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H1- for primary activation syndromes: a systematic review

Citation for published version: Nurmatov, UB, Rhatigan, E, Simons, FER, Sheikh, A & Sheikh, A 2015, 'H1-antihistamines for primary mast cell activation syndromes: a systematic review', , pp. 1052-1061. https://doi.org/10.1111/all.12672

Digital Object Identifier (DOI): 10.1111/all.12672

Link: Link to publication record in Edinburgh Research Explorer

Document Version: Peer reviewed version

Published In: Allergy

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Download date: 25. Sep. 2021 Accepted Article ManitobaWinnipeg MBCanada R3E 3P4, 504D-715 McDermot Avenue Department of Immunology, University Manitoba, of Kirkcaldy,Fife, NHS Fife, KY2 Scotland 5AH, Teviot Place, Edinburgh, EH8 9AG, Scotland Edinburgh,The UniversitySchool Medical of forPopulationCentre Sciences Health Short title: H title: Short [email protected]: Doorway 3,Teviot Place, Edinburgh EH8 9AG, UK. Tel:+44(0)131 650 2677 TheHealth Sciences, Population for Centre Corresponding author: Boston, Massachusetts, USA andHospital/HarvardBrigham Medical School, Women’s systematic review

Key words: H words: Key systematic review review systematic 4 3 2 1 Nurmatov B. Ulugbek H Article Type: Review Division of GeneralDivision of Internal MedicinePrimaryand Care, PediatricsofDepartment andChildHealth, HospitalKirkcaldy,Victoria Allergy and Respiratory Group, Research 1 -antihistamines for primary mast cell activation syndromes (MCAS): a (MCAS): syndromes activation cell mast primary for -antihistamines 1 -antihistamines for MCAS -antihistamines for 1 -antihistamines, mastocytosis, primary mast cell activationsyndrome, -antihistamines, cell primarymastocytosis, mast 1 ,

Edmund RhatiganEdmund Dr Ulugbek B. Nurmatov, Allergy Nurmatov, B. Ulugbek &Respiratory ResearchGroup,Dr 2 , F. Estelle R.Simons University of Edinburgh,School, Medical University of 3 , Aziz Sheikh 1,4 Accepted Article treatment withtreatment thesecond-generation H weeks of four found mastocytosis systemic with and cutaneous adults which enrolled33 trial,Thechlorpheniramine, , fifth (i.e. clinical practice andketotifen). in now are uncommonly dosingregimens that used and/or agents and used patients), Four 1983-93), of weresodium. (enrollingfivethe from RCTs historic(reported small 8-15 bias. Two an studiescompared H the eligibility these of judgedtobeat studies were Five criteria. or highriskmoderate of Results: 71of patients adults).(63 panel of to identifyan international andunpublished enrollingtrials, totalaexperts published Methods: treatments. treatmentofin the primary with MCAS compared pharmacologic placeboandother

Conclusions: Conclusions: reduction of itching and whealing standardizedafter skin provocation to elicit Darier’s sign. tachycardia, andheadache, gastrointestinal flares, flushing, but not symptoms), and insignificantresulted in improvements quality control life, symptom (itching,of wheals and H Objectives: withpresenting symptomsof cellrelease. mast mediator Background: ABSTRACT . or cell-stabilizingmediator-targeting with treatment and responsiveto mast medications cell-derived inmediators, accompaniedrelease arerecurrent, byan increase mast mediator cell pain whenabdominal anddiarrhea.These of disordersarediagnosed mast symptoms including manifestations and gastrointestinal headache, tachycardia, angioedema, symptoms of cell mast release suchasitching, whealing,mediator flushing, flaring, cellactivation Mast disorderssyndromes (MCAS) areagroup of typicallythat presentwith BACKGROUND PROSPERO registration: second-generation H controlled randomized theeffectiveness, trialscost-effectiveness investigating safety and of 1 -

antihistamines, and H onestudy compared 36 potentially relevant studies were identified. Of these, five crossover trials met trials crossover five Of these, identified. werestudies potentially36 relevant We systematically databases,We searched five trialthree repositories andcontacted 1-9 To assess the effectiveness and safety orally-administered of H

Primary mast cell activation syndromes (MCAS) are a group of disorders areagroupof syndromes (MCAS) cellactivation mast Primary There 1 -antihistaminestreatmentprimary in of MCAS.

is an urgent need for large, well-designed, large, an urgentneedfor double-blind, placebo- is CRD42014007518 1 - with placebo,two compared two different 1 -antihistamine -antihistamine , compared with placebo, 1 - and H 2 -antihistamines with oralcromolyn -antihistamines 1 -antihistamines Accepted Article of mediators that that are example, of H released –for mediators decreaseseffectby that release, that prevent mediator reduce the or medications sodium or cromolyn such as cell-stabilizing arerelievedbya mast and angioedema flaring, whealing,itching, flushing, such as symptoms when MCASis diagnosis 3 met of for Criterion helps to MCAS.of theconfirm helps to diagnosis to a three for a If trial period. six respondspatient month appropriately thistreatment, it to are medications typically givenina stepwise ona fashion regular daily twice-daily or basis management of of management mastocytosis. andhasto been diagnosis Analgorithm proposedfacilitate and MCAS. monoclonal MCASonlyand primary oncutaneous systemic mastocytosis, specifically on mastocytosis, prostaglandin PGD less commonly, (or the N-methylhistamine when anditsmetabolite or plasma levelsin when anaphylaxis areelevated alsoThis histamine is symptoms. criterion met in obtained baseline, at serum example, at least for 24 hours after complete resolution of tryptase when total leveliselevated andothers.typically the chemokines, Criterion2is met leukotrienes (LTC4LTD4), platelet-activating pro-inflammatory and factor, cytokines, anaphylaxis, and urticaria, spontaneous idiopathic angioedema. MCAS includes cell syndrome, but activation idiopathic mast notonly also idiopathic occurs. also MCAS effects of histamine, and anti-leukotrienes to mitigate the effects of leukotrienes. of effects and histamine, to the anti-leukotrienes of mitigate effects is unclear. evidencethis recommendation supporting andqualityvolume of the mastocytosis. However, in systemicand includingcutaneous symptoms syndromes, of cellmast activation relief primary, secondary, idiopathic. and The proposed classification system of MCAS divides thesyndromes into three categories: cutaneous mastocytosis or systemic mastocytosis, and monoclonal MCAS. and monoclonal mastocytosis, systemic or mastocytosis cutaneous For more than three decades, H

fluids can beprostaglandintryptase, histamine,D These documented. can include mediators fluids cell inbiologic mediators whenincrease in andiagnosis mast MCAS2 is of for met Criterion signs of severe recurrent or chronic systemic cell activation.mast clinicalthere are when applied MCAS shouldbe term diagnosis the that states 1 for Criterion immune urticaria,and immune chronicinflammatorysome disorders. andneoplastic 11-17

