Pharmacological treatment options for mast cell activation disease

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Abstract

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Keywords: Mast cell, Mast cell activation disease, Systemic mastocytosis, Systemic mast cell activation syndrome, Therapy

Introduction

Mast cells (MCs, Fig. ​ Fig.1) 1 ) are immune cells of hematopoietic origin found in all human tissues, especially at the environmental interfaces. They act as both effector and regulatory cells and play a central role in adaptive and innate immunity (Anand et al. 2012; Gri et al. 2012). Their important role in immunological as well as non-immunological processes is reflected by the large number of mediators (>200) including pre-stored ones such as histamine and tryptase as well as numerous mediators synthesized de novo in response to allergic or non-immune triggers such as chemokines and cytokines, by which MCs may influence other cells (Lundequist and Pejler 2011; Ibelgaufts 2016). Their evolved arrays of sensory and response mechanisms engender diverse havoc when MC dysfunction emerges.

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May-Grünwald/Giemsa stain of a resting human mast cell and a mast cell following activation-induced degranulation. Note the loss of granule staining. Mast cells obtained from the human bone marrow, magnification 1000×

The umbrella term mast cell activation disease (MCAD; Akin et al. 2010) comprises the full spectrum of primary systemic MC disease, i.e., systemic mastocytosis (SM) which is further divided into several subtypes (Valent et al. 2007; Tables ​ Tables1 1 and ​ and2), 2 ), primary MC activation syndrome (MCAS; Table ​ Table3; 3 ; Molderings et al. 2011a; Hamilton et al. 2011; Valent et al. 2012), and MC leukemia (MCL). Pathogenetically, MCAD denotes a group of polygenic MC disorders (Molderings 2015, 2016) characterized by aberrant release of variable subsets of MC mediators and also an accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (SM and MCL) or morphologically ordinary MCs due to decreased apoptosis (MCAS; Kohno et al. 2005; Aichberger et al. 2009; Karlberg et al. 2010a). According to recent molecular genetic findings (Molderings 2015, 2016; Haenisch et al. 2014; Lasho et al. 2016), the subclasses and clinical subtypes of MCAD do not represent distinct disease entities but should be more accurately regarded as variable presentations of a common generic state of MC dysfunction (Molderings et al. 2007, 2010; Hermine et al. 2008; Akin et al. 2010). Due to both the widespread distribution of MCs and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues; hence, the clinical presentation of MCAD is very diverse, sometimes to the even-further-confounding point of presenting opposite abnormalities in different patients (or even in the same patient at different times, or in different sites in the same patient at the same time). While the prevalence of SM in Europeans ranges between 0.3 and 13 per 100,000 (Haenisch et al. 2012; Cohen et al. 2014; van Doormaal et al. 2013), the prevalence of MCAS may be as high as 17 % (in Germany; Molderings et al. 2013a, b).

Table 1

WHO 2008 diagnostic criteria for systemic mastocytosis (Valent et al. 2001)

Major criterion:
1. Multifocal, dense aggregates of MCs (15 or more) in sections of the bone marrow or other extracutaneous tissues and confirmed by tryptase immunohistochemistry or other special stains
Minor criteria:
1. Atypical or spindled appearance of at least 25 % of the MCs in the diagnostic biopsy
2. Expression of CD2 and/or CD25 by MCs in the marrow, blood, or extracutaneous organs
3. KIT codon 816 mutation in the marrow, blood, or extracutaneous organs
4. Persistent elevation of serum total tryptase >20 ng/ml

Diagnosis of SM made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria

Table 2

Classification of systemic mastocytosis (modified form Valent et al. 2007)

Categories of systemic mastocytosis (SM)Subtypes
Indolent systemic mastocytosis• Smoldering systemic mastocytosis
• Isolated bone marrow mastocytosis
• Well-differentiated systemic mastocytosis
Aggressive systemic mastocytosis (ASM)• ASM in transformation
Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease• SM-acute myeloid leukemia
• SM-myelodysplastic syndrome
• SM-myeloproliferative neoplasm
• SM-chronic myelomonocytic leukemia
• SM-chronic eosinophilic leukemia
• SM-non-Hodgkin lymphoma
• SM-multiple myeloma

Table 3

Current provisional criteria to define mast cell activation syndrome (MCAS; modified from Afrin and Molderings 2014)

Major criterion
Constellation of clinical complaints attributable to pathologically increased mast cell activity (mast cell mediator release syndrome)
Minor criteria
1.Focal or disseminated increased number of mast cells in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal tract biopsies; CD117-, tryptase-, and CD25-stained)
2.Abnormal spindle-shaped morphology in >25 % of mast cells in marrow or other extracutaneous organ(s)
3.Abnormal mast cell expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)
4.Detection of genetic changes in mast cells from the blood, bone marrow, or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proven
5.Evidence (typically from body fluids such as whole blood, serum, plasma, or urine) of above-normal levels of mast cell mediators including:
Tryptase in the blood
Histamine or its metabolites (e.g., N-methylhistamine) in the urine
Heparin in the blood
Chromogranin A in the blood (potential confounders of cardiac or renal failure, neuroendocrine tumors, or recent proton pump inhibitor use were excluded)
Other relatively mast cell-specific mediators (e.g., eicosanoids including prostaglandin PGD2, its metabolite 11-β-PGF, or leukotriene E4)
6.Symptomatic response to inhibitors of mast cell activation or mast cell mediator production or action (e.g., histamine H1 and/or H2 receptor antagonists, cromolyn)

Diagnosis of MCAS made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria

This review focuses on the current state of drug therapy in SM and MCAS and describes perspectives of promising new approaches for drug treatment. Compounds in various stages of preclinical and clinical development are summarized in tables. We first describe drugs that are currently available and either are used on a regular basis in MCAD therapy or have been used successfully in single MCAD cases. In this context, it should be noted that there is no official guideline for treatment of MCAD.

