MCAS Research Update (2019): Part Two

If you missed Part One, you can find it here…

As I mentioned in a recent blog post, a lot happened in terms of MCAS research (relatively speaking) in 2019. Here is my best stab at a concise summary of the recently published literature, broken down by theme and type of research. Keep in mind that systematic reviews are much higher levels of evidence than something like a case report. Also keep in mind that though I read over 50 articles, I chose to include the ones that seemed to have the most *new* information in this blog post. In other words, this is NOT all inclusive and I’m sure I missed some great studies.

 

SYSTEMATIC REVIEW

• EDS, POTS, MCAS Connections Questioned¹
  • Researchers conducted a review evaluating the association of hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS) and postural orthostatic tachycardia syndrome (POTS). While they found an abundance of articles, only 9 papers were original research articles.
  • The authors touched on some of the limitations and controversy of researching these particular conditions. “All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS, but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear.”
  • Researchers concluded, “An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.”

 

RESEARCH STUDIES

• Restless Leg Syndrome (RLS) and MCAS²
  • 174 patients with MCAS were evaluated for RLS with two standard questionnaires. MCAS diagnosis required mast cell (MC) symptoms in ≥2 organs plus ≥1 elevated MC mediators, improvement with MC-therapy, and/or increased intestinal MC density.
  • MCAS subjects had a higher prevalence of RLS than the spouse controls (40.8% vs 12.9%). The authors concluded, “RLS appears to be associated with MCAS. Effects of MC mediators, inflammation, immune mechanisms, dysautonomia, or hypoxia may theoretically activate RLS in MCAS.”

 

• Small Intestinal Bacterial Overgrowth (SIBO) and MCAS³
  • 139 patients with MCAS and 30 controls were evaluated. SIBO diagnosis was based on a lactulose breath test (LBT) with ≥20 ppm hydrogen rise from baseline within 90 minutes. MCAS diagnosis required mast cell (MC) symptoms in ≥2 organs plus ≥1 elevated MC mediators, improvement with MC-therapy, and/or increased intestinal MC density.
  • Approximately 30% of MCAS patients had SIBO diagnoses, compared to 10% in controls. Methane-dominant SIBO was more common and correlated with constipation symptoms.
  • Patients with MCAS and SIBO experienced abdominal pain (87.1%), bloating (74.8%), constipation (66.9%), diarrhea (63.3%), nausea (61.9%), heartburn (54.0%), and dysphagia (29.5%).
  • A positive SIBO diagnostic breath test was not associated with postural orthostatic tachycardia syndrome, hypermobile Ehlers-Danlos syndrome, MC density and mediators, proton pump inhibitors, thyroid supplements, and statin medications.
  • Approximately 67% of patients with MCAS showed marked short-term improvements with antibiotic medications, compared to ~21% with no improvement, and approximately 10% of patients had adverse events that led to cessation of antibiotics.
  • The authors concluded, “SIBO with hydrogen and methane plateau patterns are common in MCAS subjects. MCAS could cause SIBO due to alterations of the GI immune system or altered motility by local release of MC mediators.”

 

• POTS, EDS and MCAS ⁴
  • Researchers determined that out of 38 patients with hEDS and 31 patients diagnosed with POTS, 23 patients had the diagnosis of both conditions.
  • Symptoms of mast cell activation (as assessed using the 2018 “diagnostic criteria”) were present in patients with confirmed diagnoses of POTS alone; with hEDS alone, and both POTS and hEDS.
  • 100% of patients in this study had both cutaneous and gastrointestinal involvement.
  • Over 95% of patients in all groups reported a significant response to H1 blockers, over 89% to H2 blockers and 80% to mast cell stabilizers.

 

• Functional Gastrointestinal Disorders (FGID) and MCAS Symptoms⁵
  • Past researchers have evaluated how many patients with MCAS typically experience gastrointestinal symptoms (a high percentage, as it turns out). This study investigated the opposite question and found that MCAS symptoms in at least 2 organ-systems existed in 1773 (85%) of all patients with FGID.

 

• Small Intestinal Mast Cells and Hereditary Alpha Tryptasemia (HAT)⁶
  • Patients diagnosed with HAT were compared with patients diagnosed with irritable bowel syndrome (IBS). CD117 staining of mast cells was conducted for duodenal and terminal ileum biopsies of all patients.
  • Compared to the IBS group, patients with HAT had an increase in the number of mast cells (averaged up to 47 per high power field), increase in size of mast cells, expressed markers characteristic of antigen-presenting cells (T cells, CD4, CXCR5) and expressed HLA-DR in biopsy tissue samples.
  • 43% of patients with HAT displayed comorbid gut inflammation. The authors concluded that the genetic defect in tryptase appears linked to a pro-inflammatory state in the intestine coordinated by mast cells.

