Prevalence of hypersensitivity reactions in various forms of mastocytosis: A pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry.

BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.

Asthma remission one, none and one-hundred thousand: the relevance of the patient's view.

OBJECTIVE: Achieving remission in severe asthma holds paramount importance in elevating patient quality of life and reducing both individual and societal burdens associated with this chronic condition. This study centers on identifying pivotal patient-relevant endpoints through standardized, reproducible methods, while also developing a patient-centric definition of remission, essential for effective disease management. METHODS: A discrete choice experiment (DCE) was conducted to assess patients' perceptions on the four primary criteria for defining severe asthma remission, as outlined by the SANI survey. Additionally, it investigated the correlation between these perceptions and improvements in the doctor-patient therapeutic alliance during treatment decision-making. RESULTS: 249 patients (70% aged between 31-60, 59% women and 82% without other pathologies requiring corticosteroids) prioritize the use of oral corticosteroids (OCS, 48%) and the Asthma Control Test (ACT, 27%) in defining their condition, ranking these above lung function and exacerbations. This preference for OCS stems from its direct role in treatment, tangible tracking, immediate symptom relief, and being a concrete measure of disease severity compared to the less predictable and quantifiable exacerbations. CONCLUSIONS: This study explores severe asthma remission from patients' perspectives using clinician-evaluated parameters. The DCE revealed that most patients highly value OCS and the ACT, prefer moderate improvement, and avoid cortisone cycles. No definitive preference was found for lung function status. Integrating patient-reported information with professional insights is crucial for effective management and future research. Personalized treatment plans focusing on patient preferences, adherence, and alternative therapies aim to achieve remission and enhance quality of life.

Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis.

BACKGROUND: Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms. OBJECTIVE: In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains. METHODS: Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed. RESULTS: We confirmed a higher incidence of HαT+ cases (n = 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT+ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT+ (10.2%) compared to HαT- (3.4%, P = .029) patients. We also confirmed that HαT+ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations. CONCLUSION: These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

Drug-induced mast cell eradication: A novel approach to treat mast cell activation disorders?

Mast cell (MC) activation is a key event in allergic reactions, other inflammatory states, and MC activation syndromes. MC-stabilizing agents, mediator-targeting drugs, and drugs interfering with mediator effects are often prescribed for these patients. However, the clinical efficacy of these drugs varies depending on the numbers of involved MCs and the underlying pathology. One straightforward approach would be to eradicate the primary target cell. To date however, no MC-eradicating treatment approach has been developed for patients with MC activation disorders. Nevertheless, recent data suggest that long-term treatment with agents effectively inhibiting KIT function results in the virtual eradication of tissue MCs and a sustained decrease in serum tryptase levels. In many of these patients, MC depletion is associated with a substantial improvement in mediator-induced symptoms. In patients with an underlying KIT D816V-positive mastocytosis, such MC eradication requires an effective inhibitor of KIT D816V, such as avapritinib. However, the use of KIT inhibitors must be balanced against their potential side effects. Here we discuss MC-eradicating strategies in various disease models, the feasibility of this approach, available clinical data, and future prospects for the use of KIT-targeting drugs in MC activation disorders.

Clinical impact and proposed application of molecular markers, genetic variants, and cytogenetic analysis in mast cell neoplasms: Status 2022.

Mast cell neoplasms are an emerging challenge in the fields of internal medicine, allergy, immunology, dermatology, laboratory medicine, and pathology. In this review, we discuss the current standards for the diagnosis and prognostication of mast cell neoplasms with special reference to clinically relevant germline and somatic gene variants. In patients with cutaneous mastocytosis or with indolent systemic mastocytosis (SM), various KIT-activating mutations act as key molecular drivers of the disease. In adults, KIT p.D816V is by far the most prevalent driver, whereas other KIT mutants are detected in nearly 40% of children. In advanced SM, including aggressive SM, SM with an associated hematological neoplasm, and mast cell leukemia, additional somatic mutations in other genes, such as SRSF2, JAK2, RUNX1, ASXL1, or RAS, may be detected. These drivers are more frequently detected in SM with an associated hematological neoplasm, particularly in male patients. Recently, hereditary alpha-tryptasemia has been identified as a genetic trait more prevalent in SM compared with healthy controls. Moreover, hereditary alpha-tryptasemia is more frequent in patients with SM with Hymenoptera venom allergy and severe mediator-related symptoms than in patients with SM without symptoms. On the basis of this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathologic criteria to establish the diagnosis and prognosis in SM.

Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation.