2 9 metabolite 11-beta-PGF-2-alpha)are elevated in24-hour urine. SecondaryMCASallergic induced include orchronicauto- diseases, 10

1 -antihistamines have been consistently recommended for 1-5 Primary MCAS includedisorders suchas clonal 1-9

1 - and/or H and/or - 2 -antihistamines to mitigate the -antihistamines mitigate to 1-5 In this review,we focus 1-8 1-5 Non-clonal Idiopathic 1-10 1-9 Such Such

2 , Accepted Article H commonly been than(newer)second-generation have more antihistamines recommended Collaboration, reviewconducted the methods the recommendedWe by Cochrane according to the METHODS antihistamines in the ofmanagement primary MCAS. for the prevention and oftreatment symptoms. such asantihistamines azelastine, chlorpheniramine, , hydroxyzine and Mastocytosis experts have typically recommended oral (old) first-generation, sedating H introduced for clinical use inthe US orinm clinicaluse introduced for Food and United States Drug Administration (USFDA) been andconsequently havenever haveneverketotifen oral been approved by regulatory use for agencies some suchasthe recommendedolder overthe class in in MCAS. use this medications for Second-generation, non-sedating H urticaria. andchronicof rhinitiscommon suchasallergic andacute medication allergic disorders over-the-counterfor purchase self- without and alsowidely usedfor are aprescription because including track chlorpheniramine most, and diphenhydramine, are widely available In this systematic review,In this systematic we soughtto investigate effectiveness the and safety H of decade, andevennewer H , , and have become widely available in thepast available in Second-generation many countries. H controlled trials (RCTs) whichH compared randomized evidence; i.e. of forms highest the onlyat literatureby appraisedlooking the We Types of study Criteria for consideringstudies for thisreview quasi-RCTs. we alsoconsidered RCTs apaucity of we anticipated However,agents. since pharmacologic Approximately 40 medications in this class are inthis Approximately 40medications H (PRISMA) guidelines. PreferredReviews detailed inthe Reporting Items andMeta-analysis Systematic for 1 1 -antihistamines. Use first-generationof H -antihistamines are the most commonly intervention used therapeutic in MCAS. 18 and have in relation to reporting our findings followed the recommendations the followed ourfindings to reporting relation inhave and 19

1 -antihistamines such-antihistamines asbilastine rupatadinearenow also and 1 -antihistamines such as , as ,-antihistamines such any other countries. Overall, first-generation Overall, anyother countries. H 1 -antihistamines inany-antihistamines is difficult disorder to available worldwide for oralworldwide administration. available for 1 -antihistamines with placeboor other 1 -antihistamines are increasinglytherefore 1,2,4,5 However, azelastine and 3,8,9,11,12

12 1 1 1 - - -

Accepted Article We includedWe studiesinvestigating the use systemicof H Types of interventions Secondary Primary stipulated primaryWe following the andsecondary measures:outcome Types of outcome measures intramuscular and intravenous administration). diagnosis of diagnosis MCASof needed to be namely: met, consensus criteria for MCAS. consensus andrecently accordingtothe systemic MCAS) mastocytosis, developed monoclonal children were including conductedin in interested We andany patients, studies infants, neonates, Types of participants • • • • • • • • • • • • Clinical improvement: prevention or prevention asassessed symptoms resolution Clinical improvement: byof any Cost-effectiveness. Elevated andplasma urine levelshistamine and 24-hour urine N-methylhistamine serum Elevated tryptase(baseline) levels Duration of hospital admissions of hospitaladmissions Number Symptom toxicity events) Drug (adverse scores life Quality of Responseto treatment with one or anti-mediatormore medications. increase A documented in cell a derived asmast such mediator serum tryptase or The symptoms and signs presence recurrent of severe to relevant or chronic levels (baseline) objective measure. plasma orplasma urine histamine systemic mast cell activation 20 as well as adults diagnosed with primary MCAS (i.e.cutaneous mastocytosis, 1 We stipulated atWe leastthat two ofthe three criteria for 1 -antihistamines (i.e. oral, 4

Accepted Article (FERS andAS). toadjudicationable toagreeon by positionwithoutrecourse a consensus otherreviewers differences two (UNof authors wereER) and existed the bias. bias; C–highrisk Where of ofparameterEach included bias; quality trial was graded:A–low of B– risk riskmoderate data; theabsenceoutcome other absenceof selective and of bias.reporting sources the of participants and personnel; blinding outcome of assessment; the addressing incomplete of quality:sequenceassess adequate allocation generation; concealment;blinding of range); description of intervention;outcome range); (primary measures secondary); withdrawals and were authors; year,age (gender, participants extracted: country and and setting; mean byabstracted bothreviewers a customizedonto dataextraction sheet. The data following reviewersindependent (FERS andAS) was were needed.Data independently then aspotentiallyclassified included. Consensus reviewers (UNandER) thenindependently the allstudies of manuscripts assessed full potentially included or excluded unsure according tothe agreed inclusion criteria. Both generated by search the strategy detailed above anddesignated each study aseither articles of ER)independently andabstracts Two titles (UN and scrutinized all reviewers Data abstraction trials.com; and www.anzctr.org.au and contacted four international subject experts. searched threeinternational www.clinicaltrials.gov;repositories: www.controlled- trial Inorderrestrictions inoursearches. to on-goingfind orunpublished we also studies Appendix2013) (see 1). There werelanguage,no publication yearor publication status of OctoberScience2013), October(EBSCO ISICINAHL 1982to (1945to 2013), host, Web 2013, MEDLINE SP, 1966 (Ovid 2013), EMBASE to October SP, (OVID 1980 toOctober October(DARE)to Effects Reviews Abstracts of of of Reviewsand Database Systematic Controlledof Register Trials (CENTRAL) toOctober 2013, The DatabaseCochrane of Cochrane Central The databases: internationalelectronic the searched following We Search methodsforidentification of studies Systematic ReviewsSystematic Interventions of the detailed usingthe eightof assessed in section methods was quasi-RCTs RCTs theincluded and of The quality (UN andER). methodological Critical appraisal the wasincluded of independently studies performed by both reviewers Quality assessment events.adverse and follow-up; to losses and . 18 sevendomains onusing focused tofollowing the We was achieved and no recourse to additional