Treatment options

Due to its genetic roots, MCAD generally is regarded as incurable. Recent mutational studies revealed that each patient has an individual pattern of genetic and epigenetic alterations which may affect the intracellular signal transduction pathways and receptive sites involved in sensory perception. As a consequence, mediator formation and release as well as inhibition of apoptosis and/or increase in proliferation are determined by individual genetic and epigenetic conditions (Fig. ​ (Fig.2) 2 ) and represent potential targets for therapy. Hence, there is need of highly personalized therapy for the disease. Unfortunately (with regard to easy detection), most genetic alterations (with a few exceptions such as certain mutations in tyrosine kinase KIT, e.g., KIT D816V ) do not alter the morphology and immunohistochemistry of the surface of the affected MCs. Thus, in most cases except for patients with the reliably identifiable D816V mutation, it cannot be decided by simple tests whether MCs found in biopsies are genetically altered MCs or physiological MCs.

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Scheme of conditions responsible in MCAD for the development of individual phenotypes

First-line treatment options

Step 1 in managing most situations of inappropriate MC activation is identifying the individual patient’s unique triggers (chemical, physical, or otherwise) as precisely as possible and then desensitizing when possible (in truth, rarely) and otherwise practicing avoidance. With respect to drug treatment, only a few clinical therapeutic trials have been conducted in SM (midostaurin, cladribine, masitinib; Table ​ Table4), 4 ), and there have been no therapeutic trials in MCAS yet. Most information about therapeutic effectiveness in MCAD has been found in small case series (Table ​ (Table4) 4 ) and single case reports, perhaps unsurprising given the mutational heterogeneity of the disease and thus the heterogeneity of its patterns of clinical presentation and therapeutic responsiveness. Therefore, in the future, it may be helpful to establish an international patient registry in partnership with existing registries so that issues related to molecular and clinical MCAD phenotypes can be adequately addressed. As the primary feature of MCAD is inappropriate MC activation (Molderings et al. 2011a, b; Pardanani 2013; Cardet et al. 2013), mainstays of first-line management are identification and avoidance of triggers plus therapies to control MC mediator production (both primary as well as secondary/reactive; Table ​ Table5) 5 ) as well as their action (Table ​ (Table6 6 ).

Table 4

Case series and clinical therapeutic trials in systemic mastocytosis and mast cell activation syndrome

CompoundNumber of patients included in the study or case seriesReferences
H1-antihistamines
Rupatadine30Siebenhaar et al. 2013
Azelastine vs. chlorpheniramine15Friedman et al. 1993
Ketotifen vs. hydroxyzine8Kettelhut et al. 1989
Chlorpheniramine plus cimetidine8Frieri et al. 1985
Continuous diphenhydramine infusion10Afrin 2015 a
Mast cell stabilizer
Cromoglicic acid (cromolyn)5Soter et al. 1979
11Horan et al. 1990
4Mallet et al. 1989
8Frieri et al. 1985
2Welch et al. 1983
2Zachariae et al. 1981
Tranilast2Katoh et al. 1996
Kinase inhibitors
Imatinib (STI571)14Droogendijk et al. 2006
20Vega-Ruiz et al. 2009
22Lim et al. 2009
17Pagano et al. 2008
12Pardanani et al. 2003
5Heinrich et al. 2008
3Hennessy et al. 2004
Nilotinib (AMN107)61Hochhaus et al. 2015
Dasatinib (BMS-354825)33Verstovsek et al. 2008
4Purtill et al. 2008
Midostaurin (PKC412)9Papayannidis et al. 2014
11Knapper et al. 2011
22Chandesris et al. 2014
89Gotlib et al. 2014
14Strati et al. 2015
Masitinib25Paul et al. 2010
Cytostatic agents
Hydroxyurea26Lim et al. 2009
5Afrin 2013 a
Cladribine (2-chlorodeoxyadenosine)22Lim et al. 2009
10Kluin-Nelemans et al. 2003
4Pardanani et al. 2004
3Pagano et al. 2008
68Barete et al. 2015
Immunomodulation
Interferon-α20Casassus et al. 2002
5Hauswirth et al. 2004
10Laroche et al. 2011
40Lim et al. 2009
8Pagano et al. 2008
6Giraldo Castellano et al. 1998
9Hennessy et al. 2004
3Worobec et al. 1996
Thalidomide16Gruson et al. 2013
IgE antibody
Omalizumab4Molderings et al. 2011b a
2Carter et al. 2007
2Lieberoth and Thomsen 2015
ß-Sympathomimetics
Isoprenaline, terbutaline5van Doormaal et al. 1986
Cyclooxygenase inhibitor
Acetylsalicylic acid4Butterfield and Weiler 2008
20Butterfield 2009

a It indicates clinical trials performed with patients with mast cell activation syndrome

Table 5

First-line drugs which can potentially be used in the treatment of mast cell (MC) activation disease and their target location and mechanisms of action

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsReferences
First-line drugs
H1-antihistamines (preferably of the second and third generations)Block mutual activation of mast cells via H1-histamine receptors; antagonize H1-histamine receptor-mediated symptoms XXChurch and Gradidge 1980
Valent et al. 2007R
Picard et al. 2013R
Nurmatov et al. 2015
Siebenhaar et al. 2013
Escribano et al. 2006R
H2-antihistaminesBlock mutual activation of mast cells via H2-histamine receptors; antagonize H2-histamine receptor-mediated symptoms XXValent et al. 2007R
Escribano et al. 2006R
Cromoglicic acid (also known as cromolyn)GPR35; modulation of chloride current XXSoter et al. 1979
Valent et al. 2007R
Yang et al. 2010
Edwards et al. 2011
Edwards and Hagberg 2010
Zhang et al. 2016
Escribano et al. 2006R
Vitamin CIncreased degradation of histamine; decrease of histamine formation by inhibition of histidine decarboxylase XXHagel et al. 2013
Johnston et al. 1992
Uchida et al. 1989
Chatterjee et al. 1975

As a rule, these drugs should be used in combination to achieve a sufficient reduction of MC activity. All drugs should be tested for tolerance in a low single dose before therapeutic use, if their tolerance in the patient is not known from an earlier application. A precondition for therapeutic success is the avoidance of identifiable triggers of MC activation; in this context, parallel to the beginning of drug therapy, gluten, cow milk protein, and baker’s yeast should be omitted from the diet for 3–4 weeks

R review article (further references therein)

