Systemic anti-inflammatory treatment of atopic dermatitis during conception, pregnancy and breastfeeding: Interdisciplinary expert consensus in Northern Europe.

Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as evidence to inform decision-making on systemic anti-inflammatory treatment is limited. This project mapped consensus across dermatologists, obstetricians and patients in Northwestern Europe to build practical advice for managing AD with systemic anti-inflammatory treatment in men and women of reproductive age. Twenty-one individuals (sixteen dermatologists, two obstetricians and three patients) participated in a two-round Delphi process. Full consensus was reached on 32 statements, partial consensus on four statements and no consensus on four statements. Cyclosporine A was the first-choice long-term systemic AD treatment for women preconception, during pregnancy and when breastfeeding, with short-course prednisolone for flare management. No consensus was reached on second-choice systemics preconception or during pregnancy, although during breastfeeding dupilumab and azathioprine were deemed suitable. It may be appropriate to discuss continuing an existing systemic AD medication with a woman if it provides good disease control and its benefits in pregnancy outweigh its risks. Janus kinase (JAK) inhibitors, methotrexate and mycophenolate mofetil should be avoided by women during preconception, pregnancy and breastfeeding, with medication-specific washout periods advised. For men preconception: cyclosporine A, azathioprine, dupilumab and corticosteroids are appropriate; a 3-month washout prior to conception is desirable for methotrexate and mycophenolate mofetil; there was no consensus on JAK inhibitors. Patient and clinician education on appropriate (and inappropriate) AD treatments for use in pregnancy is vital. A shared-care framework for interdisciplinary management of AD patients is advocated and outlined. This consensus provides interdisciplinary clinical guidance to clinicians who care for patients with AD before, during and after pregnancy. While systemic AD medications are used uncommonly in this patient group, considerations in this article may help patients with severe refractory AD.

Nipple eczema: A systematic review and practical recommendations.

The nipple is the focal point of the human breast and serves important physiological, sexual, and aesthetic purposes. It can be affected by atopic, irritant, and allergic contact eczema, which often reduce the patient's quality of life. The objective of this article is to discuss the different types of nipple eczema and highlight relevant differential diagnoses and treatment options. A systematic search of PubMed was conducted to identify and critically appraise the existing literature on the topic. All articles on nipple eczema were considered eligible, regardless of publication date, language or study design. A final of 33 manuscripts on nipple eczema remained. The scarce literature and the limited number of high-quality manuscripts impedes provision of structured data on nipple eczema. To securely reach the educative value of this manuscript, the systematic review was combined with a manual databank search and selected manual search of textbooks. The differential diagnosis of nipple eczema encompasses among others nipple psoriasis, nipple candidiasis and Paget's disease. In case of diagnostic uncertainty, swabs or biopsies are indicated. Treatment of nipple eczema needs to rapidly control the signs and symptoms of the disease, since it can have a negative effect on quality of life and can lead to premature arrest of breastfeeding. The key treatment step is starting with topical corticosteroids or calcineurin inhibitors, both of which are considered safe during lactation. Avoidance of provoking factors, such as repetitive friction, chemical agents, or allergens, can help. The use of nipple protection devices can be proposed for nursing women and sometimes adjusting of latch/suck positioning during breastfeeding is needed. Furthermore, patients should be advised to moisturize the nipple intensively and to switch to emollient wash products. Warm water compresses, black tea compresses or commercially available tannin containing topicals can provide comfort.

Tralokinumab plus topical corticosteroids in adults with severe atopic dermatitis and inadequate response to or intolerance of ciclosporin A: a placebo-controlled, randomized, phase III clinical trial (ECZTRA 7).

