, in IEN, histopathological examination shows suprabasal pustules involving the lower or entire epidermis, while immunological studies have revealed the existence of a wide range of IgA antibodies directed against Dsg1, Dsg3 and © 2014 British Association of Dermatologists
Expanding spectrum of IgA pemphigus, S. Geller et al. 651
Dsc1–3, as well as nondesmosomal cell surface proteins.2 Therefore, the target antigens in IEN remain to be fully elucidated. Linear IgA bullous dermatosis is an IgA-mediated autoimmune bullous disorder seen in children and adults, and is characterized by subepidermal blisters and linear deposits of IgA at the BMZ. It presents with tense blisters in a pearl necklace-like arrangement and urticarial plaques. There is also mucosal involvement in 50% of cases.5 LABD-causing antibodies target a cleavage product of the extracellular domain of the 180-kDa bullous pemphigoid antigen (BP180, type XVII collagen).6,7 Despite being rare, the two diseases have been amply described in the literature. However, their coexistence in one single patient has not been previously reported. Here, we present a patient with clinical and histological features typical of IGAP SPD, with a unique immunological profile of IgA reactivity to both desmosomal (Dscs 2 and 3) and hemidesmosomal (BP180) proteins. We searched the literature and found 20 similar ‘atypical’ IGAP cases that do not fit into current classification schemes, as they showed heterogeneous immunological profiles of IgA or combined IgA/IgG autoantibodies against various adhesion molecules. The reclassification of these cases under the general term ‘IGAP spectrum’ seems appropriate not only because it takes into account the wide phenotypic variability of IGAP, but also because it demarcates a clinical entity based upon pathogenetic criteria with obvious therapeutic implications.
Case report A 74-year-old woman of Romanian origin presented with a 10year history of pustular erythematous plaques covered with erosions and crusts over flexural areas. The patient’s medical history was unremarkable. Physical examination revealed a symmetric rash involving the inframammary areas, axillae and groin, consisting of well-demarcated reddish-violet plaques. Some of these lesions were annular, with central crusts and scattered pustules (Fig. 1a,b). Oral and genital mucosal surfaces were not involved. Nikolsky’s sign could not be elicited. Routine laboratory tests were within the normal range, with the exception of an elevated white blood cell count of 148 9 109 cells L 1 (normal range 40–110 9 109 cells L 1). Microbial and (a)
fungal cultures from the pustules were sterile. A comprehensive work-up showed no signs of malignancy. Examination of a skin biopsy from one of the pustular lesions showed subcorneal pustules with neutrophils, few eosinophils and numerous acantholytic cells in the superficial epidermis (Fig. 2a) with few subepidermal blisters (Fig. 2b). Direct immunofluorescence of perilesional skin revealed granular C3 deposits along the BMZ. Indirect immunofluorescence on monkey oesophagus sections revealed intercellular IgA and weak IgG staining in the basal cell layer (Fig. 2c,d). Indirect immunofluorescence of 1 mol L 1 NaCl split skin sections showed IgA depositions along the blister roof (Fig. 2e), but no IgG reactivity. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and immunoblotting (IB) were performed with recombinant Dsg1, Dsg3, Dsc1, Dsc2, Dsc3 and BP180-N (NC16A domain and the collagenous Col15 domain of BP180) as previously described.8,9 The recombinant proteins were produced and expressed in a eukaryotic system (Sf21 cells and High Five insect cells; Invitrogen, Carlsbad, CA, U.S.A.) by infection with recombinant baculovirus, and purified as described previously.8,9 Immunoblotting analysis of the patient’s serum revealed circulating IgA autoantibodies directed against Dsc2 and Dsc3, as well as against the immunodominant NC16A-domain of BP180. Weaker IgG reactivity was found against Dsc2 and Dsc3 (Fig. 3). IgA and IgG antibodies against Dsc1 were not found in the patient’s serum, and neither IgG nor IgA antibodies against Dsg1 and Dsg3 were detected by a commercially available enzyme-linked immunosorbent assay (AG kit; Euroimmun Medizinische Labordiagnostika, L€ ubeck, Germany) or IB (data not shown). Based on these findings, we classified this case as atypical IGAP with concomitant linear IgA disease. Treatment with 125 mg diamino-diphenyl sulfone (dapsone) per day cleared all lesions within a few weeks, leading to prolonged remission over the following 18 months.
Discussion IgA pemphigus is a rare autoimmune blistering disease associated with IgA autoantibodies against the keratinocyte cell (b)
Fig 1. Clinical features. Reddish plaques are covered with pustules, scales and crusts over the skin of (a) the lower abdomen and (b) right inframammary fold. © 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 171, pp650–656
652 Expanding spectrum of IgA pemphigus, S. Geller et al.
(a)
(c)
(b)
(d)
(e)
Fig 2. Results of histology and indirect immunoflorescence. (a) Skin biopsy shows subcorneal pustules with neutrophils, few eosinophils and scant acantholytic cells (arrow) in the superficial epidermis. (b) Skin biopsy shows a subepidermal blister filled with polymorphonuclear cells. (c, d) Indirect immunofluorescence using monkey oesophagus revealed (c) basal cell layer IgA staining and (d) weaker IgG staining. (e) Indirect immunofluorescence of salt split human skin shows linear IgA deposition along the epidermal side of the blister.
Fig 3. Immunoblotting with 75-kDa recombinant desmocollins (Dsc) 2 and 3, and 63-kDa BP180 NC16A show IgA and weak IgG reactivity against Dsc2 and Dsc3 (left side), and IgA reactivity to BP180 NC16A protein (right side). An anti-E-tag staining (Dscs 2 and 3, anti-E-tag mab, H1029, 1: 7500; Sigma-Aldrich, St. Louis, MO, U.S.A.) and serum of a linear IgA bullous dermatosis patient (BP180) was used as a positive control; sera from healthy individuals served as negative control. (Note that the 95-kDa bands are due to nonspecific binding.)
