Mast Cell Disorders

EDNF 2012 Conference August 2012

Mast Cell Disorders

Andrew M. Smith, MD, MS Division of Immunology, Allergy, and Rheumatology University of Cincinnati and Cincinnati VA Medical Centers August 10 and 11, 2012

Disclosures

• None

• The contents do not represent the view of the Department of Veterans Affairs or U.S. Government

Objectives

• Identify the clinical features of mast cell disorders • Explain the immunologic mechanisms of mast cell disorders • Describe appropriate evaluation and treatment of mast cell disorders

Case Presentation

• 35 year old male, previously healthy • Symptoms began in the winter of 2011 • Woke up in the middle of the night – Started with hands and feet itching – Abdominal pain, diarrhea, and vomiting – Lip swelling, quickly progresses to tongue swelling • Presented to the Emergency Department – Received epinephrine and steroids

Case Presentation

• Fall 2011 - most severe episode • Awaked in the early morning • Hives head to toe, tongue and lip swelling

• Treated with loratidine, famotidine, and prednisone daily

Case Presentation

• Further episodes: 11 times in 12 months and 4 episodes in the past 14 days – Facial/lip swelling with every episode – Faster progression to respiratory distress and low blood pressure – Most recent episodes with chest pain – Most episodes have started in the middle of the night

Case Presentation

• Allergy/Immunology consulted • “What is causing the recurrent episodes of anaphylaxis?”

• Definitions of anaphylaxis, angioedema, and urticaria

Anaphylaxis - Definition

• Difficulty in defining anaphylaxis • Traditional Definition – A systemic, immediate hypersensitivity reaction caused by immunoglobulin E (IgE)- mediated immunologic release of mediators from mast cells and basophils

Anaphylaxis World Allergy Organization definition: • A severe, life threatening, generalized or systemic hypersensitivity reaction involving two or more organ systems

• Allergic anaphylaxis – reaction mediated by an immunologic mechanism

• Non-allergic anaphylaxis – non-immunologic reaction

WAO Journal 2011; 4:13–37

Anaphylaxis - Symptoms

Signs and Percentage Signs and Percentage Symptoms Symptoms Cutaneous >90% Hypotension 30-35% • Urticaria/ 85-90% Abdominal 25-30% Angioedema • Nausea/ • Flushing 45-55% Vomiting Respiratory 40-60% • Diarrhea • Dyspnea/ 45-50% Miscellaneous Wheezing • Headache 5-8% • Rhinitis 15-20% • Substernal 4-6% Dizziness/ 30-35% pain Syncope • Seizure 1-2%

J Allergy Clin Immunol 2010;126:477-80.

Angioedema - Definition • Swelling in the deep skin tissue • Fewer sensory nerve endings • Little or no itch • May be described as painful or burning • Generally asymmetric and short lived • May occur in isolation, accompanied by urticaria, or as a component of anaphylaxis • Can be life-threatening

Cleveland Clinic Journal of Medicine January 2009 vol. 76 1 12-15

Angioedema - Locations

• Larynx – Can develop rapidly – Early symptoms: hoarse voice, throat tightness, and difficulty swallowing • Skin and mucous membranes – Mild pain and warmth may be present, burning sensation – Resolves without leaving residual markings on the skin • Bowel wall – Colicky abdominal pain, sometimes nausea, vomiting and/ or diarrhea – Bowel wall edema often visualized by abdominal CT or ultrasound

