Childhood Takayasu arteritis: disease course and response to therapy

Transcription

1 eschlmann et al. rthrts Research & Therapy (2017) 19:255 DOI /s RESERCH RTICLE Chldhood Takayasu arterts: dsease course and response to therapy Open ccess Florence. eschlmann 1, Smon W. M. Eng 2, Shehla Shekh 1, Ronald M. Laxer 1,3, Dane Hebert 4, Damen Noone 4, Marnka Twlt 5, Chrstan Pagnoux 6, Susanne M. Benseler 5 and Rae S. M. Yeung 1,2* bstract Background: Takayasu arterts (TK) s a large vessel vascults that rarely affects chldren. Data on chldhood TK are scarce. The am of ths study was to analyze the presentng features, course and outcome of chldren wth TK, compare effcacy of treatment regmens and dentfy hgh-rsk factors for adverse outcome. Methods: sngle-center cohort study of consecutve chldren fulfllng the EULR/PRINTO/PReS crtera for chldhood TK between 1986 and 2015 was performed. Clncal phenotypes, laboratory markers, magng features, dsease course and treatment were documented. Dsease actvty was assessed usng the Pedatrc Vascults Dsease ctvty Score at each vst. Outcome: dsease flare defned as new symptoms and/or ncreased nflammatory markers necesstatng therapy escalaton and/or new angographc lesons, or death. nalyss: logstc regresson tested relevant varables for flare. Kaplan-Meer analyses compared treatment regmens. Results: Twenty-seven chldren were ncluded; 74% were female, medan age at dagnoss was 12.4 years. Twenty-two (81%) chldren presented wth actve dsease at dagnoss. Treatment regmens ncluded cortcosterods alone (15%), cortcosterods plus methotrexate (37%), cyclophosphamde (19%), or a bologc agent (11%). dverse outcomes were documented n 14/27 (52%) chldren: two (7%) ded wthn 6 months of dagnoss, and 13 (48%) experenced dsease flares. The 2-year flare-free survval was 80% wth bologc treatments compared to 43% n non-bologc therapes (p = 0.03); at last follow-up, bologc therapes resulted n sgnfcantly hgher rates of nactve dsease (p =0.02). No addtonal outcome predctor was dentfed. Conclusons: Chldhood TK carres a hgh dsease burden; half of the chldren experenced flares and 7% ded. Bologc therapes were assocated wth better control of dsease actvty. Keywords: Takayasu arterts, Chldren, Bologc therapy, Vascults Background Chldhood Takayasu arterts (TK) s the most common large vessel vascults n chldren. It s characterzed by ntramural granulomatous nflammaton of the aorta and ts major branches [1, 2]. Vessel nflammaton prmarly causes wall thckenng, stenoss and thrombus formaton resultng n organ dysfuncton secondary to schema [3]; however aneurysms and dssectons can be seen [4]. Chldhood TK s a devastatng dsease wth mortalty * Correspondence: rae.yeung@sckkds.ca Equal contrbutors 1 Dvson of Rheumatology, Department of Pedatrcs, The Hosptal for Sck Chldren, Unversty of Toronto, 555 Unversty venue, Toronto, ON M5G 1X8, Canada 2 Department of Immunology, Unversty of Toronto, Toronto, ON, Canada Full lst of author nformaton s avalable at the end of the artcle rates as hgh as 35% [5 8]. The pathogeness remans unclear; however, nflammaton s a central feature. Cellmedated mmune mechansms and ther dstnct pattern of secreted pro-nflammatory cytoknes are assocated wth TK [9]. Control of vascular nflammaton and preventon of rreversble vessel njury and organ damage are the man treatment objectves n TK. Treatment recommendatons from adequately powered pedatrc and adult trals are lackng [3, 10, 11]. Most avalable evdence on mmunosuppressve agents and ther effcacy s derved from adult observatonal cohorts [12 14]. Cortcosterods are currently the manstay of treatment, but approxmately half of all patents requre addtonal mmunosuppresson [15]. Cyclophosphamde, The uthor(s) Open ccess Ths artcle s dstrbuted under the terms of the Creatve Commons ttrbuton 4.0 Internatonal Lcense ( whch permts unrestrcted use, dstrbuton, and reproducton n any medum, provded you gve approprate credt to the orgnal author(s) and the source, provde a lnk to the Creatve Commons lcense, and ndcate f changes were made. The Creatve Commons Publc Doman Dedcaton waver ( apples to the data made avalable n ths artcle, unless otherwse stated.