Table 6

Symptomatic treatment (orally as needed) in MCAD (modified from Molderings et al. 2014)

Colitis ⇒ budesonide; for some days, prednisone >20 mg/day
Diarrhea ⇒ c(h)olestyramine; nystatin; montelukast; 5-HT3 receptor inhibitors (e.g. ondansetron); incremental doses of acetylsalicylic acid (50–350 mg/day; extreme caution because of the possibility to induce mast cell degranulation); in steps test each drug for 5 days until improvement of diarrhea
Colicky abdominal pain due to distinct meteorism ⇒ metamizole; butylscopolamine
Angioedema ⇒ tranexamic acid; icatibant
Nausea ⇒ dimenhydrinate; lorazepam; 5-HT3 receptor inhibitors; NK1 antagonists such as aprepitant
Respiratory symptoms (mainly due to increased production of viscous mucus and obstruction with compulsive throat clearing) ⇒ leukotriene receptor blockers such as montelukast; if in a country available, leukotriene synthesis inhibitors such as zileuton; urgent: short-acting ß-sympathomimetic
Gastric complaints ⇒ proton-pump inhibitors (de-escalating dose-finding)
Osteoporosis, osteolysis, bone pain ⇒ bisphosphonates (vitamin D plus calcium application is second-line treatment in MCAD patients because of limited reported success and an increased risk for developing kidney and ureter stones); calcitonin; teriparatide (with caution; cases of cholestatic liver failure due to this drug have been reported); anti-RANKL drugs such as denosumab (dental clearance is required prior to treatment with bisphosphonates and anti-RANKL therapies due to risk for potentially severely morbid osteonecrosis of the jaw in patients with poor dentition or recent invasive dental work)
Non-cardiac chest pain ⇒ when needed, additional dose of a H2-histamine receptor antagonist; also, proton-pump inhibitors for proven gastroesophageal reflux
Tachycardia ⇒ AT1-receptor antagonists; ivabradine
Neuropathic pain and paresthesia ⇒ α-lipoic acid
Itches ⇒ palmitoylethanolamine-containing care products; cromolyn-containing ointment
Rheumatoid symptoms ⇒ COX2 inhibitors such as etoricoxib or celecoxib; paracetamol
Anemia ⇒ in iron-deficiency anemia, iron supplementation (whether oral or parenteral) must be given cautiously due to risk for potentially intense mast cell activation; alternatively, red blood cell transfusion should be considered
Interstitial cystitis ⇒ pentosan, amphetamines
Sleep-onset insomnia/sleep-maintenance insomnia ⇒ triazolam
Conjunctivitis ⇒ exclusion of a secondary disease; otherwise preservative-free eye drops with H1-antihistamine, cromolyn, ketotifen, or glucocorticoid for brief courses
Hypercholesterolemia ⇒ (probably due to inhibition of transport into the cells, thus independent of diet) >300 mg/dL therapeutic trial with HMG-CoA reductase inhibitor atorvastatin

Subordinate therapeutic options

Continuous diphenhydramine infusion

Occasional patients suffer nearly continuous anaphylactoid and/or dysautonomic states poorly controlled by intermittently dosed epinephrine, antihistamines, and steroids. As discussed in more detail below, some such patients are particularly triggered by a wide range of medication excipients, making it challenging for them to tolerate trials of any adulterated (non-pure) medications, and yet some modicum of stability is required to pursue medication trials in such patients. Diphenhydramine is a well-tolerated histamine H1 receptor blocker (that among other non-threatening adverse affects can cause dizziness and an increase in appetite) which can quickly suppress MC activation and is used to treat allergic reactions and anaphylaxis. However, its half-life is as short as 1 h (www.drugbank.ca/drugs/DB01075). Intermittently dosed, though, its initial therapeutic serum level rapidly declines to subtherapeutic levels and the patient seesaws into yet another flare. The safety of continuous diphenhydramine infusion was established in trials of the “BAD” regimen (diphenhydramine [Benadryl], lorazepam [Ativan], and dexamethasone) in refractory chemotherapy-induced emesis in adult and pediatric patients (Dix et al. 1999; Jones et al. 2007). In a small series of ten MCAS patients suffering almost continuous anaphylactoid/dysautonomic flares, continuous diphenhydramine infusion at 10–14.5 mg/h appeared effective in most patients at dramatically reducing flare rates and appeared safely sustainable at stable dosing for at least 21 months (Afrin 2015). Stabilization has enabled successful trials of other helpful medications, but no patient has yet successfully stopped continuous diphenhydramine infusion.

Acute and chronic immunosuppressive therapies

Though typically not first-line, acute and chronic immunosuppressive therapies can be considered (Fig. ​ (Fig.3; 3 ; Table ​ Table7) 7 ) and may be particularly appropriate for patients possibly manifesting an autoimmune component of the disease as might be suggested by the presence, for example, of anti-IgE or anti-IgE-receptor antibodies. Glucocorticoids may exert beneficial effects in MCAD, including a decrease in production of stem cell factor (SCF, and possibly other cytokines) and a decrease in MC activation, by various mechanisms which have been extensively reviewed by Oppong et al. 2013. Glucocorticoids at doses >20 mg prednisone equivalent per day are frequently needed to effectively control otherwise refractory acute (and chronic) symptoms. Their chronic toxicity profile is disadvantageous for long-term use, but such toxicities have to be accepted in some cases. The influence of azathioprine, methotrexate, ciclosporine, hydroxyurea, and tamoxifen on MC activity can vary from no to moderate effect depending on individual disease factors. As in therapy of rheumatoid arthritis, azathioprine and methotrexate can be used in daily doses lower than those used in cancer or immunosuppressive post-transplant therapy. Effective MCAD therapy with ciclosporine requires doses as high as those used in transplantation medicine (M. Raithel, personal communication). Methotrexate has to be administered parenterally to be effective (unpublished observation, G.J. Molderings), and in the risk-benefit analysis, a possible non-immunologic histamine release from MCs (Estévez et al. 1996) has to be considered. Hence, use of the compound should be limited to MCAD with methotrexate-sensitive comorbidities (e.g., rheumatoid arthritis and vasculitis).