438 Chapter 19 – IgE-Dependent Immune Responses and Allergic Disease

and intercellular adhesion molecule 1 (ICAM-1), and A Intradermal chemokines that recruit blood leukocytes. Thus, mast cell injection of activation promotes the recruitment of leukocytes into antigen tissues. The types of leukocytes that are typical of late- phase reactions are eosinophils and TH2 cells; in addition, neutrophils are often present in these reactions. Eosino- phils and TH2 cells both express CCR4 and CCR3, and the Urticaria chemokines that bind to these receptors are produced by many cell types at sites of immediate hypersensitivity • Hives reactions, including epithelial cells. The late-phase reac- Tissue mast cell tion differs from delayed-type hypersensitivity reactions, in which macrophages and TH1 cells are dominant. The late-phase reaction may occur without a detectable • Itchy, red raised lesions preceding immediate hypersensitivity reaction. Bronchial Venule asthma is a disease in which there may be repeated bouts • Turn pale when of inflammation with accumulations of eosinophils and pressed, indicating the TH2 cells without the vascular changes that are characteristic of the immediate response. In such disorders, presence of enlarged Flare Wheal Flare there may be little mast cell activation, and the cytokines blood vessels and fluid that sustain the late-phase reaction may be produced mainly by T cells. • Last minutes to hours • Resolve without GENETIC SUSCEPTIBILITY TO IMMEDIATE discoloration/scarring Vasodilation and HYPERSENSITIVITY Leakage of plasma congestion Activated fluid and protein mast cell The propensity to develop allergies is influenced by the (edema) inheritance of several genes. Abnormally high levels of IgE synthesis and associated atopy often run in families. Family studies have shown clear autosomal transmission of atopy, although the full inheritance pattern is multi- Vasodilation Vasodilation at edge at edge genic. Within the same family, the target organ of atopic of lesion of lesion disease is variable. Thus, hay fever, asthma, and eczema can be present to various degrees in different members th B Molecular and Cellular Immunology, 7 ed. of the same kindred. All these individuals, however, will Flare show higher than average plasma IgE levels. Studies of the genetics of allergic diseases in popula- tions have included genome-wide linkage analyses and, more recently, genome-wide association studies. Linkage analyses for atopy/asthma susceptibility loci identified several chromosomal regions of importance in allergic disease (Table 19-4). Each of these loci may contain several genes that may contribute to the disease. Some Wheal of the genes in these loci may regulate TH2 responses and IgE production. Other genes may have tissue-specific influences, such as airway remodeling in the asthmatic lung. One of the susceptibility loci for atopy is on chro- Anaphylaxis, mosome 5q, near the site of the gene cluster encoding FIGURE 19–8 The wheal and flare reaction in the skin. A, the cytokines IL-3, IL-4, IL-5, IL-9, and IL-13 and the Angioedema, In response to antigen-stimulated release of mast cell mediators, local IL-4 receptor. This region is of great interest because of blood vessels first dilate and then become leaky to fluid and macromol- the connection between several of the genes located here Urticaria ecules, which produces redness and local swelling (a wheal). Subse- and the mechanisms of IgE regulation and mast cell and quent dilation of vessels on the edge of the swelling produces the eosinophil growth and differentiation. Furthermore, the appearance of a red rim (the flare). B, Photograph of a typical wheal and homologous chromosomal region in mice has been linked Causes flare reaction in the skin in response to injection of an allergen. (Courtesy + of Dr. James D. Faix, Department of Pathology, Stanford University School of to a propensity for CD4 T cells in some inbred strains of Medicine, Palo Alto, California.) mice to differentiate into TH2 cells in response to model protein antigens. Among the genes in this cluster, poly- Approximately 1% of the morphisms in the IL-13 gene appear to have the strongest association with asthma. The tendency to produce IgE population is dispensed antibodies against some but not all antigens, such as outpatient epinephrine ragweed pollen, may be linked to particular class II major histocompatibility complex (MHC) alleles. This linkage

WAO Journal 2011; 4:13–37

Mast Cells and the Immune System

Immune System TYPES OF ADAPTIVE IMMUNE RESPONSES 3

Microbe Innate immunity Adaptive immunity

B lymphocytes Epithelial Antibodies barriers

Phagocytes Dendritic Effector T cells cells T lymphocytes

Complement NK cells Hours Days 0 6 12 1 4 7 Time after infection FIGURE 1–1 Innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later and consist of activation of lymphocytes. The kinetics of the innate and adaptive immune responses are approxima- tions and may vary in different infections.