2 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 2 of 10 methotrexate (), azathoprne, mycophenolate mofetl (MMF) or leflunomde have been used wth varable response [11 13, 16]. recent study suggested hgh effcacy of bologc therapes n adult TK patents wth refractory dsease course [17]. To date, t remans unclear how to best control dsease actvty and prevent organ damage n chldren wth TK. Effcacy and safety of dstnct treatment regmens reman to be determned. Indvdual rsk factors for dsease progresson and flares n chldhood TK are unknown. Therefore, the ams of the study were: 1) to descrbe the presentng clncal, laboratory and angographc features of chldhood TK patents, 2) to explore and compare effcacy and safety of chldhood TK treatment regmens and 3) to attempt to dentfy rsk factors for adverse patent outcome n chldhood TK. Methods Ths sngle-center retrospectve cohort study ncluded all consecutve chldren 18 years of age at dsease onset and dagnosed wth chldhood TK accordng to the European League aganst Rheumatsm (EULR)/Pedatrc Rheumatology Internatonal Trals Organzaton (PRINTO)/ Pedatrc Rheumatology European Socety (PReS) fnal classfcaton crtera for chldhood Takayasu arterts (nkara 2008) between January 1986 and September 2015 [18]. Pror to 2009, chldren were classfed based on the mercan College of Rheumatology crtera for vascults [19, 20]. Chldren were dentfed from the nsttutonal database. Two ndependent revewers collected all data usng standardzed forms at predefned tme ponts ncludng; at presentaton, 6 months (after nducton treatment), durng flares, medcaton change, nterventons, complcatons and last follow-up (F, SS). Ths study was performed accordng to the Declaraton of Helsnk and approved by the nsttutonal research ethcs board ( ). Data collecton: demographc features, clncal, laboratory and angographc fndngs Baselne demographc data ncludng age at symptom onset and at dagnoss, gender, ethncty and past medcal hstory were recorded. Clncal characterstcs ncluded consttutonal symptoms such as weght loss, malase and fever, as well as sgns and symptoms of organ nvolvement. rteral hypertenson was defned as blood pressure > 95th percentle for age. Blood pressure dscrepancy was defned as a dfference of 10 mmhg between lmbs. Laboratory results ncluded erythrocyte sedmentaton rate (ESR), C-reactve proten (CRP), complete blood cell count, creatnne, von Wllebrand factor antgen, antnuclear and antneutrophl cytoplasmc antbodes, protenura and hematura. Tuberculoss testng results were recorded. Vascular magng studes ncluded conventonal angography, magnetc resonance angography (MR), computed tomography angography (CT) and echocardography studes. Locaton, type and characterstcs of lesons such as stenoss (<50% lumen), narrowng, aneurysm, dlataton, dssecton, vessel wall thckenng and post-contrast enhancement were captured. Vascular magng was documented when performed wthn 1 month of the predefned data collecton tme ponts. Treatment and complcatons Current medcaton, vascular and surgcal nterventons were recorded. Dsease and treatment-related complcatons ncluded arteral dssecton, treatment-related sde effects and severe nfectons necesstatng hosptalzaton. Dsease actvty and damage Dsease actvty was assessed at each vst usng the valdated Pedatrc Vascults ctvty Score (PVS) [21] and the Indan Takayasu rterts ctvty Score (ITS2010), whch was recently valdated n adult Indan TK patents [22]. Dsease damage was assessed usng the Pedatrc Vascults Damage Index (PVDI), a damage assessment tool modfed from the adult Vascults Damage Index [23]. The PVS and PVDI were systematcally completed at each clnc vst as part of routne clncal practce at our nsttuton snce For patent vsts before 2009, the PVS and PVDI were retrospectvely completed by two ndependent revewers (F, SS); dscrepances were resolved by a thrd revewer (SMB). The ITS2010 was retrospectvely assessed for all vsts. ll three scores assess the multsystem nvolvement n chldhood TK. PVS and ITS2010 measure dsease actvty ncludng symptoms that newly occurred or worsened over the past 4 weeks or are persstent for less than 3 months. The PVS s currently the only valdated dsease actvty measurement tool n chldhood vascults and routnely used for clncal research [21]; however, t may not be optmal for assessment of dsease actvty n pedatrc large vessel vascults. The ITS2010 has been specfcally developed for assessment of dsease actvty n TK patents [22], but has not been valdated n chldren and s therefore not routnely used n chldhood TK. Gven these specfc features, both, the PVS and ITS2010 were used for assessment of dsease actvty. In contrast to the PVS and ITS2010, the PVDI assesses rreversble cumulatve dsease-related damage and only ncludes symptoms present for more than 3 months. Defntons ctve dsease was defned as PVS 1 and/or rased nflammatory markers and/or magng evdence of actve dsease ncludng new angographc lesons, vessel wall

