Expanding the Diagnostic Lens: Mast Cell Activation Syndromes and the Hidden Spectrum of Angioedema-Associated Mortality in COVID-19.

Mast Cell Regulatory Gene Variants Are Common in Mast Cell Activation Syndrome

Characterization of Mast Cell Activation Syndrome

Dyspareunia, vaginitis and dysfunctional uterine bleeding (DUB) are common problems which, despite their polygenicity, commonly appear idiopathic and treatment-refractory. Mast cell (MC) activation syndrome (MCAS) is a newly-recognised, prevalent, chronic multisystem polymorbidity of general themes of inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues. MCs produce significant quantities of heparin, too. As such, MCAS may underlie some cases of chronic dyspareunia, vaginitis or DUB. We report five such patients; all who responded well to MC-targeted treatment. We review aspects of MC biology and pathobiology of potential relevance to otherwise idiopathic persistent inflammatory or coagulopathic genital tract problems. Diagnostic testing for MCAS may be warranted in some patients with chronic dyspareunia, vaginitis or DUB (especially patients whose histories well fit the general profile of MCAS), and prospective therapeutic trials of MC-directed topical and/or systemic therapies may be warranted in such populations. Impact statement What is already known on this subject? Chronic, idiopathic, treatment-refractory female genital tract inflammation or bleeding are common problems for which mast cell (MC) disease, previously generally thought to consist of just rare cases of mastocytosis, and is seldom considered in the differential diagnosis. What do the results of this study add? The substantial prevalence of the newly recognised ‘mast cell activation syndrome’ (MCAS), featuring chronic inappropriate MC activation with little-to-no MC neoplasia, and its clinical presentation with chronic multisystem inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues, raises the possibility that MCAS might underlie the aforementioned genital tract problems, especially in patients whose larger clinical presentations fit the MCAS profile. We report five example patients (among many more we have similarly treated) who enjoyed excellent responses to safe, inexpensive MC-targeted treatments, often given just intravaginally. What are the implications of these findings for clinical practice and/or further research? Our report identifies a potentially significant new MC-focused direction, of relevance to millions of affected women worldwide, for clinical treatment as well as for basic and clinical research, which historically has yielded major advancements disappointingly disproportionate to the scope of the affected population.

Utility of glucagon-like-peptide-1-receptor agonists in mast cell activation syndrome.

Acute/baseline ratios of all 3 MC mediator metabolites can enhance diagnosis and management of mast cell activation syndrome.

Familial hypertryptasemia with associated mast cell activation syndrome

Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment.

Mast cell (MC) activation syndrome (MCAS) is a recently recognized, likely prevalent collection of heterogeneous illnesses of inappropriate MC activation with little to no MC neoplasia likely driven by heterogeneous patterns of constitutively activating mutations in MC regulatory elements including various tyrosine kinases (TKs, dominantly KIT). MCAS typically presents as chronic multisystem polymorbidity of generally inflammatory±allergic theme. As with indolent systemic mastocytosis (SM), treatment of MCAS focuses more against MC mediators than MC neoplasia, but some cases prove refractory even to the TK inhibitor (TKI) imatinib reported useful both in uncommon SM cases not bearing SM's usual imatinib-resistant KIT-D816V mutation and in some cases of MCAS (which rarely bears KIT-D816V). Most allergy is principally a MC activation phenomenon and sunitinib is a multitargeted TKI shown helpful in controlling a murine model of oral allergy syndrome. We present the first report of use of sunitinib in life-threatening MCAS refractory to multiple agents including imatinib achieving immediate, complete, sustained, non-toxic remission suggesting a new option for treatment of aggressive MC disease.

Symptoms of mast cell activation: The patient perspective

INTRODUCTION: Mast cell activation syndrome (MCAS) often presents with symptoms of irritable bowel syndrome (IBS). MCAS is a multi-systemic disorder caused by inappropriate mast cell (MC) activation causing inflammatory and allergic symptoms. IBS can be associated with small intestinal bacterial overgrowth (SIBO). This study determined the prevalence of SIBO in MCAS. METHODS: Patients with refractory gastrointestinal (GI) symptoms were evaluated for MCAS and SIBO. MCAS was diagnosed if there were typical symptoms of mast cell (MC) activation in 2 or more organ systems plus 1 or more of the following: elevation of MC chemical mediator(s), clinical improvement with MC-directed therapy, and/or increased intestinal MC density. SIBO diagnosis was based on a lactulose breath test (LBT) with ≥20 ppm hydrogen rise from baseline within 90 minutes. These LBT results were compared to our prior study of healthy controls. The effect of co-morbid syndromes and medication use was analyzed. Antibiotic therapy effects were a secondary aim. This study was IRB approved. RESULTS: There were 139 MCAS subjects (116 F, 23 M, 46.6 ± 16.9 years) and 30 controls (19 F, 11 M, 44 ± 14.0 years). GI symptoms preceded other MCAS symptoms in 66.2%. Symptoms included abdominal pain (87.1%), bloating (74.8%), constipation (66.9%), diarrhea (63.3%), nausea (61.9%), heartburn (54.0%), and dysphagia (29.5%). In these MCAS patients Rome 4 criteria for IBS-mixed (39.6%), IBS-constipation (22.3%), and IBS-diarrhea (18.7%) were met. SIBO was present in 30.9% MCAS subjects vs. 10% in controls (P = 0.023). Methane excretion in a plateau pattern was common in MCAS: 10.1% had levels ≥10 ppm and 24.5% had levels 3-9 ppm. Higher methane levels were associated with IBS-constipation compared to SIBO positive subjects: 42.9% vs. 9.3% (P = 0.02). Postural orthostatic tachycardia syndrome, hypermobile Ehlers-Danlos syndrome, MC density and mediators, proton pump inhibitors, thyroid supplements, and statins were not associated with LBT changes. Antibiotics were prescribed for 74 subjects: 67.6% had marked improvement, 5.4% had partial improvement, and 21.6% had no improvement in GI symptoms. Adverse events led to cessation of antibiotics in 9.5%. CONCLUSION: SIBO with hydrogen and methane plateau patterns are common in MCAS subjects. MCAS could cause SIBO due to alterations of the GI immune system or altered motility by local release of MC mediators. Antibiotic therapy appears to improve GI symptoms in MCAS patients.