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in primary antiphospholipid syndrome. The multicenter ATHERO-APS study.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is emerging as a novel cardiovascular risk factor. Levels of PCSK9 in thrombotic primary antiphospholipid syndrome (PAPS) have never been investigated. METHODS: Cross sectional comparison of baseline characteristics of 91 PAPS patients enrolled in the multicenter prospective ATHERO-APS cohort study. PCSK9 levels were categorized into tertiles and the association with arterial and recurrent thrombosis were assessed by univariable and multivariable logistic regression analysis. RESULTS: Median age was 51 years and 71.4% (n = 65) were women. Overall, 33% (n = 30) experienced an arterial event while 31% (n = 28) had recurrent thrombotic events. Median PCSK9 levels were 1243 (1100-1650) pg/ml. Patients in the third PCSK9 tertile (>1458 pg/ml) showed a higher prevalence of dyslipidemia, lupus anticoagulant positivity and a history of previous arterial and recurrent thrombosis than patients in the first and second tertile. PCSK9 levels were higher in arterial than venous thrombosis (1502 vs. 1180 pg/ml, p = 0.002), and in patients with recurrent vs isolated thrombosis (1680 vs. 1150 pg/m, p < 0.001). High plasma PCSK9 levels were associated with a 4-fold increase risk for arterial events and with a 10-fold increase risk for recurrent thrombosis after adjustment for confounding factors. CONCLUSION: These preliminary data suggest that PCSK9 levels are increased in PAPS patients with arterial and recurrent thrombosis. Its role as a possible therapeutic target in PAPS needs further studies.

Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022.

Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual's baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.

Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency.

INTRODUCTION: Hereditary angioedema due to C1-inhibitor (C1-INH-HAE) is a rare disease characterized by unpredictable swelling attacks that may be life-threatening when affecting the upper airways. Understanding the pathophysiology of HAE and the mechanism of bradykinin-mediated angioedema allowed the development of new therapies for the treatment of HAE: clinical trials are ongoing to expand the number of drugs available for on-demand treatment and prophylaxis. AREAS COVERED: Authors discuss the products that have been used to treat this disease for many years and present the most recently marketed products and those which are under development. EXPERT OPINION: Significant therapeutic progress has been made in HAE. In particular, drugs targeting specific molecules involved in the angioedema formation were developed and studies with new drugs are ongoing. In the coming years, more effective therapies with easier administration route options for on-demand treatment and long-term prophylaxis will be available to treat this disease and the variety of patients. Gene therapy strategies may offer a definitive treatment. High costs of current and new drugs may be a limiting factor for their availability, especially in developing countries.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Biomarkers for evaluation of mast cell and basophil activation.

Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.

Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

BACKGROUND: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. METHODS: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. RESULTS: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. CONCLUSIONS: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.

Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature.

Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hematologic diseases characterized by single- or multi-lineage cytopenia(s) with either inherited or acquired pathogenesis. Aberrant T or B cells or innate immune responses are variously involved in the pathophysiology of BMF, and hematological improvement after standard immunosuppressive or anti-complement therapies is the main indirect evidence of the central role of the immune system in BMF development. As part of this immune derangement, pro-inflammatory cytokines play an important role in shaping the immune responses and in sustaining inflammation during marrow failure. In this review, we summarize current knowledge of cytokine signatures in BMF syndromes.

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

BACKGROUND: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM. METHODS: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM. RESULTS: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly. CONCLUSION: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.

Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology.

BACKGROUND: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year. METHODS: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria. CONCLUSIONS: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema.

Flow-mediated dilation shows impaired endothelial function in patients with mastocytosis.

BACKGROUND: Mastocytosis is a rare disease characterized by clonal proliferation of mast cells (MCs) in different organs. Clinical manifestations of mastocytosis are mostly due to release of mediators from MCs and, in many cases, such as urticaria, flushing, angioedema, and anaphylaxis, are an expression of the biological effects of mediators on endothelial cells. Chronic secretion of mediators in patients with mastocytosis can lead to alteration of endothelial function. OBJECTIVE: We sought to investigate endothelial function in patients with mastocytosis using a noninvasive technique of flow-mediated dilation (FMD). METHODS: Twenty-five adult patients with indolent and advanced forms of mastocytosis and 20 healthy control subjects were enrolled in the study. Ultrasound assessment of FMD was performed by measuring changes in the diameter of the brachial artery after 5 minutes of arterial occlusion. Changes in FMD were correlated with clinical parameters and serum tryptase levels. RESULTS: Patients with mastocytosis had lower FMD compared with healthy control subjects (P < .001). Advanced and smoldering forms showed a lower FMD compared with indolent forms (P < .001). FMD inversely correlated with age and serum tryptase levels and directly with median arterial pressure and recurrent flushing episodes. No correlation was found between FMD and osteoporosis, recurrent anaphylaxis, presence of skin lesions, and long-term antihistamine treatment. CONCLUSIONS: Endothelial dysfunction, as demonstrated by FMD reduction, is detectable in patients with mastocytosis and is more severe in patients with high tryptase levels and advanced disease. Endothelial function appears to be negatively influenced by MC proliferation rather than by the severity of mediator-related symptoms.

Adverse reactions to drugs and biologics in patients with clonal mast cell disorders: A Work Group Report of the Mast Cells Disorder Committee, American Academy of Allergy, Asthma & Immunology.

Providers caring for patients with mastocytosis are tasked with the decision to consider therapeutic options. This can come with some trepidation because information available in the public domain lists numerous mast cell (MC) activators based on data that do not discriminate between primates, rodents, and MC lines; do not consider dosage; and do not take into account previous exposure and resultant clinical findings. This being said, there is support in the literature for an enhanced MC response in some patients with mastocytosis and in cases in which there is a greater incidence of adverse reactions associated with certain antigens, such as venoms and drugs. Thus this report provides a comprehensive guide for those providers who must decide on therapeutic options in the management of patients with clonal MC disease.

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual's baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where KIT-mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor KIT-mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where KIT-mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.