surface. Traditionally, the disease is classified into either SPD or IEN, depending on the histological features, immunofluorescence staining pattern and autoantibody profile. Of note, IEN IGAP cases typically show greater clinical, histological and immunological heterogeneity. The clinical and histopathological features of SPD IGAP are identical to those of subcorneal pustular dermatosis (Sneddon– Wilkinson disease), with a possible overlap between these two disorders, specifically in cases with unusual autoantibody profiles. In our patient, the clinical features and histopathological findings were compatible with subcorneal pustular dermatosis, and the presence of circulating IgA antibodies supported the diagnosis of SPD IGAP. However, detection of IgA against Dsc2 and Dsc3, but not against Dsc1 is rather uncommon for this diagnosis. ‘Atypical’ IGAP is a term used for cases that do not totally fit into either one of the two major IGAP subtypes, usually showing some discrepancy between histological features, epidermal British Journal of Dermatology (2014) 171, pp650–656
immunofluorescence staining pattern and immunological profile, as was shown in our patient. Previously reported atypical IGAP cases are summarized in Table 1. Similar to our patient, subcorneal pustular dermatoses without anti-Dsc1 IgA have been previously reported.10–12 A review of the literature indicates that SPD-like features can be associated with IgA antibodies targeting autoantigens other than Dsc1, whereas IgA reactivity against Dsc1 does not necessarily result in subcorneal pustule formation. Further underscoring the complexity of IGAP, several cases have been reported with positive direct and indirect immunofluorescence evidence for IgA autoantibodies, but no reactivity to either Dsc or Dsg,13–15 suggesting the existence of other, not yet identified, cell surface autoantigens in IGAP. Conversely, IgA autoantibodies are far more common in apparently ‘typical’ IgG-mediated pemphigus vulgaris than generally assumed, as shown in two large studies.16,17 Clearly, as more sensitive detection methods become available,9,18 the complexity of IGAP and pemphigus-related phenotypes in general is expected to further unfold. © 2014 British Association of Dermatologists
© 2014 British Association of Dermatologists
F
81
M
67
F
M
11
33
M
63
M
M
42
48
F
42
F
F
35
39
M
7
Vesicles and pustules, erythema with crust and scale Vesicles on erythema circinatum with flaccid pustules and erosions in the edges
Coalescent large pustules, some with hypopyon, and erosions
Flaccid vesicles and pustules surrounding central erosions and crusts
Annular erythema with vesicles, pustules, erosions, crusts and scales. Erythematous papules with central erosions or crusts Erythematous papules, vesicles and erosions with crusting in the periphery of annular erythema Disseminated small vesicles and pustules, erythematous plaques with desquamation and crusts Erythematous plaques with erosions and crusts Grouped flaccid pustules on erythematous base. Vesicles, crusts and erosions on tongue and vermilion of lips Pustules and erosions on verrucous plaques. Aphthae and white plaques in the oral mucosa
Oozing verrucous plaques
Age (years) Sex Clinical findings Immunofluorescence
N/P
–
N/P
IgA
–
–
IgA, IgG –
–
–
DIF: IC IgA, IgG, C3 IIF: negative
N/P
–
N/P
–
–
–
–
DIF: IC IgG, IgA IIF: IC IgA, IgG stronger in upper epidermis (HS, GPE) N/M –
–
DIF: IC IgA, BMZ IgG IIF: IC IgA (ME)
–
–
–
–
–
–
–
Dsc3
IgA, IgG –
–
–
IgG
Dsc2
Dsc1
Target antigens
IgG – (weak)
DIF: IC IgA, IgG, C3 IIF: IC IgA, IgG IC (SSS)
DIF: IC IgA, IgG, C3, entire epidermis IIF: IC IgA, lower epidermis (HS, SSS), negative (ME) DIF: IC IgA, stronger in upper epidermis IIF: IC IgA, stronger in upper epidermis (HS)
DIF: IC IgA, IgG, entire epidermis IIF: IC IgA, IgG, stronger in superficial epidermis (HS) Subcorneal pustules with dense neutrophilic DIF: IC IgA, entire epidermis infiltrate, without acantholytic cells. Papillary IIF: negative (ME, SSS) oedema and sparse lymphohistiocytic eosinophilic infiltrate in upper dermis Superficial, partly subcorneal bullae filled DIF: IC IgA, IgG, stronger in with neutrophils upper epidermis IIF: IC IgA, IgG (ME) Acantholytic cells and neutrophil DIF: IC IgA, IgG, C3, superficial infiltration in the subcorneal space epidermis IIF: IC IgA, IgG, stronger in upper epidermis (HS)
Subcorneal acantholytic bullae with numerous neutrophils Suprabasilar split with marked acantholysis. Subepidermal split. Vesicular areas with neutrophilic infiltrate. Mixed infiltrate of neutrophils and lymphocytes in superficial dermis Acanthosis, focal suprabasal acantholysis, large intraepidermal abscesses with many eosinophils. Dense, mixed infiltrate of eosinophils, neutrophils and lymphocytes in upper dermis Subcorneal pustules with acantholysis and intraepidermal pustules without acantholysis
Intraepidermal vesicles filled with neutrophils and numerous eosinophils; scant acantholytic cells
Subcorneal pustules containing neutrophils, without acantholytic cells. Neutrophils infiltrating the epidermis. Perivascular lymphocytes, neutrophils and eosinophils in upper dermis Acantholytic bullae in the upper epidermis, predominantly neutrophilic infiltrate in the epidermis
Acantholysis of midepidermis and hair follicles with neutrophilic abscesses
Histology
Table 1 Atypical cases of IgA pemphigus: review of the literature
Dsg3
–
–
N/M
Dapsone
Prednisolone, minocycline
Dapsone
Dapsone
Treatment
Dapsone
–
IgA, IgG –
Dapsone
Dapsone, prednisone
Dapsone, etretinate
–
IgA, IgG Dapsone, prednisolone
IgA, IgG Dapsone, prednisone
–
IgA, IgG –
IgA
–
–
N/P
–
IgA, IgG –
IgA, IgG –
–
–
Dsg1
Maruyama et al.31
Kowalewski et al.10
Kopp et al.30
Heng et al.29
Morizane et al.28
Bruckner et al.27
Hisamatsu et al.18
Kozlowska et al.26
Oiso et al.25
Niimi et al.14
Weston et al.13
Reference
