Introduction

Mastocytosis is a rare haematological disorder characterized by the abnormal proliferation of mast cells inside different tissues and organs, leading to allergy-like disease. Severity varies from rash with minor influence on quality of life to extremely aggressive malignant forms with high mortality.¹

Understanding mastocytosis

Types of mastocytosis

Mastocytosis can generally be divided into two types cutaneous and systemic. Cutaneous mastocytosis presents with less severe symptoms limited to the skin where abnormal mast cells are concentrated and are more common in children. In systemic mastocytosis, abnormal mast cells spread all around the body and can infiltrate multiple organs, causing more severe disease with a higher risk of life-threatening complications. By definition, systemic mastocytosis affects at least one organ other than the skin and is more common in adults.²

Malignant forms of systemic mastocytosis present with abnormal mast cell infiltration in the bone marrow and poorer prognosis compared to benign systemic forms. Mast cell leukaemia is a very rare and aggressive subtype of malignant mastocytosis that presents with both abnormal bone marrow infiltration and a high number of circulating malignant mast cells. Affected patients have a life expectancy of just a few months after diagnosis.³

Another malignant subtype is mast cell sarcoma, which is characterised by the destructive growth of abnormal mast cells inside connective tissues such as in skeletal muscles. This disease is accompanied by extreme musculoskeletal pain and also very poor prognosis.⁴

What are mast cells?

Mast cells are a type of white blood cell and is one of the most important factors of the innate immune system. Normal mast cells are involved in allergic reactions by releasing signalling molecules in response to allergens entering the body. Mast cells are derived from progenitor stem cells in the bone marrow that mature under the influence of stem cell factors, one of which is the aforementioned mast-cell growth factor. Inside mast cells, there are specialized granules that contain inflammatory mediators, with the most common one being histamine. Mast cells have receptors on their surface that bind to IgE antibodies and use them as antennae to scan for intruding allergens. When mast cells bind to allergens via attached IgE antibodies, a signal transduction cascade is triggered that unleashes the release of inflammatory mediators in the surrounding environment mediating an allergic reaction. IgE-mediated release of histamine is an important factor for the development of common conditions like allergic rhinitis (hay fever) and atopic dermatitis (eczema).⁵

Apart from the classical allergic reactions which are driven by IgE antibodies, mast cells can also be activated directly by different triggering factors, which is known as IgE-independent activation. Such reactions can happen in normal mast cells but usually do not lead to symptoms of allergy. Most episodes of mastocytosis symptoms are IgE-independent and are associated with specific non-allergenic triggers that directly facilitate the activation of mast cells. IgE-independent triggers of mast cell degranulation include temperature changes, stress, alcohol, certain foods, and medications.⁶

That is not to say people with mastocytosis cannot experience classical allergic reactions as well. In fact, IgE-mediated reactions are more common in people with mastocytosis compared to the general population. Triggers of classical allergic reactions include environmental allergens like pollen and certain foods. Patients with mastocytosis can have concomitant allergic conditions such as asthma, dermatitis, and rhinitis. The pathophysiology of mastocytosis is often complicated by dual-nature reactions, comprising both IgE-mediated allergy triggered by allergens as well as spontaneous IgE-independent activation related to non-allergenic triggers. This is due to the generally higher number of mast cells in affected patients.⁷

What causes mastocytosis?

Mastocytosis is caused by mutations in genes responsible for cell division and proliferation, generally known as proto-oncogenes. The main proto-oncogene involved in the pathogenesis of mastocytosis is KIT which encodes a tyrosine kinase receptor in mast cells with the same name. The latter stimulates the proliferation of mast cells in response to a stem cell factor known as mast cell growth factor. Abnormal activation of the KIT receptor due to so-called ‘gain-of-function’ mutations in the KIT gene leads to overactive cell division and formation of immature mast cell colonies that infiltrate tissues and cause local or systemic allergy-like reactions. The most common mastocytosis-causing mutation in the KIT gene is D816V. This mutation is significantly more common in adult mastocytosis patients than in children. Other genes less frequently associated with the occurrence of mastocytosis are TRK, mTOR, and MAPK.⁸

Symptoms and complications of mastocytosis

Excessive activation and degranulation of mast cells results in a significant inflammatory response that may affect multiple organs. Local release of histamine in the skin causes dilation of blood vessels presenting as reddening of the skin, itching and development of a rash known as urticaria pigmentosa. Patients with isolated skin mastocytosis have a much better prognosis compared to those with systemic disease.⁹

In systemic mastocytosis, an abnormal release of histamine is observed all over the body affecting practically every single organ. In the gastrointestinal tract, histamine activates the secretion of stomach acid. Histamine also causes dilation of blood vessels, reddening of the skin and reduced blood pressure. Thus, a mastocytosis episode typically presents with nausea, vomiting, and abdominal pain,¹⁰ accompanied by red and itchy skin, hypotension, and headaches (due to dilation of blood vessels in the head).¹¹

A chronic complication of systemic mastocytosis is osteoporosis chronic release of inflammatory molecules from mast cells increases the breakdown of bone tissue making bones more brittle and prone to fractures.¹² Aggressive proliferation of mast cells inside the liver, spleen, and lymph nodes may lead to organ enlargement and dysfunction.¹³ When the spleen gets enlarged it can start pooling an abnormal number of platelets, leading to their depletion from the blood, making affected patients more prone to bruising and bleeding incidents.¹⁴ The most severe complication of mastocytosis is anaphylaxis — aggressive overactivation of mast cells. The release of vast amounts of histamine can cause the dilation of multiple blood vessels at the same time, leading to severe systemic edema, hypotension, and syncope.