TABLE 1–2 Features of Innate and Adaptive Immunity

16 Chapter 2 – Cells and Tissues of the Immune System Innate Adaptive

Characteristics Speciﬁcity For molecules shared by groups of related microbes and For microbial and nonmicrobial antigens molecules produced by damaged host cells Diversity Limited; germline encoded Very large; receptors are produced by somatic TABLE 2–1 Normal Blood Cell Counts recombination of gene segments Memory Mast Cell NFunctionone Yes Nonreactivity to self Yes Yes Effector of the humoral Mean Number Components immune system Cellular and chemical barriers Skin, mucosal epithelia; antimicrobial molecules Lymphocytes in epithelia; antibodies secreted at epithelial surfaces per Microliter Normal Range Fights off worm and Blood proteins Complement, others Antibodies bacterial infections Cells Phagocytes (macrophages, neutrophils), natural killer cells Lymphocytes White blood cells (leukocytes) 7400 4500-11,000

Neutrophils 4400 1800-7700 diverse antigen receptors, antibodies, and specialized between the innate and adaptive immune systems. The lymphoid tissues, evolved coordinately within a short innate immune response to microbes stimulates adaptive time in jawed vertebrates (e.g., sharks), about 360 million immune responses and inﬂuences the nature of the adap- Eosinophils 200 0-450 years ago. The immune system has also become increas- tive responses. Conversely, adaptive immune responses ingly specialized with evolution. often work by enhancing the protective mechanisms of Innate and adaptive immune responses are compo- innate immunity, making them capable of effectively nents of an integrated system of host defense in which combating pathogenic microbes. Basophils 40 0-200 numerous cells and molecules function cooperatively. A The mechanisms of innate immunity provideB effective initial defense against infections. However, many patho- TYPES OF ADAPTIVE IMMUNE RESPONSES Lymphocytes 2500 1000-4800 genic microbes have evolved to resist innate immunity, and their elimination requires the more powerful mecha- There are two types of adaptive immune responses, called nisms of adaptive immunity. There are many connections humoral immunity and cell-mediated immunity, that are Monocytes 300 0-800