Expanding spectrum of IgA pemphigus, S. Geller et al. 653
British Journal of Dermatology (2014) 171, pp650–656
British Journal of Dermatology (2014) 171, pp650–656
F
M
F
M
25
71
25
69
Histology Eosinophilic spongiosis of the epidermis (early lesion)
Subcorneal cleft with acantholysis. Blister filled with fibrin, erythrocytes and numerous neutrophils. In the upper dermis, neutrophils that infiltrated the epidermis Flaccid vesicles, pustules Subcorneal bullae containing numerous and crusted erosions on neutrophils and few eosinophils. Focal erythematous base intercellular oedema in the epidermis. No acantholysis Annular erythema with crusts, Neutrophilic spongiosis in the epidermis malar rash-like facial erythema and marked oedema in the with vesicles on the border superficial dermis Annular erythematous plaques Intraepidermal pustules filled with with erosions in the periphery neutrophils and acantholytic cells Erythematous annular plaques Subcorneal pustules and vesicles containing with peripheral vesicles, few acantholytic cells and occasional pustules and erosions intraepidermal pustules Edematous well-demarcated Intraepidermal blisters with neutrophil erythema coalescing to annular infiltrates without patterns with vesicles on prominent acantholysis the edges Small flaccid pustules on Acantholysis and prominent subcorneal coalescent erythema with pustules with smaller pustules in crusts and erosions midepidermis. Neutrophils in oedematous upper dermis Diffuse exudative erythemas Slight spongiosis in the epidermis and without bullous or pustular sparse superficial perivascular lesions inflammatory infiltrates Annular erythematous plaques Subcorneal pustules with neutrophils, few with central crusts and eosinophils, and numerous acantholytic scattered pustules cells in superficial epidermis. Subepidermal blisters
Annular urticarial plaques with central paleness, tense vesicles Vesicles and pustules on erythematous base with crusts and erosions
Immunofluorescence
Dsc3
IgA
–
Dsg1
–
–
IgA, IgG IgA, IgG – (weak) (weak)
–
–
–
IgA
–
–
–
IgA, IgG –
IgA, IgG – –
–
–
–
Hirata et al.34
Santiago-et-SanchezMateos et al.11
Hosoda et al.33
Iida et al.15
D€ uker et al.32
M€ uller et al.9
Reference
Dapsone
Prednisolone
Present case
Arai et al.35
Dapsone/etretinate, Asahina et al.12 prednisolone, minocycline/R-CHOP
Dapsone
Acitretin, methylprednisolone
Topical steroid
Dapsone, prednisolone
Dapsone
Dapsone
N/M
IgA, IgG –
–
–
Treatment
Dsg3 –
– IgA
N/P
–
–
N/P
–
–
IgG
–
–
IgG
IgA
IgA
IgG
DIF: IC IgA, entire epidermis IgA IIF: IC IgA, IgG (ME), negative (HS) DIF: BMZ C3 – IIF: IC IgA, IgG, basal epidermis (ME), IgA – epidermal side of blister (SSS)
DIF: IC IgA, IgG, stronger in the upper epidermis IIF: IC IgA (HS)
DIF: IC IgA, entire epidermis IIF: IC IgA (HS)
DIF: IC IgA, IgG, stronger in superficial layers IIF: IC IgA, IgG (HS) DIF: IC IgA, IgG, entire epidermis IIF: IC IgG (ME), negative (SSS) DIF: IC IgA, IgG, entire epidermis
Dsc2
IgA, IgG IgA, IgG IgA, IgG N/P (weak) (weak) (weak)
Dsc1
DIF: IC IgA, stronger in superficial IgA layers IIF: IgA – interface of the stratum corneum and stratum granulosum (SSS), negative (ME, HS) DIF: negative – IIF: IC IgA, entire epidermis (HS)
DIF: IC C3
Target antigens
Dsc, desmocollin; Dsg, desmoglein; M, male; F, female; DIF, direct immunofluorescence; IC, intercellular; IIF, indirect immunofluorescence; HS, human skin; SSS, salt split skin; ME, monkey oesophagus; GPE, guinea pig oesophagus; N/M, not mentioned; BMZ, basal membrane zone; N/P, not performed.
F
F
62
74
M
48
M
F
94
56
M
80
Age (years) Sex Clinical findings
Table 1 (continued)
654 Expanding spectrum of IgA pemphigus, S. Geller et al.
© 2014 British Association of Dermatologists
Expanding spectrum of IgA pemphigus, S. Geller et al. 655
The lack of detection of epidermal intercellular deposits of IgA or IgG on direct immunofluorescence in our case is puzzling. Technical limitations and/or low levels of the pathogenic immunoglobulins could have accounted for this result. Negative direct immunofluorescence can rarely be found in pemphigus vulgaris, but is certainly more common in IGAP,17 presumably owing to the fact that IgA immune complexes are less stable and more sensitive to degradation. Several previous IgA and IgA/IgG cases of pemphigus showed no IgA staining on direct immunofluorescence, despite positive indirect immunofluorescence and immune assays.9,15,19 To the best of our knowledge, the concurrence of atypical IGAP and LABD in the same patient has not been described previously. Interestingly, a case of herpetiform bullous dermatosis with IgG antibodies to Dsc 1 and 3, as well as to LAD-1 (the 120-kDa ectodomain of BP180) was recently reported; although IgA autoantibodies to Dsc3 were also identified, their pathogenic relevance in that case was questioned.20 In light of the chronicity of the patient’s skin disorder (> 10 years), the unique autoantibody profile was probably related to epitope spreading. The possibility of a paraneoplastic autoimmune blistering disease was also considered in regard to this atypical presentation, as both IGAP and LABD have been reported in association with malignancies. The complex immunopathological profile found in paraneoplastic pemphigus (PNP) cases includes IgA antibodies against the cell surface and antibodies against the BMZ.21–24 Although our patient did not present clinical and histological features consistent with PNP, a comprehensive work-up was performed, which gave no hint of malignancy. In this case, the rapid response to treatment with dapsone further supported our conclusion that this diagnosis was unlikely. In summary, we propose the term ‘IGAP spectrum’ to account for the growing number of atypical IGAP cases associated with IgA reactivity against various autoantigens of the epidermis or BMZ as shown in this patient and an additional 20 previously published atypical cases of IGAP.