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Suggested treatment options for mast cell activation disease. All drugs should be tested for tolerance in a low single dose before therapeutic use, if their tolerance in the patient is not known from an earlier application. For further details of indication, see text

Table 7

Second- and third-line drugs which can potentially be used in the treatment of mast cell activation disease and their target location and mechanisms of action

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsReferences
Second-line drugsImmunosuppressive drugs
AzathioprineMultiple targets XXNolte and Stahl Skov 1988, Own unpublished data
CiclosporineCalcineurin inhibitor XXKurosawa et al. 1999, Broyd et al. 2005, Trojan and Khan 2012, Own unpublished data
GlucocorticoidsMultiple targets(X)XXZen et al. 2011R
HydroxyureaMultiple targetsX XLim et al. 2009, Afrin 2013
TamoxifenPrecise mechanism of action in MCAD unknownXXIn single casesButterfield and Chen 2016, Duffy et al. 2003;
MethotrexateMultiple targets ?XSagi et al. 2011, Vrugt et al. 2000
Third-line drugs
OmalizumabAnti-IgE antibody XMolderings et al. 2011b
Bell and Jackson 2012; Kibsgaard et al. 2014
Kontou-Fili et al. 2010
Etoricoxib
Acetylsalicylic acid
COX-inhibitors XButterfield and Weiler 2008
Breslow et al. 2009
Butterfield 2009
MontelukastAntagonist at cys-LT1 receptors XTolar et al. 2004
Cikler et al. 2009
Breslow et al. 2009
Turner et al. 2012
Zileuton5-Lipoxygenase inhibitor XRodriguez et al. 2011

R review article (further references therein)

Recently, the humanized anti-IgE murine monoclonal antibody omalizumab has been described in multiple case reports as safe and effective in MCAD (e.g., Molderings et al. 2011b; Kontou-Fili et al. 2010; Bell and Jackson 2012; Kibsgaard et al. 2014), though a definitive trial has yet to be conducted. Since treatment with omalizumab has an acceptable risk-benefit profile, it should be considered in cases of MCAD resistant to at least a few lines of therapy. The drug’s expense likely consigns it to third-line (or later) treatment (Table ​ (Table7). 7 ). If elevated prostaglandin levels induce symptoms such as persistent flushing, inhibition of cyclooxygenases by incremental doses of acetylsalicylic acid (ASA; 50–350 mg/day) may be used with extreme caution, since ASA can induce MC degranulation probably due its chemical property as an organic acid. The leukotriene antagonist montelukast (possibly more effective at twice-daily dosing; personal observation, L.B. Afrin) and the 5-lipoxygenase inhibitor zileuton may be useful adjuvants in people with MCAD, particularly in those with refractory gastrointestinal and urinary symptoms (Tolar et al. 2004; Turner et al. 2012; Akhavein et al. 2012).

Studies of kinase inhibitors, both on-market (e.g., imatinib, nilotinib, dasatinib) and experimental (e.g., midostaurin, masitinib), have yielded variable responses in SM ranging from no response to partial or even complete responses (Fig. ​ (Fig.3; 3 ; Table ​ Table8). 8 ). As with all drugs used in therapy of MCAD, their therapeutic success seems to be strongly dependent on the individual patient, again underscoring the observed mutational heterogeneity of the disease. In formal studies in SM patients, although some kinase inhibitors reduced MC burden as reflected by histological normalization in bone marrow and improved laboratory surrogate markers (e.g., tryptase level in blood), at best only partial improvement of mediator-related symptoms was achieved (Droogendijk et al. 2006; Gotlib et al. 2008; Verstovsek et al. 2008; Vega-Ruiz et al. 2009). There has been repeated suggestion that symptoms in MCAD may be due more to mediator release from normal MCs secondarily activated by pathologically overactive, mutated MCs (Galli and Costa 1995; Rosen and Goetzl 2005; Boyce 2007; Kaneko et al. 2009; Fig. ​ Fig.2 2 in Molderings et al. 2014), helping to explain why intensity and pattern of symptoms do not correlate with degree of MC proliferation and infiltration (Topar et al. 1998; Hermine et al. 2008; Broesby-Olsen et al. 2013; Erben et al. 2014; Quintás-Cardama et al. 2013). Distinction in pathways in the MC which promote MC proliferation vs. mediator production/release may explain why kinase inhibitors reduce MC burdens and MC-driven symptoms to different degrees (Droogendijk et al. 2006; Gotlib et al. 2008; Verstovsek et al. 2008; Vega-Ruiz et al. 2009; Table ​ Table8). 8 ). However, in some case reports, kinase inhibitors have been significantly effective at relieving symptoms. Thus, in spite of potential serious adverse effects of these drugs, a therapeutic trial may be justified in individual cases at an early stage. Partial and complete responses have been reported with some of these agents in MCAS too (e.g., Afrin 2010, 2011, 2012, 2015; Afrin et al. 2015a). Dosing of the kinase inhibitors in the individual often is considerably lower than how such drugs are dosed for other applications (e.g., imatinib, sunitinib; Afrin et al. 2015a). Possibly due to the causative mutations in multiple genes leading to simultaneous activation of multiple intracellular pathways, multitargeted kinase inhibitors such as midostaurin and sunitinib may be more effective than drugs which selectively downregulate only one intracellular pathway.

