Postural Orthostatic Tachycardia and Mast Cell Activation Syndromes

Postural Orthostatic Tachycardia and Mast Cell Activation Syndromes Leonard Weinstock, MD, FACG Specialists in Gastroenterology

Disclosures • Speakers bureau: Salix • Not a neurologist, cardiologist, or allergist

POTS and MCAS Tales of two syndromes Two new great masqueraders Blind men & the elephant Comorbid syndromes New treatment

Old Great Masqueraders Syphilis Tuberculosis Celiac Munchausen and Factitious

You have idiopathic vertigo and tinnitus You have chronic fatigue and migraine 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 (…. and it does not exist)

19 MD’s Dx after 16 yrs 25 yrs to return to health

Age 18 – Trigger-induced flushing, rash, nausea Age 20 - Bloating, constipation, bad gas Ages 23 -43 - Weak, painful dependent edema, orthostatic lightheadedness & tachycardia, syncope, body pain, and stopped sweating Ages 37 -43 - 45 Sx: above plus fatigue, brain fog, body pain, vertigo, tinnitus, dry mouth, thirst, HA, altered visual acuity, hand leg edema, cyanosis, nocturia, early satiety, pelvic outlet obstruction, … Disabled: No sleep or rest, liquid diet, straining led to syncope, unable to tolerate warm temps Mayo… Dx. . but failed 12 POTS/MCAS meds, thyroid Rx, salt, and stockings

Thinking Inside Our Own Box Tempting to think separate symptoms = Separate Diseases • • • GERD Dysphagia Nausea Abdominal pain Constipation Anal outlet disorder … remarkable ROS…Dx

My Own Blindness • 34 y. o. WF w 17 yrs abd pain, GERD, diarrhea, >250 ER visits; 5 universities • W/U and Rx – every known test, +LBT & SOD: failed CCK, 9 ERCPs, and all IBS and GERD Rx • Tachycardia w/u out of state: + tilt table • Tachycardia hospitalizations not at MBMC • Monthly IVIg Few Sx for 1 st time in 14 mo… Treating both POTS and MCAS sx

Postural Orthostatic Tachycardia Syndrome: POTS • Prevalence: 1 to 3 million (vs. 1. 6 for Crohn’s) • Tilt table test – Postural increase 30 bpm w/i 10 min – Norepinephrine increase standing • Additional testing – Quantitative sudomotor axon reflex test – Biopsy for small fiber neuropathy Schondorf. Low. Neurology. 1993.

POTS – sympathetic overdrive Flight or Fight

POTS: Sympathetic Dysfx • Sympathetic nervous system affected by autoantibodies or neurologic imbalance that trigger sympathetic receptors and result in severe postural tachycardia • GI Sx – mimics GI disorders and syndromes Deb 2015, Li 2014, Vernino 2016

POTS: Systemic Syndrome • • • Esophagus – GERD, dysphagia Stomach – gastroparesis, rapid gastric emptying Small intestine dysmotility CNS – headaches, migraines, brain fog, anxiety, depression Urinary tract - inability to empty the bladder Ocular – inability to accommodate Salivary glands – dry mouth Skin – flushing, rashes, swelling Extremities – pain, swelling, vasospasm Benarroch 2012

POTS Sx (50% percentile) • Postural lightheadedness • Palpitations • Syncope • Headache • Blurry vision • Memory problems Deb. 2015

POTS & GI Sx Nausea Abd. discomfort Bloating Diarrhea Constipation 39% 15% 24% 18% 15% N = 163 patients, 87% female Loavenbruck et al. Neurogastroenterol Motil. 2015

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

Active POTS Auto-antibodies • Alpha-1, beta-1 and -2 adrenergic Ab (extracted from man and transfer to muscle model) • Muscarinic acetylcholine Ab (isolated from man) Li. J Am Heart Assoc. 2014 Vernino et al. Abstract. 2016

POTS: Specific Causes • Traumatic brain injury • Electrical injury • Lyme disease • HPV vaccine • Pregnancy • Median arcuate ligament syndrome Kanjwal -09, 10, 11, Blitshteyn 2014, Brinth 2015

POTS and Contributing Factors • Mast cell activation disorders ~33% • Ehlers-Danlos syndrome = 30% • Autoimmune diseases = 20% – Hashimoto’s – Sjogren’s – Celiac – SLE • Deconditioning = high % Hoffman-Snyder. Neurology. 2015. Adapted from Sandroni

POTS & the SB • SB imaging – 7/12 dilated loops & A/F levels – Implications for role of SIBO Huang et al. Dig. Dis Sci. 2013.

