Scholarly article on topic 'Pharmacological treatment options for mast cell activation disease'

Pharmacological treatment options for mast cell activation disease Academic research paper on "Clinical medicine"

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Academic research paper on topic "Pharmacological treatment options for mast cell activation disease"

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DOI 10.1007/s00210-016-1247-1 REVIEW

Pharmacological treatment options for mast cell activation disease

Gerhard J. Molderings1 • Britta Haenisch2 • Stefan Brettner3 • Jürgen Homann4 • Markus Menzen4 • Franz Ludwig Dumoulin4 • Jens Panse5 • Joseph Butterfield6 • Lawrence B. Afrin7

Received: 24 March 2016 /Accepted: 11 April 2016

# The Author(s) 2016. This article is published with open access at Springerlink.com

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

* Gerhard J. Molderings molderings@uni-bonn.de

1 Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany

2 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

3 Department of Oncology, Hematology and Palliative Care, Kreiskrankenhaus Waldbröl, Waldbröl, Germany

4 Allgemeine Innere Medizin, Gastroenterologie und Diabetologie, Gemeinschaftskrankenhaus, Bonn, Germany

5 Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany

6 Program for the Study of Mast Cell and Eosinophil Disorders, Mayo Clinic, Rochester, MN 55905, USA

7 Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

Mast cells (MCs, Fig. 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.

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

Published online: 30 April 2016

Ô Springer

Fig. 1 May-Grunwald/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*

further divided into several subtypes (Valent et al. 2007; Tables 1 and 2), primary MC activation syndrome (MCAS; Table 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-

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 ofthe 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 % ofthe 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

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 etal. 2013a, b).

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. 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

Table 2 Classification of systemic mastocytosis (modified form Valent et al. 2007)

Categories of systemic mastocytosis (SM)

Subtypes

Indolent systemic mastocytosis

Aggressive systemic mastocytosis (ASM)

Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease

Smoldering systemic mastocytosis Isolated bone marrow mastocytosis

Well-differentiated systemic mastocytosis ASM in transformation

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-|-PGF2a, 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

in tyrosine kinase KIT, e.g., KITD816V) 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.

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

individual mutation pattern

specific constitutive activity of affected mast cells

individual symptomatology "phenotype"

Fig. 2 Scheme of conditions responsible in MCAD for the development of individual phenotypes

conducted in SM (midostaurin, cladribine, masitinib; Table 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 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 5) as well as their action (Table 6).

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.

Table 4 Case series and clinical therapeutic trials in systemic mastocytosis and mast cell activation syndrome

Table 4 (continued)

Compound

Compound

Number of References

patients

included

in the study

or case series

H1-antihistamines Rupatadine Azelastine vs.

chlorpheniramine Ketotifen vs. hydroxyzine Chlorpheniramine plus

cimetidine Continuous diphenhydramine infusion Mast cell stabilizer

Cromoglicic acid (cromolyn)

Tranilast Kinase inhibitors Imatinib (STI571)

Nilotinib (AMN107) Dasatinib (BMS-354825)

Midostaurin (PKC412)

Masitinib Cytostatic agents Hydroxyurea

Cladribine (2-chlorodeoxyadenosine)

4 8 2 2 2

14 20 22 17 12

3 61 33

9 11 22 89 14

Siebenhaar et al. 2013 Friedman et al. 1993

Kettelhut et al. 1989

Frieri et al. 1985

Afrin 2015a

Soteretal. 1979 Horanetal. 1990 Mallet etal. 1989 Frieri etal. 1985 Welch et al. 1983 Zachariae et al. 1981 Katoh et al. 1996

Droogendijk et al. 2006 Vega-Ruiz et al. 2009 Lim et al. 2009 Pagano et al. 2008 Pardanani et al. 2003 Heinrich et al. 2008 Hennessy et al. 2004 Hochhaus et al. 2015 Verstovsek et al. 2008 Purtill et al. 2008 Papayannidis et al. 2014 Knapper et al. 2011 Chandesris et al. 2014 Gotlib et al. 2014 Strati etal. 2015 Paul etal. 2010

