Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV).

BACKGROUND: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. OBJECTIVES: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. RESULTS: The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

Sporadic pemphigus foliaceus and class II human leucocyte antigen allele associations in the white British and Indo-Asian populations in the UK.

BACKGROUND: Pemphigus foliaceus (PF) has both genetic and environmental susceptibility factors. Current data on human leucocyte antigen (HLA) in patients with sporadic PF are limited. AIM: To better define the distribution of HLA alleles in patients with PF in the UK. METHODS: We recruited 36 patients [26 of white British (WB) descent, 10 of Indo-Asian (IA) descent] with PF who were living in the UK and 159 ethnically matched normal controls, and analysed their class II HLA DRB1 and DQB1 allele distribution. RESULTS: There was an increased frequency of DRB1*1404 in association with DQB1*0503 in IA patients with PF. The DRB1*04 allele group as a whole had an increased frequency (P < 0.001) in the WB patient group compared with controls. The alleles contributing to this significance were DRB1*0401 (P = 0.03) and DRB1*0404 (P < 0.01). CONCLUSION: This is the largest HLA association study in sporadic PF from the UK to date. There appears to be a difference in PF susceptibility alleles between WB and IA patients, highlighting the importance of racial variation in genetic susceptibility to disease development.

Integrating Spectroscopy with Potato Disease Management.

Spectral phenotyping is an efficient method for the nondestructive characterization of plant biochemical and physiological status. We examined the ability of a full range (350 to 2,500 nm) of foliar spectral data to (i) detect Potato virus Y (PVY) and physiological effects of the disease in visually asymptomatic leaves, (ii) classify different strains of PVY, and (iii) identify specific potato cultivars. Across cultivars, foliar spectral profiles of PVY-infected leaves were statistically different (F = 96.1, P ≤ 0.001) from noninfected leaves. Partial least-squares discriminate analysis (PLS-DA) accurately classified leaves as PVY infected (validation κ = 0.73) and the shortwave infrared spectral regions displayed the strongest correlations with infection status. Although spectral profiles of different PVY strains were statistically different (F = 6.4, P ≤ 0.001), PLS-DA did not classify different strains well (validation κ = 0.12). Spectroscopic retrievals revealed that PVY infection decreased photosynthetic capacity and increased leaf lignin content. Spectral profiles of potato cultivars also differed (F = 9.2, P ≤ 0.001); whereas average spectral classification was high (validation κ = 0.76), the accuracy of classification varied among cultivars. Our study expands the current knowledge base by (i) identifying disease presence before the onset of visual symptoms, (ii) providing specific biochemical and physiological responses to disease infection, and (iii) discriminating between multiple cultivars within a single plant species.

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

Crescendo response to rituximab in oral pemphigus vulgaris: a case with 7-year follow-up.

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucous membranes. Rituximab, a CD20 chimeric monoclonal antibody, has efficacy in PV management. We report a case of severe oral PV that showed a progressive response to repeated courses of rituximab, culminating in a rapid response within 4 weeks following severe relapse 4 years after initial therapy. It demonstrates the progressively shorter time to achieve partial or complete remission following rituximab infusions, combined with minimal adjuvant therapy over a 7-year follow-up period.

Immunopathological characteristics of patients with bullous pemphigoid and neurological disease.

BACKGROUND: The relationship between bullous pemphigoid (BP) and neurological disease has been the subject of numerous recent studies and BP antigens and their isoforms have been identified in the central nervous system (CNS). Whilst epidemiological data support this association, little is known about the pathomechanism behind this link and the immunological characteristics of patients with BP and neurological disease, other than multiple sclerosis (MS), has not been studied. OBJECTIVE: We aimed to compare the cutaneous immune response in BP patients with and without neurological disease, to investigate whether or not there is a distinctive immunopathological profile in patients with concomitant BP and neurological disease. METHODS: Seventy-two patients with BP were included and divided into two groups; those with neurological disease (BP+N, n = 43) and those without (BP-N, n = 29). Patients in BP+N group had a confirmed neurological disease by a hospital physician, neurologist or psychiatrist with positive neurological imaging where appropriate, or a Karnofsky score of 50 or less due to mental impairment. All sera were analysed with indirect immunofluorescence (IIF) using serial dilutions up to 1:120000, immunoblotting (IB) and Enzyme-linked immunosorbent assay (ELISA) for BP180 and BP230. RESULTS: Median antibody titres by IIF were 1:1600 vs. 1:800 for BP-N and BP+N, respectively, although the difference did not reach statistic significance (P = 0.93, Mann-Whitney U-test). ELISA values for both BP180 and BP230 did not differ significantly between the two groups. Similarly, autoantibodies to specific antigens as identified by ELISA and IB were not related to the presence of neurological disease. CONCLUSION: The results of this study indicate that patients with BP and neurological disease exhibit an immune response to both BP180 and BP230, thus the link between the CNS and the skin is not dependent on a specific antigen, but possibly both antigens or their isoforms may be exposed following a neurological insult, and play a role in generation of an immune response.

