Mast Cell Activation Syndrome (MCAS) in hEDS
Mast cell activation syndrome (MCAS) is increasingly recognized in people with hypermobile Ehlers-Danlos syndrome (hEDS), although the exact relationship between the two conditions remains an area of ongoing research. MCAS occurs when mast cells (immune cells involved in allergic and inflammatory responses) release excessive amounts of chemical mediators, such as histamine, either too easily or too often. This can lead to episodes of symptoms affecting multiple body systems that often resemble allergic reactions, even when allergy testing is normal.
In people with hEDS, MCAS may contribute to skin reactions, gastrointestinal symptoms, cardiovascular symptoms, respiratory symptoms, neurological complaints, and medication sensitivities. Because these symptoms overlap with many other conditions commonly seen in hEDS, diagnosis can be challenging. Although there is currently no cure, many people experience significant improvement through a combination of medications, trigger avoidance, and lifestyle modifications.
MCAS vs. Allergies
MCAS and allergies can produce many of the same symptoms, but they are different conditions.
An allergy occurs when the immune system reacts to a specific substance (allergen), such as peanuts, bee stings, pollen, or pet dander. During an allergic reaction, mast cells release histamine after being activated by an antibody called immunoglobulin E (IgE). Allergy testing often identifies the specific trigger.
In MCAS, mast cells release their chemical mediators too easily or too often, sometimes without an identifiable allergen. Episodes may be triggered by heat, stress, exercise, infections, certain foods, medications, or may occur without an obvious trigger. Because these reactions are not always caused by an IgE-mediated allergy, standard allergy testing is often normal.
Allergies | MCAS |
Triggered by a specific allergen | May occur with multiple triggers or no obvious trigger |
Usually IgE-mediated | Often not IgE-mediated |
Allergy testing is often positive | Allergy testing is frequently normal |
Symptoms usually occur after exposure to the allergen | Symptoms may occur unpredictably or after non-allergic triggers |
Avoiding the allergen usually prevents symptoms | Managing symptoms often involves identifying and avoiding multiple triggers |
Some people have both allergies and MCAS. Having one condition does not exclude the other.
Symptoms
MCAS causes episodes of symptoms that may affect multiple body systems. Symptoms vary considerably from person to person and often occur in flares.
Skin
Flushing
Itching
Hives
Dermatographia ("skin writing") – raised welts that appear after the skin is lightly scratched
Angioedema (rapid swelling beneath the skin)
Gastrointestinal
Abdominal pain or cramping
Bloating
Diarrhea
Nausea
Acid reflux
Food intolerances, particularly to histamine-rich foods
Cardiovascular
Lightheadedness
Palpitations
Low blood pressure
Symptoms that overlap with postural orthostatic tachycardia syndrome (POTS)
Neurological
Brain fog
Fatigue
Headaches
Anxiety
Difficulty regulating body temperature
Respiratory
Nasal congestion
Wheezing
Throat tightness
Other
Medication sensitivities
Chemical sensitivities
Episodes that resemble allergic reactions despite negative allergy testing
Common Triggers
Triggers vary considerably from person to person. A trigger that causes symptoms in one individual may have little or no effect on another, and many people find that symptoms occur only when several triggers happen at the same time.
Some people with MCAS can identify triggers, but symptoms do not always have an identifiable trigger. Symptoms may fluctuate spontaneously or because of internal biological changes that aren't obvious to the person.
Common triggers include
Heat or sudden temperature changes
Cold exposure
Emotional stress
Physical exertion
Friction or pressure on the skin
Infections
Alcohol
Histamine-rich foods
Certain medications
Strong fragrances, perfumes, cleaning products, or smoke
Insect stings
Hormonal changes
Sleep deprivation
Keeping a symptom diary that records symptoms, foods, medications, activities, illnesses, and possible triggers may help identify patterns over time. This information can also help guide diagnosis and treatment.
Possible Causes
The exact cause of MCAS remains unknown. Several theories have been proposed, although none has been conclusively proven.
