The Chronic Urticaria Registry: rationale, methods and initial implementation

Background: Chronic urticaria (CU) is a common disease, characterized by the recurrent appearance of wheals, angioedema or both for more than 6 weeks. Its underlying biology is not well understood, and many patients do not obtain sufficient relief from recommended treatments. Patient registries are rapidly growing as a form of research, because they can provide powerful, data-driven insights about the epidemiology of diseases, real-world effectiveness of treatments, rare patient types, safety monitoring, healthcare costs and opportunities for quality improvement of healthcare delivery. Objectives: The Chronic Urticaria Registry (CURE) has been designed to improve the scientific understanding, clinical treatment and healthcare planning of CU patients. This report describes the rationale, methods and initial implementation of this registry. Methods: Chronic Urticaria Registry is an ongoing, prospective, international, multicentre, observational, voluntary registry of patients with CU. Participation in CURE is open to any physician treating CU patients, regardless of location, medical specialty or type of practice setting. CURE aims to collect data on all CU patients, with no intentional selection or exclusion criteria. It collects baseline and follow-up data on the patient's demographics, history, symptoms, trigger and risk factors, therapies and healthcare utilization. Results: Chronic Urticaria Registry is a landmark achievement of the global urticaria medical community. As of 26 February 2020, 39 centres around the world have joined the registry and 35 have entered baseline data on a total of 2946 patients. Publications of this data will be forthcoming soon. Conclusions: Chronic Urticaria Registry is eagerly seeking the participation of more physicians and the support of more governmental, charitable and commercial sponsors from around the world. Here, in this paper, we invite other physicians to join this unique project to improve the lives of patients with CU

Exploring the relationship between age and health conditions using electronic health records: from single diseases to multimorbidities

Background Two enormous challenges facing healthcare systems are ageing and multimorbidity. Clinicians, policymakers, healthcare providers and researchers need to know “who gets which diseases when” in order to effectively prevent, detect and manage multiple conditions. Identification of ageing-related diseases (ARDs) is a starting point for research into common biological pathways in ageing. Examining multimorbidity clusters can facilitate a shift from the single-disease paradigm that pervades medical research and practice to models which reflect the reality of the patient population. Aim To examine how age influences an individual’s likelihood of developing single and multiple health conditions over the lifecourse. Methods and Outputs I used primary care and hospital admission electronic health records (EHRs) of 3,872,451 individuals from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care (HES-APC) dataset in England from 1 April 2010 to 31 March 2015. In collaboration with Professor Aroon Hingorani, Dr Osman Bhatti, Dr Shanaz Husain, Dr Shailen Sutaria, Professor Dorothea Nitsch, Mrs Melanie Hingorani, Dr Constantinos Parisinos, Dr Tom Lumbers and Dr Reecha Sofat, I derived the case definitions for 308 clinically important health conditions, by harmonising Read, ICD-10 and OPCS-4 codes across primary and secondary care records in England. I calculated the age-specific incidence rate, period prevalence and median age at first recorded diagnosis for these conditions and described the 50 most common diseases in each decade of life. I developed a protocol for identifying ARDs using machine-learning and actuarial techniques. Finally, I identified highly correlated multimorbidity clusters and created a tool to visualise comorbidity clusters using a network approach. Conclusions I have developed case definitions (with a panel of clinicians) and calculated disease frequency estimates for 308 clinically important health conditions in the NHS in England. I have described patterns of ageing and multimorbidity using these case definitions, and produced an online app for interrogating comorbidities for an index condition. This work facilitates future research into ageing pathways and multimorbidity

Adherence to Prescribed E-Diary Recording by Patients With Seasonal Allergic Rhinitis: Observational Study