Lim et al. 2009 Afrin 2013a Lim et al. 2009 Kluin-Nelemans et al. 2003

Pardanani et al. 2004 Pagano et al. 2008 Bareteetal. 2015

Number of patients included in the study or case series

References

Immunomodulation Interferon-a

Thalidomide IgE antibody Omalizumab

ß-Sympathomimetics

Isoprenaline, terbutaline Cyclooxygenase inhibitor Acetylsalicylic acid

20 5 10 40

5 4 20

Casassus et al. 2002 Hauswirth et al. 2004 Laroche et al. 2011 Lim et al. 2009 Pagano et al. 2008 Giraldo Castellano et al. 1998

Hennessy et al. 2004 Worobec et al. 1996 Gruson et al. 2013

Molderings etal. 2011ba Carter et al. 2007 Lieberoth and Thomsen 2015

van Doormaal et al. 1986

Butterfield and Weiler 2008 Butterfield 2009

aIt indicates clinical trials performed with patients with mast cell activation syndrome

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 often 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.

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 action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

First-line drugs

^-antihistamines (preferably of the second and third generations)

H2-antihistamines

Cromoglicic acid (also known as cromolyn)

Vitamin C

Block mutual activation of mast cells via H1-histamine receptors; antagonize H1-histamine receptor-mediated symptoms

Block mutual activation of mast cells via H2-histamine receptors; antagonize H2-histamine receptor-mediated symptoms GPR35; modulation of chloride current

Increased degradation of histamine; decrease of histamine formation by inhibition of histidine decarboxylase

X Church and Gradidge 1980

Valent et al. 2007R Picard et al. 2013R Nurmatov et al. 2015 Siebenhaar et al. 2013 Escribano et al. 2006R X Valent et al. 2007R

Escribano et al. 2006R

X Soteretal. 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 X Hageletal. 2013

Johnston et al. 1992 Uchidaetal. 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)

Acute and chronic immunosuppressive therapies

Though typically not first-line, acute and chronic immunosuppressive therapies can be considered (Fig. 3; Table 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, metho-trexate, 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 (Estevez 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).

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 7). If elevated prostaglandin levels induce symptoms such as

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 ^ cholestyramine; 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 B-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 ^ a-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 ^-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

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,

Fig. 3 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

If 1st line therapy is not sufficiently effective even at maximum doses, add:

2nd line Immuno-

suppressive

3rd line

OmaNzumab

4th line Inhibitors of tyrosine kinases and other kinases

5th line Investigational drugs

last choice

Cytoreductive drugs, polychemotherapy

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 Growth Decrease of To relieve symptoms References of action inhibition mediator release

Second-line drugs Azathioprine

Ciclosporine

Glucocorticoids

Hydroxyurea

Tamoxifen

Methotrexate Third-line drugs Omalizumab

Immunosuppressive drugs Multiple targets

Calcineurin inhibitor

Multiple targets Multiple targets Precise mechanism of action

in MCAD unknown Multiple targets

Anti-IgE antibody

(X) X X

Etoricoxib Acetylsalicylic acid

COX-inhibitors

Montelukast Antagonist at cys-LTj receptors

Zileuton

5-Lipoxygenase inhibitor

X X Nolte and StahlSkov 1988, Own

unpublished data

X X Kurosawa et al. 1999, Broyd et al. 2005,

Trojan and Khan 2012, Own unpublished data X X Zenetal. 2011R

X Lim et al. 2009, Afrin 2013

X In single cases Butterfield and Chen 2016, Duffy et al.

? X Sagi et al. 2011, Vrugt et al. 2000

X Molderings et al. 2011b

Bell and Jackson 2012; Kibsgaard et al. 2014

Kontou-Fili et al. 2010 X Butterfield and Weiler 2008

Breslow et al. 2009 Butterfield 2009 X Tolar et al. 2004

Cikler et al. 2009 Breslow et al. 2009 Turner et al. 2012 X Rodriguez etal. 2011

R review article (further references therein)

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. 3; Table 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. 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; Quintas-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 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

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 action Growth Decrease of To relieve symptoms References

inhibition mediator release

Fourth-line drugs Inhibitors of tyrosine kinases and other kinases Imatinib KIT (excluding D816X), PDGFR, X