Connective Tissue Changes
Mast cells are found throughout connective tissue. Because connective tissue is abnormal in hEDS, researchers have proposed that changes in the surrounding tissue may alter mast cell function or make mast cells more easily activated.
Immune Dysregulation
MCAS appears to involve abnormal regulation of mast cells, causing them to release inflammatory mediators more easily or more frequently than normal.
Mechanical Stress
Mast cells can respond to physical forces such as pressure, friction, or stretching. Researchers have suggested that the increased mechanical stress associated with joint hypermobility may contribute to mast cell activation, although this has not been proven.
Mast Cell Mediators
Mast cells release dozens of inflammatory chemicals, including histamine, tryptase, prostaglandins, leukotrienes, and cytokines. These substances affect many organs throughout the body and account for the wide variety of symptoms seen in MCAS.
Laboratory studies suggest that some mast cell mediators may influence connective tissue. However, it remains unknown whether they contribute to joint instability or other features of hEDS.
Prevalence
The true prevalence of MCAS in people with hEDS is unknown. Estimates vary widely because diagnostic criteria have changed over time, symptoms overlap with other conditions, and many people are never formally diagnosed.
Current estimates include
Approximately 17%–33% of people seen in specialty hEDS clinics may meet diagnostic criteria for MCAS.
Up to 40%–50% of people with hEDS report symptoms suggestive of MCAS in patient surveys.
No large population-based studies have established the true prevalence.
Because symptoms overlap with conditions such as POTS, irritable bowel syndrome (IBS), chronic urticaria (hives), medication intolerance, and anxiety disorders, some reported cases may not represent true MCAS. Conversely, because laboratory testing often must be performed during a flare and many healthcare providers are unfamiliar with the condition, some people with MCAS may never receive a diagnosis.
Diagnosis
Diagnosing MCAS can be challenging because there is no single test that confirms the condition. Symptoms fluctuate over time, often affect multiple body systems, and overlap with many other disorders commonly seen in people with hEDS.
Current diagnostic criteria generally include all of the following
Typical symptoms involving two or more body systems
Objective evidence of elevated mast cell mediators during a flare
Improvement with medications that reduce mast cell activation or block the effects of mast cell mediators
Laboratory testing has important limitations. Blood and urine markers are often abnormal only during an active flare, making testing difficult to time. As a result, some people who appear to have MCAS may not meet all formal diagnostic criteria despite having symptoms that respond well to treatment.
Diagnosis in Clinical Practice
Because laboratory testing is imperfect, many physicians experienced in treating hEDS also rely on clinical judgment when evaluating suspected MCAS.
A diagnosis may be supported by
Recurrent symptoms affecting multiple body systems
Flushing, itching, hives, or allergic-type reactions without an identifiable allergen
Reactions to multiple foods or medications
Symptoms that worsen with heat, stress, infections, or hormonal changes
Improvement with medications commonly used to treat MCAS
Other medical conditions that do not fully explain the symptoms
Keeping a symptom diary that records symptoms, possible triggers, medications, foods, and activities may help both diagnosis and treatment.
Treatment
Treatment focuses on reducing the release of mast cell mediators or blocking their effects after they are released. Because symptoms, triggers, and medication responses vary considerably from person to person, treatment is highly individualized. Most people require some trial and error before finding the combination of therapies that provides the greatest symptom relief.
People with hEDS and MCAS frequently report medication sensitivities. For this reason, many specialists recommend introducing only one new medication at a time and increasing doses gradually when appropriate. This "start low and go slow" approach makes it easier to determine whether a medication is helping and whether it is causing side effects.
Important
The information below is intended to explain medications commonly used to treat MCAS. It should not replace advice from your healthcare provider. Never start, stop, or change prescription medications without consulting the clinician managing your care.
Medications
Most medications used to treat MCAS work in one of two ways:
Blocking the effects of mast cell mediators, particularly histamine.