References 1 Robinson ND, Hashimoto T, Amagai M et al. The new pemphigus variants. J Am Acad Dermatol 1999; 40:649–72. 2 Ishii N, Ishida-Yamamoto A, Hashimoto T. Immunolocalization of target autoantigens in IgA pemphigus. Clin Exp Dermatol 2004; 29:62–6. 3 Supapannachart N, Mutasim DF. The distribution of IgA pemphigus antigen in human skin and the role of IgA anti-cell surface antibodies in the induction of intraepidermal acantholysis. Arch Dermatol 1993; 129:605–8. 4 Hashimoto T, Kiyokawa C, Mori O et al. Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997; 109:127–31. 5 Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: clinical manifestations. J Dtsch Dermatol Ges 2011; 9:844–56. 6 Pas HH, Kloosterhuis GJ, Heeres K et al. Bullous pemphigoid and linear IgA dermatosis sera recognize a similar 120 kDa keratinocyte collagenous glycoprotein with antigenic cross-reactivity to BP180. J Invest Dermatol 1997; 108:423–9. © 2014 British Association of Dermatologists
7 Zone JJ, Taylor TB, Meyer LJ et al. The 97 kDa linear IgA bullous disease antigen is identical to a protein of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998; 110:207–10. 8 Hofmann S, Thoma-Uszynski S, Hunziker T et al. Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002; 119:1065–73. 9 M€ uller R, Heber B, Hashimoto T et al. Autoantibodies against desmocollins in European patients with pemphigus. Clin Exp Dermatol 2009; 34:898–903. 10 Kowalewski C, Hashimoto T, Amagai M et al. IgA/IgG pemphigus: a new atypical subset of pemphigus? Acta Derm Venereol 2006; 86:357–8. 11 Santiago-et-Sanchez-Mateos D, Juarez Martın A, Gonzalez De Arriba A et al. IgG/IgA pemphigus with IgA and IgG antidesmoglein 1 antibodies detected by enzyme-linked immunosorbent assay: presentation of two cases. J Eur Acad Dermatol Venereol 2011; 25:110–12. 12 Asahina A, Koga H, Suzuki Y et al. IgA pemphigus associated with diffuse large B-cell lymphoma showing unique reactivity with desmocollins: unusual clinical and histopathological features. Br J Dermatol 2013; 168:224–6. 13 Weston WL, Friednash M, Hashimoto T et al. A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1998; 38:635–8. 14 Niimi Y, Kawana S, Kusunoki T. IgA pemphigus: a case report and its characteristic clinical features compared with subcorneal pustular dermatosis. J Am Acad Dermatol 2000; 43:546–9. 15 Iida K, Sueki H, Ohyama B et al. A unique case of intra-epidermal neutrophilic dermatosis-type IgA pemphigus presenting with subcorneal pustules. Dermatology 2011; 222:15–19. 16 Spaeth S, Riechers R, Borradori L et al. IgG, IgA and IgE autoantibodies against the ectodomain of desmoglein 3 in active pemphigus vulgaris. Br J Dermatol 2001; 144:1183–8. 17 Mentink LF, de Jong MC, Kloosterhuis GJ et al. Coexistence of IgA antibodies to desmoglein 1 and 3 in pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. Br J Dermatol 2007; 156:635–41. 18 Hisamatsu Y, Amagai M, Garrod DR et al. The detection of IgG and IgA autoantibodies to desmocollins 1–3 by enzyme-linked immunosorbent assays using baculovirus-expressed proteins, in atypical pemphigus but not in typical pemphigus. Br J Dermatol 2004; 151:73–83. 19 Nakajima K, Hashimoto T, Nakajima H et al. IgG/IgA pemphigus with dyskeratotic acantholysis and intraepidermal neutrophilic microabscesses. J Dermatol 2007; 34:757–60. 20 Ueda A, Ishii N, Teye K et al. Unique herpetiform bullous dermatosis with IgG antibodies to desmocollins 1/3 and LAD-1. Br J Dermatol 2013; 169:719–21. 21 Gooptu C, Mendelsohn S, Amagai M et al. Unique immunobullous disease in a child with a predominantly IgA response to three desmosomal proteins. Br J Dermatol 1999; 141:882–6. 22 Preisz K, Horvath A, Sardy M et al. Exacerbation of paraneoplastic pemphigus by cyclophosphamide treatment: detection of novel autoantigens and bronchial autoantibodies. Br J Dermatol 2004; 150:1018–24. 23 Taintor AR, Leiferman KM, Hashimoto T et al. A novel case of IgA paraneoplastic pemphigus associated with chronic lymphocytic leukemia. J Am Acad Dermatol 2007; 56:S73–6. 24 Ueda A, Ishii N, Temporin K et al. IgA pemphigus with paraneoplastic pemphigus-like clinical features showing IgA antibodies to desmoglein 1/3 and desmocollin 3, and IgG and IgA antibodies to the basement membrane zone. Clin Exp Dermatol 2013; 38:370–3.
British Journal of Dermatology (2014) 171, pp650–656
656 Expanding spectrum of IgA pemphigus, S. Geller et al. 25 Oiso N, Yamashita C, Yoshioka K et al. IgG/IgA pemphigus with IgG and IgA antidesmoglein 1 antibodies detected by enzymelinked immunosorbent assay. Br J Dermatol 2002; 147:1012– 17. 26 Kozlowska A, Hashimoto T, Jarzabek-Chorzelska M et al. Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3. J Am Acad Dermatol 2003; 48:117–22. 27 Bruckner AL, Fitzpatrick JE, Hashimoto T et al. Atypical IgA/IgG pemphigus involving the skin, oral mucosa, and colon in a child: a novel variant of IgA pemphigus. Pediatr Dermatol 2005; 22:321– 7. 28 Morizane S, Yamamoto T, Hisamatsu Y et al. Pemphigus vegetans with IgG and IgA antidesmoglein 3 antibodies. Br J Dermatol 2005; 153:1236–7. 29 Heng A, Nwaneshiudu A, Hashimoto T et al. Intraepidermal neutrophilic IgA/IgG antidesmocollin 1 pemphigus. Br J Dermatol 2006; 154:1018–20.
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30 Kopp T, Sitaru C, Pieczkowski F et al. IgA pemphigus – occurrence of anti-desmocollin 1 and anti-desmoglein 1 antibody reactivity in an individual patient. J Dtsch Dermatol Ges 2006; 4:1045–50. 31 Maruyama H, Kawachi Y, Fujisawa Y et al. IgA/IgG pemphigus positive for anti-desmoglein 1 autoantibody. Eur J Dermatol 2007; 17:94–5. 32 D€ uker I, Schaller J, Rose C et al. Subcorneal pustular dermatosistype IgA pemphigus with autoantibodies to desmocollins 1, 2, and 3. Arch Dermatol 2009; 145:1159–62. 33 Hosoda S, Suzuki M, Komine M et al. A case of IgG/IgA pemphigus presenting malar rash-like erythema. Acta Derm Venereol 2012; 92:164–6. 34 Hirata Y, Abe R, Kikuchi K et al. Intraepidermal neutrophilic IgA pemphigus successfully treated with dapsone. Eur J Dermatol 2012; 22:282–3. 35 Arai R, Okuda H, Tsuruta D et al. IgA pemphigus with non-pustular erythematous lesions and IgA antibodies to desmocollins 1 and 2. Eur J Dermatol 2013; 23:362–5.
© 2014 British Association of Dermatologists
British Journal of Dermatology
CASE REPORT
The expanding spectrum of IgA pemphigus: a case report and review of the literature S. Geller,1 A. Gat,2 T. Zeeli,1 A. Hafner,1 R. Eming,3 M. Hertl3 and E. Sprecher1 1
Department of Dermatology, Tel Aviv Sourasky Medical Center 6, Weizmann Street, Tel Aviv 64239, Israel Department of Pathology, Tel Aviv Sourasky Medical Center 6, Weizmann Street, Tel Aviv 64239, Israel 3 Department of Dermatology and Allergology, Philipps University, Biegenstrasse 10, 35037 Marburg, Germany 2
Summary Correspondence Eli Sprecher. E-mail: [email protected]
Accepted for publication 26 February 2014
Funding sources Minerva Stiftung supports Dr Shamir Geller’s research fellowship at Philipps University, Marburg, Germany.
Conflicts of interest
IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term ‘IGAP spectrum’.
None declared. DOI 10.1111/bjd.12940
What’s already known about this topic?
• •
IgA pemphigus (IGAP) is a rare variant of pemphigus. Pemphigus is traditionally subdivided into subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis.
What does this study add?
• •
A case report and a review of previous reports pointing to the need to revise the current classification of IGAP. The possibility of the existence of a spectrum of IGAP-like diseases.