CELLS OF THE IMMUNE SYSTEM Mast Cell Dysfunction

The cells that serve specialized roles in innate and adaptive • Anaphylaxis immune responses are phagocytes, dendritic cells, antigen- • Systemic mastocytosis specific lymphocytes, and various other leukocytes that C • Mast cell activationD syndrome (MCAS) function to eliminate antigens. The cells of the immune • MCAS and postural tachycardia syndrome system were introduced briefly in Chapter 1. Here we FIGURE 2–1 Morphology(POTS) of neutrophils, mast cells, describe the morphology and functional characteristics of basophils, and eosinophils. A, The light micrograph of a Wright- phagocytes, other leukocytes, APCs, and lymphocytes and Giemsa–stained blood neutrophil shows the multilobed nucleus, because how these cells are organized in lymphoid tissues. The of which these cells are also called polymorphonuclear leukocytes, and the faint cytoplasmic granules. B, The light micrograph of a Wright- numbers of some of these cell types in the blood are listed Giemsa–stained section of skin shows a mast cell (arrow) adjacent to a in Table 2-1. Although most of these cells are found in the small blood vessel, identifiable by the red blood cell in the lumen. The blood, their responses to microbes are usually localized to cytoplasmic granules in the mast cell, which are stained purple, are filled tissues and are generally not reflected in changes in the with histamine and other mediators that act on adjacent blood vessels total numbers of circulating leukocytes. to promote increased blood flow and delivery of plasma proteins and leukocytes into the tissue. (Courtesy of Dr. George Murphy, Department of Pathology,All rights reserved. Brigham and Women’s Hospital, Boston, Massachusetts.) C, The 6 Phagocytes light micrograph of a Wright-Giemsa–stained blood basophil shows the characteristic blue-staining cytoplasmic granules. (Courtesy of Dr. Jona- Phagocytes, including neutrophils and macrophages, are than Hecht, Department of Pathology, Brigham and Women’s Hospital, cells whose primary function is to identify, ingest, and Boston, Massachusetts.) D, The light micrograph of a Wright-Giemsa– destroy microbes. The functional responses of phagocytes stained blood eosinophil shows the characteristic segmented nucleus in host defense consist of sequential steps: recruitment of and red staining of the cytoplasmic granules. the cells to the sites of infection, recognition of and activation by microbes, ingestion of the microbes by the process of phagocytosis, and destruction of ingested cytoplasm contains granules of two types. The majority, microbes. In addition, through direct contact and by called specific granules, are filled with enzymes such as secreting proteins, phagocytes communicate with other lysozyme, collagenase, and elastase. These granules do cells in ways that promote or regulate immune responses. not stain strongly with either basic or acidic dyes (hema- The effector functions of phagocytes are important in toxylin and eosin, respectively), which distinguishes innate immunity, discussed in Chapter 4, and also in the neutrophil granules from those of two other types of effector phase of some adaptive immune responses, as we circulating granulocytes, called basophils and eosino- will discuss in Chapter 10. As a prelude to more detailed phils. The remainder of the granules of neutrophils, discussions of the role of phagocytes in immune responses called azurophilic granules, are lysosomes containing in later chapters, we will now describe their morphologic enzymes and other microbicidal substances, including features and briefly introduce the functional responses of defensins and cathelicidins, which we will discuss in neutrophils and macrophages. Chapter 4. Neutrophils are produced in the bone marrow and arise from a common lineage with mononuclear Neutrophils phagocytes. Production of neutrophils is stimulated by Neutrophils, also called polymorphonuclear leukocytes, granulocyte colony-stimulating factor (G-CSF). An adult are the most abundant population of circulating white human produces more than 1 × 1011 neutrophils per day, blood cells and mediate the earliest phases of inflamma- each of which circulates in the blood for only about 6 tory reactions. Neutrophils circulate as spherical cells hours. Neutrophils may migrate to sites of infection about 12 to 15 µm in diameter with numerous membra- within a few hours after the entry of microbes. If a cir- nous projections. The nucleus of a neutrophil is seg- culating neutrophil is not recruited into a site of inflam- mented into three to five connected lobules, hence the mation within this period, it undergoes apoptosis and is synonym polymorphonuclear leukocyte (Fig. 2-1A). The usually phagocytosed by resident macrophages in the EDNF 2012 Conference August 2012

426 Chapter 19 – IgE-Dependent Immune Responses and Allergic Disease

Allergen GENERAL FEATURES OF IgE-DEPENDENT First exposure IMMUNE REACTIONS to allergen

