​

Lawrence B. Afrin, M.D.

Senior Consultant in Hematology/Oncology

Department of Mast Cell Studies

AIM Center for Personalized Medicine

Purchase, New York, USA

Entire presentation copyright © 2024 by Lawrence B. Afrin, M.D. All rights reserved.

Renegade Research

Treatment of�Mast Cell Activation Syndrome

Clinicians’ Roundtable

June 29, 2024

Learning Objectives & Disclaimers

• Learning Objectives
• Understand details of:
• Treating mast cell activation syndrome (MCAS)
• Identifying/avoiding/modulating triggers
• Inhibiting production of mast cell mediators
• Inhibiting release of mast cell mediators
• Inhibiting/countering actions of released mediators
• Inappropriate treatments for MCAS
• Conflicts of Interest
• None
• Note that there are not yet any FDA-approved treatments for MCAS, and not even (yet) any “well-designed, non-randomized clinical trials,” let alone (yet) any “high-quality randomized controlled clinical trials” (there just hasn’t been time yet for such trials!), so by definition, all treatment options discussed in this presentation are ACCME Level Of Evidence (LOE) “C” (“consensus viewpoint or expert opinion”).

​

Outline

• Treating MCAS
• Goals
• General Approach
• The Mantra: Patience, Persistence, and a Methodical Approach
• “Step 1”: Identify/avoid/modulate triggers
• Issues with excipients
• “Step 2”: Antihistamines
• “Steps 3 through N”: Try various interventions which can…
• …inhibit mediator production
• …inhibit mediator release
• …inhibit/counter actions of released mediators
• Cytotoxic and cellular therapies?
• Secondary issues and comorbidities

After Years* of Mystery, The Patient Now Has a New Diagnosis of MCAS.�What Now?

• Prognosis
• Treatment

*How many general and subspecializing pediatricians and family medicine physicians will have to learn about MCAS before the years-long suffering of MCAS patients today prior to establishing an accurate diagnosis and finding effective treatment can be reduced to a period of just months (let alone weeks or days)? How widely available will genetic testing for primary/clonal MCAS have to get before a patient with suspected MCAS can be diagnosed with a single test that’s easy for the accessioning laboratory to handle?

MCAS: Prognosis

• No epidemiologic studies of prognosis yet
• Present gestalt impression:
• After the first three years, survival curves parallel the general population (similar to indolent systemic mastocytosis)
• So, like allergic diseases and ISM, reduced survival is a relatively small problem in MCAS, and instead most suffer reduced quality of life (anywhere from mild to severe, variable over time) until the disease is accurately diagnosed and effectively controlled
• Many therapies (targeting many receptors and pathways) found helpful in various MCAD/MCAS patients
• Cytotoxic chemotherapy unlikely to help MCAS
• Most pts eventually identify a significantly helpful regimen

Roberts LJ, Anthony LB, Oates JA. “Disorders of Vasodilator Hormones: Carcinoid Syndrome and Mastocytosis” in Wilson JD, Foster DW, Kronenberg HM, et al., eds., Williams Textbook of Endocrinology, 9th ed., 1998, W. B. Saunders Company, Philadelphia, pp. 1718-1732.

Lim K-H, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009;113:5727-5736.

MCAS: Prognosis

Roberts LJ, Anthony LB, Oates JA. “Disorders of Vasodilator Hormones: Carcinoid Syndrome and Mastocytosis” in Wilson JD, Foster DW, Kronenberg HM, et al., eds., Williams Textbook of Endocrinology, 9th ed., 1998, W. B. Saunders Company, Philadelphia, pp. 1718-1732.

Lim K-H, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009;113:5727-5736.

Treating MCAS

• Goals
• Inappropriate goals
• Can’t cure it (presently)
• Far too complex a disease for it to be rational to expect the disease can be controlled so well the patient will feel “perfect” (not that a chronically multisystemically ill patient can even know what “perfect” feels like)
• Not even rational to expect the disease can be controlled so well that the patient will feel significantly improved ALL of the time.

Treating MCAS

• Goals
• Therefore, the appropriate goal: feeling significantly improved (compared to the pre-treatment baseline) the majority (>50%) of the time
• Achievable in most MCAS patients, though the regimen is highly individualized
• An admittedly completely subjective goal
• There are no objective tests which can reveal when the patient has hit the goal
• No evidence that serial mediator levels (let alone biopsies) are helpful
• When the patient feels “well enough” (whatever that means to the patient) “enough of the time” (whatever that means to the patient) that it’s no longer worth it to the patient to continue trying more interventions, then the patient is at goal and likely will “cruise” with the established regimen for a long time (potentially many years, albeit still waxing/waning somewhat with some symptoms, with less frequent/severe/prolonged, and more easily managed/controlled, flares) until some major stressor comes along which may cause a permanent escalation requiring resumption of a search for more effective therapy.