 

• Vertebral Fractures and MCAD⁷
  • Osteoporosis is common in systemic mastocytosis (SM), with a prevalence of 44.9%, compared to 15% in cutaneous mastocytosis and 10% in MCAS. SM is associated with multiple vertebral osteoporotic fractures, with a prevalence of 22.5%. In comparison, osteoporotic vertebral fractures are less common (5%) in non-SM subjects.

 

• Skin Manifestations and Anaphylaxis with MCAS⁸
  • Researchers noted skin manifestations and gastrointestinal symptoms in 96% and 83% of MCAS patients, respectively. Skin manifestations included flushing, pruritis, chronic urticaria, and angioedema.
  • 48% of patients in this study had a history of idiopathic anaphylaxis, compared to previously published rates of 20% in patients with SM, but the study sample size was small (22 patients total). 22% of patients in this study met the diagnostic criteria for monoclonal MCAS and were classified as “pre-SM” patients.
  • The authors noted, “the median basal serum and bone marrow tryptase levels are within normal limits even in patients experiencing serious mast cell activation-related symptoms, showing the limited utility of these parameters to establish MCAS diagnosis.”

 

• Mast Cell Mediators⁹
  • Researchers evaluated 108 patients with signs of mast cell activation and found that 81.4% had elevations in at least one mast cell mediator. Either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was noted at baseline, during symptoms or at both time points. Very few patients (~6%) were able to get tryptase measured both at baseline as well as during an episode.
  • Single elevated mediators in order of frequency were: prostaglandin metabolites > tryptase > leukotrienes E4 > n-methyl histamine.
  • Monoclonal MCAS (~6%) and mastocytosis (cutaneous or systemic) (~4%) were rare in this patient cohort.

 

SURVEYS

• The Mastocytosis Society (TMS) Patient Perceptions Survey, Part I¹⁰
  • In 2019, TMS conducted a massive survey of 1701 patients, 93% of which reported physician-diagnosed MCAS and 4% with the diagnosis of hereditary alpha tryptasemia (HAT). It’s important to note that medical records were not reviewed in this study, and the data is based on subjective patient information.
  • Demographics included 87.8% female respondents, and 82.1% reported receiving MCAS treatment in the US. Most of these patients used H1 blockers (91.9%), H2 blockers (71.5%), and/or mast-cell stabilizers (55.9%).
  • Of respondents reporting an MCAS diagnosis, 21.5% reported no rise in mast cell mediators, while 24.8% reported elevated baseline serum tryptase, 26.0% n-methylhistamine, and 21.8% prostaglandins.
  • Dysautonomia (47.5%) and connective tissue disorders (41%) were the most common comorbidities.
  • What stands out to me the most in this study are the reports of disability related to dietary factors. 69.4% of patients reported that they were food-restricted, with only approximately 40% being able to eat greater than 20 foods.
  • 5% of patients were moderately/severely affected by anaphylaxis, 87.6% reported moderate/severe life interruption due to their illness, with about 66% reporting daily interruptions and 48% often/frequently requiring assistance with routine care needs. 68% of patients reported poor physical/mental health. The quality of life implications from this survey are profound and very concerning.

 

• The Mastocytosis Society (TMS) Survey on Mast Cell Disorders, Part II¹¹
  • The second part of this particular survey (first data was published in 2014) had 420 respondents and focused on comorbidities. It’s important to note that this research focused on a different group of patients than the one mentioned above; self-reported diagnoses included systemic mastocytosis (51.2%), cutaneous mastocytosis (23.8%), MCAS (12.4%), idiopathic anaphylaxis (4.5%), and undetermined (6.4%). Dermatologists, allergist/immunologists, and hematologists were the leading sources of initial diagnoses.

 

Summary of findings:

	self-reported prevalence	note
“confirmed” Osteopenia/Osteoporosis	31% of total respondents, 42.9% of SM patients
Cancer	13.9% of respondents
High Blood Pressure	23% of respondents	*less than US average
High Blood Cholesterol	21.5% of all respondents, 27% of age >20
Coronary artery disease	2.9% of all respondents	*less than US average
Heart attacks	2.6% of all respondents, 3% of age >20

 

• 9% of respondents indicated that at least one family member has possible MCAD, but this number may not be an accurate reflection, as it’s possible that multiple individuals from the same family participated in this particular survey.