Table 8

Kinase inhibitors which can potentially be used as fourth-line drugs in the treatment of mast cell activation disease and their target location and mechanisms of action

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsReferences
Fourth-line drugsInhibitors of tyrosine kinases and other kinases
ImatinibKIT (excluding D816X), PDGFR, Bcr-Abl, Arg/Abl2, DDR-1X(X)XPardanani et al. 2003
Droogendijk et al. 2006
Lim et al. 2009
Vega-Ruiz et al. 2009
Aman et al. 2012
Vaali et al. 2012
Quintás-Cardama et al. 2011R
Marton et al. 2015
NilotinibKIT, PDGFR, Bcr-AblX (X)Hochhaus et al. 2006
Quintás-Cardama et al. 2011R
Hochhaus et al. 2015
El-Agamy 2012
DasatinibKIT, BCR-ABL1, Lyn, Btk, TecX (X)Verstovsek et al. 2008
Hantschel et al. 2007
Gleixner et al. 2011
Quintás-Cardama et al. 2011R
SunitinibVEGFR, PDGFR, KIT, FLT3, RET, CSF1R, SRC,
313 potential kinase targets
XXXAfrin et al. 2015a
Yamaki and Yoshino 2012
Papaetis and Syrigos 2009
Bairlein 2010
MasitinibKIT, PDGFRα, Lck, LYN, FGFR3, FAKX XMarech et al. 2014
Moussy and Kinet 2014
Paul et al. 2010
Quintás-Cardama et al. 2011R
MidostaurinPKC, FLT3, KIT, PDGFR, VEGFR2XXXGotlib et al. 2014
Papayannidis et al. 2014
Knapper et al. 2011
Quintás-Cardama et al. 2011R
PonatinibBcr-Abl, KIT, FLT3, FGFR1, PDGFRα, LynX Jin et al. 2014
Gleixner et al. 2013
BafetinibKIT (excluding D816X), Abl, LynX Peter et al. 2010a
BosutinibLyn, BtkX In ASM patients ineffectiveGleixner et al. 2011
Randall et al. 2015

R review article (further references therein)

In the mastocytosis patient with significant MC burden and/or an aggressive clinical course, cytoreductive drugs are prescribed (Lim et al. 2009; Valent et al. 2010). Unfortunately, effective cytoreductive therapies in SM presently are few in number and typically offer only modest response rates, qualities, and durations. Cytoreductive options include interferon-α and 2-chlorodeoxyadenosine (cladribine, 2-CdA; Fig. ​ Fig.3 3 and Table ​ Table9). 9 ). Interferon-α is frequently combined with prednisone and is commonly used as cytoreductive therapy for aggressive SM. It ameliorates mastocytosis-related organopathy in a proportion of cases but can be associated with considerable adverse effects (e.g., flu-like symptoms, myelosuppression, depression, hypothyroidism), which may limit its use in MCAD (Simon et al. 2004; Butterfield 2005). PEGylated interferon-α has been shown to be as efficacious as and less toxic than the non-PEGylated form in some myeloproliferative neoplasms, but it has not been specifically studied in MCAD. 2-Chlorodeoxyadenosine is generally reserved for last-choice treatment of patients with aggressive SM who are either refractory or intolerant to interferon-α. Potential toxicities of 2-CdA include significant and potentially prolonged myelosuppression and lymphopenia with increased risk for opportunistic infections.

Table 9

Last-choice drugs which can potentially be used in the treatment of mast cell activation disease and their target location and mechanisms of action. R-review article (further references therein)

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsReferences
Last-choice drugs
Interferon-αMultiple targetsX (X)Simon et al. 2004
Casassus et al. 2002
Hauswirth et al. 2004
Butterfield et al. 2005
Butterfield 2005R
Yoshida et al. 2009
Lim et al. 2009
Quintás-Cardama et al. 2011R
CladribineNucleoside analogXXXTefferi et al. 2001
Kluin-Nelemans et al. 2003
Pardanani et al. 2004
Lim et al. 2009
Böhm et al. 2010
Radojković et al. 2011
Quintás-Cardama et al. 2011R
Lock et al. 2015
Barete et al. 2015

Last resorts

Polychemotherapy, including intensive induction regimens of the kind used in treating acute myeloid leukemia, as well as high-dose therapy with stem cell rescue, are approaches restricted to rare, selected patients. Allogeneic stem cell transplantation sometimes yields remissions in mastocytosis long thought impermanent (Spyridonidis et al. 2004; Nakamura et al. 2006; Bae et al. 2013; Gromke et al. 2013), though recent data may offer new hope (Ustun et al. 2014).

Investigational drugs

There are several drugs approved for indications other than MCAD which already have been successfully used in isolated cases with MCAD (Table ​ (Table10). 10 ). In cases of unsuccessful first- to fourth-line therapy, these compounds may be considered as treatment options.

Table 10

Drugs successfully (or not) used off-label to treat isolated cases of mast cell activation disease

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsReferences
Investigational drugs
ThalidomidePrecise mechanism of action unknown XDamaj et al. 2008
Gruson et al. 2013
Lenalidomide No effectKluin-Nelemans et al. 2009
Flavonoids (e.g., luteolin, quercetin, genistein)MultipleX(X)(X)Alexandrakis et al. 2003
Kempuraj et al. 2006
Min et al. 2007
Finn and Walsh 2013R
Weng et al. 2012
Lee et al. 2015
Weng et al. 2015
MiltefosineRaft modulator X(X)Weller et al. 2009
Maurer et al. 2013R
MepolizumabIL-5 antibodyX Otani et al. 2012
RituximabCD20 antibody XBorzutzky et al. 2014
RuxolitinibJAKX XYacoub and Prochaska 2016
Kvasnicka et al. 2014
CannabinoidsAgonists at the cannabinoid receptors XDe Filippis et al. 2008
Frenkel et al. 2015
Own unpublished experiences
Methylene blueGuanylyl cyclase inhibitor Anaphylaxis treatmentRodrigues et al. 2007
Evora and Simon 2007R
PimecrolimusCalcineurin inhibitorX Cutaneous symptoms; (mice)Ma et al. 2010
Correia et al. 2010
EverolimusmTOR no effectParikh et al. 2010
RibavirinPossibly suppression of activated retroviral elements in the genome which may be involved in the development of the somatic mutations in KIT and other proteins XXMarquardt et al. 1987
Molderings 2016
Own unpublished experiences

R review article (further references therein)

A variety of drugs have been shown to inhibit MC growth, to decrease MC mediator release, and/or to relieve mediator-induced symptoms in in vitro and in vivo animal models (Table ​ (Table11). 11 ). Some of these drugs are approved for certain indications (such as ambroxol, statins, mefloquine, and ruxolitinib) and, thus, may be used (if accessible given financial considerations for some agents) if MCAD patients suffer from both the disorder of indication (e.g., hypercholesterolemia—statins, mucous congestion—ambroxol, polycythemia vera—ruxolitinib) and MCAD. An important question is what the role of the other compounds without approved indications should be in clinical practice. There are several challenges that may hamper the clinical introduction of novel targeted therapies in general. Some of these challenges include inherent problems in the translation of preclinical findings to the clinic, the presence of multiple coactive deregulated pathways in the disease, and questions related to the optimal design of clinical trials (e.g., eligibility criteria and endpoints). In particular, the testing of novel targeted treatment in an isolated fashion may be problematic and may in fact underestimate the effectiveness of these novel compounds. It is reasonable to assume that combination therapy will be the key to target parallel critical pathways.

