111:
have been developed for the treatment of these diseases. Although the use of antibodies to treat diseases can be dated back to the 1800s, biologic therapy as we know it today is a relatively new concept for the treatment of inflammatory bowel disease. The previous treatment options had many shortcomings, and the introduction of biological therapy changed the way physicians treat Crohn's disease and ulcerative colitis. Even so, biologic therapy still has its faults such as high cost and risk of side effects. A lot of research is being done in fields like
616:. Anti-drug antibodies can cause negative side effects, accelerate the rate of drug clearance, and reduce the therapeutic effects of the biologic. In clinical practice, less than 50% of patients who showed an initial positive response to biological therapy were in remission after one year. The development of anti-drug antibodies can be reduced by limiting any times when there is no biologic present in the body and by taking other immunosuppressants (such as
17:
343:
260:
608:
bowel diseases, with an estimated direct cost of $ 5.9 billion annually, poses a significant economic burden on the health care system. Recently, the primary treatment cost has shifted from hospitalization to medication. The shift is due to the rising use of these expensive biologics as well as their ability to reduce the need for hospitalization.
607:
Patients often wait until after other treatment options have failed to begin biological therapy because biologics are extremely expensive. One study modeled that, in the US, the average yearly cost of biological therapy for inflammatory bowel disease was around $ 36,000. The treatment of inflammatory
442:, drug stability, and plasma half-life. It was found to have efficacy over placebo medications for 10 weeks in the treatment of moderate to severe Crohn's disease in one large trial. It is not used in the treatment of ulcerative colitis, but it is used in the treatment of rheumatoid arthritis, active
110:
Although the causes of these diseases are unknown, genetic, environmental, immune, and other mechanisms have been proposed. Of these, the immune system plays a large role in the development of symptoms. Given this, a variety of biological therapies (such as TNF inhibitors and interleukin antagonists)
562:
Ustekinumab was approved by the FDA in 2009 for the treatment of plaque psoriasis, making it the first and so far the only approved interleukin antagonist. It is also used for the treatment of Crohn's disease and psoriatic arthritis. Studies suggest that the blocking of IL-23, rather than IL-12, has
147:
began to be referred to as biologics. The definition for biologics and biological therapy has changed a lot since. The development of recombinant DNA technology in the 1970s shaped the modern understanding of what constitutes as biological therapy, which often does not include traditional biological
411:
Adalimumab was approved by the FDA in 2002, becoming the first fully human monoclonal antibody to be approved. It was initially used in the treatment of rheumatoid arthritis, but it is now also used in patients with moderate-to-severe Crohn's disease and ulcerative colitis who don't respond well to
644:
is an integrin receptor antagonist that targets beta 7 integrins. Etrolizumab has shown efficacy in phase 2 trials as well. The hope is that etrolizumab can show similar efficacy to natalizumab while avoiding the specific cellular target that is believed to have caused the instances of progressive
590:. Biosimilars are defined by the FDA as, "a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product." Currently, the only two biologic treatments for IBD that have approved biosimilars are adalimumab and infliximab.
290:
are effective in inducing clinical remission in patients with active IBD, but they can't be used long term due to the risk of steroid-dependence and harsh side effects. The other medications like 5-aminosalicylates and azathioprine are often used to reduce steroid use while maintaining remission,
477:
on the vascular endothelium increase in response to various proinflammatory cytokines. The alpha 4 integrin on inflammatory cells interacts with these adhesion molecules to allow for migration. Integrin receptor antagonists block the interaction and prevent the migration of inflammatory cells to
333:
TNF inhibiting biological therapies were initially used in IBD patients who weren't responding to conventional therapy. They proved to be very effective in some patients, shifting treatment goals from simply improving symptoms to actually changing the course of the disease by reversing mucosal
652:
A lot of research is being done to develop a biologic that can be delivered orally to address the many drawbacks associated with systemic administration. The general consensus in the field is that oral delivery of biologics directly to the diseased tissue could greatly reduce side effects, the
350:
TNF inhibitors are commonly the first drug prescribed when a patient begins biologic therapy. They have the most extensive history of clinical evidence because they have been available the longest, are the most accessible, and are often the least expensive. Initially, it was thought that TNF
648:
Another area of research is focusing on the personalization of biological therapy. The idea is to use a specific patient's biochemical or genetic profile to predict how a patient will respond to a biological therapy. The information could help inform which class of biologics to use first.
