MCAS and MMAS: Similarities and differences

The term mast cell activation disorder (MCAD) refers to any condition that causes symptoms caused by mast cell mediator release.  For symptoms to be attributed to mediator release, three criteria should be met:

1.       Common symptoms of mediator release affecting at least two organ systems. These include flushing, itching, urticaria or angioedema of skin; low blood pressure; diarrhea; itching of the nose or eyes.  

2.       Objective evidence of mediator release.  Possible lab tests indicating mediator release include elevated serum tryptase, described as 20% + 2 ng/ml above baseline during episode; elevated n-methylhistamine in 24-hour urine; and elevated D2 or F2a prostaglandin in 24-hour urine.  Serum tryptase is the preferred method of determining mediator release, but must be measured 15 minutes to 4 hours after episode. Even when drawn in this time, for various reasons, it may not be accurate. 

3.       Response to therapy that inhibits mast cell mediator activity.  This includes antihistamines, leukeotriene inhibitors, mast cell stabilizers and PAF inhibitors.

MCAD can be primary, secondary (as a reaction to another condition) or idiopathic (no identifiable reason.)

Primary types of MCAD include cutaneous mastocytosis, systemic mastocytosis (all subsets), mast cell leukemia, mast cell sarcoma and monoclonal mast cell activation syndrome.

Secondary types of MCAD include IgE allergic reactions (typical allergies), drug reactions, and conditions that cause overproduction of mast cells as a result, like some types of chronic infection, some types of autoimmune dysfunction and neoplastic conditions (not including mastocytosis, which is a primary cause.)

Idiopathic types of MCAD include idiopathic anaphylaxis and MCAS.  There have been calls to reclassify IA as being a type of MCAS, but currently they are still considered individual entities.  IA patients suffer from sudden onset of severe anaphylaxis requiring epinephrine, fluid resuscitation and IV antihistamines and steroids.  IA patients have normal baseline tryptase, n-methylhistamine and prostaglandins.  They have variable responses to antimediator therapies.  Patients presenting with such anaphylaxis having no known trigger should be evaluated for mastocytosis and MCAS.  Failing this, they will receive a diagnosis of IA. 

The following is a direct quote from a paper coauthored by Mariana Castells in 2013: “MCAS is a diagnosis of exclusion in which no mast cell anomaly or secondary disorders account for the mast cell activation disorder.”  By this definition, you cannot have MCAS and mastocytosis.  In mastocytosis patients, the mastocytosis is the primary cause of mast cell mediator release symptoms.  Because you know the primary cause of these symptoms in mastocytosis, you cannot have MCAS, which is only diagnosed when the primary cause cannot be determined.

MCAS can only be diagnosed when all primary, secondary and other idiopathic causes (IA) are ruled out.  MCAS patients must fail to meet diagnostic criteria for IA, although they may sometimes experience idiopathic anaphylaxis.  The way this is commonly distinguished is by elevated baseline labs for mast cell mediators, such as D2 prostaglandin.

Diagnosis of monoclonal mast cell activation syndrome (MMAS) occurs when clonal mast cells are found in bone marrow, but they are not aggregated and patients do not meet the criteria for diagnosis with SM.  (Please see previous posts for SM diagnostic criteria.)  Clonal mast cells in MMAS are identified by presence of the CKIT D816V mutation or by expression of receptor CD25.  In MMAS, tryptase value may be normal (>11.4 ng/ml) or elevated, with the average being 18.3 ng/ml. Urinary n-methylhistamine may be elevated.  Mediator release symptoms are present.  CM is always absent in MMAS.  MMAS patients often respond well to mediator amelioration therapies. 

In MCAS, only 33% of patients have tryptase >11.4 ng/ml.  CM is always absent in MCAS.  There is no D816V mutation or expression of CD25 in these patients.  There are no multifocal infiltrates of mast cells in bone marrow or other extracutaneous organs.  They have elevated baseline labs.  They often respond well to treatment.  33% of patients have complete resolution of symptoms after a year of treatment; 33% have major response to treatment; and 33% have minor response to treatment.  82% of patients see improvement in abdominal pain; 80%, headache; 75%, diarrhea; 58%, poor concentration and memory issues; 38%, flushing.  There is no available data on treatment responses in MMAS patients.

MCAS and MMAS patients need to avoid triggers to see continued improvement.  67% of MCAS patients are triggered by alcohol.  50% are triggered by heat and 30% are triggered by medications, compared to 37% of MMAS patients. Other triggers include radiocontrast media, invasive procedures, general anesthesia, stress, infections, fevers, exercise, pressure and friction.  Premedication with antihistamines should be administered before any invasive procedure or anesthesia.  Steroids and leukotriene inhibitors can be added if appropriate. 

46% of MMAS patients have severe anaphylactic reactions to Hymenoptera stings, while only 21% of MCAS patients do.  Severe reactions to bee stings are often a clinical sign that a patient may have an underlying mast cell disease, especially if it precipitates a drop in blood pressure, and if urticaria and angioedema are absent.  Venom immunotherapy (VIT) for bee stings should be undertaken for MMAS patients and continued for life, as discontinuing after 3-5 years shows recurrence of sensitization. 

If you are diagnosed with MCAS or MMAS, when should you get a bone marrow biopsy to rule out SM?  When you have a baseline tryptase over 20 ng/ml, anaphylaxis requiring epinephrine without a known cause, abnormal blood counts, unexplained osteoporosis, or swelling of the liver or spleen. 

Reference:

Picard, Matthieu, Castells, Mariana, et al.  2013.  Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes.  Clinical Therapeutics 35: 5 (548 – 562.)