Bcr-Abl, Arg/Abl2, DDR-1

Nilotinib KIT, PDGFR, Bcr-Abl

Dasatinib KIT, BCR-ABL1, Lyn, Btk, Tec

Sunitinib VEGFR, PDGFR, KIT, FLT3, RET, CSF1R, SRC, 313 potential kinase targets

Masitinib KIT, PDGFRa, Lck, LYN, FGFR3, FAK X

Midostaurin PKC, FLT3, KIT, PDGFR, VEGFR2

Ponatinib Bcr-Abl, KIT, FLT3, FGFR1, PDGFRa, Lyn X

Bafetinib KIT (excluding D816X), Abl, Lyn Bosutinib Lyn, Btk

(X) X Pardanani et al. 2003

Droogendijk et al. 2006 Lim et al. 2009 Vega-Ruiz et al. 2009 Aman et al. 2012 Vaali et al. 2012 Quintas-Cardama et al. 2011R Martonetal. 2015 (X) Hochhaus et al. 2006

Quintas-Cardama et al. 2011R Hochhaus et al. 2015 El-Agamy 2012 (X) Verstovsek et al. 2008

Hantschel et al. 2007 Gleixner et al. 2011 Quintas-Cardama et al. 2011R X X Afrinetal. 2015a

Yamaki and Yoshino 2012 Papaetis and Syrigos 2009 Bairlein 2010 X Marechetal. 2014

Moussy and Kinet 2014 Paul et al. 2010 Quintas-Cardama et al. 2011R X X Gotlibetal. 2014

Papayannidis et al. 2014 Knapper et al. 2011 Quintas-Cardama et al. 2011R Jinetal. 2014 Gleixner et al. 2013 Peter et al. 2010a In ASM patients ineffective Gleixner et al. 2011 Randall et al. 2015

R review article (further references therein)

drugs which selectively downregulate only one intracellu-lar pathway.

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-a and 2-chlorodeoxyadenosine (cladribine, 2-CdA; Fig. 3 and Table 9). Interferon-a 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-a has been shown to be as efficacious as and less toxic than the non-PEGylated form in some myelo-proliferative 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-a. Potential toxicities of 2-CdA include significant and potentially prolonged myelosuppression and lymphopenia with increased risk for opportunistic infections.

Last resorts

Polychemotherapy, including intensive induction regimens of the kind used in treating acute myeloid leukemia, as well as

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 action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

Last-choice drugs Interferon-a

Multiple targets

Cladribine

Nucleoside analog

(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 Quintas-Cardama et al. 2011R X Tefferi et al. 2001

Kluin-Nelemans et al. 2003 Pardanani et al. 2004 Lim et al. 2009 Böhmetal. 2010 Radojkovic et al. 2011 Quintas-Cardama et al. 2011R Locketal. 2015 Bareteetal. 2015

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 etal. 2006; Bae etal. 2013; Gromke etal. 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 10). In cases of unsuccessful first- to fourth-line therapy, these compounds may be considered as treatment options.

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 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., hypercholesterol-emia—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.

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.

Table 10 Drugs successfully (or not) used off-label to treat isolated cases of mast cell activation disease

Target location/mechanisms of Growth Decrease of To relieve symptoms action inhibition mediator

release

References

Investigational drugs Thalidomide

Lenalidomide Flavonoids (e.g., luteolin, quercetin, genistein)

Miltefosine

Mepolizumab

Rituximab

Ruxolitinib

Cannabinoids

Methylene blue

Pimecrolimus

Everolimus Ribavirin

Precise mechanism of action unknown

Multiple

No effect

Raft modulator

IL-5 antibody CD20 antibody JAK

Agonists at the

cannabinoid receptors

Guanylyl cyclase inhibitor Calcineurin inhibitor mTOR

Possibly suppression of activated retroviral elements in the genome which may be involved in the development of the somatic mutations in KIT and other proteins

Anaphylaxis treatment

Cutaneous symptoms;

(mice) no effect

Damaj et al. 2008 Gruson et al. 2013 Kluin-Nelemans et al. 2009 Alexandrakis et al. 2003 Kempuraj et al. 2006 Min et al. 2007 Finn and Walsh 2013R Weng et al. 2012 Lee etal. 2015 Wengetal. 2015 Weller et al. 2009 Maureretal. 2013R Otanietal. 2012 Borzutzky et al. 2014 Yacoub and Prochaska 2016

Kvasnicka et al. 2014 De Filippis et al. 2008 Frenkel et al. 2015 Own unpublished

experiences Rodrigues et al. 2007 Evora and Simon 2007R Ma etal. 2010 Correia et al. 2010 Parikhetal. 2010 Marquardt et al. 1987 Molderings 2016 Own unpublished experiences

