*Sylwia Fabiszewska, Grzegorz Oracz, Jarosław Kierkuś
Vedolizumab therapy in pediatric inflammatory bowel disease – case report
Leczenie wedolizumabem nieswoistych zapaleń jelit u dzieci – opis przypadku
Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw
Head of Department: Professor Marek Woynarowski, MD, PhD
Nieswoiste zapalenie jelit (NZJ) to pojęcie, które obejmuje wrzodziejące zapalenie jelita grubego (WZJG) oraz chorobę Leśniowskiego-Crohna, czyli przewlekłe choroby zapalne jelit o nieustalonej etiologii.
Uważa się, że główną rolę w patogenezie pełnią czynniki immunologiczne, genetyczne oraz środowiskowe. Najczęściej choroba jest rozpoznawana u osób młodych pomiędzy 15. a 29. rokiem życia, ale wiek, w którym się ujawnia, systematycznie ulega obniżeniu.
Leczenie jest uzależnione od fazy choroby, nasilenia objawów i od wieku pacjenta. Stosuje się leczenie żywieniowe, farmakologiczne oraz w razie braku poprawy – leczenie chirurgiczne.
Dotychczas, amerykańska Agencja Żywności i Leków (Food and Drug Administration – FDA) dopuściła leki biologiczne do leczenia choroby Leśniowskiego-Crohna wśród dzieci – infliksymab oraz adalimumab, natomiast do leczenia wrzodziejącego zapalenia jelita grubego wśród dzieci – wyłącznie infliksymab.
Cały czas trwają poszukiwania nowych leków biologicznych, które byłyby skuteczne i bezpieczne w terapii NZJ u dzieci. Szczególną uwagę zwraca się obecnie na wedolizumab, który jest już oficjalnie dopuszczony przez Agencję Żywności i Leków do leczenia NZJ u dorosłych.
Celem tego artykułu jest prezentacja dwóch przypadków klinicznych dzieci, u których zastosowano wedolizumab w leczeniu NZJ.
Inflammatory bowel disease (IBD) is a term, which includes ulcerative colitis (UC) and Crohn’s disease (CD) – chronic inflammatory bowel diseases with unknown etiology.
Disease is commonly thought to be caused by combination of immunological, genetic and environmental factors. Most often diagnosis of IBD is established among young, 15-29 years old people, but the age of diagnosis is systematically reduced.
Treatment plan depends on phase of disease, symptoms intensity and patient age.
The main type of treatment are enteral nutrition, pharmacological therapy and finally surgical intervention in case of insufficient response.
Until now, in pediatric patients U.S. Food and Drug Administration (FDA) approved biologic agents, infliximab and adalimumab as CD treatment and infliximab only as UC treatment.
Currently new biological agents are being studied as part of effective and safe IBD therapy in children. Particular attention is now given to vedolizumab which is already used and approved as part of IBD treatment algorithm in adults.
Purpose of this article is to present two cases in which vedolizumab was used in CU as well as CD therapy in pediatric patients.
Inflammatory bowel disease (IBD) is a broad term used to describe disorders of chronic inflammation of digestive tract. There are two types of IBD – ulcerative colitis and Crohn’s disease. The etiology of IBD isn’t fully discovered, but proinflammatory cytokines are considered to be the main factor in pathogenesis, which is clearly used in therapeutical options for example biological treatment.
Currently we still observe development in this area – a new biological therapy of vedolizumab has been recently widely considered as approval treatment of IBD in children.
Vedolizumab is a humanized IgG1 monoclonal antibody to the gut specific adhesion molecule – alfa4beta7 integrin that modulates gut lymphocyte trafficking. Its local effect, which is clearly big advantage of this drug has been confirmed in past research results (1).
Until now efficacy, safety and tolerability of vedolizumab in adults were established in large number of research studies. The most popular were GEMINI 1, 2 and 3. Vedolizumab was used in 300 mg intravenous doses in weeks: 0, 2, 6 and then every 4 or 8 weeks.