Table 11

Investigational drugs which might have activity against mast cell activation disease since they induce apoptosis of mast cells and/or suppress mast cell mediator release in vitro and/or in vivo

Target location/mechanisms of actionGrowth inhibitionDecrease of mediator releaseTo relieve symptomsInvestigated in vitroInvestigated in vivoReferences
Investigational drugs
ABT-737 <(R)-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-<4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl>-3-nitro-benzenesulfonamide)>BH3 mimeticX Murine BMMC, human cord blood-derived MCs, C57 MC line, MC/9 MC lineMiceKarlberg et al. 2010b
17-Allylamino-17-demethoxygeldanamycin,
Ganetespib (STA-9090)
Binding to heat shock protein 90X HMC-1, canine BMMC, C2 MC line, BR canine mastocytoma cell lines Fumo et al. 2004
Lin et al. 2008
AmbroxolMultiple X Human MCs Gibbs et al. 1999
Amitriptyline, clomipramine, maprotilineYet to be defined in MCAD X Male Wistar ratsGurgel et al. 2013
Clemons et al. 2011
BenzodiazepinesYet to be defined(X)XX Molderings et al. 2013b; Dueñas-Laita et al. 2009; Bidri et al. 1999; Fujimoto et al. 2005; Suzuki-Nishimura et al. 1989; Hoffmann et al. 2013
BI 2536 <(R)-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide>Polo-like kinase-1X HMC-1, primary human neoplastic MCs Peter et al. 2011
BLU-285 (chemical structure not yet published)KITX HMC-1.2,
P815 mouse mastosarcoma cells
Evans et al. 2015
Botulinum toxin ACleavage of the SNARE proteinsXX SD ratsPark 2013
ButaprostEP2 receptor agonist X Human lung MCs Kay et al. 2006
Cerivastatin, fluvastatin, atorvastatinUnknown in MCADXX Primary human MCs, HMC-1, P815 Krauth et al. 2006
Paez et al. 2015
Chemokine receptor antagonistsTargeting activating chemokine receptors expressed on MCs X MiceKoelink et al. 2012R
CinnamaldehydeSignaling molecules, e.g., ERK1/2, JNK, p38, Akt X Human MCs, RBL-2H3 cells Hagenlocher et al. 2015
Bibi et al. 2014R
Combined arginine and glutamineMultiple X Human intestinal MCs Lechowski et al. 2013
Coumarines (scopoletin)Yet to be defined in MCAD X HMC-1 Moon et al. 2007
Finn and Walsh 2013R
CRA1000 N-ethyl-4-[4-(3-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-6-methyl-N-(2-methylsulfanyl-4-propan-2-ylphenyl)pyrimidin-2-amine>Non-peptidic corticotropin-releasing factor antagonist X Mouse dermal MCsShimoda et al. 2010
CrenolanibFLT3X HMC-1, p815, MCs from SM patients Schittenhelm et al. 2014
CurcuminMultiple X HMC-1, murine BMMCBALB/c miceBaek et al. 2003
Kinney et al. 2015
Demethylating agents (5-azacytidine, 5-aza-2′deoxycytidine)DNA methylationX (X)HMC-1 Krug et al. 2010
Meeran et al. 2010R
EXEL-0862 (WO2004050681 A2)KIT, STAT3X HMC-1 Pan et al. 2007
Fedratinib (TG101348)JAK2 inhibitionX HMC-1 Lasho et al. 2010
GLC756 Dopamine D1 and D2 receptor agonist X RBL-2H3 cells Laengle et al. 2006
Gly-Phe-CHN2, PZ610, PZ709, PZ889 (chemical structures not yet published)Dipeptidylpeptidase-1 inhibitors LAD2 MC El-Feki et al. 2011
Histamine H4-receptor agonistHistamine H4-receptor XXHMC-1, murine MCsEx vivo guinea pig and murine heartsAldi et al. 2014
Histone deacetylase inhibitors: vorinostat, AR-42 N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide>Histone deacetylaseX HMC-1.2, primary human MCs, murine, and canine MCs Mühlenberg et al. 2009
Hadzijusufovic et al. 2010
Meeran et al. 2010R
Abdulkadir et al. 2015
Lin et al. 2010
HypothemycinInhibition of KIT and Btk X Human MCsMiceJensen et al. 2008
IMD-0354 N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide>NF-κB inhibitorX HMC-1 Tanaka et al. 2005
JTE-052 <3-<(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl>-3-oxo-propionitrile mono citrate>JAK1,2,3 inhibitor, Tyk2 inhibitor X Human MCsDBA/1J mice, Lewis ratsTanimoto et al. 2015
MefloquinePermeabilization of secretory granulesX Human and murine MCs Paivandy et al. 2014
Mylotarg (gemtuzumab ozogamicin)CD-33 targeting drugX HMC-1, human cord blood-derived MCs Krauth et al. 2007
NeramexanePossibly NMDA antagonist X HMC-1 cells Kurzen 2009
ObatoclaxBH3 mimeticX HMC-1, human neoplastic BMMC Aichberger et al. 2009
ONO-4053 (chemical structure not yet published)Prostaglandin receptor DP1 antagonistX Human BMMC Yamaguchi et al. 2016
8-OH-DPAT (7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol)5-HT1A receptorNo effectX Ritter et al. 2012
PalmitoylethanolamidePPAR-α, cannabinoid receptors, potassium channels, TRPV1 Xrat peritoneal MCs Facci et al. 1995
Mattace Raso et al. 2014R
PD180970 KIT, Bcr-Abl, PDGFRX HMC-1, P815 MCs Corbin et al. 2004
Phosphodiesterase inhibitorsPhosphodiesterase X Human lung MCs, rat MCsWistar ratsLau and Kam 2005; Eskandari et al. 2015
Babaei and Bayat 2012
Phosphatidylethanolamine, phosphatidylserineCD300aX Human cord blood-derived MCs, human lung MCs, murine BMMC Bachelet et al. 2005
Simhadri et al. 2012
Prostaglandin D2 receptor antagonistsCRTH2 X Harvima et al. 2014R
Proteases inhibitorsTryptase, chymase, cathepsins, carboxypeptidase XHuman and murine MCsMiceCaughey 2016R
Harvima et al. 2014R
RapamycinmTOR pathway inhibitorX HMC-1 Chan et al. 2013
RNAiRNA interference against KIT RNAX HMC-1 Ruano et al. 2010
Rosiglitazone, pioglitazonePPARγ X Murine BMMC Tachibana et al. 2008
SiramesineSigma-2 receptor agonistX Human and murine MCs Spirkoski et al. 2012
SitagliptinDipeptidylpeptidase-4 inhibitor X Rat peritoneal MCs Nader 2011 1845
SomatostatinSomatostatin receptors X Wistar ratsTang et al. 2005
Syk kinase inhibitorsSyk kinase X Human, murine, and rat MCs; RBL-2H3 Matsubara et al. 2006
Finn and Walsh 2013
Tandutinib (MLN518)KIT, STAT3X HMC-1, P815 MCs Corbin et al. 2004
TetracyclinesMultipleX XRat serosal MCs, HMC-1HumanSandler et al. 2005
Joks and Durkin 2011R
α-TocopherolMultipleX HMC-1 Kempna et al. 2004
Ruano et al. 2010
TranilastYet to be defined X(X)Rat peritoneal MCRats; rabbitsAdachi et al. 1999
Cooper et al. 2007
Baba et al. 2016
Whi-P131 JAK3/STAT pathway inhibitorX HMC-1 Chan et al. 2013
Bibi et al. 2014R

