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Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome (MCAS). Leonard Weinstock, MD, FACG St. Louis, Missouri. Disclosures. Speakers bureau: Salix Off label use of medications. MCAS (and POTS). You have chronic fatigue and migraine. You have dehydration and tachycardia. You have idiopathic vertigo and tinnitus.

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Mast Cell Activation Syndrome (MCAS)

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  1. Mast Cell Activation Syndrome (MCAS) Leonard Weinstock, MD, FACG St. Louis, Missouri

  2. Disclosures • Speakers bureau: Salix • Off label use of medications

  3. MCAS (and POTS) You have chronic fatigue and migraine You have dehydration and tachycardia You have idiopathic vertigo and tinnitus You have IBS and pelvic floor dysfunction You have allergies and asthma You have fibromyalgia Blind men and the elephant

  4. Outline What is mast cell activation disease? • Well known: • Allergic diseases………………… • Mastocytosis………………………. • What’s new **: • Mast cell activation syndrome …… General Clinical Theme Allergy ± Inflammation MC Neoplasia ± Allergy ± Inflammation Inflammation ± Allergy (± Aberrant Growth?) ** 2008: case report, 2010: KIT mutations, 2011: case series

  5. 45 y.o. WF sick for 25 yr 19 MD’s Found me via LDNresearchfund.org

  6. Age 18 - MCAS Sx: flush, rash, nausea w triggers Age 20 -GI Sx: bloat, constipation, rotten-egg gas Ages 23-43 - POTS Sx: orthostatic intolerance, body pain, plus delayed pressure urticaria/angioedema Ages 37-43 -45 individual Sx: no rest or sleep, liquid diet, syncope w triggers, standing, and straining for BM Mayo (AZ) -Dx/Rx: failed 12 POTS/MCAS meds, thyroid Rx, & vascular support

  7. New Rx for MCAS & POTS • LDN • IVIg • SIBO Rx Weinstock, Brook, et al. Br Med J Case Reports. January 2018.

  8. LDN for MCAS & POTS • LDN • Rebound increase in endorphins • Reduce T & B cell production • Less cytokines & antibodies • Increase Treg cells • Block TLR on microglia • Block TLR on MC • IVIg • SIBO Rx

  9. IVIg for MCAS • LDN • IVIg • DPU - FDA-indication • Binds Fc portion of autoantibodies • Binds to MC IgG receptors • SIBO Rx

  10. Antibiotic for MCAS & POTS • LDN • IVIg • SIBO Rx • Rifaximin • Low sulfide diet • Decrease cytokines & subsequent increased intestinal permeability

  11. LDN, IVIg, & Rifaximin Rx POTS MCAS SIBO Mean Severity Scores IVIg

  12. Novel Rx – life changing

  13. POTS - Pathophysiology • Mast Cell Activation – in 33% *** • Partial Autonomic Neuropathy • Leg Blood Flow Abnormalities • Hypovolemia • Hyperadrenergic • Increased Release*** • Decreased Clearance • Autoantibodies EDS is common *** Shannon. NEJM 2000. Lambert. Circ Arrhythm Electrophysiol 2008, Green. JAHA 2014

  14. Normal Mast Cells • Biology: • Produced in marrow • Immature form circulate • Migrates to sites of inflam. & T-cell activity • Lives in mucosa and by vessels/nerves • Live a few months to few years • KIT stem cell factor receptor on MC surface

  15. Normal Mast Cells • Functions: • Wound healing • Angiogenesis • Immune tolerance • Defense against pathogens • Blood-brain-barrier function

  16. Mast Cell Activation Disease Mast Cell Leukemia Extremely rare Aggressive Systemic Mastocytosis SM assoc w heme malignancy Indolent Systemic Mastocytosis Cutaneous Mastocytosis MCAS 17% per Afrin 2016

  17. MCAS vs. Mastocytosis We act bad Each have KIT mutations We are malignant Most in bone marrow and high tryptase level

  18. MCAS: prevalence • 1% – 17% • Think about potential causation in many syndromes: • Irritable bowel • Fibromyalgia • Chronic fatigue • Chronic pelvic pain

  19. Mast Cell Activation Syndrome • Onset often < 20 but unrecognized for decades • Usually multi-systemic • Sx often “inflammatory” • Perplexingly inconstant course: • Abnormalities often externally inapparent • Chronic or waxing/waning or episodic • Different sx at different times • Often no triggers but can be infections, vaccination, stress, preg. • Many MDs, many dx’s • Pts commonly cease reporting sx Molderings , Afrin 2014.

