MCAS Research Update (2019): Part One

In 2019 I published a book on MCAS, but in all reality the book was put together in 2017/2018. (Who knew the editing process could be so lengthy!) So, for the last several months I’ve been perusing the academic literature in order to determine if there have been any significant research updates since my own content came out.

As it turns out, 2019 saw a fairly large surge in the number of articles published about MCAS. This is GREAT news! I want to start by talking about a late 2019 article that addressed a modified diagnostic criteria for MCAS.

 

MCAS DIAGNOSTIC CRITERIA

In October of 2019, an article published by Weiler, Austen, Akin and colleagues¹ summarized their latest approach to the diagnosis of MCAS. The article was thorough and had some interesting sections, including detailed descriptions of various mast cell mediators and medication information as it relates to particular mediators. I highly recommended checking out the full text as it’s tough to unpack everything in a few bullets.

(Not surprisingly) the divisiveness continues… There were a few points that continue to be emphasized by this group of clinicians that differ from the opinions of other clinicians who have published suggested diagnostic criteria in the past (such as Molderings and Afrin). Regardless of whether you stand on one side of the fence or the other (or perhaps in the field next door, in my case) there were some interesting points in this article that I had not heard before.

Here are my thoughts from what appeared to be fresh/novel information as well as some take-away messages from the article:

• On mast cell mediator testing: Mediators should be measured at baseline and during an acute attack. Heparin has not been validated as a marker of mast cell activation in blood. Chromogranin A is also problematic as it resides in neuroendocrine cells. Further research is warranted to investigate whether platelet activating factor, heparin, chymase, or carboxypeptidase A3 are suitable mediators to include in future MCAS testing.
• On hereditary alpha tryptasemia (HAT): Instead of a bone marrow biopsy, a buccal (oral – cheek) swab is necessary in order to diagnose HAT. Patients with HAT also appear to have high rates of Ehlers-Danlos syndrome (EDS) and dysautonomia including POTS, but the authors do not believe that these manifestations are caused by MCAS.
• On clonality testing interpretation: The authors maintain that clonality is demonstrated by an activating KIT mutation (such as the one causing D816V) in peripheral blood or tissue. They continue to assert that surface expression of CD25 on mast cells is a surrogate marker for clonality, and that the presence of dense aggregates of spindle-shaped mast cells suggest that mastocytosis is present.
• An interesting comment on mast cell numbers in testing: “Our recommendations do not address the occurrence of local mast cell (MC) activation. An increase in MC numbers in the gastrointestinal tract or elsewhere by itself does not provide a diagnosis of MC activation or indicate that MC activatability is affected.”
• This article also contained a suggested diagnostic decision-making flow chart (below). These authors considered “symptoms” to be different cardiovascular, dermatologic, respiratory and gastrointestinal signs. They further defined “validated mast cell mediators” to include: serum tryptase, urinary n-methyl histamine, urinary 11 beta-prostaglandin F2 alpha (prostaglandin metabolite), and urinary leukotriene E4.

 

 

The first three items of the flow chart itself are not dramatically different from previous publications by these authors, but the increased specifications for genetic testing/interpretation plus the inclusion of HAT evaluation is newly laid out in this article. Also, the article does not mention the need for more than one test (or point in time) for MCAS diagnosis.

Part of their explained rationale for determining whether a genetic mutation is present includes the notion that this information could improve the diagnostic tools and treatment options in the form of new therapeutic interventions that could target the mutated gene product or associated molecular pathway in the future for patients with MCAD. The authors stated that they believe this algorithm will help prevent over-diagnosis of patients with MCAS. They also expressed concern about the trend of other disorders (such as EDS, POTS, and may more) being used to diagnose MCAS without scientific basis for being associated with mast cell activation.

The authors concluded, “Our current recommendations for diagnosing MCAS make use of the latest studies and consensus guidelines for clinically diagnosing systemic anaphylaxis in real time, regardless of whether allergen was triggered through the IgE pathway or through other pathways; our current understanding of the mediators secreted by activated MCs that best discriminate this disorder from other conditions; and the drugs that might selectively affect those mediators or MCs themselves. “

It’s important to note that as of February 2020, there appears to be another article coming down the pipe that will supposedly provide additional perspective on a diagnostic “consensus” very soon. (TBD….)

In my opinion, this article did not offer much of a difference from what’s been previously published in terms of the somewhat flawed diagnostic decision-making process. It continues to utilize subjective information such as symptoms and response to MC medications as large components of the diagnostic criteria. The main addition to testing and the decision-making flow would be the genetic component, but if that’s negative and the other criteria are met, the patient is still diagnosed with MCAS.

This article argued against some of the mediators (heparin and chromogranin A) and biopsy findings that are sometimes used to make the MCAS diagnosis, and it clarified that a high number of mast cells alone in biopsy testing is not diagnostic. (These details happen to be considered diagnostic by a separate groups of researchers; much of the published research thus far includes them going back and forth on details like this.) Sometimes it seems like the different groups of researchers/clinicians are just talking in circles around each other instead of moving forward with clinically useful progress.

On the other hand, maybe it is important to remove heparin and chromogranin A from the mediator testing list. These authors made no attempt to disguise their bias, citing Afrin’s publications as they said, “Some publications and lay press information have greatly broadened the clinical criteria for MCAS…(causing) confusion for patients and physicians alike… More concerning, however, is using the diagnosis of MCAS erroneously and missing a truly treatable underlying condition not related to MCs.”

In terms of diagnosis and our focus on mast cells in general, I still can’t help but wonder if we are barking up the wrong tree and focusing on the wrong things. That’s great if a patient has elevated prostaglandins and they respond to aspirin… but WHY are the mast cells over-reactive in the first place?! (This is a somewhat rhetorical question… and I’m not talking about genetics.) And should we be devoting so much time and energy and money to labeling patients with MCAS in the first place?! (See my recent blog post on this topic!)

Not surprisingly, the drugs required for diagnosis (also used as MCAS treatment options) in this article focused on prescription medications and did not mention any natural alternatives, nor a functional medicine or natural medicine approach to addressing the root issues triggering mast cells. (Sigh… but one can always hope for the future!)

Stay tuned for the 2019 MCAS Research Update: Part Two. Cheers!

 

Reference

Weiler, C. R., Austen, K. F., Akin, C., Barkoff, M. S., Bernstein, J. A., Bonadonna, P., Butterfield, J. H., Carter, M., Fox, C. C., Maitland, A., Pongdee, T., Mustafa, S. S., Ravi, A., Tobin, M. C., Vliagoftis, H., & Schwartz, L. B. (2019). AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. Journal of Allergy and Clinical Immunology, 144(4), 883–896. https://doi.org/10.1016/j.jaci.2019.08.02