Reducing the release of mast cell mediators before they cause symptoms.
Because mast cells release many different inflammatory mediators—not just histamine—people with MCAS often benefit from combining medications that work in different ways.
H1 Antihistamines (Usually First-Line Treatment)
What they do
H1 antihistamines block the effects of histamine throughout much of the body and are usually the first medications prescribed for MCAS.
May improve
Flushing
Itching
Hives
Dermatographia ("skin writing")
Nasal congestion
Brain fog in some people
Palpitations related to mast cell mediator release
Examples
Cetirizine (Zyrtec®)
Fexofenadine (Allegra®)
Loratadine (Claritin®)
Things to know
Newer, non-sedating antihistamines are generally preferred because they cause fewer side effects than older medications. Some people with MCAS require higher doses than those typically used for seasonal allergies, but any dose adjustments should be made under the supervision of a healthcare provider.
H2 Antihistamines
What they do
H2 antihistamines block histamine H2 receptors primarily in the stomach, helping reduce many gastrointestinal symptoms. They are commonly prescribed together with an H1 antihistamine.
May improve
Abdominal pain
Bloating
Diarrhea
Nausea
Acid reflux
Example
Famotidine (Pepcid®)
Things to know
Using both an H1 and H2 antihistamine may provide better symptom control than either medication alone in some people.
Leukotriene Inhibitors
What they do
In addition to histamine, mast cells release inflammatory chemicals called leukotrienes. Leukotriene inhibitors reduce the effects of these chemicals and are often added when antihistamines alone do not adequately control symptoms.
May improve
Persistent hives
Flushing
Wheezing
Nasal congestion
Some gastrointestinal symptoms
Example
Montelukast (Singulair®)
Things to know
Montelukast carries an FDA boxed warning because it may rarely cause mood or behavioral changes, including depression or suicidal thoughts. Anyone experiencing these symptoms should contact their healthcare provider promptly.
Mast Cell Stabilizers
What they do
Unlike antihistamines, which block the effects of histamine after it has already been released, mast cell stabilizers help reduce the release of mast cell mediators. They are often prescribed when symptoms remain inadequately controlled despite antihistamines.
Examples
Cromolyn sodium (Gastrocrom® oral solution, in the U.S.)
Ketotifen (available through a compounding pharmacy in the U.S.)
Cromolyn Sodium
What it does
Cromolyn sodium helps stabilize mast cells and is particularly useful when gastrointestinal symptoms are prominent.
May improve
Abdominal pain
Bloating
Diarrhea
Nausea
Food-related symptoms
Things to know
Because cromolyn is absorbed very poorly into the bloodstream, it is generally well tolerated. Many healthcare providers recommend starting with a low dose and increasing it gradually because people with MCAS often have medication sensitivities. Cromolyn works best when taken regularly and may take several weeks before its full benefits become apparent.
Ketotifen
What it does
Ketotifen has both antihistamine and mast cell-stabilizing properties and is often used when symptoms are not adequately controlled with antihistamines alone.
May improve
Flushing
Itching
Hives
Gastrointestinal symptoms
Symptoms affecting multiple body systems
Things to know
Oral ketotifen is not commercially available in the United States and is typically obtained through a compounding pharmacy. It may cause drowsiness, particularly when treatment is first started. Like other medications used to treat MCAS, it is often started at a low dose and increased gradually as tolerated.
Other Medications Sometimes Used
Some people continue to have symptoms despite standard treatment. Depending on an individual's symptoms and medical history, healthcare providers may recommend additional medications. These medications are generally used in selected situations and are not considered first-line treatments for MCAS.
Intranasal Corticosteroids
What they do
Intranasal corticosteroid sprays reduce inflammation inside the nose and may help control nasal symptoms associated with mast cell mediator release.
May improve
Nasal congestion
Runny nose
Sneezing
Postnasal drip
Examples
Fluticasone (Flonase®)
Triamcinolone (Nasacort®)
Budesonide (Rhinocort®)
Things to know
These medications work primarily inside the nose and have very little absorption into the bloodstream when used as directed. They are different from oral corticosteroids and do not carry the same risk of long-term systemic side effects.
