Mast cell activation disorders : a liaison between anaphylaxis and mastocytosis

The term mast cell activation disorders (MCAD) comprises a broad spectrum of heterogeneous conditions, such as mastocytosis, characterized by inappropriate mast cell activation/accumulation. The patients present with protean clinical manifestations and severity grade of symptoms may vary from case-to-case. The periodic or chronic symptoms that attributable to the local and systemic effects of mast cell mediators are common findings, where anaphylaxis appears to be one of the predominating clinical manifestations that generate a sensation of fear in most affected patients. The overall aim of this thesis was to provide data on the demographic, epidemiologic and clinical characteristic of patients with systemic mastocytosis, and to investigate the prevalence and features of mast cell mediatorinduced symptoms, in particular, anaphylaxis. In addition, the complex interaction between anaphylaxis and mast cell activation disorders was explored by identifying risk factors. In Paper I, the case presented highlighted the many faces of mastocytosis and proved also that there was a lack of recognition of mastocytosis symptoms among physician. In this particular case, a correct diagnosis required almost 20 years despite that the patient had consulted several doctors and underwent extensive medical investigations. The turning point for making right diagnosis was to confirm that this patient had an elevated level of baseline serum tryptase. In Paper II, three puzzling cases of hymenoptera venom-induced anaphylaxis (HVA) with elevated levels of baseline tryptase were discussed. Although all three patients presented with demographically and clinically similar data and received diagnosis of HVA using traditional allergy work-up, investigation of bone marrow mast cells led to changes in final diagnosis. This paper lends further support to the hypothesis of a clear-cut association between severe HVA and clonal mast cell disorders. In Paper III, we provided a comprehensive insight into patients with systemic mastocytosis (SM) with respect to allergological aspects of this disease. We reported the presence of mast cell mediator induced symptoms in 90% of SM patients, of these symptoms 63% were related to gastrointestinal symptoms. In addition, the prevalence of anaphylaxis in this cohort was found to be clearly increased (43%). Hymenoptera sting was the main elicitors (53%) followed by idiopathic anaphylaxis (39%). Anaphylaxis occurred more frequently in SM patients with atopic predisposition and patients without cutaneous engagement. Also, baseline tryptase levels were significantly lower in SM patients with anaphylaxis. In Paper IV, we presented comprehensive data on the characteristics of patients with unexplained anaphylaxis (UEA), by investigating these patients’ bone marrow mast cells. We found that 47% of patients had clonal markers of aberrant mast cells. Baseline serum tryptase levels were significantly higher (≥11.4 ng/ml) and conversely, total IgE levels were lower in patients with clonal mast cell disorders compared to patients with true idiopathic anaphylaxis. In Paper V, we sought to examine whether mast cells of patients with mast cell disorders express hyperreactivity in the skin and lower airways compared to control subjects. We also analyzed different mast cell mediators (serum tryptase and urinary histamine and prostaglandin D2 metabolites). Although we found elevated baseline levels of these mediators in patients with SM/MCAD, we found no evidence to support the hypothesis that a hyperreactive mast cell phenotype would exist in the skin or bronchial airways of these patients. In conclusion, the work presented in this thesis provides a better understanding of different phenotypes of patients with mast cell disorders. We observed a high prevalence of anaphylaxis in these patients. Our findings, thus, support that all patients with mast cell activation disorders should undergo comprehensive allergy work-up providing personal risk assessment before considering treatment and preventive measures. Our data also indicates that clonal mast cell disorders are present in a substantial subset of patients with UEA

Non-steroidal anti-inflammatory drug-induced anaphylaxis infrequent in 388 patients with mastocytosis: A two-center retrospective cohort study

BackgroundAnaphylaxis is a well-known feature of mastocytosis, particularly in relation to hymenoptera venom stings. It is therefore hypothesized that mastocytosis patients may also be predisposed to severe hypersensitivity reactions to certain medications including non-steroidal anti-inflammatory drugs (NSAIDs). For this reason, these patients are usually discouraged from using these drugs. The current study aimed to determine the prevalence and evaluate the severity of NSAID-related hypersensitivity reactions among patients with mastocytosis.MethodsA retrospective study was conducted among a total of 388 (≥18 years old) consecutive patients from two independent European mastocytosis centers, in Sweden and Italy. Patients underwent a thorough allergy work-up where self-reported NSAID-hypersensitivity reactions were re-evaluated by an allergist in the first cohort (202 patients) and results were validated in the second cohort (186 patients).ResultsOverall frequency of NSAID-hypersensitivity was 11.3% in the total study cohort. Most patients reacted with cutaneous symptoms (89%), whereas severe hypersensitivity reactions were infrequent with only 11 patients (2.8%) experiencing anaphylaxis. All NSAID-related hypersensitivity reactions had occurred before mastocytosis was diagnosed. There was no difference between the groups regarding gender, baseline tryptase levels or presence of atopy, asthma/rhinitis.ConclusionOur study indicates an approximate 4-fold increased prevalence of NSAID hypersensitivity among mastocytosis patients compared to the general population. However, most NSAID reactions were limited to the skin as the prevalence of overall anaphylaxis was infrequent. Our results support that mastocytosis patients with a known tolerance to NSAIDs can continue using these medications without special precautions, whereas those with a prior reaction to NSAIDs should undergo thorough allergy work-up, including drug challenges