 

COMMENTARY

• Tryptase Validity¹²
  • Valent and colleagues discussed the use of the 20% + 2 formula (developed in 2012) for symptomatic tryptase levels as a continued indicator of severe MC activation and MCAS, as evident by continued validations in clinical practice.

 

• Update of Practice Guidelines (Castells & Butterfield)¹³
  • The authors concluded, “Patients with nonclonal MCAS may have chronic or episodic mast cell activation symptoms with an increase in serum tryptase and/or urinary metabolites of histamine, prostaglandin D2, and leukotrienes. Symptoms of MCAS and SM can be managed by blockade of mediator receptors (H1 and H2 antihistamines, leukotriene receptor blockade), inhibition of mediator synthesis (aspirin, zileuton), mediator release (sodium cromolyn), anti-IgE therapy, or a combination of these approaches. Acute episodes of mast cell activation require epinephrine, and prolonged episodes may be addressed with corticosteroids.” Nothing significantly new to see here, folks!

 

• Update of Practice Management (Weiler et al.)¹⁴
  • See previous blog post discussing this article here!

 

• The Many Faces of Mast Cell Disorders—A House of Mirrors?¹⁵
  • I like this analogy. This author discussed the nature of “MCAS” symptoms being very nonspecific and voiced concern for MCAS becoming a catch-all diagnosis for patients with unexplained symptoms. He also discussed clinical overlap in cases of sting anaphylaxis, MCAD, idiopathic anaphylaxis and clonal MCAD. The author noted, “Indeed, as allergists, we may find ourselves “delabeling” patients more often than confirming the diagnosis.”
  • Further, he added, “The analogy of mast cell disorders with a ‘house of mirrors’ is quite apt. It seems everywhere we look we see mast cell disorders, things that look like mast cell disorders, and reflections of mast cell disorders, but not all of them are what they seem and we see things we cannot yet explain. There is a path through the mirrors, and it is with well-designed research studies. We must endorse Valent et al’s ‘call for research’ with enthusiasm.”

 

CASE REPORTS

• Medication Excipient Reactions (Schofield & Afrin)¹⁶
  • See separate blog post here

 

• Omalizumab for Non-Clonal MCAD: 3 Cases¹⁷
  • Much of the research on this drug involves investigating clonal disease (SM and monoclonal MCAS). To the researchers’ knowledge, this was the first case report on patients with MCAS.
  • Three patients were treated with the use of omalizumab at the dose of 300 mg every four weeks. Case 1 was a male with indolent systemic mastocytosis and normal tryptase; case 2 was a female (normal tryptase) with MCAS, and case 3 was a male (tryptase: 50 mcg/l) with MCAS.
  • None of the patients were responsive to treatment with antihistamines and mast cell stabilizers. Cases 1 and 2 experienced monthly anaphylaxis, and case 3 experienced weekly cutaneous and respiratory symptoms.
  • Case 1 continues to utilize monthly omalizumab therapy that began 16 months ago, as it (combined with H1, H2 and Montelukast medications) has resolved his symptoms completely.
  • Case 2 received monthly omalizumab for 16 months, with optimal disease control achieved immediately. She was able to discontinue her H1 and H2 medications 6 months after the start of her injections and has not experienced anaphylaxis in the 6 months following the discontinuation of omalizumab.
  • Case 3 began omalizumab 6 months ago in addition to H1 and H2 blockers and montelukast. He achieved a complete clinical control of the condition and noted that his tryptase decreased to 30 mcg/l 6 months following the start of treatment, with no adverse reactions.

 

• MCAS Patient with Breast Cancer¹⁸
  • A patient undergoing radiation therapy for breast cancer had a previous diagnosis of MCAS. This patient had no adverse reactions to radiation and appeared to tolerate the treatment without systemic flare-ups of symptoms.
  • The authors concluded, “Idiopathic mast cell disorders such as MCAS and primary mast cell disorders alike should not be considered a contraindication to treatment with EBRT.”