The incidence of mast cell activation syndrome (MCAS) has increased since first definition as a mastocytosis-like phenotype. Despite well-described criteria developed by the MCAS consortium, its growing rates have occurred in the context of multiple alternative criteria for MCAS diagnostics. The Vienna Consensus has defined clear diagnostic criteria for MCAS, which include, first of all, a clinical criterion characterized by severe recurrent symptoms involving two or more organs and meeting the criteria for anaphylactic response. Secondly, a laboratory criterion, has been established where the most specific and golden standard marker is a significant increase in tryptase levels, determined in blood serum for several hours (up to 4 h) after the event, being calculated as 120% of the basal tryptase level plus 2 ng/mL. Determination of other biomarkers is currently not recommended due to their lower specificity and lack of clearly set cut-off values. Third, the therapeutic response criterion, which implies that the drugs targeting mast cells, should reduce the frequency and severity of MCAS episodes. There is a classification of MCAS, which discriminates primary (clonal) and secondary (non-clonal) response from idiopathic MCAS. Primary MCAS is defined by clonal expansion of mast cells and proceeds in confirmed systemic mastocytosis, or two minor criteria for mastocytosis. Secondary MCAS is diagnosed when the mast cells are activated by known triggers. Most often, it is associated with IgE-mediated or other hypersensitivity reactions (e.g., drug-, food-, or insect-induced anaphylaxis). If neither clonal expansion, nor a trigger event for mast cell activation can be identified, the condition is classified as idiopathic MCAS. Consensus 2 clinical criteria are not specific enough to diagnose MCAS, and the use of less specific (or non-specific) laboratory tests may lead to overdiagnosis of this condition. Recent studies confirm that MCAS is quite rare. However, patients with unspecified MCAS exhibit non-specific symptoms without a clear pathogenic significance, do not respond to standard mast cell-targeted therapy, thus leading to a reduced quality of life, as well as to social stigmatization. However, it is important to understand that false diagnostics of MCAS may lead to missing the diagnosis of underlying disease not associated with mast cell activation, and appropriate treatment will be not administered to the patient.

Need to define a subgroup of patients with idiopathic mast cell activation syndrome

Utilities of Various Mast Cell Mediators in Diagnosing Mast Cell Activation Syndrome

BackgroundThis paper explores the relationship between chemical intolerance (CI) and mast cell activation syndrome (MCAS). Worldwide observations provide evidence for a two-stage disease process called toxicant-induced loss of tolerance (TILT) as a mechanism for CI. TILT is initiated by a major exposure event or a series of lower-level exposures. Subsequently, affected individuals report that common chemical inhalants, foods, and drugs (i.e., various xenobiotics) trigger multi-system symptoms.PurposeTo determine whether MCAS provides a plausible biological mechanism for CI/TILT.MethodsUsing the validated Quick Environmental Exposure and Sensitivity Inventory (QEESI), we compared patients diagnosed with MCAS (n = 147) to individuals who reported chemical intolerances (CI/TILT) following various exposures (n = 345) and to healthy controls (n = 76). Using ANOVA, we compared QEESI scores across groups. Clinical scores for the MCAS patient group were used to predict CI status using logistic regression.ResultsMore than half (59%) of the MCAS group met criteria for CI. A logistic regression model illustrates that as the likelihood of patients having MCAS increased, their likelihood of having CI/TILT similarly increased, to a near-perfect correspondence at the high ends of the QEESI and clinical MCAS scores. Symptom and intolerance patterns were nearly identical for the CI and MCAS groups.DiscussionWe present data suggesting that xenobiotic activation of mast cells may underlie CI/TILT. The strikingly similar symptom and intolerance patterns for MCAS and TILT suggest that xenobiotics disrupt mast cells, leading to either or both of these challenging conditions. Faced with patients suffering from complex illness affecting multiple organ systems and fluctuating inflammatory, allergic, and dystrophic symptoms, clinicians can now ask themselves two questions: (1) Could MCAS be at the root of these problems? (2) Could environmental exposures be driving MC activation and mediator release? Increasing our understanding of the connection between TILT and MCs has the potential to expose a new link between environmental exposures and illness, offering new opportunities for improving individual and public health.ConclusionThe close correspondence between QEESI scores and symptom patterns for MCAS and TILT patients supports xenobiotic-driven mast cell activation and mediator release (i.e., MCAS) as a plausible unifying biological mechanism for CI/TILT, with profound implications for medicine, public health, and regulatory toxicology.

Safety of COVID-19 vaccination in patients with clonal mast cell disorders