Challenges in the Diagnosis of Cutaneous Mastocytosis.

BACKGROUND: Mastocytosis is characterized by an accumulation of clonal mast cells (MCs) in tissues such as the skin. Skin lesions in mastocytosis may be clinically subtle or heterogeneous, and giving the correct diagnosis can be difficult. METHODS: This study compiles personal experiences together with relevant literature, discussing possible obstacles encountered in diagnosing skin involvement in mastocytosis and cutaneous mastocytosis (CM). RESULTS: The nomenclature of the term "CM" is ambiguous. The WHO classification defines CM as mastocytosis solely present in the skin. However, the term is also used as a morphological description, e.g., in maculopapular cutaneous mastocytosis (MPCM). This is often seen in systemic, as well as cutaneous, mastocytosis. Typical CM manifestations (MPCM), including mastocytoma or diffuse cutaneous mastocytosis (DCM), all share a positive Darier's sign, and can thus be clinically recognized. Nevertheless, distinguishing monomorphic versus polymorphic MPCM may be challenging, even for experienced dermatologists. Less typical clinical presentations, such as MPCM with telangiectatic erythemas (formerly called telangiectasia macularis eruptiva perstans), confluent, nodular or xanthelasmoid variants may require a skin biopsy for histopathological confirmation. Because MC numbers in CM have a large overlap to those in healthy and inflamed skin, detailed histopathological criteria to diagnose mastocytosis in MPCM are needed and have been proposed. D816V KIT mutational analysis in tissue is helpful for confirming the diagnosis. Biomarkers allow the prediction of the course of CM into regression or evolution of the disease. Further diagnostic measures should screen for concomitant diseases, such as malignant melanoma, and for systemic involvement. CONCLUSIONS: Whereas in typical cases the diagnosis of CM may be uncomplicated, less typical manifestations may require specific investigations for making the diagnosis and predicting its course.

Physical urticaria: Clinical features, pathogenesis, diagnostic work-up, and management.

Physical urticaria is a type of urticaria in which recurrent wheals and/or angioedema occur following exposure of the skin to a physical stimulus. It is classified according to its triggers, which may be mechanical (friction, pressure, and vibration), thermal (cold and heat), or solar electromagnetic radiation. Symptoms of different physical urticarias can develop following specific activities that expose patients to an eliciting stimulus and may be variably accompanied by mucosal involvement and systemic symptoms, including nausea, headache, or even anaphylaxis. Differentiation of physical urticaria from other chronic urticarias requires careful clinical assessment and confirmatory provocation testing, which in turn can inform appropriate management. This clinical review provides an evidence-based summary of the epidemiology, clinical features, pathogenesis, diagnostic work-up, and management of physical urticaria.

Food and drug allergy, and anaphylaxis in EAACI journals (2018).

The European Academy of Allergy and Clinical Immunology (EAACI) supports three journals: "Allergy," "Pediatric Allergy and Immunology (PAI)," and "Clinical and Translational Allergy (CTA)." One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stakeholders including the EAACI junior members. This paper summarizes the achievements of 2018 in anaphylaxis, and food and drug allergy. Main topics that have been focused are anaphylaxis, mechanisms of food allergy (FA), epidemiology of FA, food allergens, diagnosis of FA, prevention and control of FA, FA immunotherapy, drug allergy, and political agenda.

Highlights and recent developments in food and drug allergy, and anaphylaxis in EAACI Journals (2017).

This review highlights research advances and important achievements in food allergy, anaphylaxis, and drug allergy that were published in the Journals of the European Academy of Allergy and Clinical Immunology (EAACI) in 2017. Food allergy and anaphylaxis research have continued to rapidly accelerate, with increasing numbers of outstanding developments in 2017. We saw new studies on the mechanisms, diagnosis, prevention of food allergy, and novel food allergens. Drug hypersensitivity, as well as hereditary angioedema, has been highlighted in the present review as the focus of recent developments. The EAACI owns three journals: Allergy, Pediatric Allergy and Immunology (PAI), and Clinical and Translational Allergy (CTA). One of the major goals of the EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stakeholders including the EAACI junior members. This paper summarizes the achievements of 2017 in anaphylaxis, and food and drug allergy.

Management of Pediatric Urticaria with Review of the Literature on Chronic Spontaneous Urticaria in Children.