Cochrane Handbookfor Accepted Article Significant heterogeneitySignificant I the wouldbeen assumed if have was judged to be at a high risk of bias. variation). than 40% the of variability inbetween outcome trials could notbe explained by sampling children. were included RCTs 63adultparticipants, that and the study aRCTremaining eight of was which a total of 71 patients were enrolled (see Figure 1 PRISMA flow Four diagram). studies Our searchesidentified 36 potentiallypapers, relevant which in from weidentified five trials RESULTS mastocytosis; H mastocytosis; subgroup analyses agepatient on: (neonate/infant, based of type childand adult); of clinical or statistical heterogeneity. We planned heterogeneity. clinical orstatistical heterogeneity for to test We usingthe I planned presence consider significantwasWe if meta-analysisappropriate inthe to of CI. with 95%standardized differences and/or(MD) means differences asmean pooled statistics confidence intervals(95% Forwe continuousdata, CI). hoped individual calculate to and plannedas relativerisks(RR)with tocalculateindividual statistics 95% pooled and Manageranalysisdata for synthesis. data and quantitative data, For we dichotomous body evidenceuncovered. Had data of sufficient we beenavailable, use planned to Review undertook adescriptive summary data and thenundertook anarrative theof synthesis of There were insufficient comparable data to permit meta-analysis. therefore We first Data synthesis

tests. and Egger Begg andstatistically using Funnel plots publication biasgraphically using of analyseson outcomes an of basis.intention-to-treat would thenhave We evidence assessed derived whereverintendedfixed-model pooledeffect. toconduct, possible, quantitativeWe anythe absenceof statistical or clinical heterogeneity, we substantial planneda toreport effects modeling dependingwhether were tobe In on ornotthe data found homogenous. (see Tables 2a-c). Four were RCTs judged tobe at riskmoderate of bias; of these trialsrevealedthatQuality biaswere none low be of assessment at judgedto risk papers did not lead to identification of any additional studies. and experts Contacting undertaking detailed of included searches bibliographies the of 22-23 22-23 13-17 In andclinicalthe eventIn we statistical of heterogeneity toundertake had planned 21 If able topursue If a meta-analysis, wewould haveusedfixed effect orrandom The of are summarizedcharacteristics thesekey trials in Tables1a-c. 1 -antihistamine used; and the route of administration. 14 2 was greater (i.e.than 40% more

13,15-17 and the andthe fifth 2 statistic. statistic. Accepted Article placebo in 10 adults with urticaria pigmentosa, Czarnetzki et al. pigmentosa,urticaria Czarnetzki with adults placebo in10 crossover the with three ketotifentwiceIn small 2mg months RCT daily for comparing effects other than noting that none were deemed serious. adverse theplacebo.rupatadine and20 The providedlittlethese detail with authors about duringwere 20 withtreatment adverseeffectsemergent by28 participants; reported have compromised allocationhave concealment. which while ketotifen, may the experienced tiredness taking patients indeed,40%of blinded; wasoutcome the and whether was generated sequence adequate on how an little detail with reduction inpruritus and wheals; however, this studywas to beat judged highrisk of bias H treatmenta rescue (10%), with (10.6% reduction;p=0.022) andemotions (18.5% p=0.006). reduction; patientsIn three reduction;improvement p=0.007), symptoms of (17.4% functions in thedomains significant in andresulted (16.1% qualitylife reductioninItchyQoL; p=0.004), specific symptom total of weekssignificantly oncedaily fourof that thereported rupatadine 20mg mean improved In the double-blind placebo-controlled crossover RCT of rupatadine, Siebenhaar et al. Main findings (i.e. none, mild, moderate, severe and very severe). scale Likert usinga 5-point evaluated were gastrointestinal headache and manifestations Thirdly,Darier’s sign including . itching, whealing,symptoms tachycardia,flushing, flaring, analoguevisualvalidated 10cm skin standardisedscale after provocation elicit testing to validated usinga (ItchyQoL).Secondly, instrument assessed was pruritus usinga measured in adults with primary MCAS; in the first, ketotifen compared withcompared 8patients(27%) during the placebo phase. rupatadine There were two trials investigating H were There investigating two trials Description of studies and a number of evaluations of and anumber performed. were poor needsquality methodological beinterpretedto andtherefore with caution. Studies comparingStudies H of H of ofrangeA outcomes were seen across trials the (Tablesbut allconsidered 3a-c), effect the We found limited evidence evaluatingWe H Summaryevidence of 1 -antihistamines on symptoms onwith-antihistamines inpatients primary MCAS. 17 17 was (seeTable 1a). studied 1 -antihistamine against placebo 1 -antihistamine was required during the rupatadine phasethe-antihistamine was required duringrupatadine 1 -antihistamines Bothwereconducted against placebo. 1 -antihistamines against placebo.was of Onestudy -antihistamines

