TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.

BACKGROUND: A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. OBJECTIVES: To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. METHODS: We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. CONCLUSIONS: This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations.

Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a disease of the elderly and may be associated with neurological and cardiovascular diseases and diabetes. Mortality rates strongly exceed those of the background population. OBJECTIVES: To investigate the frequency of comorbidities and their temporal relation to BP. METHODS: A register-based matched-cohort study on all Danish patients with a hospital-based diagnosis of BP (n = 3281). The main outcomes were multiple sclerosis (MS), Parkinson disease (PD), Alzheimer disease (AD), stroke, diabetes types 1 and 2, malignancies, ischaemic heart disease (IHD), hypertension and eventually death. RESULTS: At baseline, patients with BP had increased prevalences of MS [odds ratio (OR) 9·7, 95% confidence interval (CI) 6·0-15·6], PD (OR 4·2, 95% CI 3·1-5·8), AD (OR 2·6, 95% CI 1·8-3·5) and stroke (OR 2·7, 95% CI 2·4-2·9). Furthermore, malignancies, cardiovascular disease and diabetes were over-represented among patients with BP: type 1 diabetes (OR 3·1, 95% CI 2·5-3·8), type 2 diabetes (OR 2·3, 95% CI 2·0-2·6), malignancies (OR 1·3, 95% CI 1·1-1·4), IHD (OR 1·7, 95% CI 1·5-1·9) and hypertension (OR 2·0, 95% CI 1·8-2·2). During follow-up, the risk of MS was significantly higher among patients with BP [hazard ratio (HR) 9·4, 95% CI 4·9-18·0], even if events during the first year after diagnosis of BP were excluded (HR 5·1, 95% CI 2·3-11·3). Patients with BP had an average increased mortality rate of 2·04 (95% CI 1·96-2·13). CONCLUSIONS: We discovered a significantly increased frequency of MS among patients with BP. At the time of diagnosis, patients with BP had an excessive number of comorbidities and an increased mortality rate over the following years.

ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.

Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid-potent steroids are proven for proactive therapy, which is long-term intermittent anti-inflammatory therapy of the frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow-band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. 'Eczema school' educational programmes have been proven to be helpful for children and adults.

Clinical heterogeneity and differential diagnosis of atopic dermatitis.

Atopic dermatitis (AD) is a chronic or chronically relapsing skin disease that usually presents for the first time before the age of 20 years. The disease displays great clinical heterogeneity and may resemble a number of different disorders, making the correct diagnosis of AD a significant challenge for physicians. Based on the Hanifin and Rajka criteria, the authors outline the common symptoms of AD and provide an overview of the differential diagnoses to help distinguish AD from other conditions within the clinic.

Alemtuzumab is effective against severe chronic lymphocytic leukaemia-associated paraneoplastic pemphigus.

Alemtuzumab (ALZ) is a monoclonal antibody used in the treatment of a variety of lymphoproliferative diseases, primarily chronic lymphocytic leukaemia (CLL). Paraneoplastic pemphigus (PNP) is a severe mucocutaneous disease, which can occur in association with B-cell malignancies. A correct diagnosis of PNP relies on distinct clinical and histopathological features, and the demonstration, by direct immunofluorescence, of intercellular and basement membrane IgG deposits in the affected tissue. PNP is often refractory to immunosuppressive drugs and frequently has a fatal outcome. We report three cases where sustained remissions of both PNP and CLL were induced by ALZ. In one of these cases, ALZ was able to reinduce a sustained remission of PNP at the reappearance of the disorder years after the primary treatment. In all cases, the PNP diagnosis was confirmed by immunofluorescence. In conclusion, ALZ should be considered as a treatment option in severe CLL-associated PNP. Patients should be carefully selected and receive appropriate infectious prophylaxis before, during and after ALZ treatment, due to the risk of opportunistic infections secondary to combined disease- and drug-induced immunosuppression.

Stereological quantification of lymphocytes in skin biopsies from atopic dermatitis patients.

Atopic dermatitis (AD) is histologically characterized by lymphocytic infiltration of the skin and quantitative assessment is required. This study introduces stereological techniques to quantify the number of lymphocytes in skin biopsies. Four-millimetre punch biopsies were taken from skin with active eczema in 8 adults with AD and from clinically normal skin from 4 of the patients. Five persons without allergy or skin disease served as controls. The mean number of lymphocytes in 4-mm skin biopsies was 469,000 and 124,000 in active eczema and in clinically normal skin, respectively. Compared with controls, the number of lymphocytes in biopsies increased by a factor of 6.8 in active eczema and a factor of 1.8 in clinically normal skin. If 20% of skin is affected by eczema the total number of lymphocytes located in the affected skin can be estimated to 1.27 x 10(10). A patient with clinically moderate AD has a considerable number of lymphocytes in the skin.

Expression and function of CD43 and CDw60 on T cells from patients with atopic dermatitis.

Signalling via the CD43 and CDw60 epitopes has been reported as providing two novel pathways of T-lymphocyte activation. In Wiskott-Aldrich syndrome, which has atopic eczema-like skin symptoms, there is a defective expression of CD43, while CDw60 is strongly expressed on T cells from rheumatoid arthritis synovial fluid and from psoriatic skin lesions, and on blood mononuclear cells from patients with cutaneous T-cell lymphoma. We therefore studied the expression and function of these phenotypes on peripheral blood mononuclear cells and on CD4+ and CD8+ T-cell subsets from patients with atopic dermatitis. We observed a significant increase in the percentage of CD43+ cells among the blood mononuclear cells in patients with atopic dermatitis and an enhanced proliferation of CD4+ T cells following stimulation with anti-CD43 antibody. There were no changes in the CDw60 expression or function after stimulation with anti-CDw60 antibody. Thus, CD43 expression was not decreased but rather increased in blood mononuclear cells from patients with atopic dermatitis, whereas CDw60 expression did not differ from healthy controls.