There are substantial knowledge gaps related to diagnosis and management of pediatric cases of chronic urticaria, and in particular chronic spontaneous urticaria (CSU). In this article we aimed to review the diagnosis and management of chronic urticaria in children and CSU in particular. We conducted a systematic review of articles published in English and French on pediatric CSU management in the last 10 years. We included experimental studies (eg, randomized controlled trials), other experimental designs (eg, nonrandomized methods of assignment, controlled before-after studies, and interrupted time series), and observational studies (eg, prospective or retrospective cohort studies, cross-sectional studies, case-control studies, and case reports). Our findings highlight the efficacy of second-generation antihistamines for the treatment of CSU in children and supports the use of omalizumab for more severe cases. However, our study also reveals severe knowledge gaps related to the best management strategy in children with more severe/refractory cases of CSU. Future studies are required to establish the beneficial effect of high doses of second-generation antihistamines as well as the effectiveness and safety of omalizumab and other biologics in young children.

Similar Efficacy with Omalizumab in Chronic Idiopathic/Spontaneous Urticaria Despite Different Background Therapy.

BACKGROUND: Data from the 3 omalizumab pivotal trials in patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) represent the largest database of patients reported to date with refractory disease (omalizumab, n = 733; placebo, n = 242). OBJECTIVE: The objective of this study was to compare results from ASTERIA I and II, which included only approved doses of H1-antihistamine as background therapy based on regulatory authority requirements, to those from GLACIAL, which permitted higher doses of H1-antihistamines as well as other types of background therapy, in a post hoc analysis. METHODS: Efficacy data from the placebo, omalizumab 150-mg, and omalizumab 300-mg treatment arms of ASTERIA I and II were pooled and analyzed (n = 162 and n = 160, respectively). The 300-mg treatment arm analyses were compared with the analysis of data from GLACIAL (n = 252) using analysis of covariance models. The key efficacy endpoint was change from baseline to week 12 in mean weekly itch severity score (ISS); other endpoints were also evaluated. Safety data were pooled from all 3 studies. RESULTS: Mean ISS was significantly reduced from baseline at week 12 in the pooled ASTERIA I and II omalizumab 150- and 300-mg treatment arms and in the GLACIAL omalizumab 300-mg arm. The weekly ISS reduction magnitude at week 12 was similar between the omalizumab 300-mg groups in the ASTERIA I and II pooled and GLACIAL studies. Similar treatment effect sizes were observed across multiple endpoints. Omalizumab was well tolerated and the adverse-event profile was similar regardless of background therapy for CIU/CSU. The overall safety profile was generally consistent with omalizumab therapy in allergic asthma. CONCLUSION: Omalizumab 300 mg was safe and effective in reducing CIU/CSU symptoms regardless of background therapy.

Childhood acute urticaria in northern and southern Europe shows a similar epidemiological pattern and significant meteorological influences.

Acute urticaria (AU) is a common condition that often presents in childhood. Although there is a general perception of cyclic annual trends in AU, no one has tried to identify any seasonal variation on its prevalence and incidence, associate environmental influences and impute geographic, ethnic, or even genetic features that may contribute to its onset. We aimed to analyze the influence of climate and geographic parameters on annual fluctuation of AU cases referred to the Emergency Departments (EDs) of Norwich (UK) and Heraklion (Crete, Greece), compare all identifiable potential triggers and severity, and calculate the prevalence and incidence of AU. Record-based data of all children up to 14 yr of age referred to both EDs between June 2005 and May 2007 were examined retrospectively. Demographic characteristics and any potential identifiable triggers of AU were recorded and compared. Poisson's regression was utilized to examine any influence of meteorological parameters on AU incidence. Edwards' test for seasonality was applied to identify any significant seasonal trend of the AU incidence within each city. Seven hundred and twenty-nine AU cases were identified (324 in Norwich and 405 in Heraklion), among 56,624 total referrals (28,931 and 27,693 cases, respectively). Respiratory infections were found to be the most commonly associated potential triggers of AU and food allergens the least. AU cases and incidence rates in both cities were equally distributed during the study period. A non-significant seasonal trend in AU incidence (October, April-May) was observed in Norwich, in contrast to a significant seasonal pattern (December, February-May) of AU in Heraklion. Temperature was inversely associated with AU incidence, while the statistically significant effect of relative humidity varied. Acute childhood urticaria shows a similar epidemiological pattern in northern and southern Europe regardless of the expected differences in genetic, geographic, and environmental background. Temperature and humidity are correlated with AU incidence. Seasonality of several acute respiratory viral infections, the most prominent associated trigger of AU, coincides with the observed AU seasonality, suggesting a potential linkage. However, this needs to be elucidated from larger epidemiological studies.