In the rupatadine trial, 33 patients wererupatadine trial,33patients enrolled the In 17 life participants was of Firstly, quality of the 14 was and inevaluated the second 17 A total 40treatment of 14 reportedsignificant a 14 In contrast, contrast, In Accepted Article antihistamines andhydroxyzineketotifen were compared. comparingStudies H primary inadults antihistamines with MCAS. relieving abdominal pain and pruritus. in effective azelastinewas more overalleffectiveness, hadcomparable chlorpheniramine taste. a bitter metallic sedation, which mayor allocation have affected not concealment and azelastine caused more effectivemore thanketotifen symptom relief,for inchildren, hydroxyzine qualitywas that moderate of suggested MCAS. Twopublishedtrials investigators wereinvestigators blinded. quality asitwas unclear how sequence random the was generated and how andparticipants the trialbecause the of moderate-to-severe taste. bitter metallic than azelastineless fatigue Additionally,mg. 8.8 two onazelastine patients droppedout of undertaken in eight children with cutaneous mastocytosis, the first-generation H cutaneous childrenthe eight in with mastocytosis, undertakenfirst-generation We found two crossover RCTs in this category Table (see 1b). Inone small study Description of studies first-generation H H

daily. agents (p>0.20). agents (p>0.20). with sedation pain(p=<0.01) andabdominal bothespecially was of similar flushing The risk (p<0.05) symptoms improving dailyin times three 1mg effectiveketotifen than more In the adults with between the adults there urticariadifference pigmentosa, wasIn nosignificant study, pediatric the In Main findings the Siebenhaar of findings et al. There wasThere different comparing H little evidence Summaryevidence of reduction; chlorpheniramine 12azelastine 8.8and4.4 mg interms or bid symptom overall of bid mg mg cutaneous wheal response histamine. to cutaneous andflare reducing theat andalso and8.8 doses) (p<0.05) and pruritus mg 4.4pain (p<0.01) (both mg 1 -antihistamine azelastine or 4.4 azelastine mg 8.8 twicemg daily placebotwice and 16 16 however, azelastine (4.4 mg dose) was more efficacious inreducing was abdominal dose) more however, mg azelastine(4.4

1 -antihistamine chlorpheniramine-antihistaminetwice with the compared 12 dailywas mg 15 1 -antihistamines hydroxyzine daily times wasfour 2 tobesignificantlymg/kg found 15 15 In the second study in 15 adults with urticaria pigmentosa, thewith pigmentosa, secondstudyIn in 15adults urticaria the 17 are promising theand point likely ofto H effectiveness 16 16 These H 1 1 -antihistamines in the in primarytreatmentthe -antihistamines of -antihistamines caused varying degrees of varying -antihistamines caused 15

Chlorpheniramine was associated with wasChlorpheniramine associated andthat inadults, 15 This study was only of moderate 16 azelastine and 1 1 - - Accepted Article administration of anH six patientswith pruritus and of four sixpatientsthe with urticaria improved with co- the Three ofthe patients four with onnausea improved cromolyn Similarly, of sodium. thefive compared compared with cromolyn in sodium eight patients. two on H inadverse fatigue was effects; reporteddifference andbyon cromolyn patients sodium five moderate moderate of bias.risk provided onhow the randomisation sequence wasthereby generated introducing a mastocytosis, thesecond-generation H systemic systemic in whichmastocytosis, with treatment the H wasOnly a category: one study in found placebo-controlled eight RCT withthis adults in Description of studies after mild liver function test abnormalities were identified. wereabnormalitiesidentified. test liver function mildafter significant reductioninwhealingsignificant itching onstandardizedprovocation and testing toelicit skin participants,a of life of improvement inthequality significant placebo. A statistically to symptom symptom control when an H primary MCAS. The only published study nodemonstrated overallsignificant difference in administered with administered theH Despite H DISCUSSION reasonable size in the context of this body literature.contextthis of of in the reasonable size of and high quality reasonablywas of 2013that in published RCT however, identify one did, other wereidentified. methodological of number problems We a the likelylow power, to 1983 in whichand 1993 ranging study populations were small, 8-15 patients; from in addition identified publishedfour RCTthis widelyheldevidence tosupport orthodoxy.We between compared compared with cromolyn 200 sodium times dailymg four (see Table 1c). MCAS, Summaryevidence of physician evaluationsof disease status at the end of both cycles treatment of (p>0.50). between the two treatment regimens, nor was there a difference between and patient scores (p>0.05)wasThere of nodifference intheindividual symptom participantsthe Main findings comparingStudies H There is little evidence comparing ThereH littleevidencecomparing is 1-9,11 1 -/H 1 -antihistamines beingrecommended andusedin primarythe of management this systematic review clearly that demonstrates isthere little high quality 2 -antihistamines, and onH onepatient 1 -antihistamines against other pharmacologic agents 1 2 -antihistamine andanH -antihistamine daily, bothgiven 200 times four weremg, 1 -antihistamine co-administeredwithH an 1 -antihistamines with otheragents in thetreatment of 1 -antihistamine rupatadine was shown tobesuperior 13 2 -antihistamine. There-antihistamine. was nosignificant

1 - andH 1 -antihistamine chlorpheniramine-antihistamine 4 mg 17 In this study of 33adults with of study this In 2 -antihistamines waswithdrawn 2 -antihistamine was-antihistamine 13 13 Little detail was 13

Accepted Article guidelines. is antihistamines now officially worldwide recommended inchronic spontaneous urticaria rather thanrather H regarding choice of H regarding choiceof any to recommendations available weareunable make data, confident limited Owingto the and methodological heterogeneity theof participants studied. weInwere a conduct unableclinical concealment. addition, meta-analysis to the becauseof measures which of (some were and potentialvalidated), not problems with allocation controlinclusion orexclusioncriteria,inconsistent arms, subjective use outcome of and treatments studypopulations heterogeneity of which of poor of2013, or most were quality sizes,small studymoderate due to sample 1983- RCTs from of small published the numbers review this of relate to limitations The main abdominal pain, despiteabdominal H that fact the studies, investigated H roleof investigated the systematicreview have the first to is aware,we this as are As identified. far studies the contactingrepositories, international expertsinthisbibliographies the andsearching field, of three published of without research languagerestrictions,international databases trial to international standards by a comprehensive performing search electronicfive of it was conducted inthat initssystematic sound methodology reviewlies this of The strength to these medications. and other second-generationand other H designed, double-blind, placebo-controlled randomized trialstoinvestigate theuseof this contemporary of trial moderately urgent high the qualityneed suggest large, well-for response studiesarealso upto second-generation needed,as four-foldthese dosesof H Only gastrointestinal symptoms, which are due to the action of histamine at H which actionsymptoms, at histamine due of the to are Only gastrointestinal patientswithMoreover severe symptoms appeared the derivethemost to greatest benefit. headache), despite significantly lessuseof rescue weremedication, all demonstrated. Darier’s sign, , and asignificant reduction in symptoms (itching, tachycardiaflushing, and City. The views presented here are those of the author and not necessarily those of The The of those necessarily not and author of the those are here presented The views City. York New in based foundation independent aprivate Fund, Commonwealth The by supported AS was Acknowledgements