R review article (further references therein)

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

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 Growth Decrease of To relieve Investigated in vitro Investigated References

of action inhibition mediator symptoms in vivo

release

Investigational drugs ABT-737 {(Ä)-4-(3-dimethylamino-l-phenylsulfanylmethyl-propylamino)-JV-¡4- [4-( 4 '-chloro-biphenyl-2 -ylmethyl)-piperazin-1 -yl]-benzoyl} -3-nitro-benzenesulfonamide)} 17-Allylamino-17-demethoxygeldanamycin, Ganetespib fsTA-9090) Ambroxol

Amitriptyline, clomipramine, maprotiline Benzodiazepines

BI 2536 {(Ä)-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxy-JV-(l -methylpiperidin-4-yl)benzamide} BLU-285 (chemical structure not yet published)

Botulinum toxin A Butaprost

Cerivastatin, fluvastatin, atorvastatin Chemokine receptor antagonists Cinnamaldehyde

Combined arginine and glutamine

BH3 mimetic

Binding to heat shock protein 90

Multiple

Yet to be defined in MCAD Yet to be defined

Polo-like kinase-1

Cleavage of the SNARE proteins EP2 receptor agonist Unknown in MCAD

Targeting activating chemokine receptors expressed on MCs Signaling molecules, e.g., ERK1/ 2, JNK, p38, Akt

Multiple

Murine BMMC, human cord blood-derived MCs, C57 MC line, MC/9 MC line

HMC-1, canine BMMC, C2 MC line, BR canine mastocytoma cell lines Human MCs

Male Wistar rats

HMC-1, primary human neoplastic MCs

HMC-1.2, P815 mouse

masto sarcoma cells

Human lung MCs Primary human MCs, HMC-1, P815

Human MCs, RBL-2H3 cells

Human intestinal MCs

SD rats

Karlberg et al. 2010b

Fumo et al. 2004 Lin et al. 2008

Gibbs et al. 1999 Gurgel et al. 2013 Clemons et al. 2011 Moiderings et al. 2013b;"

Duenas-Laita et al. 2009;

Bidri et al. 1999; Fujimoto

et al. 2005; Suzuki-Nishimura et al. 1989; Hoflrnann et al. 2013 Peter et al. 2011

Evans et al. 2015

Park 2013 Kay et al. 2006 Krauth et al. 2006 Paezetal. 2015 Koelink et al. 2012R

Hagenlocher et al.

2015 Bibi et al. 2014R Lechowski et al. 2013

Target location/mechanisms of action

Coumarines (scopoletin)

Yet to be defined in MCAD

CRA1000 {ALethyl-4-[4-(3-fluorophenyl)-3,6-dihydro-2i/-pyridin-

1-yl]-6-methyl-jV-(2-methylsulfanyl-4-propan-2-ylphenyl)pyrimidin-

2-amine} Crenolanib

Non-peptidic corticotropin-releasing factor antagonist

Curcumin

Demethylating agents (5-azacytidine,

5 -aza-2 'deoxycytidine) EXEL-0862 (W02004050681 A2) Fedratinib (TG101348) GLC756 {(3R,4aR,10aR)-l,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-l-methyl-3-[(2-pyridyl-thio) methyl]-benzo [gq]uinolinehydrochloride)} Gly-Phe-CHN2, PZ610, PZ709, PZ889 (chemical structures not yet published) Histamine Hpreceptor agonist

Multiple

DNA methylation X

KIT, STAT3 X

JAK2 inhibition X

Dopamine Dj and D2 receptor agonist

Dipeptidylpeptidase-1 inhibitors Histamine Hpreceptor

Histone deacetylase inhibitors: Histone deacetylase X

vorinostat, AR-42 {Af-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide}

Hypothemycin IMD-0354 {#-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide} JTE-052 ¡3- {(3R,4R)-4-methyl-3-[methyl-

(7i/-pyrrolo[2,3-d]pyrimidin-4-yl)-aminoj-piperidin-1 -y 1} -3 -oxo-propionitrile mono citrate}

Inhibition of KIT and Btk

NF-kB inhibitor X

JAK 1,2,3 inhibitor, Tyk2 inhibitor

Decrease of To relieve Investigated in vitro

mediator symptoms

release

Investigated in vivo

References

X HMC-1 Moon et al. 2007

Finn and Walsh 2013R

X Mouse dermal MCs Shimoda et al. 2010

HMC-1, p815, MCs from Schittenhelm et al.