R review article (further references therein), MC mast cell, BMMC bone marrow-derived mast cells

General considerations on drug treatment of MCAD

Although no biomarkers of symptomaticity or therapeutic response are yet validated, the tolerability and efficacy of most therapies tried in MCAD (starting, and escalating in dosage and composition, cautiously) become clinically evident within 1–2 months. Modest experiments with alternative dosages and/or dosing frequencies are not unreasonable. Therapies clearly shown clinically helpful should be continued; therapies not meeting this high bar should be halted to avoid the troublesome polypharmacy that can easily develop in such patients. With no predictors of response yet available, a cost-based approach to sequencing therapeutic trials in a given patient seems reasonable. It is not even clear yet that medications targeted at mediators found elevated in diagnostic testing (e.g., antihistamines in patients with elevated histamine, non-steroidal anti-inflammatory drugs in patients with elevated prostaglandins, leukotriene inhibitors in patients with elevated leukotrienes) are reliably effective, again perhaps unsurprising given the multitude of MC mediators and the complexity of the signaling networks dysregulated by the multiple mutations in MC regulatory elements present in most MCAD patients. Successful regimens appear highly personalized.

Multiple simultaneous (or nearly so) changes in the medication regimen are discouraged since such can confound identification of the specific therapy responsible for a given improvement (or deterioration). Ineffective or harmful agents should be stopped promptly. Prescribers should be aware that although rapid demonstration of intolerance of a new medication (or a new formulation of a previously well-tolerated medication) often suggests excipient reactivity as further discussed below, some active drug molecules themselves (e.g., cromolyn) sometimes cause an initial symptom flare which usually soon abates. Temporary waiver of gluten-, yeast-, and cow milk protein-containing foods during the initial 3–4 weeks of drug therapy can improve the response rate (Biesiekierski et al. 2011; Rodrigo et al. 2013; own unpublished experiences). When MCAD is suspected, therapies that strongly activate the immune system (e.g., vaccinations with live vaccines or autohemotherapy) must be given with caution (especially if similar therapies were previously already poorly tolerated), as such interventions sometimes dramatically worsen MCAD acutely and/or chronically.

Any drug can induce intolerance symptoms in the individual MCAD patient. In some MCAD patients, the disease creates such remarkable states of not only constitutive MC activation but also aberrant MC reactivity that such patients unfortunately experience a great propensity to react adversely to a wide variety of medication triggers. Those MCAD patients begin demonstrating (either acutely or subacutely) odd/unusual/weird/strange/bizarre/unexpected symptoms soon after beginning new medications. It is very important to note that such patients often demonstrate even a greater propensity to react to medication excipients (i.e., fillers, binders, dyes, preservatives) than to the active ingredients. When the patient tries one or more alternative formulations of a medication with the same active ingredient but sharing as few as possible (preferably none) of the excipients in the offending formulation, the patient may discover the medication to be at least tolerable and perhaps even quite effective. Furthermore, such a scenario obviously provides the patient (and physician and pharmacist) a great opportunity to identify one or more of the specific excipients which are triggering abnormal reactivity in the patient’s dysfunctional MCs, and it is those specific excipients—not the medication as a whole—that should be added to the patient’s allergy list and screened against all present medications being taken by the patient and against all future medications proposed for the patient. An MCAD patient’s physician would be wise to not assume, just because an excipient is very widely used in many medication products and appears innocuous and well tolerated in the vast majority of patients, that the same excipient will necessarily be tolerated well in MCAD patients (unpublished observation of the authors). Sometimes the specificity of the reaction is quite extraordinary. For example, patients who react to wood-based microcrystalline cellulose might tolerate cotton-based microcrystalline cellulose without any difficulty at all, or vice versa. In some cases, the pharmacist is unable to identify alternative commercially available formulations sharing few to none of the excipients in the offending formulation, and in those cases, a compounding pharmacist may need to be engaged to identify/develop a custom-compounded formulation the patient can tolerate. (There can be geographic and financial challenges in accessing compounding pharmacies, though.) Occasionally, MCAD patients may be so remarkably reactive to such a wide range of excipients that they can only tolerate a given medication when provided as pure drug salt, reconstituted in water (without preservatives). Intolerance symptoms can be mediated by IgE antibodies, though this scenario appears to be rare since the symptoms are usually not ameliorated by the anti-IgE monoclonal antibody omalizumab (unpublished observation, G.J. Molderings). Alternatively, they may be mediated by IgG antibodies, raising the question of whether gamma globulin (if itself tolerable) might be a helpful adjunct therapy in such patients (perhaps by directly targeting the MC surface’s IgG receptors or via indirect pathways). Recently, a MC-specific receptor termed MRGPRX2 has been identified which appears to be crucially involved in pseudo-allergic drug reactions (McNeil et al. 2015; Seifert 2015).