3 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 3 of 10 nflammaton by post-contrast enhancement and thckenng. Inactve dsease was defned by the concurrence of all three, a PVS of zero and normal nflammatory markers and nactve dsease on magng. Dsease flare was defned as occurrence of new TK symptoms and/ or ncrease of nflammatory markers necesstatng altered treatment and/or new or worsenng angographc lesons. The duraton of stable dsease pror to dsease flare was not further defned. Inactve dsease was defned by the treatng expert clncan. Treatment response was defned as a 50% reducton n the PVS at 6 months after treatment start. Outcome Prmary outcome was dsease flare or death. Secondary outcomes ncluded dsease actvty as defned above and dsease damage as measured by PVDI at last follow-up. nalyss Patents were analyzed n groups dependng on type of nducton therapy. Flare-free survval of bologc or nonbologc treatments was calculated usng Kaplan-Meer methods. s each chld could experence multple flares, a tme-to-event analyss was used. Therefore, the tme orgn for each treatment was consdered the tme when the chld was started on treatment. Logstc regresson was used to dentfy prognostc factors of adverse outcome. The followng varables were studed as potental predctors: age, gender, PVS, ITS2010, ESR, platelet count and treatment category (bologc versus nonbologc treatment). The analyss was adjusted for the number of treatment epsodes per patent. Varables wth more than 20% mssng values were excluded. Categorcal varables were compared by Fsher s exact test, odds ratos (OR) were calculated ncludng the 95% confdence ntervals (95%-CI). Contnuous varables were reported as medans wth nterquartle range (IQR), categorcal varables as percentages wth frequences. nalyses were conducted n Prsm (GraphPad 6.0 g, San Dego, C, US) and R 3.12 (Venna, ustra). Results Demographc features, clncal and laboratory fndngs total of 27 chldren wth TK (74% females) were ncluded. Twenty-two chldren (81%) had evdence of actve dsease at dagnoss. The medan age at dagnoss was 12.4 years (IQR ). The medan duraton from symptom onset to dagnoss was 6 months (IQR ). Medan follow-up duraton was 2.1 years (IQR ). Demographc features are summarzed n Table 1. The most common symptoms at presentaton were malase (48%), headaches (33%) and weght loss (30%). Blood pressure dscrepancy (67%), decreased or absent pulse (59%), arteral hypertenson (56%) and bruts over Table 1 Demographc features Patent characterstcs at baselne Patents (N = 27) Female (%) 20 (74) ge at dagnoss, years 12.4 ( ) Duraton symptom onset to dagnoss, months 6 ( ) Follow-up duraton, years 2.1 ( ) Ethncty (%) Caucasan 8 (30) san 4 (15) Black 3 (11) Hspanc 2 (7) East Indan/South san 2 (7) Mddle Eastern 2 (7) borgnal/frst Naton 2 (7) Unknown 4 (15) Values are presented as absolute numbers (%) or medans (IQR) large vessels (56%) were the most frequent fndngs on physcal examnaton. The presentng clncal features are shown n Table 2. Three patents (11%) were dagnosed wth tuberculoss at presentaton of chldhood TK. Two chldren had been dagnosed wth nflammatory bowel dsease based on classc hstopathology fndngs pror to the onset of TK. t tme of dagnoss, nflammatory markers were elevated n 21 chldren (78%). ESR was ncreased n 20/ 25 (80%), CRP n 14/19 chldren (74%). Laboratory results are presented n Table 2. The medan PVS at dagnoss was 10 (IQR 7 18), the medan ITS (IQR 10 18). ngographc features MR alone (11/27, 41%) or n combnaton wth CT or conventonal angography (3/27, 11%) was most commonly performed at dagnoss. Conventonal angography was the ntal magng modalty n 9/27 (30%) chldren, and CT n 3/27 (11%). The most frequently nvolved vessels were the abdomnal aorta (89%), the renal (67%) and carotd arteres (56%). Fgure 1 depcts the frequences of the nvolved vessels. Treatment Twenty-two of 27 chldren (81%) receved mmunosuppressve therapy (Fgs. 2 and 3). Fve (19%) were consdered to have nactve dsease at dagnoss and therefore dd not receve mmunosuppressve agents. Inducton treatment Patents wth actve dsease at dagnoss (22) receved dfferent treatment regmens. Intally, 4/27 chldren (15%) receved hgh-dose cortcosterods only, and 18 (67%) receved a combnaton of cortcosterods plus

