Director Division of Allergy and Clinical Immunology St Michaels Hospital University of Toronto Treatment of Mast Cell Activation Syndrome in Patients with Postural Orthostatic Tachycardia Syndrome and Hereditary Connective Tissue Disorders ID: 815925
Download The PPT/PDF document "Peter Vadas MD, PhD, FRCPC" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Peter Vadas MD, PhD, FRCPCDirectorDivision of Allergy and Clinical ImmunologySt. Michael’s HospitalUniversity of Toronto
Treatment of Mast Cell Activation Syndrome in Patients with Postural Orthostatic Tachycardia Syndrome and Hereditary Connective Tissue Disorders
Slide2Mast Cell
Slide3IgE-Dependent Release of Allergic Mediators
IgE
Allergens
Fc
RI
Over Minutes
Lipid mediators:
Prostaglandins
Leukotrienes
Wheezing
Bronchoconstriction
Over Hours
Cytokine production:
Specifically IL-4, IL-13
Mucus production
Eosinophil recruitment
Immediate Release
Granule contents:
Histamine, TNF-
,
Proteases, Heparin
Sneezing
Nasal congestion
Itchy, runny nose
Watery eyes
Slide4Slide5Mast cell activation diseasesA collection of disorders characterized by:Accumulation of pathological mast cells in potentially any or all organs and tissues
and/orAberrant release of variable subsets of mast cell mediators
Slide6WHO Consensus ClassificationCutaneous mastocytosisIndolent systemic
mastocytosis without AHDSmoldering systemic mastocytosisIsolated bone marrow mastocytosis
Systemic mastocytosis with an AHNMDMDS, MPD, AML, NHLAggressive systemic
mastocytosis
Mast cell leukemia
Mast cell sarcoma
Extracutaneous
mastocytoma
Slide7Mast Cell Activation DiseasesMast cell activation syndrome (MCAS)
Slide8Clinical Presentation of MCASVery diverse!Due to widespread distribution of mast cells
Great heterogeneity of aberrant mediator expression patternsSymptoms can occur in virtually all organs and tissuesSymptoms can occur in an erratic staggered mannerWax and wane over years to decades
Slide9Signs and Symptoms of Mast Cell DisordersSkin: episodic flushing, itching, hivesCVS: episodic tachycardia, hypotension, lightheadedness
GI: cramps, diarrhea, heartburn, nausea, vomiting, peptic ulcer, hepatomegaly, splenomegaly, elevated hepatic transaminases, ascitesMSK: osteoporosis, diffuse soft tissue pain
Slide10Signs and symptoms cont’dConstitutional: fatigue, headacheRespiratory: asthma-like symptoms, dyspneaNeuropsychiatric: headache, neuropathic pain, polyneuropathy, difficulty concentrating, anxiety, forgetfulness, vertigo, lightheadedness, tinnitus
Slide11Manifestations of Mast Cell Activation
Nausea*Loose stools/Diarrhea*
Abdominal cramps*Itching*
Flushing*
Headache/Mental Fog*
Hives
Angioedema
Asthma/rhinitis
Vomiting
Laryngeal edemaAnaphylaxis
Slide12Mast Cell Activation Syndrome(MCAS)Complex clinical picture of multiple mast cell mediator induced symptoms
failure to meet WHO criteria for diagnosis of SMExclusion of relevant differential diagnoses
Slide13Mast Cell Activation SyndromeMajor Criteria:Multifocal or disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other
extracutaneous organ(s)eg GI tract biopsies; CD117, tryptase and CD25-stained)
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity
Slide14MCAS - 2Minor criteriaMast cells in bone marrow or other
extracutaneous organs show an abnormal morphology (> 25%) in bone marrow smears or in histologiesMast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from bone marrow or extracutaneous organs resulting in symptoms due to mast cell mediators
Slide15MCAS - 3Evidence of a pathologically increased release of mast cell mediators including:Tryptase
in bloodN-methylhistamine in urineHeparin in bloodChromogranin A in blood
Other mast cell-specific mediators ( PGD2 in blood and urine)
Slide16Treatment of symptomatic mastocytosisH1 antihistaminesH2 antihistamines
LTRA (monteleukast)Mast cell stabilizersNalcromKetotifen
Slide17Experimental treatment of MCASThalidomidePlaquenilOmalizumab
Slide18Mendelian Inheritance of Elevated Serum Tryptase Associated with Atopy and Connective Tissue Abnormalities
Lyons JJ et al. JACI 2014
9 atopic subjects identified with elevated serum tryptase in absence of clonal mast cell disorderMultiple family members of index patients also had elevated serum
tryptase
levels
Followed an autosomal dominant pattern
Mean basal total tryptase during resting state was 21.9 ± 1.4
ng
/ml (n = 33)
Patients had hypermobile joints
Slide19Hyperadrenergic POTS in Mast Cell Activation DisordersShibao C et al. Hypertension 2005;45:385-390
177 patients with disabling orthostatic intoleranceLongstanding (> 6 months) orthostatic intoleranceIncreased heart rate of ≥ 30
bpm within 5 min of upright positionAbsence of underlying causeHistory of facial or upper trunk flushingElevated urinary N-methylhistamine
level associated with flushing episode
Slide20Clinical Characteristics5 clusters of clinical characteristicsCutaneousConnective tissue
GastrointestinalAtopic Neuropsychiatric
Slide21Cutaneous26 of 33 subjects reported:Episodic urticariaFlushing