Within the group of autoimmune bullous diseases of the skin, IgA pemphigus (IGAP) and linear IgA bullous dermatosis (LABD) are two distinct disorders mediated by IgA autoantibodies directed against adhesion molecules located in the epidermis and in the dermoepidermal basement membrane zone (BMZ), respectively. IgA pemphigus is a rare, distinct variant of pemphigus, typically presenting with pustules, erosions or crusts found at the periphery of erythematous annular plaques, and favouring intertriginous regions. Skin biopsies show histological features of intraepidermal blisters with mild acantholysis and neutrophilic infiltration. Epidermal cell surface tissue-bound IgA and circulating IgA autoantibodies are found in most cases, and usually target desmocollin (Dsc) and desmoglein (Dsg) glycoproteins, which are members of the cadherin superfamily, cal650
British Journal of Dermatology (2014) 171, pp650–656
cium-dependent cell adhesion molecules.1 IgA antibodies against nondesmosomal antigens have also been described.2 Binding of IgA antibodies to keratinocyte cell surface antigens leads to accumulation of neutrophils in the epidermis, resulting in – for reasons that are still elusive – intraepidermal blistering. Currently, IGAP is subdivided based on histopathological and immunological criteria into two subtypes: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN). SPD is characterized by subcorneal pustules and is associated with IgA reactivity against Dsc1, a desmosomal cadherin that is most strongly expressed in the uppermost epidermal layers.3,4 In contrast, in IEN, histopathological examination shows suprabasal pustules involving the lower or entire epidermis, while immunological studies have revealed the existence of a wide range of IgA antibodies directed against Dsg1, Dsg3 and © 2014 British Association of Dermatologists
Expanding spectrum of IgA pemphigus, S. Geller et al. 651
Dsc1–3, as well as nondesmosomal cell surface proteins.2 Therefore, the target antigens in IEN remain to be fully elucidated. Linear IgA bullous dermatosis is an IgA-mediated autoimmune bullous disorder seen in children and adults, and is characterized by subepidermal blisters and linear deposits of IgA at the BMZ. It presents with tense blisters in a pearl necklace-like arrangement and urticarial plaques. There is also mucosal involvement in 50% of cases.5 LABD-causing antibodies target a cleavage product of the extracellular domain of the 180-kDa bullous pemphigoid antigen (BP180, type XVII collagen).6,7 Despite being rare, the two diseases have been amply described in the literature. However, their coexistence in one single patient has not been previously reported. Here, we present a patient with clinical and histological features typical of IGAP SPD, with a unique immunological profile of IgA reactivity to both desmosomal (Dscs 2 and 3) and hemidesmosomal (BP180) proteins. We searched the literature and found 20 similar ‘atypical’ IGAP cases that do not fit into current classification schemes, as they showed heterogeneous immunological profiles of IgA or combined IgA/IgG autoantibodies against various adhesion molecules. The reclassification of these cases under the general term ‘IGAP spectrum’ seems appropriate not only because it takes into account the wide phenotypic variability of IGAP, but also because it demarcates a clinical entity based upon pathogenetic criteria with obvious therapeutic implications.
Case report A 74-year-old woman of Romanian origin presented with a 10year history of pustular erythematous plaques covered with erosions and crusts over flexural areas. The patient’s medical history was unremarkable. Physical examination revealed a symmetric rash involving the inframammary areas, axillae and groin, consisting of well-demarcated reddish-violet plaques. Some of these lesions were annular, with central crusts and scattered pustules (Fig. 1a,b). Oral and genital mucosal surfaces were not involved. Nikolsky’s sign could not be elicited. Routine laboratory tests were within the normal range, with the exception of an elevated white blood cell count of 148 9 109 cells L 1 (normal range 40–110 9 109 cells L 1). Microbial and (a)
fungal cultures from the pustules were sterile. A comprehensive work-up showed no signs of malignancy. Examination of a skin biopsy from one of the pustular lesions showed subcorneal pustules with neutrophils, few eosinophils and numerous acantholytic cells in the superficial epidermis (Fig. 2a) with few subepidermal blisters (Fig. 2b). Direct immunofluorescence of perilesional skin revealed granular C3 deposits along the BMZ. Indirect immunofluorescence on monkey oesophagus sections revealed intercellular IgA and weak IgG staining in the basal cell layer (Fig. 2c,d). Indirect immunofluorescence of 1 mol L 1 NaCl split skin sections showed IgA depositions along the blister roof (Fig. 2e), but no IgG reactivity. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and immunoblotting (IB) were performed with recombinant Dsg1, Dsg3, Dsc1, Dsc2, Dsc3 and BP180-N (NC16A domain and the collagenous Col15 domain of BP180) as previously described.8,9 The recombinant proteins were produced and expressed in a eukaryotic system (Sf21 cells and High Five insect cells; Invitrogen, Carlsbad, CA, U.S.A.) by infection with recombinant baculovirus, and purified as described previously.8,9 Immunoblotting analysis of the patient’s serum revealed circulating IgA autoantibodies directed against Dsc2 and Dsc3, as well as against the immunodominant NC16A-domain of BP180. Weaker IgG reactivity was found against Dsc2 and Dsc3 (Fig. 3). IgA and IgG antibodies against Dsc1 were not found in the patient’s serum, and neither IgG nor IgA antibodies against Dsg1 and Dsg3 were detected by a commercially available enzyme-linked immunosorbent assay (AG kit; Euroimmun Medizinische Labordiagnostika, L€ ubeck, Germany) or IB (data not shown). Based on these findings, we classified this case as atypical IGAP with concomitant linear IgA disease. Treatment with 125 mg diamino-diphenyl sulfone (dapsone) per day cleared all lesions within a few weeks, leading to prolonged remission over the following 18 months.
Discussion IgA pemphigus is a rare autoimmune blistering disease associated with IgA autoantibodies against the keratinocyte cell (b)
Fig 1. Clinical features. Reddish plaques are covered with pustules, scales and crusts over the skin of (a) the lower abdomen and (b) right inframammary fold. © 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 171, pp650–656
652 Expanding spectrum of IgA pemphigus, S. Geller et al.
(a)
(c)
(b)
(d)
(e)
Fig 2. Results of histology and indirect immunoflorescence. (a) Skin biopsy shows subcorneal pustules with neutrophils, few eosinophils and scant acantholytic cells (arrow) in the superficial epidermis. (b) Skin biopsy shows a subepidermal blister filled with polymorphonuclear cells. (c, d) Indirect immunofluorescence using monkey oesophagus revealed (c) basal cell layer IgA staining and (d) weaker IgG staining. (e) Indirect immunofluorescence of salt split human skin shows linear IgA deposition along the epidermal side of the blister.
