M. F. Jonkman

Laboratory diagnosis of paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the α2‐macroglobulin‐like‐1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum.

IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis

Background  In pemphigus circulating IgG is present with the desmosomal cadherins desmoglein (Dsg) 1 and 3. In the epidermis of patients, this IgG deposits in a pattern that is often partly granular and does not reflect the normal Dsg distribution.

Coexistence of IgA antibodies to desmogleins 1 and 3 in pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus

Background  Pemphigus is a bullous mucocutaneous autoimmune disease characterized by IgG autoantibodies to desmoglein (Dsg) 1 and/or Dsg3. Occasionally direct immunofluorescence of pemphigus skin reveals IgA depositions with an intraepidermal intercellular pattern in addition to the IgG deposition.

Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin‐332 mucous membrane pemphigoid: immunopathological findings and clinical experience in 10 Dutch patients

Background  Antilaminin‐332 mucous membrane pemphigoid (anti‐LN‐332 MMP) is a chronic subepidermal blistering disease characterized by IgG anti‐epidermal basement membrane zone (BMZ) autoantibodies against laminin‐332 (LN‐332). Patients with anti‐LN‐332 MMP have an increased relative risk of malignancy. Laboratory techniques that are difficult to obtain are needed for diagnosis of anti‐LN‐332 MMP.

Smaller Desmosomes Are Seen in the Skin of Pemphigus Patients with Anti-Desmoglein 1 Antibodies but Not in Patients with Anti-Desmoglein 3 Antibodies

TO THE EDITOR Pemphigus is a chronic mucocutaneous autoimmune blistering disease caused by autoantibodies directed against the desmosomal cadherins, desmoglein 1 (Dsg1) and/or desmoglein 3 (Dsg3). In patients with pemphigus foliaceus (PF), there is superficial blistering of the skin but not of mucous membranes, with autoantibodies directed against Dsg1. In mucosal-dominant pemphigus vulgaris (mdPV), mucous membranes are involved but not the skin, with autoantibodies directed against Dsg3. Mucocutaneous PV (mcPV) is characterized by suprabasal blistering of both the skin and mucous membranes, with autoantibodies directed against both Dsg1 and Dsg3. Desmosomes are intercellular adhering discoid junctions serving to attach neighboring cells to each other. Their diameter varies between 0.2 and 0.7mm in the epidermis. During epidermal differentiation, smaller, less well-organized desmosomes in the basal cells are replaced by larger, more electron-dense structures in the upper layers (Odland, 1958; Green and Simpson, 2007; Holthofer et al., 2007; Scothern and Garrod, 2008). Desmosomes are composed of members of at least three protein families. Desmosomal cadherins (desmogleins and desmocollins) constitute the transmembrane adhesive interface, whereas armadillo and plakin family proteins build up the cytoplasmic plaques. The cytoplasmic tail of the transmembrane desmogleins and desmocollins interacts with plakoglobin, which in turn binds to desmoplakin. Desmoplakin anchors to the intermediate filaments. The interactions are stabilized laterally by plakophilin (Green and Simpson, 2007; Waschke, 2008). In pemphigus, both anti-Dsg1 and antiDsg3 antibodies can cause acantholysis, although the actual pathomechanism is unknown. Current theories include steric hindrance, desmosomal non-assembly and disassembly, or cell signaling. We recently described the ultrastructure of the epidermis in PF patients (Van der Wier et al., 2012). We found no abnormalities in the desmosomes or in the intercellular distance in Nikolskynegative (N ) PF skin, whereas in Nikolsky-positive (Nþ ) PF skin we observed intercellular widening between the desmosomes and a slight reduction in the size and number of desmosomes in the lower epidermal layers but not in the higher ones. Full acantholysis was only observed in lesional PF skin due to a severe reduction in the size and number of desmosomes in the higher epidermal layers (Van der Wier et al., 2012). In the present study, we performed morphometric studies on the skin of PF, mdPV, and mcPV patients to determine the influence of Dsg1 and Dsg3 autoantibodies on the number and length of desmosomes. We correlated the morphometric data to the immunofluorescence staining pattern of the most important immunological effectors in pemphigus: IgG, Dsg1, and Dsg3. Skin biopsies of two human controls, and eight pemphigus patients were studied. The skin biopsies were taken from N or Nþ non-lesional skin from four Accepted article preview online 12 March 2014; published online 17 April 2014 Abbreviations: Dsg1, desmoglein 1; Dsg3, desmoglein 3; ECS, epithelial cell surface; mcPV, mucocutaneous pemphigus vulgaris; mdPV, mucosal-dominant pemphigus vulgaris; N , Nikolsky negative; Nþ , Nikolsky positive; PF, pemphigus foliaceus; PV, pemphigus vulgaris G van der Wier et al. Desmosomes in Pemphigus

Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1

Background  Junctional epidermolysis bullosa of late onset (JEB‐lo) is a rare disease characterized by blistering of primarily the hands and feet starting in childhood. The pathogenesis remains unclear.