15,16 24 the H the

1 -receptors, were-receptors, not significantlyInterestingly, improved. intwo older 1 -antihistamines hydroxyzine andazelastine were to reported reduce 1 1 -antihistamine or dosing; however, the findings from the one the from or dosing; however, findings the -antihistamine -antihistamines in the treatment of primary MCAS. 1 -antihistamines in thetreatment of primary MCAS. Dose- 2 -antihistamine properties are not typically attributed studied, inconsistent descriptions of descriptions inconsistent studied,

2 -receptors 1 - Accepted Article 1. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, Definitions, etal. MC, Carter JH, Butterfield K, Brockow M, C, Arock ValentP, Akin 1. REFERENCES authorsdeclare thathave they no relevantconflict interests. of Board. Advisory Medical Uriach the of amember FERS is of interests: Conflict Ethical approval: Funding: article. the of on drafts commented authors and all the manuscript drafted UNandER studies. appraised critically extraction, data ER undertook with together and searches, undertook UN protocol. the drafted Author’s contributions: contributions. and time their for experts of the panel thank We or staff. officers, directors, its Fund, Commonwealth 8. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous of cutaneous andtreatment L.Diagnosis Escribano DD, M, Metcalfe Castells 8. 7. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A, Esteban-Lopez Esteban-Lopez Matito A, L, Sanchez-Munoz D, de Olano Gonzalez I, Alvarez-Twose 7. syndromes. activation cell Mast C. MJ, Akin Lee 2013; 3. diagnostic Proposed syndrome: activation cell Mast DD. Metcalfe P, Valent C, Akin 2. 6. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation cell Mast NJ. Greenberger MC, Castells JL,Akin C, Hornick MJ, Hamilton 6. classification. and definition syndromes: activation cell Mast P. Valent 2013; 4. 5. Frieri M, Patel R, Celestin J. Mast cell activation syndrome: a review. aMastactivation syndrome: cell J. Patel R,Celestin FrieriM, 5. 2011; mastocytosis recommendations. practical in children: proposal. aconsensus syndromes: activation cell to mast reference withspecial celldisorders mast of classification global and criteria Immunol symptoms. cellactivation systemic mast with presenting disorders cell clonal mast of characteristics and molecular biological, al.Clinical, Vega A,et MI, 2012; Clin Immunol Immunol Clin manifestations. clinical systemic with disorder recognized anewly syndrome: Asthma Rep criteria. criteria. None. None. 12 157 111 68 J Allergy Clin J AllergyClin Immunol :259-70. :259-70. :417-24. :417-24. 2010; :215-25. :215-25. :5-8. :5-8. Not required. 2013; 2011; 125 FERS and AS conceivedthe idea for this study and t :1269-78.e2. :1269-78.e2. 13 128 :27-32 :147-52.e2. :147-52.e2. 2010; 126 :1099-104. :1099-104. Ann Allergy Asthma Immunol Asthma Allergy Ann Int Arch Allergy Immunol Allergy Arch Int Am J Clin Dermatol Am JClin Allergy ogether with UN with ogether J Allergy Clin Clin Allergy J Curr Allergy

The other other The

J Allergy

Accepted Article 13. Frieri M, Alling DW, Metcalfe DD. Comparison of the therapeutic efficacy of cromolyn cromolyn of efficacy therapeutic ofthe Comparison DD. Metcalfe DW, Alling FrieriM, 13. Urticaria Urticaria in of ketotifen theeffect study of cross-over double-blind A BM. Czarnetzki 14. pigmentosa. Rupatadine improves quality of life in mastocytosis: a randomized, double- blind, blind, double- a randomized, in qualitylife of mastocytosis: Rupatadineimproves placebo-controlled A, F,Fortsch Siebenhaar Krause K, K, MetzWeller M, M, etal. Magerl trial. 17. azelastine of and Comparison DD. Metcalfe C, Berkebile ML, BS, Santiago Friedman 16. placebo-controlled, double-blind, DD.A Metcalfe D, Bradley C, Berkebile BV, Kettelhut 15. 11. Siebenhaar Maurer Siebenhaar F, Akin C, Bindslev-Jensen, M, Broesby-Olsen S. Treatment 11. Brockow K, ValentP, Grattan C, L,Broesby-Olsen Escribano S, Hartmann K, etal. 10. of manifestations clinical and Immunology MJ. MC, Hamilton Castells Juan-C, Cardet 9. 0 Alvarez-Twose Vano-Gakvan S, I, Sanchez-Munoz L,MorgadoJM, MatitoA, Torrelo 20. 1006-12. reviewsstatement the PRISMAsystematic and meta-analyses: 2009; Moher D, Liberati A, Tetzlaff J, Altman DG.Preferred reporting items for 19. of Reviews Systematic for CochraneHandbook (editors). S Green JPT, Higgins 18. 21. Higgins GP, Thompson SG, Deeks JS, AltmanDeeks JS, DG.inconsistency SG, Measuring Thompson in Higgins GP, meta- 21. 2 andH KJ. Histamine FER, Simons Simons 12. 62 mastocytosis. Results of a double-blind . trial. clinical adouble-blind of Results mastocytosis. in systemic and cimetidine chlorpheniramine combined of withthat sodium 1993; of mastocytosis. inthetreatment chlorpheniramine mastocytosis. of pediatric inthe treatment versus hydroxyzine ketotifen of trial crossover progress. strategies in mastocytosis. Immunol Immunol Allergy Clin 2014; in N Am strategies mastocytosis. Allergy 2014; on Mastocytosis. Network EuropeanCompetence the a of proposal patients with mastocytosis: for algorithm suspected Proposed diagnostic syndrome. cell activation mast non-clonal mastocytosis. Allergy 201267:813-21. predictors the for severity cell activation episodesmast of in children with serum are alIncreased skin involvement A, et and extensive levels baseline tryptase www.cochrane-handbook.org. from available 2011, Collaboration, Cochrane The March2011]. [updated 5.1.0 Version Interventions http://dx.doi.org/10.1016/j.jac.2014.01.012. http://dx.doi.org/10.1016/j.jac.2014.01.012. analysis. (10): 92 :520-6. :520-6. BMJ J Allergy ClinImmunol J Allergy Clin Immunol Clin Allergy J 2003; 327 Dermatologica Allergy (7414):557-60. 2013; 2011; 1983; 1989; 68 128 :949-52. :949-52. Curr Allergy AsthmaRep :1139-50. :1139-50. 166 83 1 :866-70. :866-70. -antihistamines: celebrating a century of century a celebrating -antihistamines: :44-7. :44-7. Am J Med J Allergy Clin Immunol Clin J Allergy 34 1985; ; 433-47. 2013; 69 . J Clin. Epidemiol 78 :1267-74. :1267-74. :9-14. :9-14. 13 :10-8. :10-8.