Fig 3. Immunoblotting with 75-kDa recombinant desmocollins (Dsc) 2 and 3, and 63-kDa BP180 NC16A show IgA and weak IgG reactivity against Dsc2 and Dsc3 (left side), and IgA reactivity to BP180 NC16A protein (right side). An anti-E-tag staining (Dscs 2 and 3, anti-E-tag mab, H1029, 1: 7500; Sigma-Aldrich, St. Louis, MO, U.S.A.) and serum of a linear IgA bullous dermatosis patient (BP180) was used as a positive control; sera from healthy individuals served as negative control. (Note that the 95-kDa bands are due to nonspecific binding.)
surface. Traditionally, the disease is classified into either SPD or IEN, depending on the histological features, immunofluorescence staining pattern and autoantibody profile. Of note, IEN IGAP cases typically show greater clinical, histological and immunological heterogeneity. The clinical and histopathological features of SPD IGAP are identical to those of subcorneal pustular dermatosis (Sneddon– Wilkinson disease), with a possible overlap between these two disorders, specifically in cases with unusual autoantibody profiles. In our patient, the clinical features and histopathological findings were compatible with subcorneal pustular dermatosis, and the presence of circulating IgA antibodies supported the diagnosis of SPD IGAP. However, detection of IgA against Dsc2 and Dsc3, but not against Dsc1 is rather uncommon for this diagnosis. ‘Atypical’ IGAP is a term used for cases that do not totally fit into either one of the two major IGAP subtypes, usually showing some discrepancy between histological features, epidermal British Journal of Dermatology (2014) 171, pp650–656
immunofluorescence staining pattern and immunological profile, as was shown in our patient. Previously reported atypical IGAP cases are summarized in Table 1. Similar to our patient, subcorneal pustular dermatoses without anti-Dsc1 IgA have been previously reported.10–12 A review of the literature indicates that SPD-like features can be associated with IgA antibodies targeting autoantigens other than Dsc1, whereas IgA reactivity against Dsc1 does not necessarily result in subcorneal pustule formation. Further underscoring the complexity of IGAP, several cases have been reported with positive direct and indirect immunofluorescence evidence for IgA autoantibodies, but no reactivity to either Dsc or Dsg,13–15 suggesting the existence of other, not yet identified, cell surface autoantigens in IGAP. Conversely, IgA autoantibodies are far more common in apparently ‘typical’ IgG-mediated pemphigus vulgaris than generally assumed, as shown in two large studies.16,17 Clearly, as more sensitive detection methods become available,9,18 the complexity of IGAP and pemphigus-related phenotypes in general is expected to further unfold. © 2014 British Association of Dermatologists
© 2014 British Association of Dermatologists
F
81
M
67
F
M
11
33
M
63
M
M
42
48
F
42
F
F
35
39
M
7
Vesicles and pustules, erythema with crust and scale Vesicles on erythema circinatum with flaccid pustules and erosions in the edges
Coalescent large pustules, some with hypopyon, and erosions
Flaccid vesicles and pustules surrounding central erosions and crusts
Annular erythema with vesicles, pustules, erosions, crusts and scales. Erythematous papules with central erosions or crusts Erythematous papules, vesicles and erosions with crusting in the periphery of annular erythema Disseminated small vesicles and pustules, erythematous plaques with desquamation and crusts Erythematous plaques with erosions and crusts Grouped flaccid pustules on erythematous base. Vesicles, crusts and erosions on tongue and vermilion of lips Pustules and erosions on verrucous plaques. Aphthae and white plaques in the oral mucosa
Oozing verrucous plaques
Age (years) Sex Clinical findings Immunofluorescence
N/P
–
N/P
IgA
–
–
IgA, IgG –
–
–
DIF: IC IgA, IgG, C3 IIF: negative
N/P
–
N/P
–
–
–
–
DIF: IC IgG, IgA IIF: IC IgA, IgG stronger in upper epidermis (HS, GPE) N/M –
–
DIF: IC IgA, BMZ IgG IIF: IC IgA (ME)
–
–
–
–
–
–
–
Dsc3
IgA, IgG –
–
–
IgG
Dsc2
Dsc1
Target antigens
IgG – (weak)
DIF: IC IgA, IgG, C3 IIF: IC IgA, IgG IC (SSS)
DIF: IC IgA, IgG, C3, entire epidermis IIF: IC IgA, lower epidermis (HS, SSS), negative (ME) DIF: IC IgA, stronger in upper epidermis IIF: IC IgA, stronger in upper epidermis (HS)
DIF: IC IgA, IgG, entire epidermis IIF: IC IgA, IgG, stronger in superficial epidermis (HS) Subcorneal pustules with dense neutrophilic DIF: IC IgA, entire epidermis infiltrate, without acantholytic cells. Papillary IIF: negative (ME, SSS) oedema and sparse lymphohistiocytic eosinophilic infiltrate in upper dermis Superficial, partly subcorneal bullae filled DIF: IC IgA, IgG, stronger in with neutrophils upper epidermis IIF: IC IgA, IgG (ME) Acantholytic cells and neutrophil DIF: IC IgA, IgG, C3, superficial infiltration in the subcorneal space epidermis IIF: IC IgA, IgG, stronger in upper epidermis (HS)
Subcorneal acantholytic bullae with numerous neutrophils Suprabasilar split with marked acantholysis. Subepidermal split. Vesicular areas with neutrophilic infiltrate. Mixed infiltrate of neutrophils and lymphocytes in superficial dermis Acanthosis, focal suprabasal acantholysis, large intraepidermal abscesses with many eosinophils. Dense, mixed infiltrate of eosinophils, neutrophils and lymphocytes in upper dermis Subcorneal pustules with acantholysis and intraepidermal pustules without acantholysis
Intraepidermal vesicles filled with neutrophils and numerous eosinophils; scant acantholytic cells
Subcorneal pustules containing neutrophils, without acantholytic cells. Neutrophils infiltrating the epidermis. Perivascular lymphocytes, neutrophils and eosinophils in upper dermis Acantholytic bullae in the upper epidermis, predominantly neutrophilic infiltrate in the epidermis
Acantholysis of midepidermis and hair follicles with neutrophilic abscesses
Histology
Table 1 Atypical cases of IgA pemphigus: review of the literature
Dsg3
–
–
N/M
Dapsone
Prednisolone, minocycline
Dapsone
Dapsone
Treatment
Dapsone
–
IgA, IgG –
Dapsone
Dapsone, prednisone
Dapsone, etretinate
–
IgA, IgG Dapsone, prednisolone
IgA, IgG Dapsone, prednisone
–