POTS & LGI • Colonic transit time studies – 80% delayed colonic transit • Anorectal manometry – 86% had abnormalities c/w dysmotility Huang et al. Dig. Dis Sci. 2013.

Ehlers-Danlos Syndrome Point each for: Palms to floor - 1 Thumbs to wrist - 2 Pinky back 90 o - 2 Elbows hyperextend - 2 Knees hyperextend - 2 Positive if ≥ 4

POTS w/o & w EDS N = 3389 POTS pts EDS in 30% EDS pts – Less likely to report a triggering event (p=0. 009) – More likely to have life-long POTS-like Sx (p<0. 001) SR Raj et al. , Heart Rhythm Society Scientific Sessions, Chicago IL, May

GI Sx in POTS w/o & w EDS No EDS p<0. 001 p=0. 003 p<0. 001 SR Raj et al. , Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017

Ehlers-Danlos Syndrome High frequency of MCAS Immunohistochemistry analysis: increased MC in uninvolved skin Luzgina 2011. Sevenviratne. 2017

Mast Cell Activation Syndrome Ig. E T-cell cytokines and microgranules Antigens • MC w mutations in GI, skin, BM • Etiology: • T-cell Mediators interaction • Abnl microbiome Involves multiple systems Shefler. J Immunol. 2010 Afrin. Clin Ther. 2015

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

MCAS vs. Mastocytosis We act bad We are bad clones

Mast Cell Activation Syndrome • Prevalence: 1% – 17% population • Increase in number of clonal MC C-KIT (CD 117) mutation – multiple KIT mutations • Vast array of sx owing to mediators … see handout Afrin 2015.

Proposed Criteria for MCAS Dx MCAS made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria and rule out other diagnoses

Major Criteria for MCAS Constellation of complaints attributable to pathologically increased MC activity ≥ 2 organ systems w typical disorders of the skin, cardiovascular, nose, respiratory, GI, ocular, and/or Hx anaphylaxis LW: its a syndrome with supporting evidence Molderings , Afrin 2014.

Minor Criteria for MCAS � Response to MC therapy � Evidence of increased MC mediators � Focal or disseminated increased MC in BM and/or GI tract (CD 117 -, tryptase-, and CD 25 -MC express CD 2 and/or CD 25) � Spindle-shaped morphology in >25% of MC Molderings, Aafrin 2014

MCAS work up • PE – Orthostatic VS – Skin – Dermatographism – Joint hypermobility • Biopsy CD 117 stain • GI – anywhere • Skin – hives or rash • Bone marrow (to exclude SM) • Lab 50% yield: – Chromogranin A – Heparin - plasma – Histamine - plasma – Urine prostaglandin D 2 – Urine N-methylhistamine – LFT and cholesterol 15% yield: – Tryptase

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, Sub. P MC IL-1, IL-33, LPS, VIP, Butyrophillin, neurotensin, caselin, glialdin, gluten, reactive O 2, C. diff toxins, rotavirus Inflamm. & Neurotoxic Mediators IL-1, 6, 8, 13, 17, 32 Monocyte chemotactic protein-1 Prostaglandin D 2 Serotonin Tryptase TNF-alpha Vasoactive Mediators Histamine Bradykinin Endothelin IL-6, 8 Nitric oxide Serotonin Tryptase Urocortin Vasoactive GF VIP

MCAS Associated Conditions • POTS (10%) • IBS (11%) • EDS • Interstitial cystitis • CFS syndrome (3%) • Asthma (4 -20%) • Fibromyalgia (1 -10%) • Obesity (37%) • Diabetes mellitus (2 -20%) Afrin. 2016.

MCAS: Systemic Syndrome • • • Esophagus – GERD, dysphagia Stomach – gastroparesis, rapid gastric emptying Colon – diarrhea, constipation CNS – headaches, migraines, brain fog, panic attacks, anxiety, depression CVS - tachycardia Urinary tract – pain and frequency (IC) Ocular – conjunctivitis Salivary glands – swelling Skin – flushing, rashes, swelling Extremities – pain, swelling, vasospasm Constitutional – fatigue, fever, wt. loss/gain Afrin 2017

MCAS Sx (50% percentile) • Fatigue • Nausea • Muscle pain • Chills • Pre-syncope or syncope • Edema • Headaches • Dyspnea • Itching • Urticaria • Eye irritation • Heartburn Deb. 2015