Accepted Article 2 Egger G, Schneider M,Davey M, Smith Biasal. et byin detected meta-analysis a 22. T, Zuberbier Aberer W, Asero R,Bindslew-JensenC, Bizoza et Z,CanonicaGW, al. 24. Begg Mazumdar CB, M. Operatingcharacteristics a rankof correlation for test 23. simple, graphical test. simple, 2014; Allergyupdate. and revision the 2013 urticaria: of diagnosis andmanagement AAAAI/Guideline definition,classification, the The EAACI/GA2LEN/EDF/ for WAO publication bias. 69 :868-87. Biometrics BMJ 1997; 1994; 315 50 :1088-101. :629-34. Accepted Article

FigurePRISMA 1: flow diagram MEDLINE MEDLINE 8

EMBASE EMBASE 17 17

papers are included for screening for included are papers After de-duplication 36 potentially 36 potentially de-duplication After from 5 databases were identified 51 potentially relevant papers Cochrane Cochrane Included Included Library Library (n=5) 3

CINAHL CINAHL

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• • • • 31 aesre 1 Case series 4 Cohort 1 CCT 25 Conceptual 15 duplications 15 duplications

papers definedas: excluded Science Science Web of 18 18 Accepted Article Country Year; Author & versus placebo Germany 2013 Siebenhaar Germany 1983 Czarnetzki Table 1a: Detailed characteristics of included studies comparing H

17 14

Design Population study crossover controlled placebo- randomized, blind, Double- study crossover controlled placebo- randomized, blind, Double- Diagnosis) and (Age, Gender involvement. and skin mastocytosis systemic indolent and 23with mastocytosis cutaneous maculopapular chronic stable - 7with y. agemean 49.4 y/o,- 20-70 excluded. laterfemales female), 3 - 33adults (23 pigmentosa -Urticaria female 6-10 adults; nevninOtoe Notes Intervention Outcome periods (Min: treatment 28 day consecutive 2 once aday (2) Placebo a day once 20 mg Rupatadine (1) 30d). Max 25d, twiceday. a Placebo, (2) day 2 twicemg a (1)Ketotifen periods treatment Three 30 day

week end of 4 baseline and assessed at Patients Likert scale. using 5 point severity symptom Evaluation of (3) analog scale. using visual severity pruritus of assessment sign and elicit Darier’s testing to provocation skin Standardized (2) treatment. weeks of each 4 ofend at the questionnaire ItchyQoL; validated Life using Quality of ofevaluation (1) Patient arms. treatment (scale of 0-3) of (scale whealing intensity of pruritus and record of Daily patient 1 -antihistamines

provided period/process washout of No details provided period/process washout of No details Accepted Article Country Year; Author & antihistamines 1993 Friedman USA 1989 Kettelhut Table 1b: characteristics Detailed of included studies comparingdifferent types H USA

16 15 Design Population trial crossover three period randomized, blind, Double- trial crossover controlled placebo randomized, blind, Double-

Diagnosis) and (Age, Gender mast cells. mast bone marrow number of had elevated 12levels, and histamine plasma elevated 15 had pigmentosa), (urticaria mastocytosis evidence of histologic - 15had 44.1 y agemean - 25-65y, (10 female) - 15patients splenomegaly. hepato- biopsyno and marrow bonenormal aspirate, but bone marrow in cells mast and increased mastocytosis cutaneous with diffuse 2pigmentosa, urticaria 6 with mastocytosis; - Cutaneous y- 1-8 female) (2 children 8 -

Intervention Outcome Notes placebo twicedaily. daily andketotifen four2 times mg/kg (2) hydroxyzineliquid timesfour a day. hydroxyzine placebo mg twice a day & (1) ketotifen liquid1 period.treatment followed bya 4-week a 2-week washout trial arms consisting of 62 consecutive week a day) of placebotwicedoses twice a day (and 2 (3) Azelastine, 8.8 mg a day) of placebotwicedoses twice a day (and 2 (2) Azelastine, 4.4 mg placebo twice a day) (and 2doses of daya twice 12 mg, (1) Chlorpheniramine, period. a 4-week treatment 2-week wash-outand aperiods; comprising trial 3 consecutive

end of each trial each end of trial at beginning and side effects diary (0-3)and symptom daily of (2) Assessment tests biochemistry count and complete blood levels,histamine (1) Plasma week intervals 2 at assessed Patients . urinalysis. and routine histamine urinary quantitative collection for urinehr (3) 24 arm taken. study drugs which no periods in treatment three first two of following period washout 2 week

1 - period the washout serving as weeks the first two arms with 6 week trial consecutive Two