New insights into hereditary angio-oedema: Molecular diagnosis and therapy.

Hereditary angio-oedema (HAE) is a rare but potentially life-threatening condition. Three types are now recognized. Types I and II HAE involve mutations in the C1NH (SERPING1) gene, encoding the C1 inhibitor protein, whereas type III HAE involves mutations in the F12 gene, encoding coagulation factor XII (Hageman factor). They share a common final pathway leading to increased bradykinin formation. HAE must be distinguished from acquired angio-oedema with C1 esterase inhibitor deficiency, angiotensin-converting enzyme inhibitor-induced angio-oedema and the much more common histaminergic angio-oedema, occurring with or without weals. Understanding the pathogenesis of HAE is leading to the introduction of new therapies that target the bradykinin receptor or inhibit kallikrein activity, innovations that will hopefully reduce morbidity and mortality in this group of severe genetic disease.

Narrowband ultraviolet B phototherapy is beneficial in antihistamine-resistant symptomatic dermographism: a pilot study.

BACKGROUND: Symptomatic dermographism is the most common type of physical urticaria. It can be severe and poorly controlled with H1 antihistamines in some patients. Photochemotherapy (psoralen plus ultraviolet [UV] A) may help the itch of dermographism but the effect of narrowband (NB) UVB therapy has not been previously studied. OBJECTIVES: We sought to examine the clinical efficacy of NB UVB therapy for itch and whealing in symptomatic dermographism and to assess the duration of the effect during 3 months of follow-up. METHODS: Eight patients (6 female) were enrolled into an open uncontrolled prospective study. Intensity of itching and whealing was assessed with visual analog scales and the whealing response was evaluated by testing with a dermographometer at pressures of 20, 36, and 60 g/mm2 on the upper aspect of the back. NB UVB phototherapy was given for 6 weeks 3 times weekly starting at 50% of minimal erythema dose with 20% to 0% increments as tolerated. Fexofenadine (180 mg/d) was taken during the run-in period and subsequently throughout the study and follow-up as required. Patients were followed for 3 months with regular assessments every 6 weeks after completion of phototherapy. RESULTS: All patients showed an improvement in itching at the end of NB UVB treatment (mean [SD] reduction 52.3% [31.6%]). Subjective assessment of whealing revealed a significant improvement in all but two patients (mean [SD] reduction 71% [54%]). There was a small and statistically significant improvement in cumulative dermographometer-induced wheal widths at the end of phototherapy (P = .038). A time trend for the relapse of symptoms within 12 and 18 weeks after completing phototherapy was significant for both visual analog scale scores but not for dermographometer-induced whealing. LIMITATIONS: The apparent rarity of antihistamine-resistant symptomatic dermographism limited the study to a small number of participants. The severity of the condition did not permit a controlled and blinded study design. CONCLUSIONS: NB UVB phototherapy is an effective second-line treatment for patients with severe symptomatic dermographism responding poorly to fexofenadine. This therapy can lead to subjective relief of pruritus and whealing and objective reduction of whealing. NB UVB phototherapy may restore symptom control with antihistamines in some patients.

Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations.

OBJECTIVE: To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene. DESIGN: Retrospective review of medical records and evaluation of histologic findings. SETTING: The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria. PATIENTS: Twenty-two individuals from 13 families with autoinflammatory disease associated with CIAS-1/NALP3 mutations. MAIN OUTCOME MEASURES: Phenotype, genotype, skin histologic findings, and response to treatment with anakinra. RESULTS: Five heterozygous missense mutations were identified in CIAS-1/NALP3. Skin histologic findings revealed marked vascular dilatation and neutrophilic infiltration involving small vessels and eccrine glands. Serologic evidence of intense inflammation was present in untreated patients, with median serum amyloid A protein and C-reactive protein levels of 141 and 38 mg/L, respectively. Fifteen patients received anakinra for up to 39 months, all of whom achieved serologic remission and complete resolution of fever, rash, conjunctivitis, and rheumatic symptoms, without any adverse effects. Six patients had AA (reactive systemic) amyloidosis, 2 of whom died of renal failure complications before interleukin 1-inhibiting therapy was available; 1 patient underwent renal transplantation and remains clinically well taking anakinra, and in the remaining 3 patients, anakinra therapy resulted in remission of their nephrotic syndrome. CONCLUSIONS: Anakinra therapy was well tolerated and has sustained efficacy on dermatologic and rheumatic manifestations in these patients with CIAS-1/NALP3 mutations. This treatment also resulted in resolution of AA amyloidosis-associated nephrotic syndrome in all affected patients.

