REVIEW ARTICLE 7KH5ROHRI%LRORJLFV$JHQWLQWKH7UHDWPHQW RI,QÀDPPDWRU\%RZHO'LVHDVH Tri Hapsoro Guno*, Marcellus Simadibrata** *Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta **Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta Corresponding author: Marcellus Simadibrata. Division of Gastroenterology, Department of Internal Medicine, Dr. Cipto Mangunkusumo *HQHUDO1DWLRQDO+RVSLWDO-O'LSRQHJRUR1R-DNDUWD,QGRQHVLD3KRQH)DFVLPLOH (PDLOSURIPDUFHOOXVV#JPDLOFRP ABSTRACT ,QÀDPPDWRU\ERZHOGLVHDVH ,%' ZLWKPDMRUPDQLIHVWDWLRQVDV&URKQ¶VGLVHDVH &' DQGXOFHUDWLYHFROLWLV 8& LVDFKURQLFLQWHVWLQDOLQÀDPPDWRU\GLVRUGHUZLWKDQXQNQRZQHWLRORJ\ZKLFKSDWKRJHQVLVLQYROYLQJ PXOWLIDFWRULDOLPPXQHGLVRUGHUFKDUDFWHUL]HGE\FKURQLFUHODSVLQJLQÀDPPDWLRQRIWKHLQWHVWLQH0DQDJHPHQW RI,%'GHSHQGVRQVWDJHDQGORFDWLRQRIWKHLQÀDPPDWLRQFRQVLVWRIWKHFODVVLFFRQYHQWLRQDOWUHDWPHQWDQG the more new treatment with biologics agent. Biologics agent refers to monoclonal antibodies with activity GLUHFWHGDJDLQVWVSHFL¿FWDUJHWVLQYROYHGLQWKHSDWKRJHQHVLVRIFKURQLFLQÀDPPDWRU\FRQGLWLRQV$GYDQFHVLQ WKHXQGHUVWDQGLQJRIWKHVSHFL¿FPHFKDQLVPVRISDWKRJHQHVLV,%'OHGWRWKHGHYHORSPHQWRIWDUJHWHGWUHDWPHQW Today there are six biologics agent approved and used as therapy and there still many other biologics agent on UHVHDUFKSURJUHVV0DQ\UHSRUWVVKRZSRVLWLYHUHSRUWDERXWHI¿FDF\IRUWKHELRORJLFDOWKHUDS\FRPSDUHGZLWK placebo and conventional treatment for the IBD. Limited by their cost and adverse effect that possibly happened, biologics agent is still promising therapy that change the course of IBD treatment. Keywords:,QÀDPPDWRU\ERZHOGLVHDVH ,%' &URKQ¶VGLVHDVH &' XOFHUDWLYHFROLWLV 8& ELRORJLFDO therapy, biologics agent. ABSTRAK 3HQ\DNLWLQÀDPPDWRU\ERZHOGLVHDVH ,%' WHUEDJLPHQMDGLSHQ\DNLW&URKQGDQNROLWLVXOVHUDWLIPHUXSDNDQ SHUDGDQJDQNURQLVLQÀDPDWRULNGHQJDQHWLRORJL\DQJEHOXPMHODVGLNHWDKXLGDQPHOLEDWNDQJDQJJXDQ LPXQLWDVPXOWLIDNWRULDOGLNDUDNWHULVWLNDQGHQJDQLQÀDPDVLXVXV\DQJEHUXODQJVHFDUDNURQLV7DWDODNVDQD dari IBD bergantung kepada derajat penyakit dan lokasi lesi, tatalaksana terdiri dari terapi konvensional dan WHUDSLWHUEDUXGHQJDQDJHQELRORJLV$JHQELRORJLVPHUXSDNDQDQWLERGLPRQRNORQDO\DQJPHPLOLNLDNWL¿WDV PHQJKDPEDWWDUJHWVSHVL¿NGDODPSURVHVLQÀDPDVLSDGD,%''HQJDQVHPDNLQEHUNHPEDQJQ\DSHPDKDPDQ tentang mekanisme dari patogenesis IBD saat ini memicu perkembangan berbagai jenis agen biologis. Saat ini ada enam jenis agen biologis yang sudah disetujui dan digunakan sebagai terapi IBD dan banyak agen ELRORJLVODLQVHGDQJGDODPWDKDSSHQHOLWLDQ%HUEDJDLSHQHOLWLDQPHQXQMXNDQHIHNWL¿WDVWHUDSLELRORJLVDSDELOD dibandingkan dengan plasebo dan terapi konvensional. Walaupun penggunaanya masih terbatas dikarenakan masalah biaya dan efek samping yang mungkin terjadi, agen biologis tetap merupakan terapi yang menjanjikan dan dapat merubah tatalaksana IBD. Kata kunci: LQÀDPPDWRU\ERZHOGLVHDVH ,%' SHQ\DNLW&URKQNROLWLVXOVHUDWLIWHUDSLELRORJLVDJHQELRORJLV 184 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy The Role of Biologics Agent in the Treatment of Inflammatory Bowel Disease INTRODUCTION (3,'(0,2/2*< $1' 5,6. )$&725 2) ,1)/$00$725<%2:(/',6($6( +HDOWKFDUHEXUGHQIRUPDQDJHPHQWRILQÀDPPDWRU\ bowel disease (IBD) is