ITGB4-associated non-Herlitz junctional epidermolysis bullosa: report of two new cases carrying two novel ITGB4 mutations

the nonrecurrence group and 80% (4 ⁄5) of the recurrence group (Table 2). Compared with the nonrecurrence group, the recurrence group was younger, with a higher proportion also suffering from cholinergic urticaria and showing lymphocyte infiltration of the sweat glands. The duration from onset to treatment was longer, and these patients were resistant to steroid therapy. However, no statistically significant differences were identified. In general, continued anhidrosis over a long period results in abnormalities of the sweat glands and postganglionic sudomotor nerves. Treatment therefore requires long-term administration of high-dose steroids. In our patients, the duration from onset to treatment was longer for the recurrence group than for the nonrecurrence group. This suggests that changes to the sweat glands and postganglionic sudomotor nerves would have been more pronounced in the recurrence group than in the nonrecurrence group, with the possibility of steroid resistance. These changes might also mean that negative feedback from acetylcholine release by nerve terminals did not come into effect, leading to excessive release of acetylcholine by nerve terminals. We theorize that this was the reason for the higher frequency of the complication of cholinergic urticaria among patients who experienced recurrence. We also administered immunosuppressants to patients who experienced recurrent anhidrosis, but these proved ineffective. Oral ciclosporin has previously been reported as effective for treating intractable AIGA. This was attributed to the fact that ciclosporin inhibits the activity of CD3and CD4-positive T cells that infiltrate eccrine sweat glands, causing sweating. Ciclosporin was probably ineffective in our patients because lymphocyte infiltration of eccrine sweat glands was either absent or mild. Treatment of AIGA using methods other than immunosuppressants and steroid therapy has not previously been reported. Novel treatments for AIGA are thus desired. Treatment for AIGA is not consistently effective, and much remains unclear regarding the reasons for recurrent anhidrosis. Elucidation of the reasons underlying the recurrence of anhidrosis will also be important for clarifying the pathogenic mechanisms of AIGA. We believe that accumulation of more cases and further study of courses of treatment are required.

Current practice in treatment approach for bullous pemphigoid: comparison between national surveys from the Netherlands and the UK

Treatment approaches for bullous pemphigoid (BP), the most common autoimmune skin blistering disease, are largely based on national and international guidelines. We conducted a national survey among dermatologists in the Netherlands to explore the current treatment of BP, and compared the results with those of a previously published survey from the UK. Almost all responders in the Netherlands (n = 175) used very potent topical corticosteroids, both as monotherapy and as adjunctive therapy. In contrast to UK dermatologists, the majority recommended whole‐body application rather than local application to lesions. Systemic antibiotics were used by > 70% of responders. Half of the responders in the Netherlands considered systemic steroids the first‐choice treatment, with the majority also using adjunctive therapy as a routine. Despite many similarities in treatment approach between the two countries, these surveys provide an important insight into the gap between actual and recommended practice at a country level in relation to the best external evidence.

The needs of parents with children suffering from lethal epidermolysis bullosa

Background  Some subtypes of the heterogeneous genetic blistering disease epidermolysis bullosa (EB) lead to lethality in childhood. The severity and extent of blistering leaves these patients living in excruciating pain and distress their entire lives. Parents of these patients experience some specific problems, such as the unfamiliarity of EB amongst healthcare professionals and the suffering and loss of their child.

Significantly higher prevalence of circulating bullous pemphigoid-specific IgG autoantibodies in elderly patients with a nonbullous skin disorder

DEAR EDITOR, We read with interest the recent article of van Beek et al. on ‘Serum autoantibodies against the dermal– epidermal junction in patients with chronic pruritic disorders, elderly individuals and blood donors prospectively recruited’ and the recent review article of Schmidt et al. on ‘BP180and BP230-specific IgG autoantibodies in pruritic disorders of the elderly: a preclinical stage of bullous pemphigoid?’ about the association between pruritus in the elderly and the presence of bullous pemphigoid (BP)-specific IgG autoantibodies. van Beek et al. studied autoantibody reactivity against the epidermal basement membrane zone (EBMZ) by indirect immunofluorescence (IIF) microscopy, enzyme-linked immunosorbent assay (ELISA) and immunoblot. Positive reactivity in any test was found in 31% of the sera of elderly individuals (≥ 70 years; n = 93), 17% of the sera of patients with chronic pruritic disorders (n = 78) and 26% of the sera of healthy blood donors of all ages (n = 50). In our opinion these are remarkably high percentages, probably due to the false-positive rates of the immunoassays, as mentioned in the discussion of their article. van Beek et al. concluded that neither advanced age nor chronic pruritus have been verified as risk factors for autoantibodies against the EBMZ. Schmidt et al. reviewed clinical and experimental studies about the possible association between senile pruritus and BP IgG autoantibodies, and questioned whether this could be a preclinical stage of BP. Prior studies by Rieckhoff-Cantoni et al., Hofmann et al. and Feliciani et al. on the presence of circulating BP autoantibodies in elderly patients with pruritic disorders, but without blistering, reported IgG reactivity against BP180 or BP230 in 10 of 43 patients (23%), three of 25 patients (12%) and five of 15 patients (33%), respectively. The question remains whether circulating autoantibodies against BP antigens in the elderly and patients with pruritic disorders indicate the presence of a BP subtype, may identify patients with an increased risk of developing BP, or may have no clinical relevance at all. As an extension to these studies we present our results of a retrospective database study, which included 374 patients who consulted our department for a skin disorder, without blistering. Data were collected from patients in our dermatology database in whom direct immunofluorescence (DIF) and serological testing were performed at the University Medical Center Groningen. Patients were excluded if DIF was positive or if they presented clinically with blisters or erosions on skin or mucous membranes, to exclude those with an evident diagnosis of an autoimmune blistering disease. The patient characteristics are shown in Table 1. The following serological test results were studied: IIF on monkey oesophagus, IIF on salt-split skin, immunoblot testing on BP180 and BP230 antibodies, and BP180 NC16Aand BP230-specific ELISAs (MBL, Nagoya, Japan; cut-off < 9 U mL ) (Fig. 1).