4 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 4 of 10 Table 2 Presentng clncal and laboratory features Presentng features Symptoms: Patents (N = 27) Consttutonal: Malase 13 (48) Weght loss 8 (30) Fever (> 38.0 C) 5 (19) Lymphadenopathy 3 (11) Cardovascular: Claudcaton of the extremtes 6 (22) Neurologcal: Headache 9 (33) Dzzness 5 (19) Stroke/TI 3 (11) Syncope 3 (11) Chronc nausea/vomtng 5 (19) Gastrontestnal: Nonspecfc abdomnal pan 4 (15) Pulmonary: Shortness of breath 4 (15) Chest pan 3 (11) Musculoskeletal: Back pan 5 (19) Ocular: Blurred vson/uvets/retnal hemorrhage 4 (15) Fndngs on clncal exam: Blood pressure dscrepancy 18 (67) Decreased or absent pulse 16 (59) rteral hypertenson 15 (56) Bruts over large arteres 15 (56) Laboratory characterstcs: ESR, mm/h 35 (17 74) CRP, mg/dl 31.9 ( ) Hemoglobn, g/l 115 ( ) Whte blood cells, 10^9/L 8.8 ( ) Platelets, 10^9/L 366 ( ) vwf antgen, IU/mL 1.6 ( ) Impared renal functon 2 (7) N 8/22 (36) NC 2/18 (11) Clncal features present n > 10% of the patents wth chldhood TK are lsted. Impared renal functon was defned as a creatnne ncrease of > 30% of the upper normal lmt at dagnoss. Values are presented as numbers (%) or medans (IQR) TI transent schemc attack, ESR erythrocyte sedmentaton rate, CRP C- reactve proten, vwf antgen von Wllebrand factor antgen. N antnuclear antbody, NC antneutrophl cytoplasmc antbody another mmunosuppressve agent. These mmunosuppressve agents prescrbed n combnaton wth cortcosterods ncluded n ten (37%), cyclophosphamde n fve (19%), and plus a bologc agent n three (11%) chldren. The latter three chldren receved tumor necross factor alpha (TNF-α) nhbtors, two nflxmab and one adalmumab. Two of them had been already on TNF-α nhbtors for pre-exstng nflammatory bowel dsease, when dagnosed wth chldhood TK. t dagnoss of chldhood TK, both were started on hgh-dose cortcosterods and ; n addton, the TNF-α nhbtor dosng was ncreased. Therapy was chosen at the dscreton of the treatng physcan and the avalablty of the drug. PVS and ITS2010 dd not sgnfcantly dffer between the four nducton treatment groups at dagnoss. t 6 months 20/22 treated chldren survved and 18/20 survvng chldren (90%) had responded to the treatment (Fg. 3). Mantenance treatment t 6-month follow-up, all 20 survvng chldren remaned on cortcosterods at a medan dose 0.4 mg/ kg/day prednsone equvalent (IQR mg/kg/day). Mantenance treatment vared and ncluded, azathoprne, MMF and leflunomde or one of them combned wth bologcs. n overvew of the treatment regmens s shown n Fgs. 2 and 3. Co-therapes Most chldren (18/27, 67%) receved anthypertensve drugs (medan 1, 0 3). Low-dose acetylsalcylc acd was prescrbed to 15/27 (56%) and antcoagulaton to 6/27 (22%) chldren. 6 to 9-month course of anttuberculoss treatment was ntated smultaneously wth mmunosuppressve therapy n the three chldren dagnosed concomtantly wth tuberculoss. Surgcal and endovascular nterventons Eght of 27 patents (30%) requred vascular surgery or nterventon after dagnoss of chldhood TK. Eghteen procedures were performed: renal artery angoplasty (eght procedures n four patents), balloon dlataton of the aorta (four procedures n two patents) and axllaryfemoral bypass, coronary bypass and embolectomy of the femoral artery n one patent each. nother chld requred a splenorenal shunt, local thrombolyss due to thromboss and eventual nephrectomy. Two patents receved surgcal treatment pror to chldhood TK dagnoss (unlateral nephrectomy wth subsequent renal revascularsaton procedure and balloon dlataton of the aorta). Complcatons Complcatons were dvded nto dsease- and treatmentrelated complcatons. rteral dssecton was noted n three chldren (11%) at dagnoss; no new dssectons were seen durng follow-up. Cerebral nfarcton wth consecutve cranectomy (due to ncreased ntracranal