substantially high but has been IBD can be diagnosed at any age from infancy to evolved since the introduction of biologics agent in geriatrics population, with the majority of new cases WKHEHJLQQLQJRIWKHWZHQW\¿UVWFHQWXU\VLQFHLWV are diagnosed in adolescence and early adulthood. impact on reducing the need of surgeries and improved In early twentieth century the incidence of IBD rose quality of life for IBD patient.1 Pathogensis on IBD steadily in the western world but relatively rare in involving multifactorial immune disorder characterized developing nations, but over the past few decades IBD E\FKURQLFUHODSVLQJLQÀDPPDWLRQRIWKHLQWHVWLQH also found emerged in newly industrialized countries The two major manifestations of IBD were Crohn’s such as in Asia, South America and Middle East and disease (CD) and ulcerative colitis (UC) which share has evolved into a global disease with rising prevalence similar symptoms including diarrhea, hematochezia, in every continent.5,6 and abdominal pain, whereas the location and depth of Over 1 million residents in the USA and 2.5 LQÀDPPDWLRQDVZHOODVFRPSOLFDWLRQVDQGSUHYDOHQFH million in Europe are estimated to have IBD, with can differ.2,3 substantial costs for health care. From ACCESS Normally the immune system in gastrointestinal study, crude annual incidence of IBD per 100,000 tract make a complex interaction between the innate, individuals were 1.37 in Asia. Incidence of IBD adaptive immune systems and intestinal microbes under case in Indonesia was 0.88 per 100,000 individuals, homeostatic conditions. This homeostasis is disrupted with CD incidence was 0.33 and UC incidence was ZLWKUHVXOWRIXQFRQWUROOHGLQWHVWLQDOLQÀDPPDWLRQ 0.55.7 Epidemiological differences in IBD between in IBD. Therapy with most non-biological drug the western world and newly industrial ized countries (aminosalicylates, steroids and immuno-modulators) are primarily explained by genetic and environmental provide symptomatic improvement but fail to stop the LQÀXHQFHVRQGLVHDVHGHYHORSPHQW Advances in health- XQGHUO\LQJLQÀDPPDWRU\SURFHVVDQGGRQRWFKDQJHWKH care infrastructure and methodological challenges disease course. Biologics therapy for IBD have been in reporting epidemiological data also influence revolutionized the treatment of patients with Crohn’s differences in reported incidence between countries disease and have begun to have an impact on therapy and world regions. 7KH¿JXUHEHORZVXPPDUL]HWKH for refractory ulcerative colitis. Biologics therapy KLVWRULFDORI,%'IURPWKH¿UVWLQWURGXFH1 proven to be highly effective.2-4 )LJXUH7KHJOREDOSUHYDOHQFHRI,%'LQ Volume 18, Number 3, December 2017 185 Tri Hapsoro Guno, Marcellus Simadibrata )LJXUH+LVWRULFDOWLPHOLQHVRILQÀPPDWRU\ERZHOGLVHDVH ,%' WKURXJKRXWWKHZRUOG1 ,%'LVDFKURQLFLQWHVWLQDOLQÀDPPDWRU\GLVRUGHU breast-feeding prove the role of the intestinal with an unknown etiology. IBD has been thought to be PLFURELRWDLQPRGXODWLQJLQÀDPDWLRQ'LHWDU\IDFWRUV LGLRSDWKLFEXWLQÀXHQFHGE\JHQHWLFDQGHQYLURQPHQWDO VXFKDVDORZ¿EUHGLHWDQGKLJKGLHWDU\IDWLQGLHWV factors.2 It is believed to manifest in genetically are associated with IBD, whereas consumption of