MCAS Sx – 17 overlap w POTS • • • Fatigue Insomnia Flushing Poor healing Sinusitis Tachycardia Syncope Weight gain or loss Dental deterioration • • Cough Panic attacks Anxiety Multiple drug reactions Chemical sensitivity Depression Tremor Heat intolerance Explained by Comorbidity

MCAS GI Sx – 413 pts • • • Nausea w/ or w/o vomiting - 57% Heartburn - 50% Abdominal pain - 48% Chest pain - 40% Alternating D and C - 36% Dysphagia - 35% Oral irritation/sores - 30% Diarrhea - 27% Constipation - 14% Afrin – 2016

MC Detection and Activation • H&E: MC granules seen only at 100 x under oil • Request MC CD 117 staining if suspicious • Blood and urine tests may not reflect local activation vs. systemic mastocytosis where circulating mediators may be more important

POTS & MCAS Rx

POTS Rx based on P-physiology • Autonomic Neuropathy - ? • Leg Blood Flow Abnormalities – stockings, binders • Hypovolemia – salt loading, IV fluids • Hyperadrenergic state – multiple cardiac drugs • Mast Cell Activation – MCAS Rx Avoid drugs which worsen NE reuptake inhibition (ADAH, anti-depressants)

POTS Rx CV - fludrocortisone, midodrine, droxidopa, low dose beta-blocker, pyridostigmine, modafinil, ivabradine, antidiuretic hormone, erythropoietin, methylphenidate, octreotide, SSRI, Vitamin C, exercise, 10 gm-sodium diet, rapid fluid intake, 3 -4 liters water, IV hydration, compression wear GI - PPI, pelvic floor training Bennoch 2012, Garland 2015

MCAS Rx Mediator effectors & MC receptor blockers: H 1/H 2 blockers, Vit C, montelukast, zileuton, ASA Mast cell stabilizers: quercetin, cromolyn, ketotifen Advanced Rx: amalizumab, etoricoxib, hydroxyurea, tamoxifen, steroids, mercaptopurine, methotrexate, cyclosporine, initinib, sunitinib Natural: Vit B - 6, 9, 12, omega-3, α lipoic acid, N-acetylcysteine, SAMe, L. rhamnosus, Bifidobacter Bennoch 2012, Garland 2015, Afrin 2016

MCAS Rx: Diet Specific triggers (food, scents, temp. ) Gluten, yeast, cow milk protein free Molderings. Arch Pharm 2016 Low histamine Internet sources ? ? Low FODMAP – in IBS-D pts - low (n=20) vs. high (n=20) for 3 wks o Low F-diet - histamine reduced 8 -fold (p<0. 05) o Low F-diet incr. diversity Mc. Kintosh. Gut. 2017

Immune Rx for Autoimmune Autonomic Ganglionopathy • IVIg w immunomodulators • Plasmapheresis, prednisone, and immunomodulators • IVIg w Mycophenolate • Mycophenolate Cook 2016, Dupond 1999, Heafield 1996, Ishibodi 20014, Quan 2000, Soota 2016, Gibbons 2008

Immune Rx for Autonomic Neuropathy Associated w Sjogrens • Four cases – one pt with POTS Goodman. Am J Ther. 2017

Novel Rx for MCAS and POTS Researcher and on Board of Stand Up To POTS Weinstock, Myers, Brooks, Goodman. Manuscript submitted. 2017.

Naltrexone (LDN), IV immunogloblins (IVIg), and Rifaximin (R)

Rational for Combo Rx • LDN • Rebound increase in endorphins • Reduce T and B cell activity • Reduce cytokines • Block Toll-like receptor 4 on microglia and on MC • IVIg • Bind Fc portion of antibodies… • Bind to gammaglobulins which degranulate MC • Antibiotic - Rx of SIBO Weinstock, Myers, Brooks, Goodman. Manuscript submitted. 2017.

POTS & SIBO N = 27 (26 F, 27% MCAS, 42% EDS) GI Sx – Pain 96%, Bloat 92%, Nausea 85%, Constipation 73%, Diarrhea 58%, GERD 58% LBT abnl in 19/27 (69%) Antibiotics helped: GI Sx in 10/15 POTS Sx in 4/15 LDN helped: GI Sx in 7/11 POTS/MCAS Sx in 5/11 (1 POTS, 2 both, 2 MCAS)

Summary • POTS and MCAS – think about Dx for your complicated, Rx-refractory pts • Potential use for LDN, IVIg, immunomodulators, and antibiotics