Accepted Article Country & Year; Author with differentpharmacological therapies USA 1985 Frieri Table Detailed 1c: characteristics of included studies comparing H

13 Design Population trial crossover double randomized, blind, Double-

Diagnosis) and (Age, Gender splenomegaly. hepato- and 6 had on bonescans abnormalities had cells,7 mast bone marrow had elevated 6pigmentosa, 7 hadurticaria mastocytosis; - Systemic - 33-65y female) adults - 8(7

Intervention Outcome Notes 4 mg four times a a times four mg 4 chlorpheniramine (2) day. a times placebos four and cimetidine chlorpheniramine a day + times four mouth 200sodium bymg (1) Cromolyn periods. week treatment 102 consecutive four times a day. placebosodium a day +cromolyn times four 300 mg day + cimetidine (4) Patient Urinalysis (3) tests liver function blood count, (2) Complete levels. histamine and urine (1) Plasma intervals. 5 week evaluated at Patients scale) diary (0-4 symptom (5) Patient 5 scale. numerical 1- usingstatus; disease of assessment physician and

1 -antihistamines 10. end ofweek period at crossover and washout weeka 2 periods with treatment 10 week consecutive 2 Accepted Article & year year & Author year year or & Auth pharmacological therapies year & Author 3 ut Kettelh 1993 an Friedm Table of 2b: bias Risk of included studies comparingdifferent H 2013 aar Siebenh 1983 zki Czarnet TablebiasRisk of 2a: of includedcomparing studies H 1985 Frieri TablebiasRisk of : of includedcomparing studies H 1989

1 15 16 17 14

generati e sequenc e Adequat on Unclear on generati ce sequen e Adequat Unclear Yes on generati ce sequen te Adequa Yes Unclear ent concealm Allocation Yes ent concealm n Allocatio Yes Yes ent concealm n Allocatio Unclear Yes l personne andnts participa of Blinding Yes el personn nts and participa of Blinding Unclear Unclear el personn and nts participa of Blinding Yes Unclear Yes ent assessm outcome of Blinding Yes outcome outcome of Blinding ent assessm Yes Unclear ent assessm outcome of Blinding Unclear d? addresse data outcome te Incomple Yes outcome te Incomple d? addresse data Yes Yes 1 1 ed? address data outcome ete Incompl Yes Unclear -antihistaminesplacebo with -antihistaminesother with 1 -antihistamines ng reporti ve selecti Free of Yes ve selecti Free of ng reporti Yes Yes ng reporti ve selecti Free of Yes Yes

bias bias er oth e of Fre Yes oth e of Fre s bia er Yes Yes s bia er oth e of Fre Yes Yes

de Gra B de de Gra B B de de Gra C B

Accepted Article uhr&ya Main Findings Author &year placebowith 2013 Siebenhaar 1983 Czarnetzki TableSummary 3a: of main findings of included studies comparing H

17 14

severe. and 20 with rupatadine; none considered adverseemergent effects; 20 with placebo 28 reported participants - 40 treatment- non- compliance. was 1 participant withdrawn- of because therapy.rupatadine during experiencedThe second fatigue severe bone pain while taking placebo.the withdrew. 2 participants - Oneexperienced tirednessmoderate with ketotifen. 40% participants of experienced- to mild (pruritus) 0.010 p<0.025 ketotifen; with p<(whealing) and symptom Statisticallyreduction significant - eye surgerybecauseof and1 . 2withdrew; patients - 1 because ofurgent 8 (27%). during rupatadine treatment; 3 (10%) versus Fewer- patients rescuetherapyrequired p>0.05.symptoms tachycardia, andheadache, notGI but whealing,itching, flaring, flushing, Significant- improvementin day-to-day 30.3% reductionplacebo; p= 0.041. rupatadineduring treatment compared with Darier’s provocation skin toelicit sign testing for andpruritus whealing after standardized Significant- reduction in VisualAnalog Score received life, benefitrupatadine. from more ItchyQoL total score, that is,poorer quality of respectively). Those patientswith a higher emotions (17.4%, 10.6% and 18.5%, symptoms, of functions domains and in reduction thesignificant scores for p<0.004. Alsoreduction statistically ItchyQol scorewith rupatadine; 16.1% Significant improvement- in total mean 1 -antihistamines Accepted Article uhr&ya Main Findings Author & year antihistamines 1993 Friedman 1989 Kettelhut H different comparing studies included of findings main of Summary 3b: Table

16 15

less fati - Chlorpheniramine statistically associatedwith chlorpheniramine (p<0.05 andp<0.01). abdominal painwhentocompared azelastine significantly reduced pruritus and physician However, global evaluation. reductionoverall symptom andpatient and azelastineand chlorpheniramine of interms differenceNo between- statistically significant statistical difference between the two agents. azelastineboth andchlorpheniramine,no Mean histamine plasma - by levelsreduced and histamine morphine sulphate. wheal andflare response to intradermal - Azelastine statistically superior at reducing a severe of complaining taste. metallic bitter participantsazelastine, withdrew while taking was considered unrelated to the study. 2 second period with disease exacerbation that - 3- withdrawals: 1 biochemical testing not reported. - Results of serum haematological and 2 agents;the between p >0.20 - No significant difference in risk of sedation therapy levels followingwithhistamine treatment either - No significant differences in plasma or urine hydroxyzine; p<0.01. were with likelythe improve most to - Symptoms of andflushing abdominal pain scores; p<0.05. thanreducing atefficacious symptom ketotifen - Hydroxyzine was significantly more tocollected includein data analysis. final secondof arm of trial. Authors judged sufficient weeks2 final complete unable to participant1 - g ue (p<0.05). st withdrewon day 9 of