5 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 5 of 10 Carotd arteres Vertebral arteres Subclavan arteres ortc arch Pulmonary arteres Thoracc aorta Coronary arteres Celac trunk Superor mesenterc artery Renal arteres Inferor mesenterc artery bdomnal aorta Ilac arteres 56% 26% 44% 48% 19% 37% 11% 37% 41% 67% 0% 89% 26% Fg. 1 Frequency of arteral vessel nvolvement at dagnoss. Frequences (%) of patents wth any leson (stenoss, narrowng, aneurysm, dlataton, dssecton, vessel wall thckenng and post-contrast enhancement) n the ndcated vessel. Frequences of pared vessels (rght/left) are presented as one combned value pressure) and ntestnal schema requrng ntestnal resecton were documented n one chld each. Relevant treatment-assocated sde effects ncluded Cushng syndrome n 21/22 chldren on cortcosterods, transamnts defned as transamnase levels twce the upper lmt of normal n four chldren and vertebral fractures n one chld. Four severe nfectons n four chldren requred hosptalzaton ncludng one chld treated wth cortcosterods and who developed canddema. Three chldren treated wth cortcosterods and cyclophosphamde were hosptalzed for severe Epsten-Barr vrus (EBV) nfecton, varcella zoster nfecton and bacteral sepss followng bowel schema. Outcomes Prmary outcome total of 14/27 (52%) patents experenced adverse outcomes; 13 (48%) developed a dsease flare and two chldren ded (7%), one durng a flare. The frst flare occurred at a medan of 9.0 months after dagnoss (IQR ). Twenty-one flares were observed durng the study perod: 16 (76%) were dagnosed by new angographc lesons, three (14%) by both new clncal symptoms and ncrease of acute phase reactants and two (10%) by ncrease of acute phase reactants only necesstatng treatment alteraton (start of nflxmab n one, dose ncrease of cortcosterods and methotrexate n the Year of dagnoss Inducton Mantenance Patents Tme Dagnoss 6 months 12 months 18 months 24 months Medcatons Cyclophosphamde Methotrexate Events Dsease flare Death x ddtonal tme, n x months ctve tuberculoss at dagnoss Dsease status ctve dsease Inactve dsease Cortcosterods zathoprne Mycophenolate mofetl Bologc agents Fg. 2 Inducton and mantenance treatment regmens n chldren wth chldhood TK presentng wth actve dsease (N = 22). Colored lnes depct dfferent therapeutc agents. The patents are grouped accordng to ther nducton phase therapy: 1. cortcosterods (grey) only, 2. cortcosterods n combnaton wth methotrexate (lght blue), 3. cortcosterods n combnaton wth cyclophosphamde (dark blue) and 4. cortcosterods n combnaton wth bologc agents (red) and methotrexate. The tmelne s drawn to scale up to 24 months; addtonal tme of treatment s shown n months between break lnes. lso depcted are clncal events, ncludng dsease flare, death, tuberculoss nfecton at dagnoss and dsease actvty (actve/nactve) at last follow-up Leflunomde

6 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 6 of 10 ctve dsease at dagnoss Inducton treatment CS * CS ** CS *** only + + Cyclo CS + + bologcs 13 (9 17) 16 (9 19) 1 of 3 Med. PVS at pres. (IQR) Med. ITS2010 at pres. (IQR) 16 (10 21) 15 (7 22) 2 of 10 7 (7 32) 10 (6 25) 10 (5 21) 16 (13 17) 2 of 4 3 of 3 Inactve dsease at 6 months Mantenance treatment Z Pred Z Z + bologcs MMF Cyclo + Z IFX Z + IFX TCZ + IFX + IFX Chldren wth flares durng FU Inactve dsease at last FU Med. PVDI (IQR) at last FU 3 of 4 1 of 3 5 (3 7) 6 of 10 5 of 10 5 (4 6) 3 of of 3 3 of 4 3 of 3 5 (4 6) 4 (2 6) Fg. 3 Measures of dsease actvty and damage n the 22 chldhood TK patents wth actve dsease at dagnoss. The squares represent ndvdual patents. Z azathoprne, CS cortcosterods, Cyclo cyclophosphamde, FU follow-up, IFX nflxmab, ITS2010 Indan Takayasu rterts ctvty Score, MMF mycophenolate mofetl, methotrexate, PVS Pedatrc Vascults ctvty Score, PVDI Pedatrc Vascults Damage Index, TCZ toclzumab. *One chld was started on cyclophosphamde treatment at 6 weeks and ded at tme of flare at 4 months after dagnoss. **One chld was started on cyclophosphamde treatment 6 weeks after dagnoss. ***One chld ded 12 days after dagnoss other patent). The number of flares vared between one and three per patent. ll but one chld flared whle recevng mmunosuppressve therapy. Flares were treated by ntensfcaton of therapeutc regmens such as ncrease or restart of cortcosterods and/or start of an addtonal mmunosuppressve drug such as cyclophosphamde, azathoprne or a bologc agent. Fgure 2 depcts flares and ndvdual treatment regmens. When analyzng treatment epsodes separately, 19 flares occurred durng 44 non-bologc treatment epsodes (43%) compared to only two flares durng 12 bologc treatment epsodes (17%) (p = 0.18; OR 3.80, 95% CI ). Medan cortcosterod dose at tme of flare was 0.4 mg/kg/day (IQR ) prednsone equvalent. None of the patents wth nactve dsease at tme of dagnoss experenced an adverse outcome. The 2-year flare-free survval was 80% wth bologc treatments compared to 43% n non-bologc treatments when adjusted for the number of treatment epsodes per patent (p = 0.03) (Fg. 4). Bologc agents