V.A. Venning

Guidelines for the management of bullous pemphigoid

Summary These guidelines have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence‐based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines and a brief overview of epidemiological aspects, diagnosis and investigation. The guidelines reflect data available from Medline, Embase, the Cochrane library, literature searches and the experience of the authors of managing patients with bullous pemphigoid in special and general clinics for over 10 years. However, caution should be exercised in interpreting the data obtained from the literature because only six randomized controlled trials are available involving small groups of patients.

Mucosal involvement in bullous and cicatricial pemphigoid. A clinical and immunopathological study

Thirty‐six patients with bullous pemphigoid (BP) and 15 with cicatricial pemphigoid (CP) were studied for evidence of mucosal involvement both clinically and by direct immunofluorescence. Twenty‐one patients with BP and all those with CP had lesions of the mucous membranes. Eighteen patients with BP and 14 patients with CP had involvement of the oral mucosa. Lesions of the eyes, nose, pharynx, vulva and urethra also occurred in both groups. The lesions tended to be more widespread in CP patients. Twenty‐one patients with BP and 14 with CP were examined by an ophthalmologist. Fine scarring of the tarsal conjunctiva was found in both groups, but also in elderly controls. However, symblepharon occurred in one patient with BP as well as in three patients with CP, but was not seen in a group of 20 controls. Direct immunofluorescence (IF) studies showed linear deposition of IgG or C3 or both in the basement membrane zone of the skin, oral mucosa and conjunctival mucosa in both groups. The frequency of positive immunofluorescence was higher in the conjunctiva than in the lip mucosa or skin in both BP and CP patients. The significance of these findings and the relationship between BP and CP is discussed.

Acquired subepidermal bullous diseases associated with psoriasis: a clinical, immunopathological and immunogenetic study

Summary Clinical, immunopathological and immunogenetic studies of four patients with a subepidermal bullous disease associated with psoriasis were carried out to determine the true nature of the blistering disease and to investigate further the relationship between psoriasis and acquired subepidermal bullous diseases. Autoantibodies in all four patients bound to the epidermal side of salt‐split skin by indirect immunofluorescence and detected the major bullous pemphigoid (BP) antigens by immunoblotting. One had additional IgA autoantibodies binding an epidermal polypeptide of 270/280 kDa and another had circulating IgA autoantibodies which detected both BP and epidermolysis bullosa acquisita (EBA) antigens. All patients had active psoriasis at the onset of the bullous disease. Three patients were being treated with tar when blisters developed: one patient also received UVB radiation and experienced a relapse after exposure to sunlight. HLA phenotypes in three patients were determined. All the patients responded well to methotrexate. These findings demonstrate that BP is the subepidermal bullous disease most associated with psoriasis. Changes at the basement membrane zone in psoriasis may be responsible for the heterogeneous antibody response and may trigger the bullous disease, as may antipsoriatic treatment including tar and UV radiation. However, common immunogenetic mechanisms may play a crucial part in this disease association.

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

The overall aim of the guideline is to provide evidence-based recommendations on the use of biologic therapies (adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis. Biologic therapies have now been in use for over 10 years, and with accrued patient-years exposure and clinical experience, many areas that were covered in previous versions of the guideline are now part of the Summary of Product Characteristics (SPC) and/or routine care so that specific recommendations are redundant (see Toolkit A: Summary of licensed indications and posology for biologic therapy, in Supporting information 2). Therefore, in this update we focus on areas where there has been a major change in the evidence base or clinical practice, where practice is very varied and/or where clear consensus or guidelines are lacking (see section 3.1 in Supporting information 1).

Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis

Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3–4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).

The clinical expression of bullous pemphigoid is not determined by the specificity of the target antigen

Summary The major bullous pemphigoid (BP) antigen is a 220–240‐kDa polypeptide, although some BP sera recognize hands of 180–200 kDa or lower molecular weight. We have investigated to what extent this heterogeneity of the target antigen accounts for the clinical diversity of BP. Immunoblotting studies against extracts of salt‐separated epidermis were performed on sera from 39 patients with BP. The blotting patterns obtained were correlated with the clinical findings, with particular reference to prodromal itching, lesion morphology and severity, mucosal involvement, presence of milia, dapsone responsiveness and disease duration. The results confirm that the major BP antigen is a 220‐kDa polypeptide, and that the 180‐kDa polypeptide is a second and sometimes the sole BP antigen identified in immunoblots. Rarely, multiple bands of lower molecular weight were found. There was no correlation between the pattern of BP antigens detected in immunoblots and the clinical presentation and course of BP. There was considerable clinical diversity even among the nine patients showing specificity for a single 220‐kDa target antigen. Although two patients with a single 180‐kDa antigen specificity had a disease of unusually long duration, factors other than antigen specificity must determine the clinical expression of BP.

Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world.

The localization of the bullous pemphigoid and cicatricial pemphigoid antigens: direct and indirect immunofluorescence of suction blisters.

The location of in vivo bound immunoreactants was studied in 37 patients with subepidermal blistering diseases by direct immunofluorescence (IMF) on suction blisters taken from uninvolved forearm skin. The patients studied included 18 with bullous pemphigoid (BP), nine with cicatricial pemphigoid (CP), three with acquired epidermolysis bullosa (EBA) and 7 hybrid cases. The patterns of IMF in the suction blisters were: BP, epidermal 1, dermal 1, combined 4, negative 12; CP, epidermal 1, dermal 2, negative 6; EBA, dermal 2, negative 1; and ‘hybrid’ patients, epidermal 3, negative 4. The different patterns of suction blister staining could not be correlated with the clinical features of the patients in respect of mucous membrane involvement, scars or milia or a history of skin fragility. Both BP and CP are probably heterogeneous in respect of their antigen specificity, and the two diseases cannot reliably be distinguished by the patterns of direct IMF on suction blisters. In additon, some individual patients with BP have more than one target antigen as indicated by a combined pattern of suction blister fluorescence. The lack of correlation between the pattern of suction blister fluorescence and the clinical features suggests that factors other than antigen specificity determine the clinical expression of subepidermal blistering diseases.

The distribution of alpha 6 beta 4 integrins in lesional and non-lesional skin in bullous pemphigoid.

Summary The α6β4 integrin is associated ultrastructurally with the hemidesmosomes of the basal keratinocytes and with the bullous pemphigoid antigen (BPA), suggesting an important role in adhesion of epidermal cells to the basement membrane. Using an immunofluorescence technique with chainspecific monoclonal antibodies to the α and β subunits we have investigated the distribution of the α6β4 integrin in normal skin (n=3) and in BP skin (uninvolved, perilesional and lesional) [n=11]). The findings have been compared with other types of subepidermal blisters and with normal skin split by chemical means (n=2) and by suction (n=2). The distribution of α6β4 integrin was compared with that of bullous pemphigoid antigen (BPA) and with other basement membrane zone (BMZ) macromolecules, laminin, collagen type IV, collagen type VII and the BM600 antigen. In uninvolved, perilesional and early pre‐blistered lesional BP skin the distribution of both the α6 and β4 integrin subunits, BPA laminin, collagen types IV and VII and the BM600 antigen was identical to normal skin, i.e. a linear band in the BMZ. Within BP blisters, both α6 and β4 integrin subunits and BPA were absent, except in two blisters in which the integrin expression was retained in the blister roof, despite loss of BPA. The other BMZ components were expressed on the blister floor. These findings distinguished BP from linear IgA disease (patchy retention of α6β4 integrin expression along the blister roof and floor, with BPA expressed in the roof), and from blisters of the dermolytic type (recessive dystrophic epidermolysis bullosa and eosinophilic cellulites) in which all the BMZ components, including α6β4 integrin and BPA were expressed along the blister roof. In artificially split skin, α6β4 integrin and BPA were expressed along the roof of the split, whereas the other BMZ components were expressed along the floor. We conclude that although there is no widespread abnormality of α6β4 integrin expression in uninvolved BP skin, nor in early pre‐blistered lesions, loss of expression of both α6β4 integrin and BPA is a feature of most fully developed BP blisters, and is specific for BP compared with other types of subepidermal blisters. Disruption of the hemidesmosomerelated antigens appears be a prerequisite for blistering to occur in BP.

Primary cutaneous anaplastic large‐cell lymphoma with a prolonged erythrodermic prodrome

Anaplastic large cell lymphoma (ALCL) is a high grade non‐Hodgkins lymphoma recognized by the expression of the CD30 marker and by its morphology. We report a patient with a 6‐year history of a non‐specific erythroderma in whom ALCL developed with rapid and fatal dissemination to the lymph nodes and internal organs.