 

• Bee Sting: Case Report¹⁹
  • A 48-year-old male was in a car crash following anaphylaxis from a bee sting. It was subsequently determined that he had MCAS. He tolerated bee venom therapy for 6 months, and then suddenly had anaphylaxis to it.
  • He began to go downhill health wise when they reinstated the bee venom therapy. He had additional episodes of anaphylaxis, postural BP drops and systemic symptoms. This progressed to where he was unable to work and had decreased food tolerance
  • The patient began receiving Xolair injections at a very low dose (150 mg) monthly. This led to a success 5-year sustained clinical response and reduction in symptoms that allowed for him to repeat maintenance subcutaneous venom therapy thereafter..

 

• Fatal Anaphylaxis Following Insect Sting²⁰
  • This one makes me really sad. A 32-year-old male who had been stung before by yellowjackets (with no adverse reaction) was stung by a hornet while driving and went into cardiac arrest from anaphylaxis. It was later determined that he had monoclonal MCAS.

 

• Pancreatic Tumor and MCAS²¹
  • This was an interesting case about a 69-year-old male who initially presented with episodes of hives, diaphoresis, hypertension and tachycardia requiring hospitalizations. Known triggers included stings from wasps and fire ants. He responded well to epinephrine. Elevated tryptase (27 ng/ml) was recorded (the same at baseline and during symptoms).
  • Over several years he experienced these symptoms, and they progressed to include flushing, abdominal cramping and diarrhea. His bone marrow biopsy was normal, but he had elevated urinary histamine metabolites and significantly elevated chromogranin A. A further workup revealed a pancreatic neuroendocrine tumor.
  • The authors concluded, “Elevated tryptase in the peripheral blood may be associated with PanNET, or MCAS may be triggered by the presence of PanNET. In addition, episodes showed improvement with intramuscular epinephrine over many years.” Tough to determine which came first – the chicken or the egg?

 