Treating MCAS

• The Mantra (i.e., the bedrock principles for successful life-long treatment of such a biologically complex disease):
• Patience
• Persistence
• A methodical approach
• As much as possible, make just one change at a time
• Try earlier those therapies more likely to address the most bothersome symptoms (e.g., leukotriene-directed drugs or inhaled cromolyn to address particularly bothersome dyspnea once heart failure, pneumonitis, pulmonary fibrosis or hypertension, etc. have been ruled out), or, by default, proceed through therapeutic trials in more or less a cost-based order

Treating MCAS

• General Approach
• “Step 1”: Identify the patient’s triggers as precisely as possible and then do one’s best to avoid or otherwise manage them (e.g., desensitization therapy)
• Antigenic (food, environmental, occupational, drug, medication excipient, etc.)
• Physical forces
• Example of managing an unavoidable trigger: for patients triggered by changes in atmospheric pressure but who need to fly, consider “medding up” (e.g., extra antihistamines) upon boarding (so that meds are peaking in the blood during ascent) and consider “medding up” again ~20-30 minutes before the 30-minute pre-landing point when the plane is scheduled to begin descent
• Physical and/or psychological/emotional stressors

Treating MCAS

• General Approach
• “Step 1”: Identify the patient’s triggers as precisely as possible and then do one’s best to avoid or otherwise manage them (e.g., desensitization therapy)
• Most of this work will have to be done by the patient and those closest to the patient, but sometimes the patient and family/acquaintances are insufficiently aware of the broad range of possible mast cell reactivities/triggerings to perceive an “innocuous” exposure really is a trigger of at least some of the patient’s flares of assorted symptoms, and sometimes the patient is “too close to the situation” to see the obvious trigger. Careful history-taking by the physician can sometimes identify triggers not apparent to the patient or family/acquaintances.

Treating MCAS

• General Approach
• “Step 1”: Identify the patient’s triggers as precisely as possible and then do one’s best to avoid or otherwise manage them (e.g., desensitization therapy)
• Many patient keep diaries: every time a flare of any of the patient’s symptoms occur, then as soon as the patient can put two brain cells back together again, he/she should make a short entry in his/her diary:
• Where he/she was
• What he/she was doing
• What he/she most recently ingested (foods, drinks, medication products, or anything else), and any other recent topical product applications
• Any noticeable odors or other major sensory stimuli in the area at the time
• What the weather was in the area at the time
• Any significant stressors (physical or psychological/emotional) the patient was suffering at the time
• Even with keeping a diary, the trigger of any individual flare may still not be apparent at the time, but hopefully over time the patterns will become more apparent

​

Treating MCAS

• Medication Product Reactivities
• Includes “drugs” and “supplements” – they’re all foreign substances being ingested into, or otherwise applied to, the body, and they all have potential for triggering a flare of mast cell activation in one MCAS patient or another
• It is much more common for MCAS patients to adversely react to medication products than patients without MCAS
• When an MCAS patient begins reacting adversely (in any fashion) to a medication product within the first few dosings, and especially when that reaction is “atypical” for the product’s active ingredient(s) or otherwise difficult to account for given the known mechanism(s) of action of the active ingredient(s), it is FAR MORE LIKELY that it is one or more of the product’s excipients, not the active ingredient(s), which is/are triggering the patient’s dysfunctional mast cells to further activate (and thus release more of their mediators which are driving the symptoms)

Schofield JR et al. Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome. Am J Med Sci 2019 Jun;357(6):507-511.

Treating MCAS

• Medication Product Reactivities
• Adverse medication product reactions are always undesirable/unfortunate, but in an MCAS patient each such reaction is also a HUGE OPPORTUNITY to potentially identify yet another of the patient’s triggers, and accurate identification and avoidance of an MCAS patient’s triggers is “Step 1” – now and for the rest of the patient’s life – toward successfully managing the disease.
• Patients must be taught, and strongly/repeatedly encouraged, to leverage such incidents to at least TRY to identify the trigger(s) in the product…
• …and then review the rest of the medication regimen to make sure they don’t contain the trigger, too!

