The term systemic mastocytosis (SM) is used to define a heterogeneous group of rare diseases characterized by the presence of abnormal MCs in various organs and tissues ⁴ . Two critical biological findings which are linked to the pathogenesis of the disease have been described: (i) activating somatic mutations in the KIT gene (usually the KIT Asp816Val D816V mutation) and the presence of an aberrant immunophenotype associated with the expression of CD25 on (bone marrow [BM]) clonal MCs. The current World Health Organization (WHO) classification of the disease includes up to seven distinct categories that meet the diagnostic criteria for mastocytosis ( Table 1). However, the development of new, more sensitive and specific methods, such as multi-parameter flow cytometry and highly sensitive polymerase chain reaction (PCR)-based techniques for the detection of aberrant MCs present at very low frequencies ^{5– 8} and the study of the KIT mutation in purified cells ⁹ or blood ^{10– 12} or both, have led to an unprecedentedly increased rate of detection of phenotypically aberrant and KIT mutated MCs in BM and peripheral blood, pointing out not only the potential need to revise current diagnostic and classification criteria to recognize new entities with very low tumor burden associated with life-threatening symptoms such as anaphylaxis but also a potential impact on the long-term prognosis of patients with indolent forms of the disease.

Based on previous reports in the largest series of patients, indolent systemic mastocytosis (ISM) comprises around 80% of all SM cases ¹³ . Among them, around 20% of patients lack skin lesions at presentation (ISMs ⁻) ¹⁴ . Despite the great relevance and efficiency of the WHO criteria for the diagnosis of SM, in ISMs ⁻, MCs represent only a very small proportion of all nucleated BM cells (usually fewer than 10 ⁻³ BM MCs, as assessed by flow cytometry) ¹⁵ , and BM MC aggregates are frequently (around 30% of cases) not found in such patients with SM ¹⁵ , in the absence of significantly increased serum baseline tryptase levels (<20 μg/L). Consequently, the use of highly sensitive and specific methodological approaches to the study of BM MCs becomes critical in order to avoid a misdiagnosis in patients presenting with low tumor burden ¹⁶ .

The term MC activation syndrome (MCAS) encompasses a heterogeneous group of diseases which are characterized by systemic symptoms secondary to MC mediator release that (i) might or might not have a known trigger, (ii) might or might not be associated with immunoglobulin E (IgE)-specific antibodies in response to that trigger, (iii) are associated with normal or elevated baseline tryptase levels, and (iv) do not show skin lesions of mastocytosis ¹⁷ . In Table 2, the most frequent and relevant clinical symptoms suggesting an underlying MCAS are listed, and Table 3 depicts the diagnostic criteria for MCAS.

The current classification of MCAS is shown in Table 4. Based on the experience of the Spanish Network of Mastocytosis (REMA), the most relevant objective criteria to subclassify MCAS rely on the presence versus absence of clonal MCs as defined by the expression of CD25 (for example, CD25 ⁺ versus CD25 ⁻) or a KIT mutation, particularly KIT D816V, or both. When MCAS diagnostic criteria are fulfilled but there is no evidence of clonality, non-clonal-MCAS should be considered and co-existence of allergy or other underlying diseases should be confirmed or ruled out ¹⁸ .

Careful counseling must be given to patients, caretakers, and their physicians to avoid triggers that evoke MC mediator release ^{32, 33} ( Table 5). In addition, detailed training to manage MC activation-associated episodes should be provided to patients as well as their physicians.

Anti-mediator therapy for primary MCAS aims at inhibiting production, interfering with release, blocking the specific receptors, or antagonizing the effects of MC mediators. It is used both to treat and to prevent acute and chronic MC mediator release-associated symptoms ³² . The specific anti-mediator administration schedule (on demand or continuous administration) should be carefully selected for the individual patient on the basis of the intensity or severity (or both) of the signs and symptoms observed during the most severe acute episodes or anaphylaxis as well as the MC mediator-related symptoms recorded between acute episodes ¹⁹ .