Background: Complete diagnosis and therapy of seasonal allergic rhinoconjunctivitis require evidence that exposure to the sensitizing pollen triggers allergic symptoms. Electronic clinical diaries, by recording disease severity scores and pollen exposure, can demonstrate this association. However, patients who spontaneously download an e-diary app show very low adherence to their recording. Objective: The objective of our study was to assess adherence of patients with seasonal allergic rhinitis to symptom recording via e-diary explicitly prescribed by an allergist within a blended care approach. Methods: The @IT-2020 project is investigating the diagnostic synergy of mobile health and molecular allergology in patients with seasonal allergic rhinitis. In the pilot phase of the study, we recruited Italian children (Rome, Italy) and adults (Pordenone, Italy) with seasonal allergic rhinitis and instructed them to record their symptoms, medication intake, and general conditions daily through a mobile app (Allergy.Monitor) during the relevant pollen season. Results: Overall, we recruited 101 Italian children (Rome) and 93 adults (Pordenone) with seasonal allergic rhinitis. Adherence to device use slowly declined during monitoring in 3 phases: phase A: first week, ≥1267/1358, 90%; phase B: second to sixth week, 4992/5884, 80% to 90%; and phase C: seventh week onward, 2063/2606, 70% to 80%. At the individual level, the adherence assessed in the second and third weeks of recording predicted with enough confidence (Rome: Spearman ρ=0.75; P<.001; Pordenone: ρ=0.81; P<.001) the overall patient adherence to recording and was inversely related to postponed reporting (ρ=-0.55; P<.001; in both centers). Recording adherence was significantly higher during the peak grass pollen season in Rome, but not in Pordenone. Conclusions: Adherence to daily recording in an e-diary, prescribed and motivated by an allergist in a blended care setting, was very high. This observation supports the use of e-diaries in addition to face-to-face visits for diagnosis and treatment of seasonal allergic rhinitis and deserves further investigation in real-life contexts

WAO consensus on DEfinition of Food Allergy SEverity (DEFASE).

BACKGROUND: While several scoring systems for the severity of anaphylactic reactions have been developed, there is a lack of consensus on definition and categorisation of severity of food allergy disease as a whole. AIM: To develop an international consensus on the severity of food allergy (DEfinition of Food Allergy Severity, DEFASE) scoring system, to be used globally. METHODS PHASE 1: We conducted a mixed-method systematic review (SR) of 11 databases for published and unpublished literature on severity of food allergy management and set up a panel of international experts. PHASE 2: Based on our findings in Phase 1, we drafted statements for a two-round modified electronic Delphi (e-Delphi) survey. A purposefully selected multidisciplinary international expert panel on food allergy (n = 60) was identified and sent a structured questionnaire, including a set of statements on different domains of food allergy severity related to symptoms, health-related quality of life, and economic impact. Participants were asked to score their agreement on each statement on a 5-point Likert scale ranging from "strongly agree" to "strongly disagree". Median scores and percentage agreements were calculated. Consensus was defined a priori as being achieved if 70% or more of panel members rated a statement as "strongly agree" to "agree" after the second round. Based on feedback, 2 additional online voting rounds were conducted. RESULTS: We received responses from 92% of Delphi panel members in round 1 and 85% in round 2. Consensus was achieved on the overall score and in all of the 5 specific key domains as essential components of the DEFASE score. CONCLUSIONS: The DEFASE score is the first comprehensive grading of food allergy severity that considers not only the severity of a single reaction, but the whole disease spectrum. An international consensus has been achieved regarding a scoring system for food allergy disease. It offers an evaluation grid, which may help to rate the severity of food allergy. Phase 3 will involve validating the scoring system in research settings, and implementing it in clinical practice

WAO consensus on definition of food allergy severity (DEFASE)

Background: While several scoring systems for the severity of anaphylactic reactions have been developed, there is a lack of consensus on definition and categorisation of severity of food allergy disease as a whole. Aim: To develop an international consensus on the severity of food allergy (DEfinition of Food Allergy Severity, DEFASE) scoring system, to be used globally. Methods phase 1: We conducted a mixed-method systematic review (SR) of 11 databases for published and unpublished literature on severity of food allergy management and set up a panel of international experts. Phase 2: Based on our findings in Phase 1, we drafted statements for a two-round modified electronic Delphi (e-Delphi) survey. A purposefully selected multidisciplinary international expert panel on food allergy (n&nbsp;=&nbsp;60) was identified and sent a structured questionnaire, including a set of statements on different domains of food allergy severity related to symptoms, health-related quality of life, and economic impact. Participants were asked to score their agreement on each statement on a 5-point Likert scale ranging from "strongly agree" to "strongly disagree". Median scores and percentage agreements were calculated. Consensus was defined a priori as being achieved if 70% or more of panel members rated a statement as "strongly agree" to "agree" after the second round. Based on feedback, 2 additional online voting rounds were conducted. Results: We received responses from 92% of Delphi panel members in round 1 and 85% in round 2. Consensus was achieved on the overall score and in all of the 5 specific key domains as essential components of the DEFASE score. Conclusions: The DEFASE score is the first comprehensive grading of food allergy severity that considers not only the severity of a single reaction, but the whole disease spectrum. An international consensus has been achieved regarding a scoring system for food allergy disease. It offers an evaluation grid, which may help to rate the severity of food allergy. Phase 3 will involve validating the scoring system in research settings, and implementing it in clinical practice

Atopic dermatitis in adults : epidemiological studies of comorbidity and studies of patients on systemic treatment

Background: Atopic dermatitis (AD) is one of the most common chronic skin disorders globally. It is an itchy inflammatory skin disease that can have a detrimental impact on health-related quality of life. In recent years, AD has been associated with non-atopic conditions, though this requires further exploration. Novel understanding of AD pathogenesis has recently led to development of the first biological treatment. The overall aims of the thesis were to assess cardiovascular disease (CVD), autoimmune disease and depression among adults with AD, and to investigate the response to, and some adverse events from, systemic treatment that includes the first biological for AD. Methods: Register-based, case-control studies were conducted to assess CVD and autoimmune comorbidity among patients with AD. The source population comprised the entire Swedish population aged ≥ 15 years. Cases, including all those with an inpatient diagnosis of AD (from 1968) and/or a specialist outpatient diagnosis of AD (from 2001) through 2016, were matched by sex and age to healthy controls (104,832 cases of AD, 1,022,435 controls). Patients were classified as having severe AD if they had received systemic pharmacotherapy for AD or had been treated in a dermatological ward with AD as the main diagnosis. Otherwise, AD was classified as non-severe. The clinical cohort studies and the case-series used data from a register containing prospectively collected data from adult patients with AD on systemic treatment at the Karolinska University Hospital from 2017. The register was launched for national use in 2019. Result: Studies I–II: After multivariable adjustments for comorbidities and socioeconomic status, AD was associated with angina pectoris (adjusted odds ratio (aOR) 1.13, 95% confidence interval (CI) 1.08–1.19). Non-severe AD was associated with myocardial infarction (aOR 1.15, 95% CI 1.07–1.23) among men. Severe AD was associated with ischaemic stroke, with similar estimates in men and women (aOR 1.19, 95% CI 1.07–1.33). Diabetes mellitus, hyperlipidaemia, and hypertension were more prevalent in patients with severe AD than in controls, and hyperlipidaemia and hypertension were also more prevalent in patients with non-severe AD than in controls. Having AD was significantly associated with having one or more autoimmune diseases as compared with controls: (aOR 1.97, 95% CI 1.93–2.01), and this association was significantly stronger for having multiple autoimmune diseases than for having only one. The association was strongest for autoimmune disorders involving the skin, the gastrointestinal tract or the connective tissue. Studies III–V: In a caseseries of 10 patients with severe, long-lasting AD and most often also previous eye disease, 9/10 developed eye complications during dupilumab treatment, most commonly conjunctivitis (7/10). In a cohort study of patients treated with dupilumab (n = 12), weight gain (mean 6.1 kg, range 0.1–18.0 kg, p = 0.002) was seen after 1 year on treatment. In spite of these adverse events, dupilumab was very effective and safe. More than half of patients with moderate-to-severe AD eligible for systemic treatment (n = 60) had depressive symptoms, 25% of whom presented with moderate-to-severe depression and 5% of whom had pronounced suicidal ideation. Systemic treatment for AD significantly reduced depressive symptoms, in addition to relieving symptoms of AD. Conclusion: AD was associated with CVD and several autoimmune disorders. More than half of the patients with moderate-to-severe AD in routine dermatological care had depressive symptoms. Dupilumab was very effective and safe overall, but was associated with ocular adverse events and weight gain in these small studies. Systemic treatment for AD significantly reduced depressive symptoms in parallel with reducing AD symptoms

The nurse of the Mediterranean

During the First World War Malta did not take an active part in the fighting. Britain was joined in an ‘entente’ a friendship agreement with France since 1904 and later with Russia in 1907. On the other hand Germany was allied to the Austrian- Hungerian Empire, hence when the Great War started in July 1914 there were France, Britain and Russia on one side and Germany and Austria-Hungary on the other. The British fleet “ruled the waves”, hence with France and Britain as allies, to be joined later by Italy, the Mediterranean was more or less an allied lake, with Malta in the centre.peer-reviewe

The Potential of Clinical Decision Support Systems for Prevention, Diagnosis, and Monitoring of Allergic Diseases