Treating MCAS

• Medication Product Reactivities
• Sometimes spreadsheets (medication products vs. ingredients) help reveal the patterns
• The ingredient lists of well-tolerated products can be leveraged just as much as the ingredient lists of triggering products: by definition, all of the excipients in a well-tolerated product are not triggers, even if they appear in a triggering product
• One must look for what is in the triggering product which is NOT in the well-tolerated products

Treating MCAS

• Medication Product Reactivities
• Resources for the patient in investigating ingredient lists to try to identify triggering excipients:
• The patient’s pharmacist – and if the patient’s pharmacist is not willing to at least try to help the patient with this, it’s time to get a new pharmacist.
• Consider, too, formally consulting a pharmacologist (often found only at academic centers) offering Medication Therapy Management (“MTM”) services, as this sort of hunting for triggers, and hunting for more tolerable alternative formulations, are exactly the services MTM pharmacologists specialize in offering

Treating MCAS

• Medication Product Reactivities
• Resources for the patient in investigating ingredient lists to try to identify triggering excipients:
• Medication product databases
• Available from many governmental drug regulatory agencies:
• U.S.: FDA – DailyMed (https://dailymed.nlm.nih.gov/dailymed/)
• Canada: Health Canada (https://health-products.canada.ca/dpd-bdpp/)
• U.K.: MHRA (https://products.mhra.gov.uk/)
• Australia: TGA (https://www.tga.gov.au/)
• Often challenging for laymen to navigate and use effectively; take the time to teach the patient how to use his/her relevant database

Treating MCAS

• General Approach
• “Step 1”: Explicitly acknowledge to the patient:
• Trigger identification (let alone avoidance) is HARD.
• Even once triggers are clearly identified, accidental exposures may still occur, even to the most alert individuals
• Knowledge is power: knowing the pattern of reactivity to a given trigger often helps the patient recognize the fact of an exposure – and often helps the patient make better choices in managing the flare
• The patient should expect to NOT be able to pinpoint the trigger of a flare far more often than to have success with this…
• …but if he/she does not even TRY to identify the trigger, the outcome will be a foregone conclusion: the patient WILL continue exposing himself/herself to the trigger and WILL continue suffering flares (to at least some extent) of symptoms no matter what treatments he/she is prophylactically using

​

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient (competitively blocking histamine from engaging H1/H2 receptors on many cells, including mast cells and neurons)
• The patient likely will be on antihistamines for decades to come; why settle for a suboptimal regimen? Different patients respond differently to different products, whether it’s a drug-based or excipient-based phenomenon. Spend the time to find which H1 blocker and which H2 blocker are optimal for the individual pt.
• Identify the H1 blocker (preferably non-sedating) which best serves the patient and the H2 blocker which best serves the pt.
• Consider starting with trial rotations (2-4 weeks each, standard dose for the selected drug taken every 12 hours) of each of the non-sedating H1 blockers (in the U.S.: loratadine, cetirizine, fexofenadine, levocetirizine, and prescription desloratadine)
• U.S. patients often can easily access another four non-sedating H1 blockers on the Canadian market (rupatadine, bilastine, ebastine, and acrivastine) via the Canadian mail-order pharmacy of their choice; mizolastine, too, is available in some European countries

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient.
• After identifying, and switching to, the optimal non-sedating H1 blocker, some patients prefer to try doubling the dosing (e.g., loratadine 20 mg twice daily rather than 10 mg twice daily); again, only 2-4 weeks is needed to see whether this is significantly more helpful than “entry-level” dosing, and if it is not, the patient should revert to entry-level dosing
• Some patients can identify the drug’s effect is significantly wearing off shortly (1-4 hours) before the next 12-hour dosing is due, in which case it is reasonable to try escalating to dosing every 8 hours, again taking only 2-4 weeks to determine whether this is significantly more helpful, and if not, dosing should be reverted to every 12 hours

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient.
• After identifying the optimal non-sedating H1 blocker drug, dose, and frequency, the patient should “pile on top” similar rotating trials of the H2 blockers (famotidine and cimetidine ar readily available OTC in the U.S.; nizatidine is available outside the U.S. (e.g., Canadian pharmacies) and reportedly started returning to the U.S. market in May 2022; ranitidine is starting to become available again outside the U.S. (e.g., Canadian pharmacies) and even inside the U.S. The standard dose for the selected drug should be used, taken each time a dose of the optimal non-sedating H1 blocker is taken.

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient.
• For patients already on H1 and/or H2 blockers, in the interests of trying to make just one change in the regimen at a time, try to keep everything else unchanged/stable and just have the patient rotate from his/her present H1 blocker through the others to find the optimal one, then (after switching to the optimal one) rotate from his/her present H2 blocker through the others to find the optimal one in that class. One change at a time in an MCAS patient’s regimen whenever possible!