Prognostic factors in pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Pemphigus typically has a chronic course, although there is great variability in disease duration (DD) and time taken to disease remission (DR) between individuals with the disease. The reasons for this are unclear. OBJECTIVES: To explore the prognostic influence of epidemiological, clinical, immunological and genetic factors on disease course and remission in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). METHODS: This was a retrospective study of patients with PV and PF, recruited from a single UK centre. Direct and indirect immunofluorescence and enzyme-linked immunosorbent assay studies for antidesmoglein (Dsg) antibodies were used to assess immunological factors. Polymerase chain reaction with sequence specific primers (PCR-SSP) was used to assess the Class II human leukocyte antigen status of patients. Prognostic endpoints investigated were time to initial first DR and total DD. RESULTS: Ninety-five patients were recruited (79 PV and 16 PF). Patients of Indo-Asian origin were significantly associated with longer DD than White-British patients (P = 0.029). In addition, younger age at onset was associated with a worse prognosis in terms of DD: the mean age at presentation of patients with DD of < 5 years was 49 years (SEM = 3.4) compared with 40 years (SEM = 1.9) in those with DD > 5 years (P = 0.039). A higher initial intercellular antibody titre on normal human skin substrate was associated with a greater time to initial DR (P = 0.007) and high anti-Dsg 3 levels at baseline were associated with a longer total DD (P = 0.03). CONCLUSIONS: Ethnic group, age at presentation, initial intercellular antibody titre and initial Dsg 3 antibody levels all had a significant impact on prognosis of pemphigus.

Immunobullous dermatosis associated with Waldenström macroglobulinaemia treated with rituximab.

Waldenström macroglobulinaemia (WM) is a chronic lymphoproliferative disorder characterized by the presence of a monoclonal IgM paraprotein. Specific cutaneous features of WM include neoplastic cell infiltrates, IgM storage papules and IgM bullous dermatosis. We report a patient with subepidermal bullous disease associated with WM. Immunofluorescence identified IgM deposition along the basement membrane zone (BMZ) with circulating anti-BMZ IgM antibodies reacting with the dermal side of salt-split skin. The autoantibodies did not react with type VII collagen or laminin 332. Following failed treatment with doxycycline, prednisolone, intravenous immunoglobulin and dapsone, the patient was successfully treated with a modified RCVP regimen (rituximab, cyclophosphamide and prednisolone). To our knowledge, this is the first reported case of IgM bullous disease of WM treated with rituximab.

Factors influencing aster leafhopper (Hemiptera: Cicadellidae) abundance and aster yellows phytoplasma infectivity in Wisconsin carrot fields.

In Wisconsin, vegetable crops are threatened annually by infection of the aster yellows phytoplasma (AYp), the causal agent of aster yellows (AY) disease, vectored by the aster leafhopper, Macrosteles quadrilineatus Forbes. Aster leafhopper abundance and infectivity are influenced by processes operating across different temporal and spatial scales. We applied a multilevel modeling approach to partition variance in multifield, multiyear, pest scouting data sets containing temporal and spatial covariates associated with aster leafhopper abundance and infectivity. Our intent was to evaluate the relative importance of temporal and spatial covariates to infer the relevant scale at which ecological processes are driving AY epidemics and identify periods of elevated risk for AYp spread. The relative amount of aster leafhopper variability among and within years (39%) exceeded estimates of variation among farm locations and fields (7%). Similarly, time covariates explained the largest amount of variation of aster leafhopper infectivity (50%). Leafhopper abundance has been decreasing since 2001 and reached its minimum in 2010. The average seasonal pattern indicated that periods of above average abundance occurred between 11 June and 1 August. Annual infectivity appears to oscillate around an average value of 2% and seasonal periods of above average infectivity occur between 19 May and 15 July. The coincidence of the expected periods of high leafhopper abundance and infectivity increases our knowledge of when the insect moves into susceptible crop fields and when it spreads the pathogen to susceptible crops, representing a seasonal interval during which management of the insect can be focused.