Histamine receptor blockers. The biologic effects of histamine released from MCs, through its binding to histamine receptors (mainly H1 and H2 histamine receptors), include (i) increased vascular permeability, (ii) vasodilatation, (iii) contraction of non-vascular smooth muscle, (iv) increase of exocrine gland secretion, and (v) stimulation of the peripheral nervous system; these effects result in symptoms such as pruritus, urticaria, edema, bronchoconstriction, gastric hypersecretion, abdominal cramping, diarrhea, headache, hypotension, and anaphylaxis ³⁴ . The effects of H1 blockers are described in Table 6.

Some H1 antihistamines such as desloratadine and ketotifen have MC-stabilizing properties, and therefore they might also decrease the release of MC mediators ^{35, 36} . Ketotifen has been reported to be effective in the treatment of bone disease as well as cutaneous, gastrointestinal, and neuropsychiatric symptoms in mastocytosis ^{37– 39} . Patients with associated depression might benefit from doxepin because of its effects as an antidepressant and H1 histamine blocker ⁴⁰ . Rupatadine also has an antagonistic effect against platelet-activating factor, a lipid-derived mediator which is newly synthesized and released by MCs upon their activation, resulting in hypotensive episodes and flushing ⁴¹ .

Some patients with mastocytosis require a combination of different H1 blockers to achieve a good control of symptoms ³² . The use of non-sedating H1 blockers is recommended for patients who require daily maintenance therapy; in turn, the use of sedating H1 antihistamines that have a fast-acting effect which makes them suitable drugs to treat acute MC mediator release episodes, frequently in association with corticosteroids or epinephrine or both, and also to prevent MC degranulation during risk situations might be administered at night or on demand ^{32, 42} .

Cromolyn sodium. Cromolyn sodium is an MC stabilizer that has been proven to inhibit MC activation and MC release of mediators both in vitro and in vivo despite its limited systemic absorption following ingestion; this suggests an inability of the drug to enter cells and the need for a potential interaction with an as-yet-unidentified cell surface receptor to induce its biologic activity ⁴³ ( Table 6). Side effects include headache, sleepiness, irritability, abdominal pain, diarrhea, and constipation, most of which are attenuated by progressive introduction of the drug ⁴⁴ . In addition, 0.21–4% cromolyn sodium water-soluble creams, as well as aqueous-based skin lotion, may be effective at improving cutaneous symptoms (for example, pruritus and flaring of lesions) ^{32, 34, 45, 46} .

Antagonists of arachidonic acid metabolites. MCs synthesize de novo mediators and release arachidonic acid metabolites through the action of lipoxygenase and cyclooxygenase enzymes; thus, they produce leukotrienes and prostaglandins (PGs), respectively. Prostaglandin D2 is generated almost entirely by MCs and rapidly converted into active metabolites of prolonged activity rather than the parent compound, such as α11β-PGF2; the two PGs share a biological activity and induce bronchoconstriction, increase of vascular permeability, and vasodilatation, and at the same time they have chemoattractive properties for eosinophils, basophils, and Th2 lymphocytes ⁴⁷ and are involved in the development of flushing and possibly also hypotensive episodes in patients with c-MCAS and mastocytosis ⁴⁸ ( Table 6).

Aspirin. Non-steroidal anti-inflammatory drugs, especially aspirin, can also inhibit the activation of MCs and their degranulation in some patients with mastocytosis; therefore, this therapy is recommended in patients with known tolerance to these drugs.

Glucocorticoids. The mechanism of action and the effects of glucocorticoids are shown in Table 6. Short cycles of low doses of either prednisone (0.3 mg/kg per day) or oral budesonide (0.1 mg/kg per day) may improve abdominal pain refractory to treatment with cromolyn. Topical corticosteroids may be used for patients who present with skin symptoms, especially among cases with limited skin involvement; however, evidence supporting their topical use is either anecdotal or based on small series of patients ⁴⁹ .

Anti-immunoglobulin E therapy. Successful anti-IgE therapy has been documented in some conditions such as severe persistent allergic asthma, chronic urticaria ⁵⁰ , idiopathic anaphylaxis ⁵¹ , and mastocytosis ( Table 6). Until more information based on clinical trials becomes available, omalizumab in MC diseases should be restricted to selected patients with severe symptoms which have proven unresponsive to intensive anti-mediator therapy ³³ .