tea predisposed individuals who has an abnormal immune was protective for IBD in Asia.1 response toward intestinal microbes after exposure to environmen tal triggers. Untill now 163 loci are 3$7+2*(1(6,6$1',0081(0(&+$1,606,1 known to confer susceptibility to Crohn’s disease ,1)/$00$725<%2:(/',6($6( ,%' and/or ulcerative colitis. Genes with the strongest Human intestine service as a immune system with associations are involved in the immune response to complex interaction occured. Idiopathic intestinal microbes, such as innate sensing of bacteria (NOD2), LQÀDPPDWLRQVVXFKDV,%'RFFXUZKHQEDODQFHRIWKLV WKHLQÀDPPDWRU\UHVSRQVHWRPLFUREHV ,/5 DQG immune system disrupted. Initially T-helper-1 (Th1) autophagy (ATG16L1).1 cells have been thought to play an important role in Environmental exposures contribute to the etiology pathogenesis related to the chronicity of intestinal of IBD. Many of them have been studied, but none LQÀDPPDWLRQHVSHFLDOO\LQ&'ZKHUHDV7KFHOOV funda mentally can explain the truth pathogenesis have been thought to play an important role mainly of IBD. In the western world, smoking is the most in UC. Recently, additional factor like activation of consistently studied environmental determinant of Th17 cells and imbalance of Th17/T regulatory (Treg) IBD. The hygiene hypothesis postulates that children in cells are recognized to be an important component of industrialized and high urbanization society have less IBD pathogenesis. Some other cells show to involved exposure to microbes early in life, such that infections in the pathogenesis of IBD as can be viewed in this later will trigger an abnormal host immune response. Figure below.2,3 Risk of IBD associated with antibiotic use in childhood, )LJXUH3URLQÀDPPDWRU\LPPXQHFHOOVDQGWKHLUFURVVWDONLQSDWLHQWVZLWK,%'3 T reg FHOO UHJXODWRU\ 7 FHOO 7*) WUDQVIRUPLQJ JURZWK IDFWRU 7H W\SH 7 KHOSHU FHOO 7H2: type 2 7 KHOSHU FHOO7H W\SH 7 KHOSHU FHOO7H W\SH 7 KHOSHU FHOO 1. FHOO QDWXUDO NLOOHU FHOO ,/ LQWHUOHXNLQ ,)1LQWHUIHURQ71)WXPRUQHFURVLVIDFWRU 186 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy The Role of Biologics Agent in the Treatment of Inflammatory Bowel Disease (SLWKHOLDODQG&RPPHQVDO%DFWHULD ,QQDWH DQG$GDSWLYH ,PPXQLW\ LQ ,QÀDPPDWRU\ Epithelial surface of intestine acts as a barrier %RZHO'LVHDVH ,%' from harmful pathogens and place where commensal The innate immune system serve as first line microorganisms live. The imbalance interaction defensive against external pathogens. It provides between imune system with microbes develop chronic rapid and non-specific protection from pattern LQWHVWLQDOLQÀDPPDWLRQZKHQFHUWDLQHQYLURQPHQWDO recognition of pathogens. Human intestine innate factors triggers the genetically susceptible hosts. The immune system is composed of intestine epithelia, intestinal epithelial cell (IEC) layer make crypts and macrophages, monocytes, neutrophils, eosinophils, villi of intestine which contain different cells including basophils, dendritic cells (DCs), and natural killer enterocytes, goblet cells, neuroendocrine cells, Paneth cells. Intraluminal pathogens communicate with innate cells, M cells, and