All allergic reactions share common features, although Activation of TH2 cells B cell TH2 cell they differ greatly in the types of antigens that elicit and stimulation of these reactions and their clinical and pathologic IgE class switching Anaphylaxismanifestations. in B cells G The hallmarks of allergic diseases are the activation of Whereas TH2 cells and the production of IgE antibody. IgE-secreting Mechanism healthy individuals either do not respond or have B cell harmless T cell and antibody responses to common Production of IgE IgE environmental antigens, atopic individuals develop strong TH2 responses and produce IgE on exposure to these potentially allergenic substances. G The typical sequence of events in immediate hyper- Mast cell sensitivity consists of exposure to an antigen, activation of TH2 cells and B cells specific for the antigen, Binding of IgE to production of IgE antibody, binding of the antibody FcεRI on mast cells to Fc receptors of mast cells, and triggering of the mast cells by re-exposure to the antigen, resulting in the FcεRI release of mediators from the mast cells and the subsequent pathologic reaction (Fig. 19-1). Binding of IgE to mast cells is also called sensitization because IgE-coated mast cells are ready to be activated on Repeated exposure antigen encounter (i.e., they are sensitive to the to allergen antigen). We describe each of these steps in the fol- lowing sections. G There is a strong genetic predisposition for the development of atopy. Many susceptibility genes are associated with these disorders. These genes are thought to influence different steps in the development and reac- Activation of mast cell: tions of immediate hypersensitivity. We will discuss release of mediators some of the major known susceptibility genes and their likely roles later in the chapter. G The antigens that elicit immediate hypersensitivity, Mediators also called allergens, are usually common environmental proteins and chemicals that can modify pro- Vasoactive amines, teins. Allergens include a wide variety of structurally lipid mediators Cytokines distinct molecules. G The cytokines produced by TH2 cells are responsible for many of the features of immediate hypersensitivity. Immediate hypersensitivity is the prototypic Immediate TH2-mediated disorder, in contrast to delayed-type hypersensitivity Late phase hypersensitivity, which is the classical TH1-mediated reaction (minutes reaction (2-4 immune reaction. after repeat hours after G The clinical and pathologic manifestations of immedi- exposure repeat exposure ate hypersensitivity consist of the vascular and smooth to allergen) to allergen) muscle reaction that develops rapidly after repeated Molecular and Cellular Immunology,exposure to the allergen 7th (theed. immediate reaction) and FIGURE 19–1 Sequence of events in immediate hyper- a delayed inflammatory reaction. All these reactions sensitivity reactions. Immediate hypersensitivity diseases are initi- may be triggered by IgE-mediated mast cell activation, ated by the introduction of an allergen, which stimulates TH2 reactions but different mediators are responsible for different and IgE production. IgE sensitizes mast cells by binding to FcεRI, and components of the immediate and late-phase reac- subsequent exposure to the allergen activates the mast cells to secrete tions. Because mast cells are present in connective the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. tissues and under epithelia, these tissues are the most common sites of immediate hypersensitivity reactions. Some immediate hypersensitivity reactions may be triggered by nonimmunologic stimuli, such as exercise and exposure to cold. Such stimuli induce mast cell degranulation and the release of mediators without

ROLE OF MAST CELLS, BASOPHILS, AND EOSINOPHILS IN IMMEDIATE HYPERSENSITIVITY 435

Anaphylaxis *Vasodilation Histamine, leukotrienes,

prostaglandins *Vascular leak • Pathophysiologic Biogenic amines activity (e.g., histamines) * Broncho- • Smooth muscle spasm, Lipid mediators constriction (e.g., PAF, mucus secretion, PGD2, LTC4) vasodilatation, increased vascular permeability * Intestinal hypermotility

• Clinical correlates Activated mast cell Cytokines • Wheeze, urticaria, (or basophil) (e.g., TNF) Inflammation angioedema, flush, itch, Lipid mediators * diarrhea and abdominal (e.g., PAF, PGD2, LTC4) pain, hypotension, and Enzymes Tissue rhinorrhea (e.g., tryptase) damage

Cationic granule proteins Killing of (e.g., major basic protein, parasites and eosinophil cationic protein) host cells th Molecular and Cellular Immunology, 7 ed. Enzymes Tissue Eosinophil (e.g., eosinophil damage peroxidase)

FIGURE 19–6 Biologic effects of mediators of immediate hypersensitivity. Mast cells and basophil mediators include biogenic amines and enzymes stored preformed in granules as well as cytokines and lipid mediators, which are largely newly synthesized on cell activation. The biogenic amines and lipid mediators induce vascular leakage, bronchoconstriction, and intestinal hypermotility, all components of the immediate response. Cytokines and lipid mediators contribute to inﬂammation, which is part of the late-phase reaction. Enzymes probably contribute to tissue damage. Activated eosinophils release preformed cationic proteins as well as enzymes that are toxic to parasites and host cells. Some eosinophil granule enzymes probably contribute to tissue damage in chronic allergic diseases.