1 - Accepted Article uhr&ya Main findings Author & year with other pharmacological agents 1985 Frieri TableSummary 3c: of main findings of included studies comparing H / or DIPHENHYDRAMINE/ or or DIPHENHYDRAMINE/ or DOXYLAMINE/ / or / or PYRILAMINE/or / or or / or CETIRIZINE/ or / or LORATADINE/ or / or / or / or / or / 6. 5. 1 or 2 or 3 or 4 syndrom*.mp. cell activation mast 4. monoclonal eruptiva perstans.mp. 3. teleangiectasia macularis 2. urticaria pigmentosa.mp. or Urticaria Pigmentosa/ Systemic/ Mastocytosis,Mastocytosis/ or Mastocytosis.mp. or or Cutaneous/ Mastocytosis, 1. Search strategy: format MEDLINE Appendix 1 13

and H histamine levels following either treatment. levelsfollowingeither histamine change Nosignificant in urine or plasma - diseasestatus. of physician assessment differences Nosignificant and inpatient - therapy.antihistamine dizziness after 24 hours. dizziness after 2 experienced severe generalized pruritus and abnormalities after5abnormalities weeks ofH patient 1 developed test liver - function mild days. and nausea)of flushing andwithdrew 7after exacerbationdisease (predominant symptoms combined H combined between cromolyn diary), sodium and scoresdailya (assessed using symptom patient differencein Nostatistically - significant sodium) urticaria improved withH urticaria therapy.antihistamine 4of 6patients with - 5 patients 5complained - (2with H fatigue of treatment.antihistamine mean symptom 3.1 symptom scores versus mean 3.2, from pruritusfrom improved withH 5 6 patients suffering of sodium. cromolyn patients 3of 4with - nausea improved with respectively. - 2patientson - cromolyn withdrew:sodium 1 / or / or CLEMASTINE/ or DIMENHYDRINATE/ 2 -antihistamines, 3 with cromolyn 1 - and H 2 -antihistamine therapy: 1 - and H nd experienced a -antihistamines 1 - andH 1 - and H and - 2 - 2 - 2 -

1 - st

Accepted Article tromethamine or dexchlorpheniraminechloropyraminetromethaminecarebastine or Actifed or or or or orpicumastor protopine NCO650or or orlodoxamidemequitazine Zaditen ortritoqua orOtrivine-Antistinor Valoid oror PiritonDimotane Periactin or or Periactin Tavegil orUcerax Ataraxor Phenergan or polaramine or alomide orpolaramine rizaben).mp. or or or antivert ortinsetped optimine or stugeron histadyl sibelium or stugeron or forte or or dramamine orclistin or pbz-sr tussirex ortacarylor ebastelhismanal or orkestine or or nightcalm orpanadolnightor clarityn or medinex Benadrylor Livostindirect or opatanol or emadine or or or optilast relestat nytol ordreemon orPheniramine Dimethindene orbrompheniramine orChlorpheniramine antihistamin$ or or orOxatomide orHydroxyzine orCy or KetotifenCarbinoxamine or or orAzatadine or or Doxylamine oror Diphenhydramine Dimenhydrinate or Clemastine or Promethazine orMethdilazineTripelennamine or or Pyrilamine or Antazoline or Levocetirizine or Cetirizine or or or Doxepin or Loratadine or or Fexofenadine or Ebas or or Azelastine or Mianserinor M Actifed or or carebastine dexchlorpheniramineor or lodoxamidetromethaminemequitazine or or orprotopine orproxicromil temelastine or or Atarax or PhenerganOtrivine-Anti orZaditen oror Mizollen Vallerganor Piriton or orDimotane Periactin or Periactinor Ucerax Tavegil or H1 Antagon Histamine exp CHLORPHENIRAMINE/ or / orPHENIRAMINE/ orDIMETHINDENE/ orBROMPHENIRAMINE/ or or / or or HYDROXYZINE/ MECLIZINE/ or CYPROHEPTADINE/ or KETOTIFEN/ This article This protectedis by Allcopyright. rights reserved. H (Histamine And syndrome)activation cell orcutaneous or systemic(mastocytosis mastocytosis mast ormonoclonal mastocytosis Search strategy: format free-field 568. and and7 and animals)).sh. oras topic.sh. or clinicaltrialsplacebo.ab. randomly.ab. or trial.ti.)(animals not (humans 7. ((randomized controlled orrandomized.ab. clinical trialor trial).pt. controlled or 1 antagonistsor Neoclarityn or Telfast or VallerganXyzalMizollen or or or ethapyrileneor CinnarizineFlunarizine or or Terfenadine orOlopatadineMizolastine or picumastNCO or 650ormirtazapine or line or Tranilast or temelastine or proxicromil stin or Valoid oror stin or Tranilast or allergy or nyquil or sinequan or xepin allergy ornyquil orsinequan clizine orBuclizineTriprolidineclizine or tine orDesloratadineor Astemizoletine or or Xyzal(Neoclaritynor Telfast or ists/ Accepted Article ((single ordoubleor triple SAMEtreble) or (mask*or blind*)) or(random* placeboor prospective) multicenter or or or ((controlled clinical) SAME trial*) or And histadyl or sibelium forte or or alomide or polaramine rizaben) or ortussirexantivert dramamine clistin or or pbz-sr xepinor or or sinequan allergynyquil or or optilastorrelestat nytol or ordreemon ornightcalm or panadolnightmedinex orclarityn or Chlorpheniramine or antihistamin* or Benadryl orLivostindirect or opatanol oremadine or or Cyclizine or or BuclizineTriprolidine or or Dimethindene orPheniramine MeclizineHydroxyzineor AzatadineDiphenylpyralineor Cyproheptadineor or DimenhydrinateDiphenhydramine or or CarbinoxamineClemastineKetotifen or or or or PyrilamineAntazoline orTripelennamine or Phenyltoloxamine or or Doxylamine Promethazine orAlimemazine orMethdilazineAcrivastine orDoxepin or Tartrate or Fexofenadine or orDesloratadine or As Azelastine orTerfenadine orOlopatadine or orLoratadine or Levocabastine or Mianserinor Methapyrilene orFlunarizineor This article This protectedis by Allcopyright. rights reserved. or tinset ped or optimine or stugeron or stugeronstugerontinset ped oroptimine or or or CinnarizineEmedastineEpinastine or or or tacaryl or hismanal or kestine or ebastel or or or kestine or hismanal tacaryl temizole or Levocetirizine or CetirizineLevocetirizine or or temizole or