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient.
• Occasional MCAS patients with obvious substantial issues in the central nervous system (“neurologic,” “cognitive,” and/or “psychiatric”) from the disease may warrant trials as well (in place of, or even in addition to, the non-sedating H1 blockers) of the “sedating” H1 blockers (which at routine doses will penetrate the blood-brain barrier, in contrast to the non-sedating H1 blockers, which at routine doses cannot so penetrate), albeit starting at cautious doses to try to minimize potential sedation
• Sedating H1 blockers (with more usefully longer half-lives than diphenhydramine’s 1-2 hours) on the U.S. market include doxepin, cyproheptadine, hydroxyzine, chlorpheniramine, clemastine, and carbinoxamine ; diphenhydramine and dimenhydrinate remain useful for “rescue” and are available IV, and IV cetirizine is available in some countries, too.
• All H2 blockers penetrate into the central nervous system

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient.
• Some MCAS patients actually report the “sedating” H1 blockers do not sedate them but rather make them “wake up,” at least at lower doses, showing that such drugs help inhibit mast cell activation leading to release of mediators impacting the central neurons to cause a sense of fatigue.

Treating MCAS

• General Approach
• “Step 2”: Identify the antihistamine regimen which is optimal for the individual patient
• Some patients find slightly higher doses (e.g., loratadine 20-30 mg instead of 10 mg) to be more effective
• Some patients find q8h to be more effective than q12h, especially if symptoms relapse before the next q12h dosing
• H1 and H2 blockers are extremely well tolerated; intolerance of any of these products “right out of the starting gate” strongly suggests excipient reactivity (not drug intolerance), and each incident of suspected excipient reactivity is a very valuable learning experience which should not be squandered (i.e., investigate the product’s excipients to try to identify the trigger, and then explore alternative formulations not containing the suspected trigger).

Treating MCAS

• General Approach
• “Steps 3 through N”: Try, try, try, try, try, try, try more interventions (one at a time whenever possible! medications, dietary changes, desensitization therapies, stress reduction, etc.) – and then keep trying some more.
• Still appropriate with each failure to re-consider the differential diagnosis, but if no better diagnosis identified, best diagnosis remains MCAS and the clinical and therapeutic heterogeneity of the disease must be accepted and further MCAS treatment should be pursued.
• No way at present to predict which medications are most likely to help which patients…
• …but most MCAS patients eventually find a significantly helpful regimen.
• The only way to “lose” at this “game” is to stop trying.
• The cost of any given drug bears no relationship to its likelihood for helping the individual MCAS patient
• Ergo, in general, until more scientifically based guidance is available, consider starting with cheap drugs and escalating in cost as needed

Treating MCAS

• “Steps 3-N”: Inhibition of mediator production
• NSAIDs
• COX1/COX2 blocking: typically, simple aspirin
• Can be a trigger in some, so probe the history carefully, consider starting cautiously (81 mg bid or less, possibly even in the doctor’s office), also consider a desensitization protocol if necessary
• Dosing can be doubled, as tolerated, every 2-7 days to maximal efficacy
• In my experience, dosing above 325 mg bid will eventually cause one or more of the typical toxicities
• Selective COX2 blocking: celecoxib (100-300 mg bid), often well tolerated and effective even if COX1/COX2 blockers are not; sulfa allergy is not a contraindication (N Engl J Med 2003 Oct 23;349(17):1628-35)
• Vitamin C
• Preferably: slow-release formulation, 500-1000 mg q12h; beware of risk for increasing oxalate production/nephrolithiasis, consider checking urinalysis and plasma/urine oxalate levels before starting such treatment (and consider monitoring if elevated levels before treatment is started)
• Vitamin D
• Preferably: 4000-10000 units qd (or 50,000 units q week), though lower doses, too, occasionally help

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “Steps 3-N”: Inhibition of mediator production
• Quercetin (250-1000 mg bid-qid)
• Water-soluble (and more expensive) quercetin chalcone or quercetin phytosome may be more effective (dosing is roughly half that of regular/plain quercetin)
• Ketotifen
• Oral: in the U.S., usually compounded, though occasionally commercial formulations are sourced from foreign pharmacies; dosing usually starts at 1 mg bid, escalating roughly weekly as tolerated in steps of 1 mg bid to maximal efficacy or a maximum dose of 4-6 mg bid-tid
• Eyedrops: commercially available, typically as a (preservative-laden) multi-dose bottle; at least one formulation of preservative-free sterile single-use ampules now available at least in the U.S.