ncluded nflxmab (5 mg/kg at 0, 2 and then every 4 weeks) n nne treatment epsodes, adalmumab (40 mg every 2 weeks) n one and toclzumab (8 mg/kg monthly) n two. Two chldren ded from TK, both wthn 6 months of dagnoss. four-year-old boy presented wth a 3- month hstory of arteral hypertenson, blood pressure dscrepancy between lmbs and absent pedal pulses. Conventonal angography revealed nvolvement of the abdomnal aorta, the superor mesenterc, celac and blateral renal arteres. Hgh-dose cortcosterods, antcoagulaton and quntuple anthypertensve therapy were started. Cyclophosphamde was added 1 month after dagnoss due to progressve dsease. He ded 4 months after dagnoss followng dsease flare wth uncontrollable hypertenson and massve ntestnal schema wth sepss. 13-year-old grl presented wth a 3-week hstory of consttutonal symptoms, cough, chest pan, headaches and arteral hypertenson. MR showed extensve nvolvement of the abdomnal aorta, celac, superor mesenterc, pulmonary, renal and lac arteres. She receved hgh-dose cortcosterods, cyclophosphamde, antcoagulaton and quadruple anthypertensve therapy. She ded of uncontrollable dsease and massve left mddle cerebral arteral nfarcton followng an embolsm of a left ventrcular thrombus and mult-organ falure 12 days after dagnoss. The treatment regmens of both chldren are shown n Fg. 2. Predcton No addtonal prognostc factors of adverse outcome were dentfed usng logstc regresson. None of the putatve predctve varables were ndependently assocated wth an ncreased rsk for adverse outcome; therefore, none were able to dentfy hgh-rsk chldren early on. Secondary outcomes t last follow-up at a medan of 2.1 years, eght of 20 survvng patents (40%) wth actve dsease at dagnoss had contnued actve dsease, whle 12 of 20 (60%) were consdered nactve. ll 20 survvng patents remaned on mmunosuppressve treatment at last follow-up vst. Medan PVS was 0 (IQR 0 0) and medan ITS (IQR 0 1) at last follow-up vst. Of the eght chldren wth ongong dsease actvty, two receved bologc agents and sx non-bologc mmunosuppressve therapes. Most of the patents on non-bologc drugs were dagnosed earler n the study perod, pror to frst avalable publcatons of successful treatment of chldhood TK wth bologc agents [10] (Fg. 2). Importantly, 9/12 chldren wth nactve dsease on treatment had

7 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 7 of 10 a % of flare free epsodes P = 0.10 Treatment Cortcosterods + bologc agents Cortcosterods + cyclophosphamde /azathoprne/mmf ± cortcosterods Cortcosterods only Censored events Last follow up Medcaton change b Tme (months) % of flare free epsodes P = 0.03 Censored events Last follow up Medcaton change Treatment Bologc agents Non bologc agents Tme (months) Fg. 4 Flare-free survval n the 22 chldhood TK patents wth actve dsease at dagnoss. a Flare-free survval separated nto dfferent treatment groups (bologcs N = 12; cyclophosphamde N = 10; cortcosterods only N = 4; methotrexate/azathoprne/mycophenolate mofetl/leflunomde N = 30 treatment epsodes), adjusted for the number of treatment epsodes. b Flare-free survval grouped nto bologc therapy (N = 12 treatment epsodes) and non-bologc therapy (methotrexate, azathoprne, mycophenolate mofetl, leflunomde, cortcosterods, cyclophosphamde, N = 44 treatment epsodes), adjusted for the number of treatment epsodes receved bologcs; three were treated wth non-bologc therapes ncludng cortcosterods, and azathoprne (p = 0.02, OR 21.00, 95% CI ). The fve chldren wth bochemcally nactve dsease at dagnoss mantaned nactve dsease wthout treatment throughout the study perod untl last follow-up. The most commonly accrued dsease damage at last follow-up were vessel stenoss (100% of survvng chldren), absent pulses (70%), claudcaton of the extremtes (33%), cerebrovascular accdents (26%) and sezures (11%). Medan PVDI was 4 (IQR 3 6) and dd not sgnfcantly dffer n the four treatment groups. Dscusson Ths study analyzed one of the largest contemporary chldhood TK cohorts to date. The clncal presentaton of chldhood TK was heterogeneous. Overall, 81% of chldren presented wth sgns and symptoms of systemc nflammaton, actve vessel wall dsease and crtcal organ perfuson. Vascular nvolvement was hghly varable; the abdomnal aorta and the renal arteres were most commonly affected. Chldhood TK has a dramatc morbdty and early mortalty; 48% experenced dsease flares and two chldren ded wthn months of dagnoss. The comparatve analyss of treatments revealed that chldren treated wth bologc therapes had sgnfcantly fewer flares and acheved nactve dsease status more frequently suggestng a potental beneft of bologc agents over non-bologc mmunosuppressve drugs. Chldren wth TK presented wth hghly varable clncal phenotypes reflectng the varable locaton and extent of vascular nflammaton. The most common clncal fndngs at presentaton were consttutonal symptoms, headaches, blood pressure dscrepancy, decreased perpheral pulses and hypertenson correspondng to data from