  20. MCAS: Mediators • 200 mediators • Histamine • Proteases (tryptase) • Heparin • Pro-inflammatory cytokines (TNF-α…) • Vascular permeability/dilators • Leukotrienes • Platelet aggregation factor • Antimicrobials www.Cells-Talk.com

  21. MCAS: Systemic Syndrome • Constitutional – fatigue, fever, wt. loss, obesity • CNS – migraines/HA, brain fog, panic attacks, anxiety, depression, insomnia • Esophagus – GERD, dysphagia, chest pain • Stomach – gastritis, dyspepsia, nausea • GI – abdominal pain, diarrhea, constipation • Liver – increased enzymes • Immune – poor healing Afrin. Am J Med Sci. 2017. Divoux. J Clin Endocrinol Metab. 2012.

  22. MCAS: Systemic Syndrome • CVS – tachycardia, chest pain • Urinary tract – interstitial cystitis, frequency • Ocular – conjunctivitis • Salivary glands – swelling • Skin – flushing, hives, rashes, swelling, itching • Pulmonary – asthma, dyspnea, cough • Extremities – pain, swelling, vasospasm, numbness Afrin. Am J Med Sci. 2017. Divoux. J Clin Endocrinol Metab. 2012.

  23. MCAS Sx (50% percentile) • Nausea • Chills • Edema • Eye irritation • Dyspnea • Heartburn • Fatigue • Muscle pain • Pre-syncope or syncope • Headaches • Itching • Urticaria Afrin. Am J Med Sci. 2017.

  24. Intestine-derived MC-activation Triggers CNS-originated MC-activation Triggers IL-1, IL-33, LPS, VIP, Butyrophillin, neurotensin, caselin, glialdin, gluten, histamine, reactive O2, C. diff toxins, rotavirus Adenylate cyclase, Activating peptide, Calcitonin gene-related peptide, Corticotrophin releasing hormone, Myelin basic protein, Nerve growth factor, Neurotensin, Substance P MC Vasoactive Mediators Histamine Bradykinin Endothelin IL-6, IL-8 Nitric oxide Serotonin Tryptase Urocortin Vasoactive GF VIP Inflamm. & Neurotoxic Mediators IL-1,6,8,13,17,32 Monocyte chemotactic protein-1 Prostaglandin D2 Serotonin Tryptase TNF-α

  25. MCAS Triggers T-cell interaction Abnl microbiome Lyme disease H. pylori Ehlers-Danlos T-cell cytokines & microgranules IgE and IgG Antigens Mediators Many receptor types Shefler. J Immunol. 2010. Afrin. Clin Ther. 2015.

  26. Microbiome & MC Activity Theory: dysbiosis and/or SIBO leads to MC activation and effector memory T and B cells • SCFA (butyrate) and other microbial factors inhibits MC degran. & TNF-α … dysbiosis alters this • Stressed rats develop MC hyperplasia in GI tract possibly d/t incr. intestinal permeability • Mycoplasma and Strep. pneumoniae induced MC degran. Afrin, Khoruts. Clin Ther. 2015.

  27. Proposed Criteria for MCAS Dx MCAS made by either: 1) Two major criterion 2) One major criterion plus one minor criteria or 3) Three minor criteria and rule out other diagnoses Molderings , Afrin 2016.

  28. MCAS: Major Criteria 1. Constellation of complaints attributable to pathologically increased MC activity ≥2 organ systems w typical disorders: skin, CVS, resp, GI, nasal, ocular, and/or anaphylaxis 2. Biopsy of extracutaneous tissue showing mast cells Molderings , Afrin 2016.