GEMINI 2 study focused on adult patients with moderately to severely active CD in whom 1 or more prior CD therapies had failed. Vedolizumab showed significant improvement in the primary endpoint of clinical remission (CDAI score ≤ 150 points) at six weeks compared to placebo (14.5 vs. 6.8%) (2).
At week 52, 39.0% of the patients receiving vedolizumab every 8 weeks and 36.4% of those receiving vedolizumab every 4 weeks were in clinical remission, as compared with 21.6% of patients receiving placebo (2).
In the secondary endpoint at week 52, the proportions of patients who had a CDAI-100 response and who had glucocorticoid-free remission were significantly greater in the groups receiving vedolizumab every 8 weeks and every 4 weeks than in the placebo group (2).
Adverse events affected at least 5% of patients who received vedolizumab (at least one dose of study drug).
The most common adverse events reported in the vedolizumab arm were CD exacerbation, arthralgia, pyrexia, nasopharyngitis, headache, nausea and abdominal pain. The most common adverse events reported in the placebo arm were CD exacerbation, headache, arthralgia, pyrexia, abdominal pain, nausea and nasopharyngitis (2).
GEMINI 3 study is focused on moderately to severely active CD patients who had previously failed therapy with TNFα antagonists. Vedolizumab was not significantly more effective than placebo (15.2 vs. 12.1%) in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10 – 26.6% of those given vedolizumab and 12.1% of those given placebo achieved clinical remission. Additionally 39.2% of patients with previous TNF antagonist failure given vedolizumab and 22.3% of those given placebo had a CDAI-100 response at week 6. Adverse event results were similar among all groups. Vedolizumab (similar to TNF antagonists) may have also a more pronounced effect in TNF antagonist-naive patients than in patients with prior TNF antagonist failure (3).
GEMINI 1 was about vedolizumab as induction and maintenance therapy for ulcerative colitis. Vedolizumab demonstrated greater efficacy as CU therapy in adults compared to CD therapy and was significantly more effective than placebo in inducing clinical remission at week 6 among TNF-naive patients (53.1 vs. 26.3%), as well as in TNF-failure population (39.0 vs. 20.6%). Vedolizumab is relatively more effective in TNF-naive patients than TNF-failure patients (53.1 vs. 39.0%) (4).
As the most common adverse effects of vedolizumab were reported: nasopharyngitis, headache, arthralgia, and nausea. Longer-term safety trials are needed but based on evidence to date, there is no evidence of a higher odds of serious infections from the newly available biologic therapies, such as vedolizumab, compared to the anti-TNF agents (5) and also the progressive multifocal leukoencephalopathy (PML) associated with vedolizumab has not been reported (6).
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1. Wyant T, Leach T, Sankoh S et al.: Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut 2015; 64(1): 77-83.
2. Sandborn WJ, Feagan BG, Rutgeerts P et al.: Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369(8): 711-721.
3. Sands BE, Feagan BG, Rutgeerts P et al.: Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014; 147(3): 618-627.
4. Feagan BG, Rubin DT, Danese S et al.: Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2017; 15(2): 229-239.
5. Wheat CL, Ko CW, Clark-Snustad K et al.: Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. BMC Gastroenterol 2017; 17(1): 52.
6. Cherry LN, Yunker NS, Lambert ER et al.: Vedolizumab: an α4β7 integrin antagonist for ulcerative colitis and Crohn’s disease. Ther Adv Chronic Dis 2015; 6(5): 224-233.
7. Ledder O, Assa A, Levine A et al.: Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Pediatric IBD Porto Group of ESPGHAN.Crohns Colitis 2017; 11(10): 1230-1237.
8. Singh N, Rabizadeh S, Jossen J et al.: Multi-Center Experience of Vedolizumab Effectiveness in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22(9): 2121-2126.