Joost M. Meijer

Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid.

IMPORTANCEnAnti-p200 pemphigoid is a rare subepidermal autoimmune blistering disease characterized by autoantibodies against a 200-kDa protein in the basement membrane zone. Anti-p200 pemphigoid is probably often misdiagnosed because of low availability of diagnostic assays and expertise and classified as bullous pemphigoid or epidermolysis bullosa acquisita.nnnOBJECTIVEnTo clinically characterize patients with anti-p200 pemphigoid, identified by using indirect immunofluorescence microscopy on skin substrates deficient in type VII collagen and laminin-332 (knockout analysis), to validate this technique by immunoblot with dermal extract, and to incorporate direct immunofluorescence serration pattern analysis in the diagnostic algorithm.nnnDESIGN, SETTING, AND PARTICIPANTSnThis was a retrospective study performed from January 2014 to June 2015 with biobank patient materials and clinical data for the period 1998 to 2015 from the single national referral center on autoimmune bullous diseases. Patients were selected based on a dermal side binding on 1-mol/L salt (sodium chloride)-split human skin substrate by indirect immunofluorescence microscopy, not diagnosed epidermolysis bullosa acquisita or anti-laminin-332 mucous membrane pemphigoid.nnnMAIN OUTCOMES AND MEASURESnIndirect immunofluorescence microscopy knockout analysis was performed and diagnosis of anti-p200 confirmed by immunoblot with dermal extract. Clinical, histological, and immunological findings were registered. Autoantibodies against laminin γ1 were determined by immunoblot.nnnRESULTSnTwelve patients with anti-p200 pemphigoid (7 male and 5 female; mean age, 66.6 years) were identified using the indirect immunofluorescence microscopy knockout analysis. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients.nnnCONCLUSIONS AND RELEVANCEnPredominance of blisters on hands and feet may be a clinical clue to the diagnosis of anti-p200 pemphigoid. Direct immunofluorescence microscopy serration pattern analysis and indirect immunofluorescence microscopy knockout analysis are valuable additional techniques to facilitate the diagnosis of anti-p200 pemphigoid.

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.

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).

Allergic contact dermatitis caused by dimethylthiocarbamylbenzothiazole sulfide (DMTBS) in canvas shoes : in search of the culprit allergen

During rubber vulcanization, new compounds can be formed.

Automatic Differentiation of u- and n-serrated Patterns in Direct Immunofluorescence Images

Epidermolysis bullosa acquisita (EBA) is a subepidermal autoimmune blistering disease of the skin. Manual u- and n-serrated patterns analysis in direct immunofluorescence (DIF) images is used in medical practice to differentiate EBA from other forms of pemphigoid. The manual analysis of serration patterns in DIF images is very challenging, mainly due to noise and lack of training of the immunofluorescence (IF) microscopists. There are no automatic techniques to distinguish these two types of serration patterns. We propose an algorithm for the automatic recognition of such a disease. We first locate a region where u- and n-serrated patterns are typically found. Then, we apply a bank of B-COSFIRE filters to the identified region of interest in the DIF image in order to detect ridge contours. This is followed by the construction of a normalized histogram of orientations. Finally, we classify an image by using the nearest neighbors algorithm that compares its normalized histogram of orientations with all the images in the dataset. The best results that we achieve on the UMCG publicly available data set is (84.6%) correct classification, which is comparable to the results of medical experts.

Contact dermatitis caused by a new rubber compound detected in canvas shoes

In 2015 and 2016, female patients in Flanders consulted a dermatologist because they developed skin lesions after wearing a specific brand of canvas shoes.

Serration pattern analysis for differentiating epidermolysis bullosa acquisita from other pemphigoid diseases

Background: Direct immunofluorescence (DIF) microscopy of a skin biopsy specimen is the reference standard for the diagnosis of pemphigoid diseases (PDs). Serration pattern analysis enables the differentiation of epidermolysis bullosa acquisita (EBA) from other PDs using DIF microscopy alone. However, practice gaps need to be addressed in order to implement this technique in the routine diagnostic procedure. Objective: We sought to determine and optimize the technical requirements for serration pattern analysis of DIF microscopy and determine interrater conformity of serration pattern analysis. Methods: We compared serration pattern analysis of routine DIF microscopy from laboratories in Groningen, The Netherlands and Lübeck, Germany with 4 blinded observers. Skin biopsy specimens from 20 patients with EBA and other PDs were exchanged and analyzed. Various factors were evaluated, including section thickness, transport medium, and biopsy specimen processing. Results: The interrater conformity of our 4 observers was 95.7%. Recognition of serration patterns was comparable in samples transported in saline and in Michels medium and with section thicknesses of 4, 6, and 8 &mgr;m. Limitations: Limitations include our small sample size and the availability of 20 samples that were compared retrospectively. Conclusion: DIF serration pattern analysis is not restricted by variation in laboratory procedures, transport medium, or experience of observers. This learnable technique can be implemented as a routine diagnostic method as an extension of DIF microscopy for subtyping PD. Graphical abstract: Figure. No caption available.

Patient Support Groups and International Centers for AIBD

Patients and their families should be informed about disease, prognosis, available treatment options, process of clinical follow-up, and possible adverse events or complications. Patients should also be informed about the existence of local or national patient support groups or patients’ associations. These associations contribute to promote knowledge of the disease and improve patients’ access to information, healthcare, and social services, and they can help in referring patients to centers of expertise for AIBD.

Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP) is the subgroup of pemphigoid which affects mucous membranes. Several subtypes are classified based on clinical symptoms and target antigens, such as ocular mucous membrane pemphigoid (OMMP), localized vulvar pemphigoid (LVP), and anti-laminin 332 MMP (anti-LN-332 MMP). Autoantibodies are directed against various structural proteins in the epidermal basement membrane zone (EBMZ), with the 180-kD antigen (BP180) as the main target antigen. Other antigens, such as BP230, α6β4 integrin, and laminin 332, can also be targeted by autoantibodies. Clinically, MMP is characterized by erosions and blistering of the oral mucosa (85 %), conjunctiva (65 %), and, less frequently, the nose (20–40 %), esophagus (5–15 %), pharynx (20 %), larynx (5–10 %), and genitals (20 %). Clinical severity is highly variable in the different subtypes of MMP. Progressive scar formation is a severe complication in active disease in OMMP and anti-LN-332 MMP, resulting in blindness or upper airway obstruction when not treated accurately. Previously, the term cicatricial pemphigoid was used synonymously for MMP. However, at present, the term refers to the rare clinical phenotype with scarring skin lesions. Patient’s and doctor’s delay is frequently seen in MMP. For an accurate diagnosis, direct immunofluorescence microscopy (DIF) and detection of circulating autoantibodies in serum are mandatory. Management and prognosis of MMP depends on the severity and extent of the disease and involves a stepwise approach with first-choice treatment with oral corticosteroids (CS), often used in combination with adjuvant immunosuppressive drugs to reduce the adverse effects caused by long-term CS use.

Drug-Induced Pemphigoid and Linear IgA Disease

Drug-induced pemphigoid and drug-induced linear IgA disease can be difficult to differentiate from bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), and linear IgA disease (LAD) because of only minor differences in clinical, histopathologic, and immunopathologic features. However, differentiation can be of major importance because of a different approach, treatment, and outcome. Diagnosis is mainly based on the time relation between start of the suspected drug(s) and onset of the lesions. Drug-induced BP and drug-induced LAD tend to be self-limiting after withdrawal of the culprit drug.