8 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 8 of 10 publshed pedatrc reports [7, 8, 24]. The majorty presented wth ncreased nflammatory markers ncludng CRP and ESR. Whle the senstvty of these markers s hgh for actve TK, they lack specfcty [3, 25]. The dsease heterogenety reflects our nablty to dentfy chldhood TK patents at rsk for treatment falure and dsease flare, whch reman a serous concern. We documented a flare rate of 48%, consstent wth recent pedatrc seres (37 4%) [6 8]. Early mortalty rate was hgh (7%); however, mortalty rates as hgh as 27% have been reported n chldhood TK [6, 26, 27]. Chldren treated wth bologc agents had sgnfcantly better outcomes compared to chldren treated wth nonbologc therapes. Flare-free survval rates were hgher for bologc therapes (TNF-α nhbtors or toclzumab) compared to non-bologc therapes (80% versus 43% at 2 years, p = 0.03). Further, chldren recevng bologc therapes were more lkely to acheve nactve dsease at last follow-up compared to chldren treated wth nonbologc agents (, azathoprne, MMF) (p = 0.02). Overall, the medcatons used had reasonable safety profles over the short observaton perod. In the pathogeness of TK, TNF-α and nterleukn-6 (IL-6) were shown to play an mportant role n promotng vascular nflammaton [28, 29]. The effectveness of TNF-α nhbtors was reported n one pedatrc [10] and several adult TK case seres [12, 17, 30, 31]. Meknan recently found sgnfcantly better flare-free survval of adult TK patents refractory to non-bologc agents when recevng bologc treatments [17]. Bologc therapes have been used n ndvdual patents ncluded n recent pedatrc seres, but ther effcacy has not been systematcally evaluated. Flocamo reported four chldren started on TNF-α nhbtors, ether for refractory dsease or as frst-lne agent [10]. Two chldren acheved remsson; the two others had a partal response [10]. The data on TNF-α nhbton n TK are encouragng, as ther role has remaned unclear for a long tme. Contradctory results have orgnated from reports of patents, who developed TK, whle treated wth TNF-α nhbtors for other dseases [32, 33]. Interestngly, two of our patents were dagnosed wth chldhood TK, whle beng treated wth a TNF-α nhbtor for nflammatory bowel dsease. Both chldren responded well to hgh-dose cortcosterods, the ncrease of the bologc agent dosng and the addton of. common genetc background between TK and ulceratve colts has recently been suggested wth regard to the hgh rate of co-occurrence of these two dseases [34, 35]. Therapy wth the IL-6 nhbtor toclzumab seems promsng; sterod-sparng effects wth good clncal and laboratory responses have been descrbed n both pedatrc [36 38] and adult TK seres [12, 17, 39 41]. Meknan documented equvalent effcacy and safety of TNF-α nhbtors and toclzumab n adult TK patents refractory to non-bologc therapes [17]. In chldhood TK, toclzumab has been reported to be effectve and well tolerated n a total of 11 TK chldren refractory to cortcosterods and non-bologc mmunosuppressves [36 38]. In 2008, EULR publshed treatment recommendatons for large vessel vascults n adults [42]. These nclude the use of hgh-dose cortcosterods for nducton of remsson and the consderaton of an mmunosuppressve agent such as or azathoprne. These are evdence level three recommendatons from descrptve studes; data from clncal trals are not yet avalable. To date, there are no recommendatons for chldhood TK. Clearly, further studes ncludng multcenter collaboratons are needed to prospectvely evaluate the potental beneft of bologc agents n chldhood TK. Untl more evdence s avalable, our data and the recent reports suggest the consderaton of bologc agents n chldhood TK patents wth crtcal organ perfuson or end organ damage at dagnoss and n those wth severe, treatment refractory dsease course. Ths study has several lmtatons. The sample sze was small. However, ths cohort represents one of the largest worldwde. Ths retrospectve study s spannng three decades durng whch dagnostc and therapeutc management has evolved. s there s no standardzed treatment