Discontinuation of biological therapy in children with inflammatory rheumatic diseases

Uvod: Biološki lijekovi iznimno su unaprijedili liječenje juvenilnog idiopatskog artritisa (JIA). Usprkos sigurnosti i učinkovitosti, još uvijek postoje dvojbe vezane uz njihovu uporabu obzirom na visoke troškove liječenja te povećani rizik razvoja infekcija i malignih bolesti. U recentnim smjernicama za liječenje JIA jasno je definirano vrijeme uvođenja bioloških lijekova. Međutim, vrijeme obustavljanja navedene terapije po postizanju kliničke remisije, kao i rizik relapsa bolesti, ostaju nejasni. Cilj: ovog istraživanja bio je utvrditi trajanje kliničke remisije tijekom terapije biološkim lijekovima te rizik relapsa po prekidu njihove aplikacije u bolesnika s JIA. Metode i ispitanici: U istraživanje su uključena djeca oboljela od juvenilnog idiopatskog artritisa (JIA) liječena anti-TNF, anti-IL-1 i anti-IL-6 pripravcima u Zavodu za imunologiju i reumatologiju, Klinike za pedijatriju, KBC-a Zagreb u Referentnom centru za pedijatrijsku i adolescentnu reumatologiju Ministarstva zdravstva RH, u razdoblju od 2010. do 2015. godine. Rezultati: Od 71 pacijenta oboljela od JIA liječenih biološkom terapijom, s obzirom na uspješno postignutu i održavanu remisiju, u njih 17 (9 djevojčica i 8 dječaka) ukinuli smo biološku terapiju. Biološka terapija započeta je u prosjeku nakon 2 godine (0,1-13) trajanja bolesti. Liječenje biološkom terapijom u prosjeku je trajalo 34 mjeseca (3-66), a pacijenti su u postignutoj remisiji u prosjeku bili 27 mjeseci (3-60) prije prekida iste. Rani relaps, unutar 6 mjeseci, razvilo je 5/17 pacijenata (29,4%), dok je jedna pacijentica (5,9%) razvila relaps u idućih 6 mjeseci. Jedanaest pacijenata (64,7%), do kraja ovog istraživanja, nije razvilo relaps bolesti te su ostali u remisiji, u prosjeku 11 mjeseci (6-51). Zaključak: Iako se prekid biološke terapije još uvijek temelji samo na iskustvima pedijatrijskih reumatologa, zbog ozbiljnih posljedica koje može uzrokovati dugotrajna primjena biološke terapije, smatramo da u djece oboljele od JIA koja su postigla dugotrajnu remisiju treba pokušati smanjiti ili prekinuti istu. Dobiveni rezultati pokazali su da je 65% pacijenata ostalo u kliničkoj remisiji nakon ukinuća biološke terapije. Razvoj primjerenih smjernica koje definiraju vrijeme i način prekida biološke terapije predstavlja jedan od esencijalnih ciljeva u liječenju i praćenju bolesnika s navedenom bolešću.Introduction: Biologic medications have highly advanced the treatment of juvenile idiopathic arthritis (JIA). Despite their safety and efficiency, there are still doubts related to their use due to expensive cost and increased risk of infections and malignant diseases. The introduction of biologics is clearly defined in recent guidelines, but the time of cessation after achieving clinical remission, as well as the risk of disease relapse is still unclear. Aim: The aim of the present study was to establish the length of clinical remission during biological therapy and the risk of relapse after ceasing its application in patients with JIA. Methods: The study included children diagnosed with JIA who were treated with tumor necrosis factor inhibitors (TNFi), anti-IL-1 and anti-IL-6 agents at the Department of Pediatrics, Division of Immunology and Rheumatology, University Hospital Centre Zagreb, at the referral centre for pediatric and adolescent rheumatology Ministry of Health, Republic of Croatia in the period from 2010 to 2015. Results: Out of 71 patients diagnosed with JIA who were treated with biologics, due to successfully achieved and maintained remission on treatment, we discontinued the therapy in 17 patients (F/M 9/8). Biologics was started after a median of 2 (range 0,1-13) years of the disease duration. The median treatment duration was 34 (3-66) months, with a median duration of remission on medication 27 (3-60) months before withdrawal of therapy. Early disease flares (within 6 months after withdrawal) were observed in 5/17 (29,4%) patients, while one patient (5,9%) relapsed within the next 6 months. 11/17 (64,7%) patients haven’t relapsed and remained in remission during follow up period, on average 11 (6-51) months. Conclusion: Although the disruption of biological therapy is still based only on the experience of pediatric rheumatologists, because of the serious consequences that can result in long-term use of biological therapy, we conclude that the biological therapy should be cut down or discontinued in children with JIA who reached long-term remission. Our data show that 65% of the patients remained in clinical remission after withdrawal of therapy. Developing appropriate guidelines that define the time and method of ceasing biological therapy represents one of the essential goals of treating and following up on patients with this disease