Proton Pump Inhibitors (PPIs)
What they do
Proton pump inhibitors reduce stomach acid production and may be added when acid reflux, heartburn, or gastritis remain troublesome despite treatment with H2 antihistamines.
May improve
Acid reflux
Heartburn
Gastritis-related symptoms
Examples
Omeprazole (Prilosec®)
Pantoprazole (Protonix®)
Esomeprazole (Nexium®)
Things to know
These medications help control excess stomach acid but do not directly stabilize mast cells. They are used to manage gastrointestinal symptoms rather than treat the underlying mast cell disorder.
Doxepin
What it does
Doxepin is a tricyclic antidepressant that also strongly blocks both H1 and H2 histamine receptors. At low doses, it is sometimes prescribed when itching, hives, flushing, or sleep disruption remain difficult to control.
May improve
Itching
Hives
Flushing
Sleep disturbance related to itching
Things to know
Doxepin commonly causes drowsiness and is often taken at bedtime. Treatment is usually started at a low dose and adjusted gradually as tolerated.
Aspirin (Selected Patients Only)
What it does
In some people with MCAS, prostaglandins released by mast cells contribute significantly to symptoms such as flushing. Low-dose aspirin may reduce prostaglandin production and improve these symptoms.
May improve
Flushing
Symptoms related to elevated prostaglandins
Things to know
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can improve symptoms in some people but worsen mast cell activation in others. Because responses vary considerably, these medications should only be started under the guidance of a healthcare provider familiar with MCAS.
Benzodiazepines
What they do
Some benzodiazepines, particularly diazepam, have demonstrated mast cell-stabilizing effects in laboratory studies in addition to reducing anxiety. They are occasionally prescribed when anxiety and mast cell activation appear to reinforce one another.
Things to know
Benzodiazepines are not considered routine treatment for MCAS. Because they can cause sedation, dependence, and withdrawal symptoms, they are generally reserved for selected situations and are used under close medical supervision.
Medications for Specific Symptoms
People with MCAS may also be prescribed medications to treat symptoms affecting particular organs or body systems. For example, inhalers may be used to treat wheezing or asthma-like symptoms, while topical medications may help relieve skin symptoms. Although these treatments do not directly reduce mast cell activation, they can improve symptom control and quality of life.
Advanced Treatment Options
Some people continue to have significant symptoms despite standard therapy. In these situations, referral to an allergist or immunologist familiar with MCAS is often appropriate. Additional treatment options may include:
Omalizumab (Xolair®)
What it does
Omalizumab is a biologic medication that targets immunoglobulin E (IgE), an antibody involved in allergic responses. Although it is not specifically approved for MCAS, some people with treatment-resistant disease experience meaningful improvement.
May improve
Recurrent flushing
Gastrointestinal symptoms
Frequent allergic-type reactions
Recurrent anaphylaxis
Things to know
Because omalizumab is an injectable medication that can occasionally cause allergic reactions itself, it is usually prescribed and monitored by a specialist.
Corticosteroids
What they do
Short courses of corticosteroids may occasionally be used to treat severe or prolonged MCAS flares that do not respond adequately to other therapies.
Examples
Prednisone (Deltasone®)
Methylprednisolone (Medrol®)
Dexamethasone (Decadron®)
Things to know
Because long-term corticosteroid use can cause significant side effects—including osteoporosis, weight gain, diabetes, cataracts, adrenal suppression, and increased infection risk—these medications are generally reserved for short-term use during severe flares or when other treatments have not provided adequate symptom control. They are not considered a first-line treatment for MCAS because safer long-term treatment options are usually available.
Epinephrine (EpiPen®, Auvi-Q®, etc.)
People who have experienced anaphylaxis (a severe, life-threatening allergic reaction) or who are considered at high risk may be prescribed an epinephrine autoinjector.