BACKGROUND: Patients with severe atopic dermatitis (AD) not controlled with topical therapy have limited treatment options. Ciclosporin A (CSA) is a commonly used, broad immunosuppressant in AD, but treatment with CSA requires monitoring for potentially serious adverse effects. In a previous phase III trial, tralokinumab plus topical corticosteroids (TCS) as needed provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab plus TCS in adult patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA. METHODS: In this 26-week, multicentre, parallel, randomized, double-blind, placebo-controlled, phase III trial, European adults with severe AD were randomized 1 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks plus TCS as needed. The primary endpoint was a 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: In total, 277 patients were randomized. At week 16, more patients treated with tralokinumab plus TCS vs. placebo plus TCS achieved EASI 75 [64·2% vs. 50·5%; difference 14·1% (95% confidence interval 2·5-25·7); P = 0·018], which increased further up to week 26. Improvements in AD severity were accompanied by early improvements in patient-reported outcomes, including Dermatology Life Quality Index, Patient-Oriented Eczema Measure, pruritus and sleep interference. Tralokinumab plus TCS also showed a higher EASI75 response at week 16 among patients who had previously failed CSA therapy vs. placebo plus TCS (57% vs. 41%). The overall incidence of adverse events was similar between treatment arms. CONCLUSIONS: Tralokinumab 300 mg plus TCS as needed was effective and well tolerated in patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA.

Development of a patient-reported experience measure for chronic inflammatory skin diseases.

BACKGROUND: Patient involvement and high-quality patient-provider interactions are critical factors for quality of care in chronic inflammatory skin diseases. Also, assessing the patient's perspective contributes to optimizing care delivery and patient's experience. Until today, no user-friendly tools to measure patient experiences exist within immunodermatology. OBJECTIVES: The aim of this study was to identify the relevant items for patient's experience in immunodermatology and develop a concise questionnaire to assess patient's experience in routine clinical care. METHODS: Potential relevant items for measuring patient's perspective of immunodermatology care were identified by a literature search. From this longlist, a shortlist from patient's perspective was distilled by semi-structured interviews with a diverse patient group. This list was reduced to final items using a modified Delphi method in a multi-stakeholder focus group. For each item, one question was formulated to generate the Patient-Reported Experience Measure (PREM) questionnaire. A first internal validation was achieved by an email round. RESULTS: Forty longlist items were categorized into five domains (access to care, patient centeredness, access to information, care process and satisfaction). During interview rounds, 19 shortlist items were selected if mentioned by ≥40% of interviewees. Via the focus group, the most important items were chosen by participant consensus. For each item, a question was formulated. The final PREM covers 11 items (plus 2 in case of a first consult). The first internal validation showed that the tool is clear, understandable and has an ideal length. CONCLUSION: This short user-friendly PREM can be used in scientific and routine settings to improve care for patients who suffer from chronic inflammatory skin diseases.

Hidradenitis suppurativa is associated with childhood and lifetime traumatic events: a case-control study.

BACKGROUND: Negative life events in childhood can increase the susceptibility to autoimmune and inflammatory diseases. Hidradenitis suppurativa (HS) is a systemic inflammatory disease affecting the apocrine sweat glands, characterized by abscesses, fistulas and inflammatory nodules. It is unknown whether adult HS is associated with traumatic events. OBJECTIVE: To investigate the association between childhood and total lifetime traumatic events and the presence of HS. METHODS: We conducted a matched (1 : 3) case-control study with 71 HS patients and 213 controls. Patients were matched on age, gender and level of education. Questionnaires on general and demographic information, as well as the Traumatic Experience Checklist and the Hospital Anxiety and Depression Scale, were completed. RESULTS: The number of traumatic events (OR: 1.20 per trauma, P value < 0.05), and childhood traumatic events (yes vs. no, OR 3.59, P value < 0.05) and the number of childhood traumatic events (OR 1.35 per trauma, P value < 0.05) were correlated with an increased risk of developing HS. Detailed analysis showed that childhood emotional traumatic events (OR 5.03, P value < 0.05) were significantly associated with the development of HS. CONCLUSION: Number of lifetime traumatic events and childhood traumatic events are associated with HS. This association is strongest for emotional childhood traumas. The increased prevalence of childhood traumas in HS patients can be one of the underlying mechanisms leading to systemic inflammation in these patients.

Overview on vitamin D and sunbed use.