  29. MCAS: Minor Criteria • Response to MC therapy • Evidence of increased MC mediators • Spindle-shaped morphology in >25% of MC • MCs in marrow express CD2 and/or CD25 • (and no other disease explains symptoms) Molderings, Afrin 2016

  30. MCAS: W/U • PE • Orthostatic pulses • Skin • Dermatographism • Joint hypermobility • Lab 50% yield: • Chromogranin A • Histamine (plasma) • Heparin (plasma) • Prostaglandin D2 (plasma) • 15% yield: • Urine 2,3,-dinor 11-beta-PGF2-α or prostaglandin D2 • Urine N-methylhistamine • Urine leukotriene E4 • Tryptase (if high do marrow) • Biopsy • Ileum>duod>stom.>colon • Bladder • Marrow: exclude SM

  31. MCAS: W/U • Lab tests • Only 4 different chemicals of a possible 200 can be tested • Temperature sensitive – needs cold centrifuge and keep cold until frozen • Urine needs to be kept cold • Need to be off PPI, NSAID, ASA, Vit C/D, berberine • H1/H2 probably OK --- still would go without • It can take 3 rounds of testing - $$$$

  32. MCAS: W/U • Other helpful lab tests • Cholesterol • Liver chemistries • CBC • For bleeding or clotting history: PT/PTT • For clotting: anti-cardiolipin antibodies • IgE (can increase MC activity) • Tryptase • Best as a gauge of total body load of mast cells

  33. MCAS: W/U • Biopsies • MCAS – tissue speckled with MC • I usually see 30-70/hpf • Often round in shape • Mastocytosis – cells are in aggregates and are mainly spindle shaped - >100/hpf • CD117 is best stain – attaches to KIT protein (transmembrane tyrosine kinase) • We are reporting a case of MC on epiploic appendagitis as a cause of chronic pain

  34. MC Detection & Activation • H&E: MC granules only at 100x under oil • CD117 stain is ideal (>20/HPF) • Labs may not detect focal/primary GI MC activation Jakate. Arch Path Lab Med. 2006.

  35. MC Counts in Diarrhea Pts Chronic intractable diarrhea (N=47) Controls (N=50) Chronic diarrhea diseases (IBD, celiac, CC/LC) (N=63) Control - 13.3 +/- 3.5 led to count of >20 MC to be abnl Chronic intractable diarrhea - 33/47 (70%) increased MCs Sx controlled by H1/2 blocker (±cromolyn) in 22/33 (67%) No increase in MC with other causes of chronic diarrhea. Jakate. Arch Path Lab Med. 2006.

  36. MC Count Controversy • Controls: 100 (58 F/42 M, 56 yrs) • IBS pts: 100 (82 F/18 M, 43 yrs) • MCAS pts: 10 (9 F/1 M, 41 yrs) • Mean MC counts per HPF (i.e., avg 5 HPFs): • Controls: 19 (7-39) (?? Totally asx??) • IBS: 23 (9-45) • MCAS: 20 (12-31) (small group of pts) • Controls vs. IBS, P<0.001 • Controls vs. MCAS, not significant Doyle. Am J Surg Pathol. 2014.

  37. Duodenal White Spots and Mast Cells

  38. Mantra of MCAS Rx Try to make >50 better than baselineAttempts take patience and persistenceOne drug change at a time. Factor in cost.Try to direct Rx at most bothersome symptom but recognize mediator cause and effect not definitive Afrin. MCAS Symposium. 2018.

  39. Tenets of MCAS Rx Identify and avoid triggersBlock receptors of mediatorsInhibit mediator productionInhibit mediator release Molderings. Naumyn S Ach Pharm. 2016.

  40. MCAS Rx Identify triggers:Allergens/triggers Food – gluten, dairy, hist. Drugs and ExcipientsOdorsElectricalVibrationHormonalAtmospheric Molderings. Naumyn S Ach Pharm. 2016.