Drugs which should not be used in MCAD

Several drugs have the ability to trigger MC mediator release. A compilation of drugs known to be associated with a high risk of release of mediators from MCs is given in Table ​ Table12. 12 . However, there often are therapeutic alternatives to these drugs (Table ​ (Table12 12 ).

Table 12

Compilation of drugs associated with a high risk of release of mediators from mast cells and their therapeutic alternatives (compiled from Mousli et al. 1994; Sido et al. 2014; Afrin et al. 2015b; McNeil et al. 2015)

Substance groupDrugs with proven or theoretical high risk of mast cell activationTherapeutic alternatives
Intravenous narcoticsMethohexital
Phenobarbital
Thiopental
Propofol
Ketamine
Etomidate
Midazolam
Muscle relaxantsAtracurium
Mivacurium
Rocuronium
Cis-atracurium
Vecuronium
AntibioticsCefuroxim
Gyrase inhibitors
Vancomycin
Roxithromycin
Selective dopamine- and norepinephrine reuptake inhibitorsBupropionAmitriptyline, doxepine, clomipramine, maprotiline
Selective serotonin reuptake inhibitorsAll
Anticonvulsive agentsCarbamazepine, topiramateClonazepam
Opioid analgesicsmeperidine, morphine, codeineremifentanil, alfentanil, fentanyl, oxycodon, piritramid
Peripheral-acting analgesicsAcidic non-steroidal anti-inflammatory drugs such as ASS or ibuprofenParacetamol, metamizol
Local anestheticsAmide-type: lidocaine
articaine
Ester-type: tetracaine,
procaine
prefer amide-Type, e.g., bupivacaine
Peptidergic drugsIcatibant, cetrorelix, sermorelin, octreotide, leuprolide
X-ray contrast mediumIodinated contrast medium
Gadolinium chelate
Non-ionic contrast media: iohexol, iopamidol, iopromida, ioxilan, ioversol, idolatran, iodixanol
Plasma substitutesHydroxyethyl starch
Gelatine
Albumin solution, 0.9 %-NaCl solution, Ringer’s solution
Cardiovascular drugsACE inhibitors
ß-Adrenoceptor antagonists
Sartans, calcium channel antagonists, ivabradine, and much else

Conclusions and future perspectives

The therapeutic management of individuals with MCAD is complex and requires reviewing the entire spectrum of symptoms. The paucity of randomized, controlled studies makes treatment of refractory disease challenging and requires patience, persistence, and a methodical approach on the parts of both patient and managing provider(s). Delayed control of the symptoms may increase morbidity. Effective therapy often consists simply of antihistamines and MC-stabilizing compounds supplemented with medications targeted at specific symptoms and complications (Table ​ (Table13). 13 ). Current treatment options for refractory disease are based mainly on observational studies and case reports. Until larger randomized, controlled trials become available to give more guidance on therapy for refractory disease, clinicians should use the available data in conjunction with their clinical expertise and the adverse effect profile of the available drugs to make treatment decisions. More research is certainly needed to better understand MCAD pathobiology, in particular to determine which deregulated genes contribute to a specific symptom or symptom cluster. The greatest challenge in translational research for the discovery of new rational therapies requires a highly interactive interdisciplinary approach engaging basic science labs and clinicians. Understanding of the key components might hasten the progress of novel treatment for all these devastating MCAD phenotypes.

Table 13

Schematic summary of selected potential targets of pharmacological interventions in MCAD

Targets of drugs located in the plasma membrane
Histamine H1 receptorH1-antihistamines
Histamine H2 receptorH2-antihistamines
CB1/CB2 cannabinoid receptorsCannabinoids
cysLTR1 leukotriene receptorCysLTR1 antagonists, e.g., montelukast
ß-Adrenoceptorß-Sympathomimetics
EP2 receptorEP2 receptor agonist, e.g., butaprost
Chemokine receptorsChemokines
FcεRIIgE antibody, e.g., omalizumab
FcγRIIIIgG
Siglec-8Siglec-8 ligand
CD300aPhosphatidylethanolamine, phosphatidylserine
Targetting released mast cell mediators
TryptaseTryptase inhibitor, e.g., nafamostat
ChymaseChymase inhibitor, e.g., BCEAB (4-[1-[bis-(4-methyl-pheny)-methyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid)
Cathepsin GCathepsin G inhibitor, e.g., RWJ355871 (β-ketophosphonate 1)
TNFαInfliximab, adalimumab
IL-4Pascolizumab
IL-5e.g., mepolizumab
IL-6e.g., sirukumab
IL-17e.g., secukinumab
Intracellular inhibition of mediator formation
HistamineHistidine decarboxylase inhibition, e.g., by vitamin C
Leukotrienes5-Lipoxygenase inhibitors, e.g., zileuton
ProstaglandinsCyclooxygenase inhibitors, e.g., acetylsalicylic acid, etoricoxib
Inhibition of cytosolic pathways
Signaling pathways containing protein kinasesInhibitors of protein kinases (see Table ​ Table8 8 )
mTOR pathwaye.g., rapamycin, everolimus
Apoptotic pathwaysStimulation of apoptosis by, e.g., ABT-737, obatoclax
Intranuclear targets
Histone deacetylaseHistone deacetylase inhibitors, e.g., vorinostat
DNA methylationDemethylating agents, e.g., 5-azacytidine, 5-aza-2′deoxycytidine
DNANucleoside analog cladribine

Acknowledgments

The publication of this article was financially supported by the Förderclub Mastzellforschung e.V.

References