Vitamin D seems to be associated with a protective effect in a vast range of diseases, including cardiovascular, autoimmune and oncologic conditions. Since ultraviolet (UV) B light is the most important prerequisite for the cutaneous synthesis of vitamin D, sunbeds are able to increase serum vitamin D levels, although only transiently in most cases. In this scenario, the artificial tanning industry relentlessly tries to promote the use of sunbeds as a 'safe' therapeutic measure to achieve an adequate serum vitamin D status. The World Health Organization classified UV-emitting tanning devices, as well as the whole UV spectrum, as group-1 carcinogens, as they significantly increase the risk of melanoma and non-melanoma skin cancer. In case of vitamin D deficiency or insufficiency, the current risk-benefit ratio is therefore in favour of vitamin D supplementation instead of sunbed use. Artificial tanning devices should never be considered as an option to achieve an appropriate vitamin D status. Their supposedly beneficial effects, vastly publicised by the artificial tanning industry, are not worth the carcinogenic risk associated with sunbed use.

Skin lesions, differential diagnosis and practical approach to potential survivors of torture.

As the international refugee crisis has reached new proportions (BMJ, 355, 2016 and i5412), survivors of torture increasingly present in treating physicians with an array of acute or chronic skin lesions. Physicians should be aware of common presentations and likely differential diagnoses in order to avoid mislabelling or under-recognizing torture. Survivors of torture also frequently suffer from psychological sequelae, such as post-traumatic stress disorder, and appropriate referrals are essential in order to improve recovery trajectory. Skin sequelae are the most common physical findings of torture. Not all skin lesions seen in tortured survivors are due to perpetrator inflicted injuries, and many dermatological conditions can mimic lesions typical of torture, as can scars as a result of folk remedies or cultural practices specific to geographical regions. Medical documentation of torture includes injury and lesion description. While forensic dermatology and other forensic specialties use an injury description taxonomy, and the standard dermatologic taxonomy uses an anatomic description, they are complementary sciences for lesions inflicted by torture. This results in an opportunity for learning across disciplines in order to improve evidence documentation for survivors of torture. This article describes features of common skin lesions consistent with torture, including their clinical appearances, differential diagnoses, patterns of injury and appropriate clinical descriptions.

JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis.

BACKGROUND: Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation. OBJECTIVE: Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis. METHODS: 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis. RESULTS: Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions. CONCLUSION: JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

The roadmap for allergology in Europe: The subspecialty of allergology as "stop-over" on the way to a full specialty. An EAACI position statement.

The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.

[A new case of pityriasis rubra pilaris-like eruption associated with ponatinib, a tyrosine kinase inhibitor]. / Un nouveau cas d'éruption de type pityriasis rubra pilaire associée à l'inhibiteur de tyrosine kinase ponatinib.

BACKGROUND: Pityriasis rubra pilaris (PRP) is a cutaneous syndrome of unknown origin. Most cases are sporadic and acquired. Herein we report a fifth case of PRP-like eruption associated with ponatinib, a tyrosine kinase inhibitor (TKI). PATIENTS AND METHODS: A 60-year-old woman presented at the dermatology department with an erythemato-squamous eruption present for 2weeks. The patient was also being treated in haematology for recurrence of acute lymphoblastic leukaemia. Treatment with ponatinib had been initiated 6weeks earlier. Despite the low specific cutaneous histology, a diagnosis of induced PRP-like eruption was made based on the characteristic clinical aspect. Treatment with local corticosteroids resolved the eruption. DISCUSSION: The literature contains 6 reported cases of PRP-like eruptions associated with TKI, including 4 with ponatinib. The eruption began from 2weeks to 2-3 months after treatment induction. Prescribed topical corticosteroids have yielded mixed results. A better understanding of the physiopathology of these eruptions associated with TKI could shed light on the pathogenic mechanisms in relation to idiopathic PRP.

Adrenaline in anaphylaxis treatment and self-administration: experience from an inner city emergency department.