IgA, IgG –
IgA
–
–
N/P
–
IgA, IgG –
IgA, IgG –
–
–
Dsg1
Maruyama et al.31
Kowalewski et al.10
Kopp et al.30
Heng et al.29
Morizane et al.28
Bruckner et al.27
Hisamatsu et al.18
Kozlowska et al.26
Oiso et al.25
Niimi et al.14
Weston et al.13
Reference
Expanding spectrum of IgA pemphigus, S. Geller et al. 653
British Journal of Dermatology (2014) 171, pp650–656
British Journal of Dermatology (2014) 171, pp650–656
F
M
F
M
25
71
25
69
Histology Eosinophilic spongiosis of the epidermis (early lesion)
Subcorneal cleft with acantholysis. Blister filled with fibrin, erythrocytes and numerous neutrophils. In the upper dermis, neutrophils that infiltrated the epidermis Flaccid vesicles, pustules Subcorneal bullae containing numerous and crusted erosions on neutrophils and few eosinophils. Focal erythematous base intercellular oedema in the epidermis. No acantholysis Annular erythema with crusts, Neutrophilic spongiosis in the epidermis malar rash-like facial erythema and marked oedema in the with vesicles on the border superficial dermis Annular erythematous plaques Intraepidermal pustules filled with with erosions in the periphery neutrophils and acantholytic cells Erythematous annular plaques Subcorneal pustules and vesicles containing with peripheral vesicles, few acantholytic cells and occasional pustules and erosions intraepidermal pustules Edematous well-demarcated Intraepidermal blisters with neutrophil erythema coalescing to annular infiltrates without patterns with vesicles on prominent acantholysis the edges Small flaccid pustules on Acantholysis and prominent subcorneal coalescent erythema with pustules with smaller pustules in crusts and erosions midepidermis. Neutrophils in oedematous upper dermis Diffuse exudative erythemas Slight spongiosis in the epidermis and without bullous or pustular sparse superficial perivascular lesions inflammatory infiltrates Annular erythematous plaques Subcorneal pustules with neutrophils, few with central crusts and eosinophils, and numerous acantholytic scattered pustules cells in superficial epidermis. Subepidermal blisters
Annular urticarial plaques with central paleness, tense vesicles Vesicles and pustules on erythematous base with crusts and erosions
Immunofluorescence
Dsc3
IgA
–
Dsg1
–
–
IgA, IgG IgA, IgG – (weak) (weak)
–
–
–
IgA
–
–
–
IgA, IgG –
IgA, IgG – –
–
–
–
Hirata et al.34
Santiago-et-SanchezMateos et al.11
Hosoda et al.33
Iida et al.15
D€ uker et al.32
M€ uller et al.9
Reference
Dapsone
Prednisolone
Present case
Arai et al.35
Dapsone/etretinate, Asahina et al.12 prednisolone, minocycline/R-CHOP
Dapsone
Acitretin, methylprednisolone
Topical steroid
Dapsone, prednisolone
Dapsone
Dapsone
N/M
IgA, IgG –
–
–
Treatment
Dsg3 –
– IgA
N/P
–
–
N/P
–
–
IgG
–
–
IgG
IgA
IgA
IgG
DIF: IC IgA, entire epidermis IgA IIF: IC IgA, IgG (ME), negative (HS) DIF: BMZ C3 – IIF: IC IgA, IgG, basal epidermis (ME), IgA – epidermal side of blister (SSS)
DIF: IC IgA, IgG, stronger in the upper epidermis IIF: IC IgA (HS)
DIF: IC IgA, entire epidermis IIF: IC IgA (HS)
DIF: IC IgA, IgG, stronger in superficial layers IIF: IC IgA, IgG (HS) DIF: IC IgA, IgG, entire epidermis IIF: IC IgG (ME), negative (SSS) DIF: IC IgA, IgG, entire epidermis
Dsc2
IgA, IgG IgA, IgG IgA, IgG N/P (weak) (weak) (weak)
Dsc1
DIF: IC IgA, stronger in superficial IgA layers IIF: IgA – interface of the stratum corneum and stratum granulosum (SSS), negative (ME, HS) DIF: negative – IIF: IC IgA, entire epidermis (HS)
DIF: IC C3
Target antigens
Dsc, desmocollin; Dsg, desmoglein; M, male; F, female; DIF, direct immunofluorescence; IC, intercellular; IIF, indirect immunofluorescence; HS, human skin; SSS, salt split skin; ME, monkey oesophagus; GPE, guinea pig oesophagus; N/M, not mentioned; BMZ, basal membrane zone; N/P, not performed.
F
F
62
74
M
48
M
F
94
56
M
80
Age (years) Sex Clinical findings
Table 1 (continued)
654 Expanding spectrum of IgA pemphigus, S. Geller et al.
© 2014 British Association of Dermatologists
Expanding spectrum of IgA pemphigus, S. Geller et al. 655
The lack of detection of epidermal intercellular deposits of IgA or IgG on direct immunofluorescence in our case is puzzling. Technical limitations and/or low levels of the pathogenic immunoglobulins could have accounted for this result. Negative direct immunofluorescence can rarely be found in pemphigus vulgaris, but is certainly more common in IGAP,17 presumably owing to the fact that IgA immune complexes are less stable and more sensitive to degradation. Several previous IgA and IgA/IgG cases of pemphigus showed no IgA staining on direct immunofluorescence, despite positive indirect immunofluorescence and immune assays.9,15,19 To the best of our knowledge, the concurrence of atypical IGAP and LABD in the same patient has not been described previously. Interestingly, a case of herpetiform bullous dermatosis with IgG antibodies to Dsc 1 and 3, as well as to LAD-1 (the 120-kDa ectodomain of BP180) was recently reported; although IgA autoantibodies to Dsc3 were also identified, their pathogenic relevance in that case was questioned.20 In light of the chronicity of the patient’s skin disorder (> 10 years), the unique autoantibody profile was probably related to epitope spreading. The possibility of a paraneoplastic autoimmune blistering disease was also considered in regard to this atypical presentation, as both IGAP and LABD have been reported in association with malignancies. The complex immunopathological profile found in paraneoplastic pemphigus (PNP) cases includes IgA antibodies against the cell surface and antibodies against the BMZ.21–24 Although our patient did not present clinical and histological features consistent with PNP, a comprehensive work-up was performed, which gave no hint of malignancy. In this case, the rapid response to treatment with dapsone further supported our conclusion that this diagnosis was unlikely. In summary, we propose the term ‘IGAP spectrum’ to account for the growing number of atypical IGAP cases associated with IgA reactivity against various autoantigens of the epidermis or BMZ as shown in this patient and an additional 20 previously published atypical cases of IGAP.