Hymenoptera venom immunotherapy. Specific VIT is recommended for mastocytosis and c-MCAS patients with IgE-mediated anaphylaxis to hymenoptera venom; however, it should be managed as a high-risk procedure. VIT has proven effective and safe in these patients ^{52– 56} ; it has a rate of protection from re-stings of 86%, and the frequency of systemic reactions to VIT ranges from 5–25% ^{14, 57} , most of which (75%) were associated with rush inductions (versus 25% using conventional induction) ⁵⁷ . Whenever adverse reactions to VIT prevent the protective maintenance dose of 100 μg per month from being reached, prophylactic anti-mediator therapy, changes in the extract, and administration of omalizumab therapy may be useful ^{57, 58} . Furthermore, in patients who present anaphylaxis after re-sting, despite the administration of a standard maintenance dose, it is recommended that maintenance doses be increased to 200 μg ⁵⁷ . An extended maintenance administration (even lifelong) is proposed ^{14, 57} since cases presenting with fatal reactions after discontinuation of VIT have been described ^{59, 60} .

Ultraviolet irradiation. In vitro studies demonstrated that long-wave ultraviolet radiation (psoralen plus ultraviolet A or ultraviolet A alone) and narrowband ultraviolet B phototherapy irradiation interfere with the release of histamine from skin-activated MCs and induce MC apoptosis ^{61– 63} ; all of them were employed as a second-line therapy to treat cutaneous symptoms (pruritus, whealing, and flare reactions) in patients with typical mastocytosis skin lesions who were not responsive to first-line therapies with anti-mediator drugs ^{40, 64– 66} . There is no information regarding whether these therapies are useful in ISMs ⁻ and c-MCAS cases. In addition, fading of hyperpigmented skin lesions (frequently temporary) can be observed in some cases. Furthermore, responses of life-threatening MC mediator release episodes in children with bullous diffuse cutaneous mastocytosis have been reported ⁶⁷ .

Treatment of bone mass loss. This is a frequent finding in both ISMs ⁺ and advanced mastocytosis but is less frequently observed among primary MCAS cases, particularly ISMs ⁻ and c-MCAS. Fractures are usually developed as a consequence of severe osteoporosis or large osteolytic lesions. Local MC infiltration and disturbances in bone remodeling which are due to the release of MC mediators such as interleukin-6 (IL-6), histamine, heparin, receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, or sclerostin are involved in the pathogenesis of bone manifestations in mastocytosis ^{68, 69} . Calcium and vitamin D supplements, combined with bisphosphonates, are usually the first choice for osteopenia and osteoporosis, respectively ^{70– 72} . Other therapies such as estrogen replacement in postmenopausal women and denosumab or interferon-alpha ^{73, 74} in patients with severe osteoporosis at risk of pathologic bone fractures unresponsive to conventional treatments might also be considered. Regarding peptidergic/peptidomimetic drugs such as teriparatide, caution is urged since these drugs have been associated with driving MC activation via MRGPRX2 ⁷⁵ .

Selective serotonin reuptake inhibitors. MCs contain numerous mediators, including neurotransmitters (for example, serotonin), cytokines, and chemokines, that play a role in stress response, behavior, and emotion regulation ^{76, 77} . Furthermore, the elevation of the circulating levels of tumor necrosis factor-alpha and IL-6 with, for example, endotoxin leads to depressive symptoms, and it has been previously described that some selective serotonin reuptake inhibitors (SSRIs) such as citalopram can reduce endotoxin-induced symptoms ⁷⁸ . Based on this information, together with their good tolerability profile, SSRIs have emerged as an option to improve symptoms of depression in patients with mastocytosis ⁷⁹ .

With regard to pregnancy, two different series of women with mastocytosis have been reported in the literature ^{80, 81} . The larger series ⁸¹ included 45 pregnancies and deliveries in women with non-aggressive categories of the disease. Based on their results, anti-mediator therapy (dexchlorpheniramine, loratadine, cetirizine, ranitidine, oral corticosteroids, and adrenaline), if required during pregnancy, as well as systematic administration of prophylactic anti-mediator therapy at the beginning of labor based on drugs with a good well-known safety profile, is recommended ⁸¹ .