  41. MCAS Rx Block actions of released mediators:Antihistamines H1 – oral (cont. IV diphenhydramine when severe) H2 – oral (different doses and types impt)DAO (Diamine oxidase)Leukotriene inhibitor (montelukast – 10-20 mg bid) Molderings. Naumyn S Ach Pharm. 2016.

  42. MCAS Rx Inhibit production of mediators:Vitamin C (500-1000 mg BID) Quercetin (500 mg QID)Ketotifen (2-4 mg BID) Vitamin D (1000 IU daily)Vitamin E (?) Afrin. Exp Hematol Oncol. 2013; 2: 28. Molderings. Naumyn S Ach Pharm. 2016.

  43. MCAS Rx Inhibit production of mediators (cont.):Lipoxygenase inhibitors (zileutin)NSAIDs (watch for anaphylaxis)HydroxyureaSteroids (acute use only) Afrin. Exp Hematol Oncol. 2013; 2: 28. Molderings. Naumyn S Ach Pharm. 2016.

  44. MCAS Rx IInhibit release of mediators (stabilize MCs):Cromolyn (oral and/or inhaled – watch for initial flare)Pentosan (especially with interstitial cystitis)BenzodiazepinesCannabinoidsLDNAlpha lipoic acidN-acetylcysteineOmalizumabTyrosine kinase inhibitors (see next)JAK inhibitor(Ruxolitinib) Molderings. Naumyn S Ach Pharm. 2016.

  45. MCAS Rx IInhibit release of mediators (cont.):Tyrosine kinase inhibitors (and current FDA IND status)Imatinib (CML, mastocytosis) Tofacitinib (RA) *** Dasatinib (CML) Nilotinib (CML) Sunitinib (renal cell Ca & GIST) ****** MCAS case reports Afrin. Eur J Haematol. 2015. Afrin. Eur J Haematol. 2017.

  46. MCAS Rx IInhibit release of mediators (advanced):IV immune globulin (IVIg)InterferonmTOR (chemoRx – sirolimus) Somatostatin (10-30 mg sc long-acting octreotide) TNF antagonist Interleukin antagonist Future Rx – tryptase inhibitors, H3 inhibitor, stem cell Rx Molderings. Naumyn S Ach Pharm. 2016.

  47. MCAS Rx Tips from Dr. Afrin GI – Cromolyn Inflammation – Aspirin, Cox 1 or 2 High histamine – Vitamin C and diamine oxidase Respiratory – Montelukast , cromolyn via nose and nebulizer Deep bone pain – Hydroxyurea Urticaria – Omalizumab Severe pts with multidrug failure – Imatinib Dercums disease – Imatinib Afrin. MCAS Symposium. 2018.

  48. MCAS Rx Tips from Dr. Afrin (cont.) Eye sx – Topical cromolyn, ketotifen, or other anti-histamines Epistaxis – Nasal cromolyn or anti-histamines Dyspareurnia – Douches with diphenhydramine or cromolyn Sensory neuropathy – Alpha lipoic acid, imatinib Anaphylaxis – Epi, glucagon (if on beta blocker) Tachycardia – Ivabradine Nausea – PPI, aprepitant (also for migraines) Peri-operative Rx – H/1H2, benzodiazapine, steroids Afrin. MCAS Symposium. 2018.

  49. Other ideas: Rx Microbiome Treat dysbiosis, SIBO, and SIFO which lead to MC activation and memory T & B effector cells • Treat SIBO to decrease T-cell & cytokines • FODMAP to increase SCFA (butyrate) • Stressed rats develop MC hyperplasia d/t increased intestinal permeability • Balance microbiome to reduce MC degran. • Treat candida Afrin, Khoruts. Clin Ther. 2015.

  50. Improve Gut Permeability General • Treat underlying disease • Diets Specific Rx • SBI • Zinc • Glutamine • Curcumin • Probiotics Sanz Fernandez. Animal. 2014. Wang, Am J Physiol Cell Physiol. 2017. Rapin. Clinics (Sao Paulo). 2010. Lopeuso. Eur Rev Med Pharmacol Sci. 2015.

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