Use epinephrine immediately if symptoms of anaphylaxis develop, including
Difficulty breathing
Swelling of the tongue or throat
Difficulty swallowing
Severe dizziness or fainting
Rapid progression of symptoms affecting multiple body systems
After using epinephrine, seek emergency medical care immediately.
A Practical Approach to Treatment
Treatment is usually introduced gradually rather than all at once. A typical approach may include:
Not everyone requires every step. Some people achieve good symptom control with one or two medications, while others benefit from combining several medication classes. Because medication sensitivities are common in hEDS and MCAS, introducing one medication at a time often improves tolerability and makes it easier to determine which treatments are providing benefit.
What to Expect From Treatment
The goal of treatment is to reduce the frequency and severity of symptoms, not necessarily eliminate them completely. Some people improve with relatively simple measures such as antihistamines, while others require several medications working together. Although identifying and avoiding personal triggers can be helpful, many people continue to experience spontaneous flares despite trigger management because mast cell activity can fluctuate unpredictably.
Finding the most effective treatment plan often takes time. Because symptoms and triggers vary considerably from person to person, medications may need to be adjusted over time in consultation with your healthcare provider.
Managing MCAS Flares
Even with daily treatment, many people continue to experience periods when their symptoms suddenly worsen. These episodes, often called MCAS flares, occur when mast cells release larger amounts of inflammatory mediators than usual. The severity of a flare can range from mild itching or flushing to severe reactions affecting multiple body systems.
Many of the same triggers discussed earlier—including heat, infections, emotional stress, alcohol, certain foods, medications, and hormonal changes—can also trigger MCAS flares.
During a Flare
If your symptoms begin to worsen, your healthcare provider may recommend:
Taking your medications exactly as prescribed, including any "as needed" antihistamines that are part of your treatment plan.
Removing yourself from the trigger whenever possible.
Moving to a cool environment if heat is a trigger.
Resting and avoiding further physical exertion.
Drinking fluids if tolerated, particularly if dizziness or POTS symptoms are present.
Using rescue medications prescribed by your healthcare provider.
People with wheezing or asthma symptoms may require an inhaler during a flare, while those with severe or prolonged symptoms may occasionally require a short course of corticosteroids prescribed by their physician.
When to Seek Emergency Care
Most MCAS flares are uncomfortable but not life-threatening. However, severe reactions can progress rapidly and require emergency medical treatment.
Call 911 or seek emergency medical care immediately if you develop
Difficulty breathing
Swelling of the tongue or throat
Difficulty swallowing
Fainting or loss of consciousness
Severe dizziness associated with low blood pressure
Symptoms of anaphylaxis (a severe, life-threatening allergic reaction)
If you have been prescribed an epinephrine autoinjector, use it immediately if symptoms of anaphylaxis occur, then seek emergency medical care.
Lifestyle Modifications
Medications are only one part of treating MCAS. Identifying and avoiding your personal triggers is often equally important and may significantly reduce the frequency and severity of flares.
Helpful strategies include:
Identify Your Triggers
Keeping a symptom diary may help identify patterns that are not immediately obvious.
Consider recording
Foods
Activities
Temperature exposure
Stress levels
New medications
Infections
Hormonal changes
Environmental exposures
Reduce Trigger Exposure
When possible
Avoid extreme heat or cold.
Limit friction or prolonged pressure on the skin.
Wear loose-fitting clothing if pressure triggers symptoms.
Choose fragrance-free soaps, detergents, lotions, and cleaning products if chemical sensitivities are present.
Pace activities to avoid overexertion.
Stay well hydrated, particularly if POTS is also present.
Dietary Changes
Some people notice improvement by reducing foods that are naturally high in histamine.
Common examples include
Aged cheeses
Fermented foods
Processed meats
Alcohol
Certain fish
Vinegar-containing foods
Not everyone with MCAS benefits from a low-histamine diet, and overly restrictive diets may lead to nutritional deficiencies. If dietary changes become extensive, consultation with a registered dietitian may be helpful.