Slide22GastrointestinalCrampy abdominal painUrgency diarrheaGastroesophageal
refluxIBS-like symptomsEosinophilic esophagitis
Slide23Atopic31 or 33 subjects had atopic symptoms incl:Environmental allergies
Asthma
Slide24MusculoskeletalChronic MSK painHypermobile connective tissue phenotype
Slide25TriggersHeatExerciseVibrationEmotional stress
Non-specific foodsMinor physical traumaUnprovoked
Slide26None of subjects met WHO criteria for either systemic mastocytosis or monoclonal mast cell activationMast cell aggregates not presentNo aberrant expression of CD2/CD25KIT D816V mutation absent
Spindle shaped mast cells seen in only 1 patient
Slide27Co-segregation of POTS, EDS and MCASCheung I and Vadas P JACI 2014
Patients with POTS and hypermobility often describe symptoms of mast cell activationParticipants with diagnoses of POTS and EDS were recruited from throughout North America through an online support group
Slide28Inclusion CriteriaFormal diagnosis of POTS by a cardiologistFormal diagnosis of EDS by a dermatologist, including a Beighton
score of ≥ 5/9 and a diagnostic skin biopsyCompletion of a questionnaire for MCAS based on diagnostic criteria and validated symptoms (Akin et al 2010)
Slide29Results63 subjects returned completed questionnaires15 of 63 participants completed questionnaires and supplied required documentation
12 of 15 participants had formal diagnoses of POTS (80%)9 of 15 (60%) were diagnosed with both POTS and EDS
Slide30Results6 of 9 patients (67%) with both POTS and EDS had validated symptoms of a mast cell disorder, suggestive of MCASA mast cell disorder may frequently co-segregate with POTS and a collagen disorder such as EDS
Slide31SUMMARYStrong evidence to suggest that mast cell disorders may be seen in individuals with EDS and POTSPatients with co-existent mast cell disorders (including MCAS) may have elevated
tryptase if disorders are familialMore often, tryptase levels are normal and diagnosis is made based on validated symptoms and response to therapy with receptor antagonists and mast cell stabilizers
Slide32Treatment of MCAS in Patients with POTS and EDS-3 Karan Gandhi, Juan Guzman MD, Roberto Londono MD and Peter Vadas MD PhD
The effects of anti-mediator therapy were examined in individuals with diagnoses of MCAS, POTS and EDS-3
Patients were included if a diagnosis of POTS had been confirmed with a tilt-table test and….EDS-3 confirmed by skin biopsy and elevated Beighton score and …
Patient reported validated symptoms of MCAS
Slide33Response to treatment was assessed based on self-reported changes in symptoms
Slide34Postural Orthostatic Tachycardia SyndromeA form of dysautonomia characterized by orthostatic intolerance commonly presenting with dizziness, lightheadedness, palpitations, blurred vision and, in some cases, syncope.
Usually confirmed by a positive tilt table testHR > 120 bpmChange in HR > 30 bpm
in adult and > 40 bpm in teens
Slide35Ehlers-Danlos Syndrome Hypermobile TypeCommonly diagnosed by skin biopsy evaluated under TEM
Beighton hypermobility score (> 5/9)Exclusion of other causes of hypermobilityMay be inherited in an autosomal dominant mannerNo validated genetic tests
Slide36EDS-3Affects multiple organ systemsMainly characterized by joint hypermobility, dislocations, subluxations, joint pains, velvety or hyper-extensible skinTEM reveals disorganized collagen bundles in the papillary and reticular dermis
Flower-like collagen fibrilsWidened collagen fibril spacing
Slide37Mast Cell Activation SyndromeInappropriate degranulation of mast cells resulting in symptoms affecting multiple organ systemsDegranulation results in release of histamine, prostaglandins, cytokines and lipid mediators
No curative therapyTreatment typically entails a combination of mediator antagonists and mast cell stabilizers
Slide38MCAS Diagnostic CriteriaCutaneous: flushing, pruritus, urticaria, angioedema
Gastrointestinal: nausea, vomiting, diarrhea, crampy abdominal painCardiovascular: hypotensive syncope or near syncope, tachycardia
Respiratory: wheezing, throat/chest tightnessA decrease in the frequency, severity or resolution of symptoms with anti-mediator
therapy
Evidence
of an increase in a validated urinary or serum marker of mast cell activation
S
erum
tryptase, prostaglandin D2
24 hr urinary N-methylhistamine, prostaglandin D2, 11β-prostaglandin F2α
Slide39Slide40Slide41DiscussionAnti-mediator therapy led to self-reported improvement in cutaneous (4/5)gastrointestinal (3/3)
respiratory (5/5)All patients reported at least some positive response to therapyOnly 2/5 patients reported a positive response to cardiovascular symptoms
Slide42Doses of each drug were optimized for individual patients to minimize side effects and maximize symptomatic benefitsResults suggest that anti-mediator therapy is an effective treatment to control MCAS associated symptoms in patients with POTS and EDS-3Anti-mediator therapy seems to be most effective for cutaneous, gastrointestinal and respiratory symptoms
Slide43Karan Gandhi Ingrid Cheung Juan Guzman MD Roberto Mendoza MD
Scott Walsh MD