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “Steps 3-N”: Inhibition of mediator production
• Lipoxygenase inhibitors (leukotriene synthesis inhibition, e.g., zileuton 600 mg q6h or extended release 1200 mg q12h)
• Possibly also hydroxyurea (old, cheap RNA synthesis inhibitor; in my experience, often helpful in MCAS patients suffering significant “deep bone pain”)
• 200-1000 mg qd, typically started at 500 mg qd, escalating in 2-4 weeks to max 1000 mg qd; an occasional patient feels better with split (q12h) dosing
• Yes, technically it’s a “chemotherapy” drug, but it’s such mild “chemotherapy” that NIH and other bodies recommend hydroxyurea for life (and typically taken at higher doses than useful in MCAS) for significantly symptomatic sickle cell anemia, so it can’t be that risky, and indeed the data show no significant risk from this.
• Excipient reactivity (especially to the half-pink/half-purple Hydrea 500 mg capsule most commonly initially dispensed) is not uncommon; if this happens, consider a trial switch to another formulation (e.g., the all-green Droxia 200 mg capsule)
• Steroids?
• Fine for acute use
• Chronic toxicities well known

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “Steps 3-N”: Inhibition of mediator release (“stabilization”)
• Cromolyn (oral (100-200+ mg bid-qid) and/or inhaled (20 mg bid-qid) – non-absorbed)
• Nasal and ophthalmic preparations also available OTC (but contain preservatives)
• Topical formulations (e.g., oral, vulvovaginal, skin) can easily be compounded at home
• Can trigger flares 1st few days; tachyphylaxis can abrogate efficacy
• Some pts do poorly with generic oral cromolyn, better with Gastrocrom
• Benzodiazepines and imidazopyridines
• e.g., lorazepam or clonazepam (0.125-1 mg q12h or q8h), flunitrazepam, zolpidem
• Cannabinoids (cannabidiol usually more helpful than THC); endocannabinoids (e.g., palmitoylethanolamide (PEA))
• Low-dose naltrexone (e.g., typically 1.0-6.0 mg/d either qd or split bid)
• Alpha lipoic acid (300 mg bid)
• N-acetylcysteine (600 mg bid)
• Pentosan (especially for interstitial cystitis), 100 mg bid-tid
• Glycopyrrolate (especially for diaphoresis), 0.5-2.0 mg qd-bid
• Omalizumab (anti-IgE monoclonal Ab; 150-375 mg subcutaneously q2-4wks)
• Azathioprine, hydroxychloroquine, cyclosporine, other immunosuppressants? (standard dosing as in other diseases)
• Lithium now known to inhibit mast cell activation, may be useful especially in “depressed” MCAS pts who actually have bipolar affective disorder type 2
• Metformin now known to inhibit mast cell activation; useful in MCAS/”PCOS”?

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “Steps 3-N”: Inhibition of mediator release (“stabilization”)
• Tyrosine kinase inhibitors
• Imatinib (FDA approved for CML, mastocytosis; started in MCAS at ~100 mg qd, but 200 mg/d (typically qd) seems (by my experience) to be the “sweet spot” in MCAS)
• Dasatinib (FDA approved for CML; started in MCAS at ~20 mg qd, but 40 mg/d (typically qd) seems to be the “sweet spot” in MCAS)
• Sunitinib (FDA approved for renal cell carcinoma and gastrointestinal stromal tumor (GIST); in MCAS, only 6.25-12.5 mg qd, no more!)
• Nilotinib and bosutinib (FDA approved for CML; nilotinib reportedly very occasionally helps SM; I have not seen benefit yet in MCAS)
• Midostaurin (FDA approved in AML, ASM/MCL): little experience in MCAS, haven’t seen a successful application in MCAS yet
• Avapritinib (FDA approved in ASM and GIST): registration trials suggest this helps activation, too, but not yet tested in MCAS
• Masitinib (investigational, beneficial in SM (including in dogs/cats!) but not approved yet for humans): clinical trial in MCAS recently opened

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “Steps 3-N”: Inhibition of mediator release (“stabilization”)
• Sex hormone manipulation?
• Low-dose progesterone and/or testosterone (MC activation inhibitors)
• Estrogen axis inhibitors
• Estrogen receptor blockers: selective ERMs (SERMs, e.g., clomiphene, tamoxifen, toremifene, raloxifene)
• Estrogen synthesis inhibitors: aromatase inhibitors (e.g., letrozole, anastrozole, exemestane)
• JAK inhibitors (e.g., tofacitinib, upadacitinib, baricitinib)?
• SSRIs sometimes helpful (fluvoxamine may have more anti-inflammatory activity than the others); also, SNRIs/NDRIs
• Immune globulin? (e.g., IVIG 0.5-1 g/kg q3-4wks)
• Interferon (preferably pegylated form, 22.5-90 mcg q week) rarely tried, often difficult to tolerate
• mTOR inhibitors?
• GLP-1 agonists?
• Somatostatin? (for refractory diarrhea, long-acting formulation, 10-30 mg subcutaneously q 4 weeks if a trial of the short-acting formulation seems helpful)

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Afrin LB et al. Successful targeted treatment of mast cell activation syndrome with tofacitinib. Eur J Hamaetol 2017 Aug;99(2):190-193.