and a bronchoconstrictor. PGD2 also promotes neutrophil shunt arachidonic acid toward production of leukotri- chemotaxis and accumulation at inﬂammatory sites. enes, discussed next. PGD2 synthesis can be prevented by inhibitors of cyclo- The major arachidonic acid–derived mediators pro- oxygenase, such as aspirin and other nonsteroidal anti- duced by the lipoxygenase pathway are the leukotri- inﬂammatory agents. These drugs may paradoxically enes, especially LTC4 and its degradation products LTD4 exacerbate asthmatic bronchoconstriction because they and LTE4. LTC4 is made by mucosal mast cells and

ROLE OF MAST CELLS, BASOPHILS, AND EOSINOPHILS IN IMMEDIATE HYPERSENSITIVITY 435

Anaphylaxis Vasodilation Neutral proteases: tryptase Vascular leak • Pathophysiologic Biogenic amines (e.g., histamines) activity Broncho- Lipid mediators constriction • Further activation of mast (e.g., PAF, PGD2, LTC4) cells

• Clinical correlates Intestinal hypermotility • Can magnify response due Activated to further mast cell mast cell Cytokines (or basophil) (e.g., TNF) activation Inflammation Lipid mediators • Tissue damage (e.g., PAF, PGD2, LTC4)

Enzymes *Tissue (e.g., tryptase) damage

Systemic Mastocytosis

• Excess growth of mast cells and accumulation in 1 or more organs • 93% of cases due to a mutation of c-kit gene (KIT D816V) • Symptoms are due to mast cell mediator release • Rare: 1 in 20,000-40,000 – More common in Caucasians

Systemic CNS: 10-90% Const: 12-56% Mastocytosis Symptoms

• GI – abdominal pain, Resp: 4-57% diarrhea, nausea/vomiting CV: 5-30% • Skin – itching/flushing, fixed skin lesions • Cardiovascular (CV) – fast GI: 5-80% heart rate, loss of consciousness, anaphylaxis • Nervous system (CNS) – headache, confusion Skin: 8-95% • Musculoskeletal (MS) – bone pain • Constitutional – weakness, MS: 9-75% fatigue, malaise • Respiratory – shortness of breath, nasal symptoms

Annals of allergy, asthma & immunology. 2010 Jan;104(1):1-10.

Systemic Mastocytosis

• Presence of at least 1 major and 1 minor or 3 minor criteria in bone marrow or other organ • Major – Excessive mast cells on bone marrow biopsy*** • Minor – Excessive atypical mast cells – c-KIT D816V mutation – Mast cells with surface markers (CD2, CD25, CD117) – Serum tryptase >20 ng/mL

Systemic Mastocytosis

• Neuroendocrine evaluation – Rule out pheochomocytoma, VIPoma, carcinoid syndrome

• Multispecialty approach likely necessary

Systemic Mastocytosis

• Avoid triggers • Block mast cell – Alcohol related symptoms – Spicy foods – H1 Antihistamines – NSAIDs – H2 Antihistamines – Narcotics – Epinephrine – Intense exercise – Cromolyn – Stinging insects – LTRA – Stress – Steroids • Chemotherapy only if severe

MCAS

• Newly recognized disorder • No excessive growth of mast cells • Symptoms are due to mast cell mediator release • Demographics – Females: 89% of cases in one series – Can happen in any age group – On average, 4.6 years before referral

CNS: 83% MCAS Symptoms

• Abdominal pain (94%) Resp: 39% • Dermatographism (89%) CV: 17% • Flushing (89%) • Headache (83%) • Poor concentration and GI: 94% memory (67%) • Diarrhea (67%) • Nose and eye symptoms Skin: 89% (39%) • Asthma (39%) • Anaphylaxis (17%)

The Journal of allergy and clinical immunology. 2011 Jul;128(1):147-52 e2.