SM patients 2014

X HMC-1, murine BMMC BALB/c mice Baek et al. 2003

Kinney et al. 2015

(X) HMC-1 Krugetal. 2010

Meeran et al. 201 OR HMC-1 Pan etal. 2007

HMC-1 Lasho etal. 2010

X RBL-2H3 cells Laengle et al. 2006

LAD2 MC

X HMC-1, murine MCs

HMC-1.2, primary human MCs, murine, and canine MCs

Human MCs HMC-1

Ex vivo guinea pig and murine hearts

El-Feki et al. 2011 Aldi etal. 2014

Muhlenberg et al.

Hadzijusufovic et al.

Meeran etal. 201 OR Abdulkadir et al. 2015 Lin etal. 2010 Jensen et al. 2008 Tanaka et al. 2005

X Human MCs DBA/1 J mice, Tanimoto et al. 2015

Lewis rats

Target location/mechanisms of action

Growth Decrease of inhibition mediator release

Mefloquine

Mylotarg (gemtuzumab ozogamicin)

Neramexane Obatoclax

ONO-4053 (chemical structure not yet published)

8-OH-DPAT (7-(Dipropylamino)-5, 6,7,8-tetrahydronaphthalen-l-ol) Palmitoylethanolamide

PD180970 {6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylanilino)-8-methylpyrido[2,3-d]pyrimidin-7-one} Phosphodiesterase inhibitors

Permeabilization of secretory X

granules

CD-33 targeting drug X

Possibly NMDA antagonist

BH3 mimetic X

Prostaglandin receptor DP 1 X

antagonist

5-HT1A receptor No effect

PPAR-a, cannabinoid receptors, potassium channels, TRPV1

KIT, Bcr-Abl, PDGFR X

Phosphodiesterase

Phosphatidylethanolamine, phosphatidylserine

Prostaglandin D2 receptor antagonists Proteases inhibitors

Rapamycin RNAi

Rosiglitazone, pioglitazone

Siramesine

Sitagliptin

Somatostatin

Syk kinase inhibitors

CD300a X

Tryptase, chymase, cathepsins,

carboxypeptidase mTOR pathway inhibitor X

RNA interference against X

KIT RNA PPARy

Sigma-2 receptor agonist X

Dipeptidylpeptidase-4 inhibitor Somatostatin receptors Syk kinase

Tandutinib (MLN518)

KIT, STAT3

To relieve Investigated in vitro Investigated References

symptoms in vivo

Human and murine MCs

HMC-1, human cord blood-derived MCs HMC-1 cells HMC-1, human

neoplastic BMMC Human BMMC

X rat peritoneal MCs

HMC-1, P815 MCs

Human lung MCs, rat MCs Wistar rats

Human cord blood-derived MCs, human lung MCs, murine BMMC

X Human and murine MCs Mice

HMC-1 HMC-1

Murine BMMC Human and murine MCs Rat peritoneal MCs X Wistar rats

Human, murine, and rat

MCs; RBL-2H3 HMC-1, P815 MCs

Paivandy et al. 2014

Krauth et al. 2007

Kurzen 2009 Aichberger et al. 2009

Yamaguchi et al. 2016

Ritter et al. 2012

Facci et al. 1995 Mattace Raso et al.

2014R Corbin et al. 2004

Lau and Kam 2005; Eskandari et al. 2015 Babaei and Bayat 2012

Bachelet et al. 2005 Simhadri et al. 2012

Harvima et al. 2014R Caughey 2016R Harvima et al. 2014R Chan et al. 2013 Ruano et al. 2010

Tachibana et al. 2008 Spirkoski et al. 2012 Nader 2011 1845 Tang et al. 2005 Matsubara et al. 2006 Finn and Walsh 2013 Corbin et al. 2004