Treating MCAS

• Blockade of released mediators (or counter-mediator Rx)
• H1/H2 antihistamines (even cont. IV diphenhydramine (10-15 mg/hr, often must be a preservative-free formulation) in severely afflicted pts)
• Often impressive benefits even absent rhinosinusitis and dyspepsia
• Can also stabilize mast cells via blocking their autoexcitatory H₁/H₂ receptors
• Diamine oxidase (10-40K units 15 min. before meals)
• Leukotriene antagonists (receptor blockers and synthesis inhibitors)
• e.g., montelukast and zafirlukast (blockers), zileuton (synthesis inhibitor)
• Some pts react to generic montelukast, then do better with other formulations
• Blockers usually more helpful at bid dosing than qd dosing
• Benefits often extend beyond the respiratory tract
• Calcium/vitamin D, bisphosphonates, denosumab (standard dosing for all) for osteoporosis/osteopenia
• Stimulants (e.g., Adderall, Ritalin, Vyvanse, Concerta) sometimes helpful for fatigue/ADD
• TNF antagonists (etanercept, adalimumab, infliximab, golimumab, certolizumab) and IL-1 antagonists (e.g., anakinra), IL-1β antagonists (e.g., canakinumab)?
• Good biological rationales and anecdotal responses, but no studies or reports specifically in MCAS yet
• Some data for these drugs showing efficacy in diseases possibly driven or aggravated by MCAS (e.g., canakinumab for sickle cell pain crises)
• In development: inhibitors of tryptase, chymase, H₃ receptors, etc. etc.

MCAS: Treatment

• Note there are “complementary” treatments, too, in these various therapeutic categories. For example:
• Inhibition of mediator production and/or release
• Vitamin C
• Vitamin D
• Alpha lipoic acid
• N-acetylcysteine
• Palmitoylethanolamide (PEA)
• Cannabidiol (CBD)

1. Hagel AF et al. Naunyn Schmiedebergs Arch Pharmacol 2013 Sep;386(9):789-93.

2. Molderings GJ et al. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

MCAS: Treatment

• Many “natural herbs and supplements,” too, have anti-inflammatory activity and can help control MCAS via COX-1/-2, MAPK, NFkB, and other pathways, e.g.:�

1. Maroon JC et al. Surg Neurol Int 2010;1:80.

2. Attiq A et al. Front Pharmacol 2018 Sep 7; 9:976. doi: 10.3389/fphar.2018.00976.

• Flavonoids (e.g., quercetin, luteolin, ruten)
• Stilbenoids (e.g., resvera-trol)
• Alkaloids (e.g., berberine)
• Lion’s mane
• Elderberry
• Omega-3 essential fatty acids
• White willow bark

​

• Turmeric/curcumin
• Green tea
• Pycnogenol
• Boswellia
• Cat’s claw
• Capsaicin
• Ginseng

​

MCAS: Treatment

• Non-pharmacologic therapies occasionally can be helpful, too
• For example, certain behavioral re-training programs
• Typically require longer periods (3-6 months) to see improvement than required by most pharmacological interventions
• Mechanisms unclear, but seems likely related to the known close interactions – even physical abutment! – of neurons and mast cells throughout the body, with constant mediator “cross-talk” between such dyads

1. Blennerhassett MG et al. Cell Tissue Res 1991 Jul;265(1):121-8.

2. Theoharides TC et al. Trends Pharmacol Sci 2004 Nov;25(11):563-8.

3. Theoharides TC. Life Sci 1990;46(9):607-17.

4. Barbara G et al. Gastroenterology 2007 Jan;132(1):26-37.

5. Newson B et al. Neuroscience 1983 Oct;10(2):565-7,569-70.

6. Van Nassauw L et al. Autonom Neurosci 2007 Apr 30;133(1):91-103.

Shown with permission from ref. 6 below.

Treating MCAS

• Rarely (if ever): Cytotoxic therapy
• Alkylators, taxanes, etc.
• Fludarabine, cladribine, cytarabine, etc.
• Alemtuzumab, daclizumab
• Cytotoxic therapy a more reasonable consideration for advanced mastocytosis

Treating MCAS

• Hypothetical: Cellular therapy
• Allogeneic stem cell transplantation
• Likely to be extremely challenging
• What preparative regimen might reliably work?
• The most needful pts are the most seriously afflicted, but the most seriously afflicted are the most likely to be intolerant of various aspects of the treatment