References 1 Robinson ND, Hashimoto T, Amagai M et al. The new pemphigus variants. J Am Acad Dermatol 1999; 40:649–72. 2 Ishii N, Ishida-Yamamoto A, Hashimoto T. Immunolocalization of target autoantigens in IgA pemphigus. Clin Exp Dermatol 2004; 29:62–6. 3 Supapannachart N, Mutasim DF. The distribution of IgA pemphigus antigen in human skin and the role of IgA anti-cell surface antibodies in the induction of intraepidermal acantholysis. Arch Dermatol 1993; 129:605–8. 4 Hashimoto T, Kiyokawa C, Mori O et al. Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997; 109:127–31. 5 Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: clinical manifestations. J Dtsch Dermatol Ges 2011; 9:844–56. 6 Pas HH, Kloosterhuis GJ, Heeres K et al. Bullous pemphigoid and linear IgA dermatosis sera recognize a similar 120 kDa keratinocyte collagenous glycoprotein with antigenic cross-reactivity to BP180. J Invest Dermatol 1997; 108:423–9. © 2014 British Association of Dermatologists
7 Zone JJ, Taylor TB, Meyer LJ et al. The 97 kDa linear IgA bullous disease antigen is identical to a protein of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998; 110:207–10. 8 Hofmann S, Thoma-Uszynski S, Hunziker T et al. Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002; 119:1065–73. 9 M€ uller R, Heber B, Hashimoto T et al. Autoantibodies against desmocollins in European patients with pemphigus. Clin Exp Dermatol 2009; 34:898–903. 10 Kowalewski C, Hashimoto T, Amagai M et al. IgA/IgG pemphigus: a new atypical subset of pemphigus? Acta Derm Venereol 2006; 86:357–8. 11 Santiago-et-Sanchez-Mateos D, Juarez Martın A, Gonzalez De Arriba A et al. IgG/IgA pemphigus with IgA and IgG antidesmoglein 1 antibodies detected by enzyme-linked immunosorbent assay: presentation of two cases. J Eur Acad Dermatol Venereol 2011; 25:110–12. 12 Asahina A, Koga H, Suzuki Y et al. IgA pemphigus associated with diffuse large B-cell lymphoma showing unique reactivity with desmocollins: unusual clinical and histopathological features. Br J Dermatol 2013; 168:224–6. 13 Weston WL, Friednash M, Hashimoto T et al. A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1998; 38:635–8. 14 Niimi Y, Kawana S, Kusunoki T. IgA pemphigus: a case report and its characteristic clinical features compared with subcorneal pustular dermatosis. J Am Acad Dermatol 2000; 43:546–9. 15 Iida K, Sueki H, Ohyama B et al. A unique case of intra-epidermal neutrophilic dermatosis-type IgA pemphigus presenting with subcorneal pustules. Dermatology 2011; 222:15–19. 16 Spaeth S, Riechers R, Borradori L et al. IgG, IgA and IgE autoantibodies against the ectodomain of desmoglein 3 in active pemphigus vulgaris. Br J Dermatol 2001; 144:1183–8. 17 Mentink LF, de Jong MC, Kloosterhuis GJ et al. Coexistence of IgA antibodies to desmoglein 1 and 3 in pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. Br J Dermatol 2007; 156:635–41. 18 Hisamatsu Y, Amagai M, Garrod DR et al. The detection of IgG and IgA autoantibodies to desmocollins 1–3 by enzyme-linked immunosorbent assays using baculovirus-expressed proteins, in atypical pemphigus but not in typical pemphigus. Br J Dermatol 2004; 151:73–83. 19 Nakajima K, Hashimoto T, Nakajima H et al. IgG/IgA pemphigus with dyskeratotic acantholysis and intraepidermal neutrophilic microabscesses. J Dermatol 2007; 34:757–60. 20 Ueda A, Ishii N, Teye K et al. Unique herpetiform bullous dermatosis with IgG antibodies to desmocollins 1/3 and LAD-1. Br J Dermatol 2013; 169:719–21. 21 Gooptu C, Mendelsohn S, Amagai M et al. Unique immunobullous disease in a child with a predominantly IgA response to three desmosomal proteins. Br J Dermatol 1999; 141:882–6. 22 Preisz K, Horvath A, Sardy M et al. Exacerbation of paraneoplastic pemphigus by cyclophosphamide treatment: detection of novel autoantigens and bronchial autoantibodies. Br J Dermatol 2004; 150:1018–24. 23 Taintor AR, Leiferman KM, Hashimoto T et al. A novel case of IgA paraneoplastic pemphigus associated with chronic lymphocytic leukemia. J Am Acad Dermatol 2007; 56:S73–6. 24 Ueda A, Ishii N, Temporin K et al. IgA pemphigus with paraneoplastic pemphigus-like clinical features showing IgA antibodies to desmoglein 1/3 and desmocollin 3, and IgG and IgA antibodies to the basement membrane zone. Clin Exp Dermatol 2013; 38:370–3.
British Journal of Dermatology (2014) 171, pp650–656
656 Expanding spectrum of IgA pemphigus, S. Geller et al. 25 Oiso N, Yamashita C, Yoshioka K et al. IgG/IgA pemphigus with IgG and IgA antidesmoglein 1 antibodies detected by enzymelinked immunosorbent assay. Br J Dermatol 2002; 147:1012– 17. 26 Kozlowska A, Hashimoto T, Jarzabek-Chorzelska M et al. Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3. J Am Acad Dermatol 2003; 48:117–22. 27 Bruckner AL, Fitzpatrick JE, Hashimoto T et al. Atypical IgA/IgG pemphigus involving the skin, oral mucosa, and colon in a child: a novel variant of IgA pemphigus. Pediatr Dermatol 2005; 22:321– 7. 28 Morizane S, Yamamoto T, Hisamatsu Y et al. Pemphigus vegetans with IgG and IgA antidesmoglein 3 antibodies. Br J Dermatol 2005; 153:1236–7. 29 Heng A, Nwaneshiudu A, Hashimoto T et al. Intraepidermal neutrophilic IgA/IgG antidesmocollin 1 pemphigus. Br J Dermatol 2006; 154:1018–20.
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30 Kopp T, Sitaru C, Pieczkowski F et al. IgA pemphigus – occurrence of anti-desmocollin 1 and anti-desmoglein 1 antibody reactivity in an individual patient. J Dtsch Dermatol Ges 2006; 4:1045–50. 31 Maruyama H, Kawachi Y, Fujisawa Y et al. IgA/IgG pemphigus positive for anti-desmoglein 1 autoantibody. Eur J Dermatol 2007; 17:94–5. 32 D€ uker I, Schaller J, Rose C et al. Subcorneal pustular dermatosistype IgA pemphigus with autoantibodies to desmocollins 1, 2, and 3. Arch Dermatol 2009; 145:1159–62. 33 Hosoda S, Suzuki M, Komine M et al. A case of IgG/IgA pemphigus presenting malar rash-like erythema. Acta Derm Venereol 2012; 92:164–6. 34 Hirata Y, Abe R, Kikuchi K et al. Intraepidermal neutrophilic IgA pemphigus successfully treated with dapsone. Eur J Dermatol 2012; 22:282–3. 35 Arai R, Okuda H, Tsuruta D et al. IgA pemphigus with non-pustular erythematous lesions and IgA antibodies to desmocollins 1 and 2. Eur J Dermatol 2013; 23:362–5.
© 2014 British Association of Dermatologists