References

1. Kohn, A., & Chang, C. (2019). A review of the evidence for the existence of and relationship between hypermobile Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). The Journal of Immunology, 202(1 Supplement).
2. Weinstock, L. B., Walters, A. S., Brook, J. B., Kaleem, Z., Afrin, L. B., & Molderings, G. J. (2020). Restless legs syndrome is associated with mast cell activation syndrome. Journal of Clinical Sleep Medicine. https://doi.org/10.5664/jcsm.8216
3. Weinstock, L. B., Brook, J., Kaleem, Z., Afrin, L., & Molderings, G. (2019). Small Intestinal Bacterial Overgrowth Is Common in Mast Cell Activation Syndrome. American Journal of Gastroenterology, 114(Supplement), S670. https://doi.org/10.14309/01.ajg.0000594304.61014.c5
4. Chang, A. R., & Vadas, P. (2019). Prevalence of Symptoms of Mast Cell Activation in Patients with Postural Orthostatic Tachycardia Syndrome and Hypermobile Ehlers-Danlos Syndrome. Journal of Allergy and Clinical Immunology, 143(2), AB182. https://doi.org/10.1016/j.jaci.2018.12.558
5. Wilder-Smith, C. H., Drewes, A. M., Materna, A., & Olesen, S. S. (2019). Scandinavian Journal of Gastroenterology Symptoms of mast cell activation syndrome in functional gastrointestinal disorders. https://doi.org/10.1080/00365521.2019.1686059
6. Shirley, J. F., Drourr, J., Edwards, W. T., Tuna, K., Ryan, L. K., Alli, A., Tang, Y., & Glover, S. C. (2019). Mast Cells in Patients with Hereditary α-Tryptasemia Promote HLA-DR Expression and a Th2-Polarizing Microenvironment in the Gastrointestinal Tract. The Journal of Immunology, 202(1 Supplement).
7. Degboé, Y., Eischen, M., Apoil, P., Mailhol, C., Dubreuil, P., Hermine, O., Paul, C., Bulai Livideanu, C., & Laroche, M. (2019). Higher prevalence of vertebral fractures in systemic mastocytosis, but not in cutaneous mastocytosis and idiopathic mast cell activation syndrome. Osteoporosis International, 30(6), 1235–1241. https://doi.org/10.1007/s00198-019-04918-7
8. Casassa, E. A., Mailhol, C., Tournier, E., Laurent, C., Degboe, Y., Eischen, M., Kirsten, N., Moreau, J., Evrard, S. M., Mansat-De Mas, V., Lamant, L., Dubreuil, P., Apoil, P. A., Hermine, O., Paul, C., & Bulai Livideanu, C. (2019). Mast cell activation syndrome: High frequency of skin manifestations and anaphylactic shock. In Allergology International (Vol. 68, Issue 1, pp. 119–121). Japanese Society of Allergology. https://doi.org/10.1016/j.alit.2018.07.003
9. Butterfield, J. H. (2020). Survey of Mast Cell Mediator Levels from Patients Presenting with Symptoms of Mast Cell Activation. International Archives of Allergy and Immunology, 181(1), 43–50. https://doi.org/10.1159/000503964
10. Jennings, S. V., Slee, V. M., Hempstead, J. B., Slee, A. M., Castells, M. C., Akin, C., & Bowman, A. S. (2019). The Mastocytosis Society Mast Cell Activation Syndrome Patient Perceptions Survey. Journal of Allergy and Clinical Immunology, 143(2), AB427. https://doi.org/10.1016/j.jaci.2018.12.962
11. Russell, N., Jennings, S., Jennings, B., Slee, V., Sterling, L., Castells, M., Valent, P., & Akin, C. (2018). The Mastocytosis Society Survey on Mast Cell Disorders: Part 2-Patient Clinical Experiences and Beyond. The Journal of Allergy and Clinical Immunology. In Practice, 0(0). https://doi.org/10.1016/j.jaip.2018.07.032
12. Valent, P., Bonadonna, P., Hartmann, K., Broesby-Olsen, S., Brockow, K., Butterfield, J. H., Triggiani, M., Lyons, J. J., Oude Elberink, J. N. G., Arock, M., Metcalfe, D. D., & Akin, C. (2019). Why the 20% + 2 Tryptase Formula Is a Diagnostic Gold Standard for Severe Systemic Mast Cell Activation and Mast Cell Activation Syndrome. International Archives of Allergy and Immunology, 180(1), 44–51. https://doi.org/10.1159/000501079
13. Castells, M., & Butterfield, J. (2019). Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management. In Journal of Allergy and Clinical Immunology: In Practice (Vol. 7, Issue 4, pp. 1097–1106). American Academy of Allergy, Asthma and Immunology. https://doi.org/10.1016/j.jaip.2019.02.002
14. 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
15. Golden, D. B. K. (2019). The Many Faces of Mast Cell Disorders—A House of Mirrors? In Journal of Allergy and Clinical Immunology: In Practice (Vol. 7, Issue 4, pp. 1139–1141). American Academy of Allergy, Asthma and Immunology. https://doi.org/10.1016/j.jaip.2019.02.003
16. Schofield, J. R., & Afrin, L. B. (2019). Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome. In Am J Med Sci (Vol. 357, Issue 6).
17. Caminati, M., Olivieri, E., Zanotti, R., & Bonadonna, P. (2019). Omalizumab and Systemic mast cell activation diseases: a treatment opportunity for non-clonal disorder? Journal of Allergy and Clinical Immunology, 143(2), AB151. https://doi.org/10.1016/j.jaci.2018.12.458
18. Landy, R. E., Stross, W. C., May, J. M., Kaleem, T. A., Malouff, T. D., Waddle, M. R., & Vallow, L. A. (2019). Idiopathic mast cell activation syndrome and radiation therapy: A case study, literature review, and discussion of mast cell disorders and radiotherapy. Radiation Oncology, 14(1). https://doi.org/10.1186/s13014-019-1434-6
19. Berry, R., Hollingsworth, P., & Lucas, M. (2019). Successful treatment of idiopathic mast cell activation syndrome with low‐dose Omalizumab. Clinical & Translational Immunology, 8(10). https://doi.org/10.1002/cti2.1075
20. Blank, S., Pehlivanli, S., Methe, H., Schmidt-Weber, C. B., Biedermann, T., Horny, H. P., Kristensen, T., Amar, Y., Köberle, M., Brockow, K., & Stömmer, P. E. (2020). Fatal anaphylaxis following a hornet sting in a yellow jacket venom-sensitized patient with undetected monoclonal mast cell activation syndrome and without previous history of a systemic sting reaction. Journal of Allergy and Clinical Immunology: In Practice, 8(1), 401-403.e2. https://doi.org/10.1016/j.jaip.2019.06.021
21. Khan, F., Ledford, D. K., Weston, E., & Sher, M. R. (2019). An Usual Presentation of Mast Cell Activation Syndrome and Pancreatic Neuroendocrine Tumor (PanNET). Journal of Allergy and Clinical Immunology, 143(2), AB181. https://doi.org/10.1016/j.jaci.2018.12.555