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Treating MCAS

• “The hard part”: Picking what to try next
• No biomarkers yet available for predicting which interventions will help which symptoms in which pts
• Consider the patient’s symptoms vis-à-vis how the different drugs are classically used and vis-à-vis available reports of use in MCAS
• Oral cromolyn for gastrointestinal issues?
• Aspirin or celecoxib for inflammatory issues?
• Vitamin C or diamine oxidase for pts with elevated histamine (or histamine metabolites)?
• Montelukast and nasal/nebulized cromolyn for respiratory issues?
• Hydroxyurea for deep bone pain?
• Omalizumab for moderately reactive patients?
• Imatinib (after failing at least 3-4 other classes of therapies) for patients with inappropriately robust erythropoiesis or Dercum’s disease or severe hypertriglyceridemia?
• Topical antihistamines/NSAIDs/cromolyn/ketotifen/montelukast for alopecia or poor wound healing?
• Ophthalmic antihistamines, cromolyn, or ketotifen for eye issues?
• Nasal antihistamines or cromolyn for frequent epistaxis?
• Intravaginal antihistamines/cromolyn/ketotifen/benzodiazepines for refractory dysfunctional uterine bleeding, dyspareunia, vulvovaginitis
• Oral rinses with antihistamines/cromolyn/ketotifen for persistent gingivodental troubles?
• Alpha lipoic acid (or even imatinib?) for sensory neuropathies?

Treating MCAS

• Treatment of secondary issues
• For example:
• Ivabradine (1.25 mg qd - 7.5 mg bid) for significantly symptomatic, otherwise idiopathic tachycardia
• Proton pump and NK-1 inhibitors for significant nausea/vomiting
• SSRIs/SNRIs/tricyclics for depression (even lithium for monophasically depressed bipolar affective disorder)
• Frequent mistake by patients and providers: Assuming a symptom (new or old, chronic or acute) is directly due to MCAS
• MCAS does not render one immune to developing other disease
• Regardless of the likelihood that a symptom may ultimately stem from MCAS, rule out other reasonable diagnostic considerations before assuming MCAS is the (direct) cause!
• Illnesses secondary to mast cell disease require full treatment until the mast cell disease is controlled, and even then…
• “…the horse is sometimes already out of the barn”: malignancy and autoimmunity rarely, if ever, spontaneously remit simply with control of the underlying mast cell disease

Treating MCAS

• Treatment of secondary issues: anaphylaxis
• Never forget epinephrine is (almost) always the “go-to” drug for frank anaphylaxis
• Remember, this is virtually *never* IV treatment
• When are they anaphylaxing?
• When they can’t breathe and/or can’t swallow
• Note 20% of anaphylaxers have hypertensive anaphylaxis, not hypotensive
• Note that worsening to epinephrine may be reactivity to preservative, may require preservative-free epinephrine
• Many MCAS patients never experience anaphylaxis or anaphylactoid events…
• …so many MCAS patients can reasonably choose to not carry epinephrine…
• …but if they do choose to carry it, they ought to carry two doses
• Beta blockers have potential to interfere with epinephrine and thus are relatively contraindicated in MCAS
• Work-around if beta blockers are needed: glucagon (like epinephrine, also available as an intramuscular auto-injector)
• The patient should carefully read the product insert and patient instructions for his/her device at the time of purchase and be familiar to the point of reflexic action with how to use them since there’s a good chance he/she won’t be thinking carefully when anaphylaxing

Treating MCAS

• Treatment of secondary issues: anaphylaxis
• Teach your patient the steps in using epinephrine (epi) to treat anaphylaxis:
• Step 1: Don’t use the epi. First, call for help because when you get to the point of needing epi, you likely need help, but you may lose consciousness shortly and then you won’t be able to call for help.
• Step 2: Don’t use the epi. Lie down flat (if in a vehicle, pull over, park/idle, and unlock the vehicle) because you may lose consciousness shortly and you don’t need a fall complicating your anaphylaxis.
• Step 3: Use the epi per your product’s instructions.
• Step 4 (hardest step): Wait 5 minutes for effect, then apply second dose if no trend toward improvement and no help yet on-site or imminently arriving. OK during this time to take extra doses of H1/H2 blockers ± steroids ± benzodiazepines ± any other supportive care medications (e.g., bronchodilators) which seem appropriate given the particular symptoms being suffered.
• Professional medical assistance is needed beyond this point.
• Patients who frequently suffer anaphylaxis will need to judge which events require further professional evaluation.

MCAD: Perioperative Management

• PLANNING: Pre-operative consultation with an MCAD-aware anesthesiologist is highly recommended
• Identify historical triggers (especially peri-/intra-operative drugs, e.g., local anesthetics, antibiotics) as best as possible so they can be avoided
• Have the surgeon and the anesthesiologist read – well in advance of the surgery/procedure – any of the review articles readily available on perioperative management of mast cell disease (e.g., Dewachter et al., Anesthesiology 2014)
• Note perioperative problems in mastocytosis patients are due to mast cell activation, not neoplastic loads of mast cells, so guidance for perioperative management of MCAS is the same as for mastocytosis
• Prepare and maintain a relaxing, comfortable OR environment (decrease triggering stress for the patient)

Dewachter P et al. Perioperative management of patients with mastocytosis. Anesthesiology 2014;120:753-9.

