Does Mast Cell Activation Syndrome Underlie Multiple Ills?

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly under-recognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population.

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading.

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome, and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2src18, the group has grown from about 35 to nearly 65src multidisciplinary professionals.

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment.

In an interview with Medscape Medical News, Grach said “the meeting was an exciting example of how not only research but also medicine is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, Chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview with Medscape Medical News, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify…We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.”

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2src11 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna, Vienna, Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria:

Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 2src% + 2 ng/mL.
Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn, Bonn, Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2src2src. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples:

Constitutional: Chronic fatigue, flushing, or sweats
Dermatologic: Rashes or lesions
Ophthalmologic: dry eyes
Oral: Burning or itching in mouth
Pulmonary: Airway inflammation at any/all levels
Cardiovascular: Blood pressure lability or co-diagnosis of POTS is common
Gastrointestinal: Reflux, dysphagia, or malabsorption
Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
Neurologic: Headaches or sensory neuropathies
Psychiatric: Depression or anxiety
Endocrinologic: Thyroid disease or dyslipidemia
Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition.

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2src2src update of the broader “consensus-2” criteria, told Medscape Medical News, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along…If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on…then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “2src% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted.

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.”

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, Virginia, “When mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He told Medscape Medical News, “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2src25 and publish those results in 2src26.

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X: @MiriamETucker.