Stress Management
Emotional stress is a common trigger for many people with MCAS.
Helpful strategies include
Mindfulness
Relaxation exercises
Deep breathing
Counseling
Cognitive behavioral therapy (CBT)
Gentle yoga or stretching, if tolerated
Stress reduction is unlikely to eliminate symptoms completely, but it may reduce the frequency or severity of flares.
Supportive Supplements
Some people report improvement with supplements, although scientific evidence supporting their use remains limited. Supplements should not replace prescribed medications and may not be appropriate for everyone.
Commonly used supplements include
Quercetin: A plant-derived flavonoid that has demonstrated mast cell-stabilizing properties in laboratory studies.
Vitamin C: May help support histamine metabolism in some individuals.
DAO (Diamine Oxidase): May help break down histamine from food in people who are sensitive to dietary histamine but does not prevent mast cells from releasing histamine.
Always discuss supplements with your healthcare provider before starting them, particularly if you have medication sensitivities or take prescription medications.
Botox
Botox is not a treatment for MCAS. Current evidence does not suggest that Botox commonly triggers mast cell activation, nor is there evidence that MCAS reduces its effectiveness.
People with a history of severe allergic reactions may occasionally receive individualized premedication before certain medical procedures, but this is based on the individual's medical history rather than Botox itself.
When to See a Specialist
Consider evaluation by a specialist if:
Symptoms suggest MCAS but the diagnosis remains uncertain.
Symptoms continue despite treatment.
You experience recurrent episodes suggestive of anaphylaxis.
Medication or food sensitivities significantly interfere with daily life.
Multiple body systems are affected without another clear explanation.
Depending on your symptoms, your care team may include
An allergist/immunologist to evaluate MCAS, recommend testing, and prescribe medications.
A gastroenterologist for persistent gastrointestinal symptoms.
A cardiologist or POTS specialist if significant dizziness, palpitations, or other orthostatic symptoms are present.
A pharmacist or prescribing clinician to review medication reactions, interactions, and treatment options.
Current Research
Although MCAS is increasingly recognized in people with hEDS, many questions remain unanswered about the relationship between the two conditions. Researchers have not yet established exactly how the two conditions are biologically connected. More research is needed to better understand their relationship and to improve diagnosis and treatment.
Current research suggests
Several biological mechanisms have been proposed to explain the association between hEDS and MCAS, but none has been conclusively proven.
Mast cell mediators may influence connective tissue and the autonomic nervous system, but it is unknown whether they contribute directly to the development of hEDS or dysautonomia.
Differences in diagnostic criteria have made it difficult to compare studies or determine the true prevalence of MCAS.
More high-quality research is needed to better understand the relationship between hEDS and MCAS and to improve diagnosis and treatment.
Although debate continues regarding the exact relationship between hEDS and MCAS, many people with hEDS experience symptoms that improve with treatments directed at mast cell activation. Continued research is expected to clarify the relationship between these conditions and lead to more effective diagnostic tools and therapies.
Summary
Mast cell activation syndrome (MCAS) is increasingly recognized in people with hypermobile Ehlers-Danlos syndrome (hEDS). It occurs when mast cells release excessive amounts of inflammatory mediators, such as histamine, causing episodes of symptoms that may affect multiple body systems. Symptoms often resemble allergic reactions but frequently occur despite normal allergy testing.
Diagnosing MCAS can be challenging because symptoms overlap with many other conditions, laboratory testing is often difficult to obtain during a flare, and no single test confirms the diagnosis. Treatment typically combines medications, trigger avoidance, and lifestyle modifications. Finding the right combination of therapies often takes time, but many people experience meaningful improvement with an individualized treatment plan.
Although much remains to be learned about the relationship between MCAS and hEDS, increasing awareness of the condition has improved recognition and expanded treatment options. Ongoing research is expected to improve diagnosis and lead to more effective therapies in the future.
