Utility of Glucagon-Like-Peptide-1-Receptor Agonists in Mast Cell Activation Syndrome, 2025, Lawrence B. Afrin M.D, Blitsheyn et al

Mij

Mij

Senior Member (Voting Rights)

Abstract​

Introduction: Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses rooted in inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis.

Due to great heterogeneity in the underlying MC regulatory gene mutational profiles present in most cases and resulting great heterogeneity in aberrant expression of the hundreds of potent mediators known to be expressed by MCs, MCAS presents with great heterogeneity but dominantly manifests as chronic multisystem polymorbidity of generally inflammatory, allergic, and dystrophic behaviors. MCAS’s heterogeneity at multiple levels poses challenges for identifying optimal individual treatment. Targeting commonly affected downstream effectors of the disease’s various symptoms may yield clinical benefit independent of the root/upstream mutational profile in the individual patient.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) engage with GLP-1 receptors present on many types of cells, including MCs. These drugs are already approved for management of a few chronic inflammatory diseases (e.g., diabetes mellitus type 2, obesity, obstructive sleep apnea) but are increasingly being appreciated to help in a wide range of other inflammatory diseases (e.g., Alzheimer’s disease).

Methods: We present the first case series showing utility of a variety of GLP-1RAs for managing refractory MCAS in a diverse assortment of such patients.

Results: Among 47 cases (age range 15-71, 89% female), 89% demonstrated clinical benefit with GLP-1RAs for a broad range of problems associated with MCAS. Conclusion: GLP-1RAs may have substantial benefit in MCAS. Randomized controlled trials are needed to assess the efficacy, and identify optimal dosing, of GLP-1RA treatment in MCAS.
LINK
 
From the snippets I can access:
This was a retrospective case series in which the 47 subjects were selected by the authors from their panels of patients for having been definitively diagnosed with MCAS (per consensus-2 criteria48) and treated to at least some extent (for any indication) with at least one GLP-1RA drug.
Click to expand...
In our cases reported herein, we found generally rapid emergence (typically within several days, sometimes even within the first 24 hours) of significant multisystem improvements (most of an “anti-inflammatory” nature) in most, with an overall clinical benefit rate of 89%. Weight loss was seen in 93% of those with clinical benefit (median and maximum weight loss 10.6% and 36.9%, respectively); no patient became underweight.
Click to expand...
I don’t know how many (if any) were treated for MCAS specifically, which would affect the ethics of continuing to use the treatment for MCAS without now prioritising a trial.
 
There’s an excel file in the appendix with the following fields:


Case Number (Initials of Contributing Author)

Gender: F, female, M, male

Age at Onset of Symptoms Consistent with MCAS

Age at Diagnosis of MCAS

Chief Complaints at Diagnosis of MCAS

Diagnostic Evidence of MCAS: Abnormal Labs and/or Increased Mast Cell Density per High Power Field (MCD/HPF)

MCAS-Targeted Treatments Failed

MCAS Targeted Treatments With Partial Response

Age at which GLP-1 Receptor Agonist Therapy Was Initiated

GLP-1 Receptor Agonist Therapy: Formulation(s), Route, On-Label or Off-Label, Dose(s), Frequency(ies)

Time (Days) from Initiation of GLP-1 Receptor Agonist Therapy to Subjective or Objective Observation of Initial Clinical Response

Duration (Months) of Response to GLP-1 Receptor Agonist Therapy

Is Response to GLP-1 Receptor Agonist Therapy Ongoing? (Yes, No, Not Applicable)

Specific Clinical Improvements Reported and/or Observed to GLP-1 Receptor Agonist Therapy

Adverse Events Reported and/or Observed from GLP-1 Receptor Agonist Therapy

Adverse Events Which Led to Discontinuation from GLP-1 Receptor Agonist Therapy

Pre-Treatment Weight (Pounds)

Pre-Treatment Weight (kg)

Pre-Treatment BMI (kg/m2)

Nadir Weight (Pounds) on GLP-1 Receptor Agonist Therapy To Date

Nadir Weight (kg) on GLP-1 Receptor Agonist Therapy To Date

Nadir BMI (kg/m2) on GLP-1 Receptor Agonist Therapy To Date

% Reduction in Weight
 
hallmarkOvME said:
I don't understand what this means. Could you please rephrase with plainer language?
Click to expand...
I agree, I don’t quite understand myself either!

They looked at cases that were treated with GLP-1RA drug for any reason, and that had been diagnosed with MCAS (I don’t known if the diagnoses were retrospective as well).

I think what I was trying to get at, is that extensive off-label use of medications is unethical. If you think you have something that might work, you do a trial on it.

From the article, it’s clear that some of the authors are already using GLP-1RA drugs for MCAS. I think that has to stop until they have done proper trials.
 
Kitty said:
They're experimenting on people, which is entirely unethical.

They're asking sick people to pay to be experimented on by people who by definition can't know what they're doing, which is entirely unethical.

They're denying people access to potentially useful therapies by not trialling them properly, which is entirely unethical.
Click to expand...
So they're unethical because they're unethical? Doesn't consent make it ethical?

Who can't know what they're doing?

What is a "proper" trial. By what standard?

Does the phrase "entirely" unethical imply partial ethicality?
 
hallmarkOvME said:
Unethical how?
Click to expand...
See Kitty’s response. And this debate for a lot of details about experimenting with treatments.
hallmarkOvME said:
What makes a trial "proper"?
Click to expand...
It meets the bare minimum standards in a way that makes the data interpretable and reasonably reliable. Essentially avoiding all of the mistakes that can make it appear like there is something that is not.

For treatment trials, it usually involves control groups with placebo, sufficient blinding of allocation for the participants and relevant outcome measurements. There are ways to get around specific aspects in certain scenarios, but that’s context specific.
 
Recently a new understanding of mast cell (MC) disease has emerged, with common allergy/atopy and rare, neoplastic mastocytosis comprising the readily recognizable tip of an iceberg of “MC activation disease” (MCAD), while the hidden bulk of the iceberg consists of complex, heterogeneous presentations of “MC activation syndrome” (MCAS), featuring chronic multisystem polymorbidity with general themes of inflammation, allergic-type phenomena, and growth dystrophisms of a wide variety of sorts. These general themes and the many other symptoms which can be seen in various MCAS patients unsurprisingly are consequent to the known effects of the majority of the hundreds of potent mediators MCs are known to express.
Click to expand...
The authors seem to be saying that MCAS can present in all sorts of ways, and that all sorts of drugs may or may not be useful in particular cases. That makes it very hard to prove or disprove MCAS as a clinically useful entity.
 
ChronicallyOverIt said:
This “paper” had been floating around my CFS groups, it’s mostly about MCAS, but lots of ppl using it to justify the use of GLP1 in ME/CFS since now in some circles ME/CFS is “comorbid” with MCAS. After reading these case reports I have to agree MCAS seems to encompass anything under the sun in these case studies. There doesn’t seem to be a real mechanism of action described in this paper. Just that GLP1 bring down inflammation in obesity and type 2 diabetes, mast cell has receptors for glp1, so it must bring down inflammation in MCAS. Please read all the highlighted case reports, there’s quite a few where the patient was obese so no wonder they felt better being on a GLP1 and losing weight…. The case reports seem to have any and every symptom logged as MCAS.
Click to expand...
Quoting ChronicallyOverIt's post from the GLP-1ra thread about this paper.
 
You must log in or register to reply here.
Back
Top Bottom