Target location/mechanisms Growth Decrease of To relieve Investigated in vitro Investigated References

of action inhibition mediator symptoms in vivo

release

Tetracyclines Multiple X X Rat serosal MCs, HMC-1 Human Sandler et al. 2005

Joks and Durkin 2011R

a-Tocopherol Multiple X HMC-1 Kempna et al. 2004

Ruano et al. 2010

Tranilast Yet to be defined X (X) Rat peritoneal MC Rats; rabbits Adachi et al. 1999

Cooper et al. 2007 Baba et al. 2016

Whi-P131 {4-[(6,7- JAK3/STAT pathway X HMC-1 Chan et al. 2013

dimethoxyquinazolin- inhibitor Bibi et al. 2014R

4-yl)amino]phenol}

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

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 group Drugs with proven or theoretical high risk Therapeutic alternatives

of mast cell activation

Intravenous narcotics

Muscle relaxants

Antibiotics

Selective dopamine- and

norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors Anticonvulsive agents Opioid analgesics Peripheral-acting analgesics

Local anesthetics

Peptidergic drugs X-ray contrast medium Plasma substitutes Cardiovascular drugs

Methohexital Phenobarbital Thiopental

Atracurium

Mivacurium

Rocuronium

Cefuroxim

Gyrase inhibitors

Vancomycin

Bupropion

Carbamazepine, topiramate meperidine, morphine, codeine Acidic non-steroidal anti-inflammatory

drugs such as ASS or ibuprofen Amide-type: lidocaine articaine

Ester-type: tetracaine, procaine

Icatibant, cetrorelix, sermorelin, octreotide,

leuprolide Iodinated contrast medium Gadolinium chelate Hydroxyethyl starch Gelatine ACE inhibitors ß-Adrenoceptor antagonists

Propofol

Ketamine

Etomidate

Midazolam

Cis-atracurium

Vecuronium

Roxithromycin

Amitriptyline, doxepine, clomipramine, maprotiline Clonazepam

remifentanil, alfentanil, fentanyl, oxycodon, piritramid Paracetamol, metamizol

prefer amide-Type, e.g., bupivacaine

Non-ionic contrast media: iohexol, iopamidol, iopromida,

ioxilan, ioversol, idolatran, iodixanol Albumin solution, 0.9 %-NaCl solution, Ringer's solution

Sartans, calcium channel antagonists, ivabradine, and much else

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

Targets of drugs located in the plasma membrane Histamine H1 receptor Histamine H2 receptor CB1/CB2 cannabinoid receptors cysLTR1 leukotriene receptor ß-Adrenoceptor EP2 receptor Chemokine receptors FceRI FcyRID Siglec-8 CD300a Targetting released mast cell mediators Tryptase Chymase

Cathepsin G

Intracellular inhibition of mediator formation Histamine Leukotrienes Prostaglandins Inhibition ofcytosolic pathways Signaling pathways containing protein kinases mTOR pathway Apoptotic pathways Intranuclear targets Histone deacetylase DNA methylation DNA

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 12. However, there often are therapeutic alternatives to these drugs (Table 12).

H1-antihistamines H2-antihistamines Cannabinoids

CysLTR1 antagonists, e.g., montelukast

B-Sympathomimetics

EP2 receptor agonist, e.g., butaprost

Chemokines

IgE antibody, e.g., omalizumab IgG

Siglec-8 ligand

Phosphatidylethanolamine, phosphatidylserine Tryptase inhibitor, e.g., nafamostat

Chymase inhibitor, e.g., BCEAB (4-[1-[bis-(4-methyl-pheny)-methyl]-3-

(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid) Cathepsin G inhibitor, e.g., RWJ355871 (p-ketophosphonate 1) Infliximab, adalimumab Pascolizumab e.g., mepolizumab e.g., sirukumab e.g., secukinumab

Histidine decarboxylase inhibition, e.g., by vitamin C

5-Lipoxygenase inhibitors, e.g., zileuton

Cyclooxygenase inhibitors, e.g., acetylsalicylic acid, etoricoxib

Inhibitors of protein kinases (see Table 8) e.g., rapamycin, everolimus

Stimulation of apoptosis by, e.g., ABT-737, obatoclax

Histone deacetylase inhibitors, e.g., vorinostat Demethylating agents, e.g., 5-azacytidine, 5-aza-2'deoxycytidine Nucleoside analog cladribine

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 13). Current treatment options for refractory disease are based mainly on

Table 13 Schematic summary of selected potential targets of pharmacological interventions in MCAD

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.

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

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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