protocol for TK, varous therapeutc regmens have been used by dfferent pedatrc rheumatologsts throughout the study perod, but nterestngly, dsease actvty measures dd not dffer between the varous treatment groups (Fg. 3). Statstcal bas-reducng strateges such as propensty score analyss were not feasble due to the small numbers n the ndvdual groups. Because of small patent numbers, we were also not able to adjust for dfferences n magng evaluaton, concomtant treatment and other potental confounders of pre- and post-bologc era n the statstcal analyss. The PVS was valdated, but may not be the optmal dsease actvty measurement tool for chldhood TK [21]. However, there s no unversally accepted dsease actvty measure for chldhood TK to date. Fnally, our patents were cared for at a tertary referral hosptal and may represent the more severe end of the dsease spectrum. Conclusons Ths contemporary, large chldhood TK cohort study demonstrates the sgnfcant dsease burden wth more than 50% of affected chldren experencng adverse outcomes ncludng dsease flares or death. The results of ths study provde mportant nformaton regardng treatment effcacy and safety n chldhood TK. Bologc therapes ncludng TNF nhbtors and ant-il-6 agents

9 eschlmann et al. rthrts Research & Therapy (2017) 19:255 Page 9 of 10 resulted n sgnfcantly hgher 2-year flare-free survval and hgher rates of nactve dsease at last follow-up compared to non-bologc therapes. Based on ths nformaton, current treatment approaches to chldhood TK may need to be revsed. bbrevatons N: ntnuclear antbody; NC: ntneutrophl cytoplasmc antbody; Z: zathoprne; CRP: C-reactve proten; CS: Cortcosterods; CT: Computed tomography angography; Cyclo: Cyclophosphamde; ESR: Erythrocyte sedmentaton rate; IFX: Inflxmab; IL-6: Interleukn-6; ITS2010: Indan Takayasu rterts ctvty Score; MMF: Mycophenolate mofetl; MR: Magnetc resonance angography; : Methotrexate; PVS: Pedatrc Vascults Dsease ctvty Score; PVDI: Pedatrc Vascults Damage Index; TK: Takayasu arterts; TCZ: Toclzumab; TI: Transent schemc attack; TNF-α: Tumor necross factor alpha; vwf antgen: von Wllebrand factor antgen cknowledgements We thank the Dvson of Rheumatology at The Hosptal for Sck Chldren and all rheumatologsts nvolved n the care of these chldren. We thank Suzanne Tam for the valuable techncal support. Fundng F s supported by the Rhyner-Bangerter Foundaton, Starr Foundaton, Swss League aganst Rheumatsm, Foundaton W!, lberta Chldren s Hosptal Research Insttute Foundaton, Dawson Jarock Foundaton and SckKds Foundaton. RSMY s supported by the Hak-Mng and Deborah Chu Char n Pedatrc Translatonal Research. valablty of data and materals The dataset used and analyzed durng the current study s avalable from the correspondng author on reasonable request. uthors contrbutons F, SMB and RSMY contrbuted to the study concept and desgn, data collecton, and analyss and nterpretaton of data. SS, RML, DH, DN, MT and CP contrbuted to data collecton. SWME contrbuted to analyss and nterpretaton of data. ll authors were nvolved n draftng the manuscrpt or revsng t crtcally for mportant ntellectual content. ll authors read and approved the fnal verson to be publshed. Ethcs approval and consent to partcpate The need for consent was waved for ths retrospectve chart study of de-dentfed data by the Research Ethcs Board of the Hosptal for Sck Chldren, Unversty of Toronto. REB approved fle number Competng nterests The authors declare that they have no competng nterests. Consent for publcaton Not applcable. Publsher s Note Sprnger Nature remans neutral wth regard to jursdctonal clams n publshed maps and nsttutonal afflatons. uthor detals 1 Dvson of Rheumatology, Department of Pedatrcs, The Hosptal for Sck Chldren, Unversty of Toronto, 555 Unversty venue, Toronto, ON M5G 1X8, Canada. 2 Department of Immunology, Unversty of Toronto, Toronto, ON, Canada. 3 Department of Medcne, Unversty of Toronto, Toronto, ON, Canada. 4 Dvson of Nephrology, Department of Pedatrcs, The Hosptal for Sck Chldren, Unversty of Toronto, Toronto, ON, Canada. 5 Rheumatology, Department of Pedatrcs, lberta Chldren s Hosptal, Unversty of Calgary, Calgary, B, Canada. 6 Vascults clnc, Dvson of Rheumatology, Mount Sna Hosptal, Unversty of Toronto, Toronto, ON, Canada. Receved: 28 June 2017 ccepted: 9 October 2017 References 1. Brunner J, Feldman BM, Tyrrell PN, Kuemmerle-Deschner JB, Zmmerhackl LB, Gassner I, et al. Takayasu arterts n chldren and adolescents. 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