BACKGROUND: Anaphylaxis is a life-threatening emergency of which reliable epidemiological data are lacking. This study aimed to analyze how quickly patients presenting with anaphylaxis were treated in emergency and whether treatment followed the European Academy of Allergy and Clinical Immunology (EAACI) guidelines. METHODS: Patient data were collected between April 2009 and April 2013. Emergency doctors completed a questionnaire for adult patients presenting at the emergency department (ED) of the St. Pierre hospital in Brussels with anaphylaxis. Inclusion criteria were based on the Sampson criteria of anaphylaxis. Data were analyzed using a Microsoft Excel database. RESULTS: About 0.04% (100/230878) of all emergency visits in adults presented with anaphylaxis. 64% of patients received their first medical help later than 30 min after symptom onset. 67% of patients received adrenaline, 85% oral antihistamines, and 89% received IV glucocorticosteroids. 46/100 patients were discharged directly from the ED, of which 87% received further medical prescriptions for self-administration: 67% corticosteroids, 83% antihistamines, and 9% intramuscular adrenaline. 74% were instructed to consult an allergologist for adequate diagnosis. 54/100 patients were hospitalized. CONCLUSION: The majority of patients were treated according to the EAACI guidelines for management of anaphylaxis, but only a minority received the recommended adrenaline auto-injector for self-administration at discharge. Because the majority of patients received medical help later than 30 min after symptom onset, adrenaline auto-injector prescription is a necessity. The low rate of doctors prescribing adrenaline auto-injectors in the ED setting underlines the need to train doctors of various backgrounds in prevention and treatment of anaphylaxis and the close collaboration with allergologists.

Therapy of ulcus cruris of venous and mixed venous arterial origin with autologous, adult, native progenitor cells from subcutaneous adipose tissue: a prospective clinical pilot study.

BACKGROUND: The stromal vascular fraction (SVF) of adipose tissue consists of cellular subpopulations with distinct regenerative potential. OBJECTIVE: To investigate the regenerative capacities of autologous SVF cells in the treatment of chronic leg ulcers of venous (VLU) and arterial-venous (AVLU) origin. METHODS: Multimorbid ulcer patients received a singular topical treatment with 9-15 × 106 SVF cells, separated from abdominal lipoaspirates by digestion with collagenase and neutral protease and applied immediately after isolation. The primary endpoints were the change in wound size 12 weeks after treatment and evaluation of adverse events. Secondary endpoints included the time to complete wound epithelialization and change in pain levels. Postoperative wound treatment modalities and treatment of comorbidities were not intensified compared with pre-operative management. Follow-up period was at least 6 months. RESULTS: Sixteen elderly ulcer patients (seven with VLU, nine with AVLU) were treated as described. All VLU patients (median ulcer size: 48.25 cm2 ) and four of nine AVLU patients showed complete epithelialization of the ulcers within 71-174 days. In three patients with large ulcerations on both legs, ulcerations on the non-treated, contralateral leg also epithelialized. Patients reported a considerable rapid decrease in pain intensity by 2.5 points on average on a visual scale from 1 to 5 within the first 2 weeks after treatment. The patients were followed up for 9-44 months (median: 30 months). No severe side-effects were observed. CONCLUSIONS: The use of SVF cells presents an effective, minimally invasive option for the treatment of VLU and AVLU even in multimorbid patients. In patients with larger predominantly ischaemic AVLU and comorbidities, one-time application of the used amounts of SVF cells was not sufficient in the majority of cases.

Pollen derived low molecular compounds enhance the human allergen specific immune response in vivo.

BACKGROUND: Besides allergens, pollen release bioactive, low molecular weight compounds that modulate and stimulate allergic reactions. Clinical relevance of these substances has not been investigated to date. OBJECTIVE: To elucidate the effect of a non-allergenic, low molecular weight factors from aqueous birch pollen extracts (Bet-APE < 3 kDa) on the human allergic immune response in vivo. METHODS: Birch and grass pollen allergic individuals underwent skin prick testing with allergen alone, allergen plus Bet-APE < 3 kDa, or allergen plus pre-identified candidate substances from low molecular pollen fraction. Nasal allergen challenges were performed in non-atopic and pollen allergic individuals using a 3 day repeated threshold challenge battery. Subjects were either exposed to allergen alone or to allergen plus Bet-APE< 3 kDa. Local cytokine levels, nasal secretion weights, nasal congestion and symptom scores were determined. RESULTS: Skin prick test reactions to pollen elicited larger weals when allergens were tested together with the low molecular weight compounds from pollen. Similar results were obtained with candidate pollen-associated lipid mediators. In nasal lining fluids of allergic patients challenged with allergen plus Bet-APE < 3 kDa, IL-8 and IgE was significantly increased as compared to allergen-only challenged patients. These patients also produced increased amounts of total nasal secretion and reported more severe rhinorrhea than the allergen-only challenged group. CONCLUSIONS: Low molecular compounds from pollen enhance the allergen specific immune response in the skin and nose. They are therefore of potential clinical relevance in allergic patients.