Drug-induced urticaria.

Urticaria is characterised by transient swellings of the skin, which fluctuate over hours. Deeper swellings of the subcutaneous and submucosal tissue are known as angio-oedema. Drug-induced urticaria has been reported with a wide range of drugs and vaccines. NSAIDs and antibiotics are the drugs most commonly associated with urticaria, although reliable data from prospectively controlled studies is scarce. Spontaneous reports of drug-induced urticaria to the Committee on Safety of Medicines, UK, over a 40-year period also implicate bupropion, selective serotonin re-uptake inhibitor antidepressants, angiotensin-converting enzyme inhibitors (ACEI), H2 and H1 antihistamines, and systemic antifungals. New evidence suggests that selective COX-2 inhibitors may be tolerated in patients with aspirin-sensitive urticaria. The safety of angiotensin II receptor antagonists in patients with angio-oedema induced by ACEI has not yet been established.

Autoimmune urticaria.

A growing body of evidence shows that at least 40% of patients with unexplained (idiopathic) chronic urticaria have clinically relevant functional autoantibodies to the high-affinity IgE receptor on basophils and mast cells. The term "autoimmune urticaria" is used for this subgroup of patients presenting with continuous ordinary urticaria. This article reviews the evidence for the autoimmune hypothesis and other nonantibody serum histamine-releasing factors in the etiopathogenesis of urticaria; defines autoimmune urticaria; looks at how autoimmune urticaria fits into existing classifications of urticaria; proposes diagnostic criteria that may be useful to the clinician; and reviews the management implications for patients with this subset of chronic disease.

Classification of anti-FcepsilonRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity.

BACKGROUND: Circulating autoantibodies against FcepsilonRI, IgE, or both occur in approximately one third of patients with chronic idiopathic urticaria (CIU), but not all autoantibodies initiate histamine release. OBJECTIVE: We sought to classify patients with CIU into subsets on the basis of serum bioactivity and immunoreactivity and to examine the relationship between newly defined subtype and disease severity. METHODS: Sera from patients with CIU (n = 78), dermog-raphism (n = 15), and cholinergic urticaria (n = 10) and sera from healthy subjects (n = 39) were analyzed by means of Western blot analysis for anti-FcepsilonRI autoantibodies and for histamine release from basophils and dermal mast cells. In vivo reactivity of autologous serum was tested by means of intradermal injection, and CIU severity was determined on the basis of clinical interview. RESULTS: We classified sera from patients with CIU into 5 subsets: immunoreactive histamine-releasing anti-FcepsilonRI autoantibodies (n = 20 [26%]); immunoreactive anti-FcepsilonRI autoantibodies without histamine-releasing activity (n = 12 [15%]); anti-IgE-like autoantibodies (n = 7 [9%]); serum containing a mast cell-specific histamine-releasing factor (n = 7 [9%]); and sera with no identifiable factor (n = 32 [41%]). Patients with serum histamine-releasing activity had more severe urticaria than patients without such activity. Positive skin test responses to autologous sera were associated with histamine-releasing anti-FcepsilonRI autoantibodies but not with non-histamine-releasing anti-FcepsilonRI autoantibodies. Neither healthy subjects nor patients with dermographism or cholinergic urticaria had his-tamine-releasing anti-FcepsilonRI autoantibodies. CONCLUSION: These data support the specificity of functional anti-FcepsilonRI autoantibodies to CIU. The identification of distinctive subsets of patients suggests that other pathogenic mechanisms occur in CIU in addition to direct ligation of FcepsilonRI by autoantibodies causing dermal mast cell degranulation. Elucidating these mechanisms might lead to new treatments for CIU.