[Abdominal skin affection caused by ectopic gut mucosa]. / Hudaffektion på abdomen forårsaget af ektopisk tarmslimhinde.

We report a case of skin affection on the abdomen in a 75 year-old woman with an ileostomy. The lesion developed during a period of two years on a site distant from the patient's present ostomy. However, it was located on the site of a former ileostomy removed 25 years ago. The lesion was due to proliferation of remaining gut mucosa.

Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin.

In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.

A monoclonal anti-interleukin 8 antibody (WS-4) inhibits cytokine response and acute lung injury in experimental severe acute necrotising pancreatitis in rabbits.

BACKGROUND: Interleukin 8 (IL-8) has recently been proposed to have an important role in mediating the development of the systemic sequelae associated with severe acute pancreatitis. AIMS: To define the role of IL-8 in acute pancreatitis by neutralising its effects with a monoclonal anti-IL-8 antibody (WS-4), in a rabbit model of severe acute pancreatitis. METHODS: Acute pancreatitis was induced by retrograde injection of 5% chenodeoxycholic acid into the pancreatic duct and duct ligation. Twenty rabbits were divided equally into two groups: acute pancreatitis controls received physiological saline and the treated group received WS-4, 30 minutes before induction of acute pancreatitis. RESULTS: Pretreatment of animals with WS-4 resulted in significant down regulation of serum IL-8 and tumour necrosis factor alpha (TNF-alpha) from three to six hours after induction of acute pancreatitis (p = 0.011 and 0.047 for IL-8 and 0.033 and 0.022 for TNF-alpha, respectively). In addition, a significant reduction in the CD11b and CD18 positive cells and the amount of interstitial neutrophil infiltration in the lungs from WS-4 treated animals was seen. In contrast, WS-4 did not alter the amount of pancreatic necrosis and the serum concentrations of amylase, lipase, calcium, and glucose. CONCLUSION: WS-4 cannot change the amount of pancreatic necrosis induced by injection of 5% bile acid, but does reduce the acute lung injury, presumably through inhibition of circulating IL-8 and TNF-alpha, and CD11b/CD18 in lung tissue. Therefore, a role of IL-8 in the progression of acute pancreatitis and the development of its systemic complications is suggested.

CD19-selected B lymphocytes synthesize, secrete and migrate in the presence of IL-8. TNF-alpha and gammaIP-10 are also B lymphocyte migratory factors.

B lymphocytes are responsible for antigen uptake and presentation, as well as antibody production. These reactions require close cell-to-cell contact between B lymphocytes and monocytes. In this study we demonstrate that interleukin 8 (IL-8), gamma-immune protein 10 (gammaIP-10) and tumour necrosis factor alpha (TNF-alpha) all induce a significant chemokinetic response of human B lymphocytes. Among the cytokines tested, rIL-8 was the strongest B lymphocyte migratory factor with a migratory index (MI) of 2.03+/-0.32, (P<0.002), followed by rTNF-alpha (MI=1.89+/-0.17, P<0.001) and rgammaIP-10 (MI=1.63+/-0.17, P<0.001). We did not observe B lymphocyte migration towards rIL-1alpha, rIL-2, rIL-4, rIL-10, interferon gamma (rINF-gamma) or transforming growth factor beta (rTGF-beta). Furthermore, we report that human B lymphocytes have a constitutive IL-8 mRNA expression and protein secretion in vitro. Resting as well as stimulated B lymphocytes secrete on average 1.5 ng IL-8/ml medium/24 h (2x10(6) B lymphocytes). Our data indicate a possible mechanism by which B lymphocytes make contact with other cells, during immuno-inflammatory processes.

Expression of cytokines and their receptors by psoriatic fibroblast. I. Altered IL-6 synthesis.

Interleukin(IL-)6 is overproduced in psoriatic lesions. We investigated the contribution of dermal fibroblasts to the local IL-6 production. Fibroblasts (passageno. 2 to 6) derived from lesional psoriatic (PP) and normal human (NN) skin were used to analyse the secretion of IL-6, and the related cytokines IL-1, IL-8 and TNF-alpha, and the expression of their corresponding mRNA by bioassay, ELISA and Northern hybridization, respectively. PP fibroblasts cultured under serum-free conditions produced increased amounts of bioactive IL-6 when compared to NN fibroblasts. Differences were partially restored in the presence of growth factors or serum. The serum-induced IL-6 production reached a maximum within 24 h after seeding and remained unchanged in PP fibroblasts, whereas comparable amounts of IL-6 were produced only 6 days later in NN fibroblasts. There was a clear expression of IL-6 mRNA in both types of fibroblasts under serum-free conditions. Unexpectedly, fetal calf serum, inactivated fetal calf serum as well as human serum completely inhibited the expression of IL-6 mRNA in all the PP fibroblast cultures investigated. NN fibroblasts were clearly less sensitive to this inhibiting effect of serum. Furthermore, medium supplemented with serum-free component or calcium also repressed IL-6 mRNA expression in PP fibroblasts in contrast to NN fibroblasts. Cycloheximide fully restored the repressing effect of serum indicating that serum induced a labile repressor protein. PP and NN fibroblasts produced negligible amounts of IL-1 and TNF-alpha, but the production of IL-8, however, was comparable to that of IL-6. Our results show a differently regulated IL-6 synthesis in PP fibroblasts in vitro, suggesting an active contribution of dermal fibroblasts to the local IL-6 production in psoriasis.