Seasonal patterns of aster leafhopper (Hemiptera: Cicadellidae) abundance and aster yellows phytoplasma infectivity in Wisconsin carrot fields.

In Wisconsin, vegetable crops are threatened annually by the aster yellows phytoplasma (AYp), which is obligately transmitted by the aster leafhopper. Using a multiyear, multilocation data set, seasonal patterns of leafhopper abundance and infectivity were modeled. A seasonal aster yellows index (AYI) was deduced from the model abundance and infectivity predictions to represent the expected seasonal risk of pathogen transmission by infectious aster leafhoppers. The primary goal of this study was to identify periods of time during the growing season when crop protection practices could be targeted to reduce the risk of AYp spread. Based on abundance and infectivity, the annual exposure of the carrot crop to infectious leafhoppers varied by 16- and 70-fold, respectively. Together, this corresponded to an estimated 1,000-fold difference in exposure to infectious leafhoppers. Within a season, exposure of the crop to infectious aster leafhoppers (Macrosteles quadrilineatus Forbes), varied threefold because of abundance and ninefold because of infectivity. Periods of above average aster leafhopper abundance occurred between 11 June and 2 August and above average infectivity occurred between 27 May and 13 July. A more comprehensive description of the temporal trends of aster leafhopper abundance and infectivity provides new information defining when the aster leafhopper moves into susceptible crop fields and when they transmit the pathogen to susceptible crops.

Antigen identification using skin deficient in basement-membrane protein: a novel tool for the diagnosis of subepidermal immunobullous diseases.

Common unifying features of the subepidermal blistering diseases are the presence of tense blisters clinically and demonstration by immunofluorescence of linear deposition of immunoreactants along the dermoepidermal junction. Further characterization of subtype is possible by identification of the target antigen by immunoblotting. However, immunoblotting is time-consuming and may not be practical for routine use in the laboratory. In this report, we describe a simple technique to identify the target antigen by indirect immunofluorescence, using epidermolysis bullosa skin as substrate.

Evaluating the use of the interferon-γ response to Mycobacterium tuberculosis-specific antigens in patients with psoriasis prior to antitumour necrosis factor-α therapy: a prospective head-to-head cross-sectional study.

BACKGROUND: Targeted biological therapies have transformed the treatment of chronic inflammatory disease. However, reactivation of latent tuberculosis infection (LTBI) is a significant risk with the use of antitumour necrosis factor (anti-TNF)-α therapy and screening is mandatory prior to treatment. The tuberculin skin test (TST) may be difficult to interpret in patients with inflammatory disease or receiving immunosuppressive therapies. OBJECTIVES: The aim of this study was to evaluate and compare the QuantiFERON(®) -TB Gold In-Tube (QFR) and T-SPOT.TB (TSTB) interferon-γ-release assays (IGRA) against the TST in a cohort of patients commencing anti-TNF-α therapies for chronic inflammatory disease. METHODS: A prospective cross-sectional study was undertaken at a London tertiary referral centre. Demographic data collected included TB risk factors. TST, QFR and TSTB were performed in all patients. RESULTS: Seventy patients with chronic plaque psoriasis were included in the study. Agreement between QFR and TSTB, excluding indeterminate results, was 89% (κ = 0.567), between QFR and TST 85% (κ= 0.313) and 81% (κ = 0.244) between TSTB and TST. There was no significant association with concomitant immunosuppression and either TST or IGRA results. Seven patients received chemoprophylaxis for LTBI diagnosed after clinical risk assessment together with positive TST and/or IGRA. Three patients had positive results in all three tests. CONCLUSIONS: While there was moderate overall agreement between QFR and TSTB and fair correlation between TST, QFR and TSTB, there were a number of discordant results, suggesting that a three-pronged approach using TST, QFR and TSTB may be of additional benefit.