MCAS

• Clinical history • Laboratory evaluation – Serum total tryptase, 24-hour urine for histamine, N-methylhistamine, prostaglandin D2 • Rule out other causes, including systemic mastocytosis (bone marrow biopsy) – Neuroendocrine evaluation

MCAS

MCAS and POTS

• Postural tachycardia syndrome (POTS) – Rare, disabling condition – High heart rate with standing – More common in young females – Unclear cause • Poor nerve signaling (neuropathic) • Excessive adrenal activation (hyperadrenergic) – Some patients with flushing, suggesting mast cells might be involved

CNS: 63% Const: 88% MCAS and POTS Symptoms

• GI – nausea/vomiting, Resp: 38% diarrhea • Skin – flushing CV: 100% • Cardiovascular (CV) – fast heart rate, lightheadedness, GI: 38% loss of consciousness • Nervous system (CNS) – headache, confusion • Constitutional – weakness, Skin: 100% fatigue, dizziness, malaise, anxiety • Respiratory – shortness of breath, nasal symptoms

Hypertension. 2005 Mar;45(3):385-90.

MCAS and POTS

• Tilt table testing • Evaluation and treatment as with MCAS • Trigger avoidance – Exercise – Prolonged standing – After meals – Premenstrual – Heat intolerance – Emotional stress

Case Presentation Mast Cell Neuroendocrine Evaluation Evaluation • Tryptase with episode – 26.7 • Urine/serum metanephrines – NL (elevated) • Urine/serum catecholamines – • Urine histamine with episode – NL elevated • GI scope for carcinoid – NL • Urine 5’-HIAA – NL • Baseline tryptase – NL • VIP – NL • Cortisol – NL • Bone marrow – NL • Neurokinin A – NL • CT scan of chest and abdomen – NL

Case Presentation

• Best diagnosis: MCAS

• The patient was transitioned to more appropriate treatment

Epinephrine Autoinjector

Treatment

• H1-Antihistamines – Decrease itch, flush, urticaria, sneezing, and rhinorrhea – Do not prevent or relieve obstruction to airflow or hypotension/shock – Cetirizine, doxepin, cyproheptadine • H2-Antihistamines – Ranitidine

Ann Emerg Med 2000;36:462-8.

Treatment

• Glucocorticoids • Pharmacologic effects – Switch off transcription of activated genes that encode pro-inflammatory proteins • Clinical relevance – Onset of action takes several hours – Used to prevent and relieve mast cell related symptoms

Ann Allergy Asthma Immunol 2005;95:217-26.

Treatment

• Leukotriene modifying agents (LTMA) – Montelukast, zafirlukast, zileuton

• Cromones (mast cell stabilizer) – Cromolyn – GI symptoms only

• Dosing very important

Case Presentation

• Changed to: – Cetirizine 20mg twice a day (H1) – Ranitidine 300mg twice a day (H2) • Start slow prednisone wean • Reviewed epinephrine autoinjector use and indications

Case Presentation

• He has had only one mild episode including facial flushing, nausea and stomach pain – No Emergency Department visit • Added zafirlukast 20mg twice a day (LTMA) • No episodes since then

Resources

• Bains SN, Hsieh FH. Current approaches to the diagnosis and treatment of systemic mastocytosis. Annals of allergy, asthma & immunology. 2010 Jan;104(1):1-10. • Hamilton MJ, Hornick JL, Akin C, et al. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. The Journal of allergy and clinical immunology. 2011 Jul;128(1):147-52 e2. • Shibao C, Arzubiaga C, Roberts LJ, 2nd, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005 Mar;45(3):385-90. • Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. American journal of hematology. 2012 Apr;87(4):401-11.

Resources

• American Academy of Allergy, Asthma, and Immunology – http://www.aaaai.org • The Mastocytosis Society – http://www.tmsforacure.org • The Elephant Project – Dr. Peter Vadas and Sarah Leach • [email protected]

Conclusions

• Mast cell disorders are relatively rare but severe • Patient history is extremely important • Extensive evaluation and a multispecialty approach may be necessary to rule out all probable causes • Good outcomes with appropriate treatment

Questions