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© Borgis - Postępy Nauk Medycznych 3/2014, s. 197-201
*Anna Wiernicka, Maciej Dądalski, Monika Szychta, Grzegorz Oracz, Jarosław Kierkuś
Leczenie biologiczne wrzodziejącego zapalenia jelita grubego u dzieci
Biological therapy for pediatric ulcerative colitis
Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warszawa
Head of Department: prof. Józef Ryżko, MD, PhD
Streszczenie
Wrzodziejące zapalenie jelita grubego jest przewlekłą chorobą zapalną jelit o nieznanej etiologii. Obecnie główną rolę w patogenezie przypisuje się cytokinom prozapalnym, główną z nich jest czynnik martwicy nowotworów (TNF-α). Postępy w zrozumieniu patogenezy choroby doprowadziły do wprowadzenia nowych opcji terapeutycznych, mianowicie leków biologicznych. Amerykańska Agencja Żywności i Leków (FDA) do dnia dzisiejszego zarejestrowała trzy przeciwciała monoklonalne skierowane przeciwko TNF-α do leczenia pacjentów dorosłych ze średnio ciężką i ciężką postacią wrzodziejącego zapalenia jelita grubego, którzy niedostatecznie odpowiedzieli na standardowe leczenie lub leczenie jest źle tolerowane bądź istnieją przeciwwskazania do konwencjonalnej terapii. Należą do nich infliximab, adalimumab i golimumab. Jedynie infliximab został zarejestrowany przez agencję do leczenia pacjentów pediatrycznych, pomimo to adalimumab również jest wykorzystywany w terapii u dzieci z wrzodziejącym zapaleniem jelita grubego. Celem poniższej pracy jest podsumowanie aktualnej wiedzy na temat leków biologicznych mających zastosowanie w terapii wrzodziejącego zapalenia jelita grubego u dzieci. Obecnie przeciwciała monoklonalne stanowią integralną część algorytmu leczniczego i prawdopodobnie wraz z czasem coraz częściej będą wykorzystywane w terapii.
Summary
Ulcerative colitis is a chronic inflammatory bowel disease of unknown etiology. Actually, the main pathogenic role is attributed to pro-inflammatory cytokines, the major one is Tumour Necrosis Factor alpha (TNF-α). The advances in understanding the pathogenesis of inflammatory bowel disease have led to the introduction of new therapeutic options, biological agents. Till now U.S. Food and Drug Administration (FDA) approved three monoclonal antibodies against TNF-α to treat adults with moderate to severe ulcerative colitis with an inadequate response to conventional therapy, or who are intolerant, or have medical contraindications for such therapy. These are: infliximab, adalimumab and golimumab. Only infliximab has been approved by the agency to treat children, nonetheless adalimumab is also used in treatment of pediatric patients with ulcerative colitis. The purpose of this review is to summarize the current knowledge on the use of biologics in pediatric ulcerative colitis. Currently, this new therapeutic options are the integral part of the pediatric ulcerative colitis treatment algorithm and with time probably will be used more extensively.



Ulcerative colitis (UC) is an idiopathic chronic disease associated with inflammation in gastrointestinal tract. Genetic, environmental and immunologic factors are considered to take part in the etiology. Actually, the main pathogenic role is attributed to pro-inflammatory cytokines such as TNF-α, IL-1β, IL-8, IL-12. Pediatric UC is characterized by a variable clinical course ranging from mild to severe, unresponsive to conventional therapy. Diarrhea, hemochezia and abdominal pain are the most common signs of the illness, likewise the constipation can be an early symptom (1, 2). In children compared to adult patients the distribution of disease is more extensive, most of them (over 80%) have pancolitis (1, 3). Diagnosis of the disease in the early childhood is associated with more aggressive clinical course, which is often refractory to corticosteroid treatment, requiring intensification of therapy (4-6). Treatment strategy depends mainly on disease severity. Pediatric UC treatment comprises use of corticosteroids, 5-amionosalicylates 5-ASA (mesalazine, sulfasalazine), immunomodulators: thiopurines (azatioprine AZA, mercaptopurine 6-MP), calcineurin inhibitors (ciclosporin, tacrolimus), antibiotics, probiotics and biological agents. Finally, colectomy is always a viable option that must be discussed whenever treatment escalation is considered.
The latest advances in understanding the pathogenesis of inflammatory bowel disease have led to the introduction of new therapeutic options, namely biological agents. Currently U.S. Food and Drug Administration (FDA) approved three monoclonal antibodies against pro-inflammatory cytokine Tumour Necrosis Factor alpha (TNF-α) to treat adults with moderate to severe ulcerative colitis. These are: infliximab, adalimumab and golimumab. Only infliximab has been approved by the agency to treat children 6 years and older, however, adalimumab is used out of label in pediatric patients by drawing on data from adults. The aim of this paper is to review the biologics used in the treatment of ulcerative colitis in children.
The first anti-TNF antibody approved for use in adults was infliximab (Remicade, Janssen Biotech). It is a chimeric monoclonal antibody consisting of 3/4 human and 1/4 murine sequences. It binds to both circulating and cell-bound forms of the proinflammatory cytokine TNF-α, thereby neutralizing TNF-α and causing apoptosis of activated lymphocytes (7, 8). Historically, indications for this medication have been extended from treatment of refractory Crohn’s disease in adults only to induction and maintenance therapy in luminal and fistulizing Crohn’s disease in adults and children, as well as treatment of adults and now (since 2011) children with moderate-to-severe ulcerative colitis unresponsive to conventional treatment (9-11). According to actual ECCO and ESPGHAN evidence-based consensus guidelines about management of pediatric ulcerative colitis infliximab should be considered for treatment of children with persistently active, or steroid-dependent UC, uncontrolled by 5-ASA and thiopurines and may be considered for steroid-refractory (oral or intravenous) disease (12). In Poland, the drug is approved for the treatment of severely active ulcerative colitis in children and adolescents aged 6 to 17 years with an inadequate response to conventional therapies, including corticosteroids and 6-MP or AZA, or who are intolerant, or have medical contraindications for such therapies. The medication is given as an intravenous infusion, the recommended dose is 5 mg/kg (3 induction infusions in scheme 0, 2, 6 weeks, then if patient responded to the treatment subsequent infusions every 8 weeks for maintenance). In some cases, especially when a patient has lost response it is recommended to increase the dosage to 10 mg/kg or to reduce the interval between doses (13). To optimize the treatment it is advisable to measure infliximab level and antibodies to infliximab (14). If there are low levels and negative antibodies, then dose escalation may be indicated. Undetectable infliximab levels in the presence of antibodies may indicate loss of response and the need for dose escalation or switching to a different drug. Normal infliximab level suggests primary nonresponse or an alternative diagnosis as a cause of symptoms.

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otrzymano: 2013-12-20
zaakceptowano do druku: 2014-02-06

Adres do korespondencji:
*Anna Wiernicka
Department of Gastroenterology,
Hepatology and Feeding Disorders
Children’s Memorial Health Institute
Al. Dzieci Polskich 20, 04-730 Warszawa
tel. +48 (22) 815-73-84
a.janowska@czd.pl

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