MCAD: Perioperative Medications

• In general:
• Intensified perioperative H1/H2 blockers
• ± benzodiazepines (also addressing MC-surface receptors!)
• ± steroids
• ± other supportive drugs (e.g., bronchodilators) prn
• Again, epinephrine is always the go-to drug for anaphylaxis
• Occasional patients need preservative-free epinephrine
• Remember, too, glucagon is the “workaround” for patients on beta blockers
• Same approach for emergency management of flares, too
• Can also consider adding NSAIDs if known to be tolerated

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Dewachter P et al. Perioperative management of patients with mastocytosis. Anesthesiology 2014;120:753-9.

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

MCAS: Key Nursing Care Issues

• Patient-Professional Trust Issues
• An MCAS patient’s distrust of health care professionals (MDs, RNs, etc.) is born out of years of:
• Professionals not listening to patient’s complaints
• Professionals denying/dismissing/mocking patient’s complaints
• Misdiagnoses of psychosomatism & Munchausen’s (& by proxy) despite careful case review showing such just isn’t possible
• Note neuropsychiatric issues (most common psych issues: anxiety, depression) are COMMON in MCAS but almost always are SECONDARY to the MCAS
• Repeated failure to think of, and establish, convincing/unifying diagnoses
• Repeated failure to find significant/explanatory abnormalities in tests
• Repeated failure of empirically tried treatments to provide significant benefit
• Repeated failure to identify sensible directions for further investigation

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MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Substances
• Foods
• Odors/fragrances
• MCAS patients CAN smell, and react to, food odors in the nurses’ lounge at the opposite end of the ward
• Chemicals (detergents, soaps, petroleum-based products…), whether natural or artificial, whether liquid or solid or aerosolized
• Environmental exposures: pollens, molds, animal danders, etc.
• Medication products (ESPECIALLY EXCIPIENT INGREDIENTS!)
• When an MCAS patient tells you he/she can only tolerate certain formulations of a drug, he/she is not kidding!
• Intolerable formulation = risk for anaphylaxis or other serious rxns
• These are the patients with the “impossible” reactivities, i.e., reactivities to medications “everybody” tolerates, reactivities to “inert” implanted materials, apparent reactivities to saline

MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Activities
• MCAS is highly associated with chronic fatigue syndrome (CFS)
• Poor stamina, unusual post-exertional fatigue
• MCAS is highly associated with postural orthostatic tachycardia syndrome (POTS)
• Poor tolerance of orthostatic changes
• Significant lability of BP and/or pulse is COMMON
• MCAS is highly associated with hypermobile Ehlers Danlos Syndrome (hEDS)
• Diffuse pain; sometimes trivially easy joint dislocations
• MCAS patients often easily bruise/bleed from trivial triggers
• Aberrant heparin release by dysfunctional mast cells in a particular site + very short half-life of heparin at body temperature = significant LOCAL bleeding with no detectable significant SYSTEMIC coagulopathy

MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Physical forces
• Changes in TEMPERATURE (note, too, their frequent dysautonomias include frequent poor temp./sweat regulation)
• Changes in PRESSURE (sometimes as subtle as changes in air pressure, such as with an approaching storm)
• Loud noises (misophonia)
• Low wavelengths (bass tones, vibrations)
• High wavelengths (high audio tones, ultraviolet (e.g., from not only sun but also fluorescent lights!), radio (WiFi!), gamma (radiotherapy))
• Electric shocks (static electricity exposures)
• Curiously, ECT usually is well tolerated, possibly due to mast-cell-stabilizing pre-medications

Treatment of MCAS: What’s next?

• Predictive biomarkers
• Prognostically predictive?
• Therapeutically predictive?
• Can’t feasibly test all the mediators
• Will mutational profiling offer the best predictions?
• More (and better) targeted therapies
• Clinical trials and official drug approvals for MCAS

Summary

Questions?

Questions later?

drafrin@aimcenterpm.com

• Treatment of MCAS
• Principles: patience, persistence, a methodical approach (one change at a time whenever possible)
• Step 1: Identify and avoid triggers; reconsider occult triggers if treatments unhelpful
• Step 2: Identify optimal antihistamine regimen
• Steps 3-N: Try, try, try, try, try, try the many other treatments shown helpful in various MCAS patients until the patient reaches the goal of feeling well enough for enough of the time that it’s not worth it to him/her to keep trying yet more MCAS-targeted medications in the hope of achieving an even better baseline degree of control over the disease…but be willing to resume such trials if the disease undergoes an escalation in the baseline misbehavior of the dysfunctional mast cells.

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