Symptom management

Lifestyle changes

In order to minimise the occurrence of mastocytosis episodes, patients need to identify what specifically triggers their symptoms and avoid those triggers on a daily basis. As triggers range from foods to sudden surges of strong emotions it is practically impossible to live a normal life without sacrifices and patients need to take multiple medications to alleviate their symptoms.

Medications for mastocytosis

Patients with mastocytosis, especially those with a systemic disease, usually have to take multiple medications simultaneously. Treatment of mastocytosis greatly resembles that of classical allergic reactions, but in severe disease types, the usage of drugs for haematological malignancies like tyrosine kinase inhibitors is not uncommon.

• Antihistamines - both H1 and H2 receptor inverse agonists
• Leukotriene inhibitors
• Mast cell stabilizers
• Corticosteroids
• Vasoconstrictors
• Tyrosine kinase inhibitors
• Monoclonal antibodies - omalizumab

Allergy-like symptoms like rash, skin itching, conjunctivitis, and rhinitis can be treated with different anti-allergic drugs. The most common class of anti-allergic drugs is the H1 receptor inverse agonists (previously known as H1 receptor blockers). These medicines bind to H1 histamine receptors on allergy-prone tissues (nasal mucosa, skin, conjunctiva, etc.) and shut down the signal transduction pathways inside cells that are responsible for these symptoms. Examples include cetirizine, loratadine, and fexofenadine. They can be taken both systemically (oral forms) and locally (eye drops, skin creams, and gels). An important consideration to have with using drugs of this class is that some of them can cross the blood-brain barrier and have sedative effects. Therefore, patients should be careful whenever they take these drugs in the daytime and avoid operating machinery, including driving a car.¹⁵

H2 receptor inverse agonists (e.g., famotidine and ranitidine), on the other hand, shut down the effect of histamine on gastric cells and suppress the overproduction of stomach acid, therefore treating the gastric complications of mastocytosis. These medications also have known anti-allergic properties and can be combined with H1 receptor-acting drugs for patients not responding to antihistamine monotherapy.¹⁶

Mast cells produce many different mediators of inflammation other than histamine. One such family of mediators are the leukotrienes. In contrast to histamine, they are not stored in granules inside mast cells but are produced de novo following IgE-mediated activation. Montelukast and zafirlukast are inhibitors of leukotriene receptors while zileuton is an inhibitor of leukotriene synthesis. Both leukotriene receptor and synthesis inhibitors may be useful as adjuvants for prolonged therapy.¹⁷

Mast cell stabilizers block degranulation and release of inflammatory mediators including both histamine and leukotrienes. The exact mechanism by which this happens is not yet fully understood but it is believed that IgE-regulated calcium channels on mast cells are involved. An example of a mast cell stabilizer is cromolyn sodium which has been shown to improve symptoms of mastocytosis episodes.¹⁸

Corticosteroids are a class of hormonal drugs with primarily anti-inflammatory, anti-allergic, and immunosuppressive effects. Topical corticosteroids are used for cutaneous manifestations of mastocytosis when the effect of antihistamines is not satisfactory.¹⁹ Oral and even injected corticosteroids are used to control episodes of systemic mastocytosis.²⁰ Examples of corticosteroids include naturally occurring hormones like cortisol and synthetic analogues like methylprednisolone and dexamethasone. These drugs bind to intracellular receptors causing modulation of genes involved with pro-inflammatory and anti-inflammatory effects. This genomic effect requires prolonged exposure to the drug in order to take effect. Corticosteroids are also believed to have rapid non-genomic effects on immune cells responsible for the fast onset of some beneficial effects shortly after drug exposure.²¹ Healthcare providers should be cautious about prescribing corticosteroids for longer periods of time due to the risk of developing Cushing’s syndrome.²²

In case of anaphylactic shock, vasoconstrictors like epinephrine are used as intramuscular injections, often in the form of auto-injector devices. Epinephrine constricts blood vessels normalising blood pressure and also dilates the bronchi making it easier for patients to breathe.²³

Tyrosine kinase inhibitors are a relatively newer class of medication that act on key signals of cell division and proliferation, known as tyrosine kinases. Mutated mast cells in mastocytosis produce an excess of tyrosine kinases (KIT) that cause uncontrolled growth. Tyrosine kinase inhibitors can shrink the populations of abnormal cells and the severity of mastocytosis symptoms. Tyrosine kinase inhibitors are used for the treatment of malignant systemic mastocytosis. Examples include midostaurin, imatinib, and avapritinib. Midostaurin and avapritinib act on the KIT receptor interfering with mast cell signals inhibiting cell proliferation and release of histamine. Both have shown efficacy in patients with advanced systemic mastocytosis, including mast-cell leukaemia.^24,25,26

Omalizumab is a monoclonal antibody indicated for use in asthma and urticaria²⁷ but is also used off-label for the prevention of anaphylaxis in patients with systemic mastocytosis.²⁸ It binds to circulating IgE antibodies (essentially being an anti-antibody antibody) preventing them from attaching to mast cells, thus indirectly suppressing degranulation.²⁹ Subcutaneous omalizumab has been shown to reduce the incidence of anaphylaxis and improve cutaneous symptoms in patients with systemic mastocytosis.³⁰

Conclusion

At first glimpse, mastocytosis seems like a simple allergic disease. What lies below, however, is a chronic debilitating condition with a high disease burden and risk of severe complications with a potentially fatal outcome. Patients should be educated about how to live a fulfilling life while minimizing the triggers of episodes. Healthcare providers should also be aware of how to differentiate mastocytosis from other similar haematological conditions and regularly monitor for the occurrence of malignancy.