Clinical decision support systems (CDSS) aid health care professionals (HCP) in evaluating large sets of information and taking informed decisions during their clinical routine. CDSS are becoming particularly important in the perspective of precision medicine, when HCP need to consider growing amounts of data to create precise patient profiles for personalized diagnosis, treatment and outcome monitoring. In allergy care, several CDSS are being developed and investigated, mainly for respiratory allergic diseases. Although the proposed solutions address different stakeholders, the majority aims at facilitating evidence-based and shared decision-making, incorporating guidelines, and real-time clinical data. We offer here an overview on existing tools, new developments and novel concepts and discuss the potential of digital CDSS in improving prevention, diagnosis and monitoring of allergic diseases

Autoantibodies as biomarkers in autoimmune diseases

The immune system plays a critical role in the homeostasis and protection of our body, but its dysregulation is often associated with the pathogenesis of autoimmune diseases. The cellular and molecular components of the immune system have been explored as therapeutic targets or biomarkers with the aim of curing autoimmunity. Although studied since decades, autoantibodies’ use as biomarker in clinical trials is still limited to a handful of well-known markers. The aim of the thesis was to test autoantibody profiling as an exploratory tool to identify new biomarkers in the context of clinical trials conducted in three autoimmune diseases. In the first part of the PhD, I tested a large set of autoantibodies on baseline serum samples from a phase III anti-IL17 clinical trial of Psoriatic Arthritis, with the aim of identifying a group of biomarkers that could discriminate between responders and non-responders to the treatment. Numerous autoantibodies of either IgG, IgM and IgA isotype were found more expressed in clinical non-responders when compared to responders. Such autoantibodies were directed against molecules related to IL17 pathway, a commensal bacterium (Lachnospiraceae) and antigens linked to Rheumatoid Arthritis. Overall, these markers allowed a discrimination of 40% of non-responders from responders population, which was judged as a too low sensitivity in order to start the development of a companion diagnostic. However, the technical knowledge acquired during this first project was fundamental for the rest of the PhD. In the second part of the PhD, I applied autoantibody profiling, using a targeted set of antigens, on serum samples from a phase II anti-IL17 treatment clinical trial of Hidradenitis Suppurativa (HS). The aim of this project was to demonstrate the presence of autoantibodies that could support the hypothesis of an autoimmune component of HS pathogenesis. We found IgG anti-Carboxyethyl-lysine (CEL) autoantibodies with specific high levels in HS when compared to healthy volunteers and other comorbidities such as Crohn’s disease and Ulcerative Colitis. B-cells producing anti-CEL antibodies were detected in HS lesional skin as well. Sera with high levels of anti-CEL autoantibodies activated macrophages and complement pathway in presence of CEL-BSA. The majority of IgG anti-CEL antibodies was of IgG2 subclass and no cross-reactivity with similar molecules such as Carboxymethyl-lysine and Octopine was found. Overall, these results suggested a role for oxidative stress and advanced glycation events in the pathogenesis of HS. In the third part of the PhD, I detected anti-FceR1a autoantibodies in serum from Chronic Spontaneous Urticaria (CSU) from a phase II clinical trial of anti-IgE treatment. It was hypothesized that patients expressing anti-FceR1a autoantibodies may activate mast cells degranulation in an IgE-free manner, which would make them resistant to anti-IgE treatment. The results showed no correlation between the presence of anti-FceR1a autoantibodies and clinical response to IgE treatment. The detection of the soluble form of FceR1a (sFceR1a) at different time-points throughout the treatment showed a dose-dependent decrease of sFceR1a concentration, similarly to what already published for FceR1a expression on basophils surface. The data showed in this thesis suggested that sFceR1a might be a substitute mechanistic marker of cell-bound FceR1a. In conclusion, although autoantibody profiling did not allow identifying specific markers for anti-IL17 treatment response in PsA, the knowledge acquired during this project was critically important. Indeed, the same approach allowed the finding of anti-CEL autoantibodies abundance and specificity in HS and the testing of anti-FceR1a autoantibodies and sFceR1a in CSU, which gave new insights in these diseases. The results presented in this thesis show the potential and limitations of autoantibodies profiling when applied to clinical trials of autoimmune diseases

Enriched mannose glycosylation contributes to Act d 2 allergenicity.

Allergens are responsible for the Th2 response in patients as part of complex mixtures of proteins, fatty acids and other molecules. Plant allergens have hitherto been included in several protein families that share no common biochemical features. Their physical, biochemical and immunological characteristics have been widely studied, but no definite conclusion has been reached about what makes a protein an allergen. N-glycosylation is characteristic of plant allergen sources but is not present in mammals