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection

BackgroundPatients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD.MethodsA retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively.ResultsDuring VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re‐stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient‐based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom‐specific IgG4 concentrations increased during VIT (P < .001) although tryptase and IgE were unaltered.ConclusionBoth safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re‐stings.Patients with clonal mast cell disorders (cMCD) convey increased risk for venom‐induced anaphylaxis and lifelong venom‐immunotherapy (VIT) is recommended, when appropriate. VIT appears to be rather safe and effective in cMCD patients, as the risk of severe adverse reactions are rare. Elevated levels of venom‐specific IgG4 correlates with protection from re‐sting anaphylaxis in cMCD patients during VIT.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153084/1/all13980.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153084/2/all13980_am.pd

Global Classification of Mast Cell Activation Disorders:An ICD-10-CM–Adjusted Proposal of the ECNM-AIM Consortium

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM–adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.</p

Clinical Outcomes of Adults with Systemic Mastocytosis: A 15-Year Multidisciplinary Experience

Systemic mastocytosis (SM) is a rare, clonal, clinically heterogeneous disorder of the mast cells (MCs), and mainly affects adults. The present study aims to describe the clinical and laboratory features as well as the outcomes of SM. A 15-year retrospective study was conducted on 195 consecutive SM patients (aged &ge; 18 years) diagnosed in 2006&ndash;2020 at the Multidisciplinary Mastocytosis Center at Karolinska University Hospital. Patients with indolent SM (ISM) represented the most common SM variant (88.2%). Furthermore, the frequencies of aggressive SM and SM with associated non-mast-cell hematological neoplasm were 4.1% and 7.7%, respectively. The prevalence of SM in the adult population of the Stockholm region was estimated to be 10.6/100,000 inhabitants, and the mean incidence of SM cases in the Stockholm region was 0.77/100,000 people per year. In this series, tryptase levels were below 20 ng/mL in 51 patients (26%). Osteoporosis was present in 21.9% of all cases. Interestingly, there was no progression from ISM to advanced SM variants in our study. Furthermore, overall survival was significantly better in ISM patients compared to advanced SM patients (p &lt; 0.0001). Our data suggest that the early recognition and correct diagnosis of SM has prognostic significance

Table1_Non-steroidal anti-inflammatory drug-induced anaphylaxis infrequent in 388 patients with mastocytosis: A two-center retrospective cohort study.pdf

BackgroundAnaphylaxis is a well-known feature of mastocytosis, particularly in relation to hymenoptera venom stings. It is therefore hypothesized that mastocytosis patients may also be predisposed to severe hypersensitivity reactions to certain medications including non-steroidal anti-inflammatory drugs (NSAIDs). For this reason, these patients are usually discouraged from using these drugs. The current study aimed to determine the prevalence and evaluate the severity of NSAID-related hypersensitivity reactions among patients with mastocytosis.MethodsA retrospective study was conducted among a total of 388 (≥18 years old) consecutive patients from two independent European mastocytosis centers, in Sweden and Italy. Patients underwent a thorough allergy work-up where self-reported NSAID-hypersensitivity reactions were re-evaluated by an allergist in the first cohort (202 patients) and results were validated in the second cohort (186 patients).ResultsOverall frequency of NSAID-hypersensitivity was 11.3% in the total study cohort. Most patients reacted with cutaneous symptoms (89%), whereas severe hypersensitivity reactions were infrequent with only 11 patients (2.8%) experiencing anaphylaxis. All NSAID-related hypersensitivity reactions had occurred before mastocytosis was diagnosed. There was no difference between the groups regarding gender, baseline tryptase levels or presence of atopy, asthma/rhinitis.ConclusionOur study indicates an approximate 4-fold increased prevalence of NSAID hypersensitivity among mastocytosis patients compared to the general population. However, most NSAID reactions were limited to the skin as the prevalence of overall anaphylaxis was infrequent. Our results support that mastocytosis patients with a known tolerance to NSAIDs can continue using these medications without special precautions, whereas those with a prior reaction to NSAIDs should undergo thorough allergy work-up, including drug challenges.</p

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM–Adjusted Proposal of the ECNM-AIM Consortium

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM–adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia

European Competence Network on Mastocytosis (ECNM): 20-Year Jubilee, Updates, and Future Perspectives

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients