Mast Cell Activation Syndrome MCAS Leonard Weinstock MD

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 idiopathic vertigo and tinnitus You have allergies and asthma You have dehydration and tachycardia Blind men and the elephant You have IBS and pelvic floor dysfunction You have fibromyalgia

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

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

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

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

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

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

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

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

Novel Rx – life changing

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

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

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

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

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

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

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.

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

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.

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.

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

Intestine-derived MC-activation Triggers CNS-originated MC-activation Triggers Adenylate cyclase, Activating peptide, Calcitonin gene-related peptide, Corticotrophin releasing hormone, Myelin basic protein, Nerve growth factor, Neurotensin, Substance P MC IL-1, IL-33, LPS, VIP, Butyrophillin, neurotensin, caselin, glialdin, gluten, histamine, reactive O 2, C. diff toxins, rotavirus Vasoactive Mediators Inflamm. & Neurotoxic Mediators IL-1, 6, 8, 13, 17, 32 Monocyte chemotactic protein-1 Prostaglandin D 2 Serotonin Tryptase TNF-α Histamine Bradykinin Endothelin IL-6, IL-8 Nitric oxide Serotonin Tryptase Urocortin Vasoactive GF VIP

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

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.

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.

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.

MCAS: Minor Criteria � Response to MC therapy � Evidence of increased MC mediators � Spindle-shaped morphology in >25% of MC � MCs in marrow express CD 2 and/or CD 25 �(and no other disease explains symptoms) Molderings, Afrin 2016

MCAS: W/U • PE – Orthostatic pulses – Skin – Dermatographism – Joint hypermobility • Biopsy • Lab 50% yield: – Chromogranin A – Histamine (plasma) – Heparin (plasma) – Prostaglandin D 2 (plasma) – 15% yield: – Urine 2, 3, -dinor 11 -beta-PGF 2 -α • Ileum>duod>stom. >colon or prostaglandin D 2 • Bladder – Urine N-methylhistamine • Marrow: exclude SM – Urine leukotriene E 4 – Tryptase (if high do marrow)

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 – H 1/H 2 probably OK --- still would go without – It can take 3 rounds of testing - $$$$

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

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 – CD 117 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

MC Detection & Activation • H&E: MC granules only at 100 x under oil • CD 117 stain is ideal (>20/HPF) • Labs may not detect focal/primary GI MC activation Jakate. Arch Path Lab Med. 2006.

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 H 1/2 blocker (±cromolyn) in 22/33 (67%) No increase in MC with other causes of chronic diarrhea. Jakate. Arch Path Lab Med. 2006.

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.

Duodenal White Spots and Mast Cells

Mantra of MCAS Rx Try to make >50 better than baseline Attempts take patience and persistence One 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.

Tenets of MCAS Rx Identify and avoid triggers Block receptors of mediators Inhibit mediator production Inhibit mediator release Molderings. Naumyn S Ach Pharm. 2016.

MCAS Rx Identify triggers: Allergens/triggers Food – gluten, dairy, hist. Drugs and Excipients Odors Electrical Vibration Hormonal Atmospheric Molderings. Naumyn S Ach Pharm. 2016.

MCAS Rx Block actions of released mediators: Antihistamines H 1 – oral (cont. IV diphenhydramine when severe) H 2 – oral (different doses and types impt) DAO (Diamine oxidase) Leukotriene inhibitor (montelukast – 10 -20 mg bid) Molderings. Naumyn S Ach Pharm. 2016.

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.

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

MCAS Rx Inhibit release of mediators (stabilize MCs): Cromolyn (oral and/or inhaled – watch for initial flare) Pentosan (especially with interstitial cystitis) Benzodiazepines Cannabinoids LDN Alpha lipoic acid N-acetylcysteine Omalizumab Tyrosine kinase inhibitors (see next) JAK inhibitor (Ruxolitinib) Molderings. Naumyn S Ach Pharm. 2016.

MCAS Rx Inhibit 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.

MCAS Rx Inhibit release of mediators (advanced): IV immune globulin (IVIg) Interferon m. TOR (chemo. Rx – sirolimus) Somatostatin (10 -30 mg sc long-acting octreotide) TNF antagonist Interleukin antagonist Future Rx – tryptase inhibitors, H 3 inhibitor, stem cell Rx Molderings. Naumyn S Ach Pharm. 2016.

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.

MCAS Rx Tips from Dr. Afrin (cont. ) Eye sx – Topical cromolyn, ketotifen, or other antihistamines 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/1 H 2, benzodiazapine, steroids Afrin. MCAS Symposium. 2018.

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.

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.

FODMAP Free IBS-D pts given low (n=20) vs. high (n=20) FODMAP for 3 wks o Histamine reduced 8 -fold (p<0. 05) o Increased diversity Mc. Kintosh. Gut. 2017.

Serum Bovine Immunoglobulin Antigen Penetration TNFα IL-6 Y Y Immune Activation Lamina propria Y Y Y Lumen Epithelial Cells Y Tight Junction Proteins Ig. Gs No Immune Activation Immune Exclusion IL-10 Lymphocytes Dendritic Cells Petschow. Clinical Exp Gastroenterol. 2014. Steric Exclusion Dendritic Cells

Stem Cell Therapy • Reduces inflammatory cytokines • Increases anti-inflame. cytokines • Reduces apoptosis • Activates SCs in tissues • Helps tissue support cells • Stimulates revascularization • Protection vs. neurotoxins • Secretion of antimicrobial peptide LL-37 • UC SC has growth factors - immune modulation

SCT: Asthma • 4 -armed controlled study: OVA-induced asthmatic mouse model • h. UC-MSCs via trachea • Reduce MCs & leukocytes in BALF (P<0. 05) • Reduction in Th 17 cells in lung (0. 24% vs 2. 90%, P<0. 05) • IL-6 and TGF-β suppressed (0. 23 vs 2. 30 and 0. 56 vs 6. 60, both P<0. 01) Ren NN. Zhonghua Yi Xue Za Zhi. 2017.

SCT: Interstitial Cystitis • IC rat model: 1 wk UC-MSC improved voiding fxn, repair of bladder damage, reduced MC infiltration, and less apoptosis, IL-1β, IL-6, & TNF-α in bladder • Human uroepithelial IC cell model: co-culture with UC -MSC inhibited apoptosis and apoptosis enzyme (caspase) and increased growth stimulators (p-AKT & p-m. TOR) Xie. Biochem Biophys Res Commun. 2018.

Regeneration Paracrine Inflammation Fibrosis Autoimmune reaction Th-1 INF TGF MC Apoptosis TNF Adapted from Kim. Curr Urol Rep. 2016.

MCs and Autoimmune Relationship MC trigger MC Autoimmune modulator Tissue damage See - Brown. Front Immunol. 2012. • T-cell differentiation and migration to distant tissues • Activating stimulus • Mediators damage Examples: RA, MS, DM, Pemphigoid

MCAS: Prognosis • No formal studies yet • Survival curves parallel general population (similar to indolent systemic mastocytosis) • Most suffer reduced Qo. L • Many therapies (targeting many receptors and pathways) found helpful in various MCAS pts • Most pts eventually get helpful therapy Lim K-H, et al. Blood 2009; 113: 5727 -5736.

MCAS and Cancer N = 828 MCAS pts 68 develop a solid tumor before Dx of MCAS • Melanoma • Lung * • Breast • Cervix * • Testicle • Bladder * Highest risk at environmental levels – skin, lungs and GU tract * Both German and US Molderings. F 1000 Research. 2017.

MCAS and Cancer • Inflammation common in cancer • MCs may promote cancer development • Treating MCAS may reduce cancer • Increased surveillance of MCAS patients may be necessary Molderings. F 1000 Research. 2017 .

MCAS Summary • Common disorder • Numerous symptoms and systems • Answer to many diagnostic dilemmas • Patience in Rx often successful Molderings. F 1000 Research. 2017 .

Back up slides

POTS: Clinical & Dx • 170/100, 000; 85% F; 20 -40 common ages • Tilt table test (vs. screen w ortho vital signs) – Increase in 30 bpm w/i 10 min – NE increases in hyperadrenergic POTS • Additional testing – Quantitative sudomotor axon reflex test (56%) – Skin Bx - small fiber neuropathy in 50% Schondorf. Low. Neurology. 1993. Peltier. Clin Aut Res. 2010.

POTS & SIBO • Decreased peristalsis with sympathetic overdrive • Increased frequency of SB dilated loops in POTS pts loops in POTS Huang. Dig Dis Sci. 2013

LDN on MCAS and POTS • Regulating T-cell production decreasing cytokine mediators (which directly cause MC activation) • Block Toll receptors which stimulate MC and also reduce neuro-inflammatory pain via microglia • Endorphins improve intestinal dysmotility in POTS by directly increasing the MMC which prevents small intestinal stasis and subsequent SIBO • May reduce autoimmune Ab production in POTS by B-lymphocyte regulation

LDN in POTS and MCAS N = 27 (26 F, 27% MCAS, 42% EDS) LBT abnl in 19/27 (69%) LDN helped: GI Sx in 7/11 POTS/MCAS Sx in 5/11: 1 POTS, 2 both, & 2 MCAS Weinstock, Brook, et al. Br Med J Case Reports. January 2018.

IVIg in POT/MCAS 5 other POTS/MCAS pts • Marked - all sx, Marked - POTS (not GI), 50% - all sx, 20% better but severe AE, 1 starting Rx Online interviews of POTS pts • 9/13 helped: miraculous, got my life back, life changing, sensational, huge improvement, magic, amazing; 4 no help and/or AE

Antibiotics in POTS and MCAS N = 27 (26 F, 27% MCAS, 42% EDS) LBT abnl in 19/27 (69%) Antibiotics helped: GI Sx in 10/15 POTS Sx in 4/15 Weinstock, Brook, et al. Br Med J Case Reports. January 2018.