598:
Biologics are known to sometimes cause harsh side effects. Currently, Biologics are only delivered systemically. They can't be delivered orally because the harsh environment of the gastrointestinal tract would breakdown the drug before it could reach the diseased tissue. Because systemic
581:
version is usually made. With conventional small-molecule drugs, it is possible to create a generic that is exactly the same as the original because small-molecule drugs can be characterized down to a single atom. However, the structure of biologics is far more complex and can't be fully
351:
inhibitors inactivate the proinflammatory cytokine by direct neutralization, but TNF signaling is a very complex process. Many recent studies suggest that TNF inhibitors may act with a more complex mechanism than simple blockade. They are all administered systemically either
460:
Golimumab is a fully human IgG1 monoclonal antibody that was first approved by the FDA in 2009 to treat rheumatoid arthritis. Since, it has been approved to also treat psoriatic arthritis, ankylosing spondylitis, and moderately to severely active ulcerative colitis.
519:
that is located primarily on cells in the gastrointestinal tract. It is promoted as being gut specific due to the localization of alpha 4 beta 7 integrin in the gastrointestinal tract and was the first biologic to be made specifically for inflammatory bowel disease.
380:
is a mouse-human chimeric antibody to TNF-α. The FDA approved it in 1998, making it the first approved TNF inhibitor. Infliximab has shown significant success in treating both Crohn's disease and ulcerative colitis, but it is also approved for the treatment of
334:
inflammation and preventing long-term complications and surgery. Although there are strong initial responses in some patients, biologic therapies also have their downsides, and there is still a debate as to what the most effective treatment strategy is.
1864:
Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OØ, Innes A (September 2005). "A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease".
214:
was discovered at New York
University's School of Medicine. Infliximab works by binding to TNF, stopping its inflammatory effects. It was initially used for the treatment of Crohn's disease and it became the first FDA approved
611:
Overtime, patients can lose response to biologics even after an initial positive response. Because biologics are foreign substances to the body, they can prompt an immunological response causing the development of
1592:
Inoue S, Matsumoto T, Iida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M (September 1999). "Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity".
603:
is exaggerated leading to many side effects such as lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, injection site reactions, and additional systemic side effects.
496:
monoclonal antibody that inhibits the alpha 4 integrin. It was the first integrin receptor antagonist, receiving FDA approval in 2004 for the treatment of Crohn's disease. It was approved for the treatment of
771:
Kalinski P, Mapara MY (June 2006). "9th Annual
Meeting of the Regional Cancer Consortium for the Biological Therapy of Cancer. 16-18 February 2006, UPMC Herberman Conference Center, Pittsburgh, PA, USA".
44:
or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause,
412:
conventional treatment. Adalimumab showed effectiveness in patients with Crohn's disease, but less than that of infliximab. It was the best selling drug in 2017 with sales upwards of $ 18 billion.
1901:
909:
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de
Villiers WJ, Present D, Sands BE, Colombel JF (December 2005).
544:, both of which contribute to inflammation. Interleukin antagonists, the most recent class of biologics available for use in IBD, inhibit the action of IL-12 and IL-23 by binding to the p40
179:
became the first fully licensed monoclonal antibody in 1986 for its use in treating kidney transplant rejection. Since then, over 70 monoclonal antibodies have been approved by the
1335:
1992:
2218:
863:, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P (May 2002). "Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial".
473:
called integrins instead of cytokines like TNF. Integrins mediate adhesion, signaling, and migration in many different types of cells. During active periods of disease,
231:
are currently the most common biologics used in the treatment of both Crohn's disease and ulcerative colitis. The other main categories of biologics that treat IBD are
2249:
2244:
291:
but their actual effect on the state of the disease and the need for surgery remains unknown. Patients with Crohn's disease that developed complications, including
640:
are both IL-23 specific antagonists, opposed to ustekinumab which targets both IL-12 and IL-23, that have shown efficacy in phase 2 trials for Crohn's disease.
2208:
586:. Thus, it is impossible to prove whether two biologics are exactly the same in every aspect. There are no generic versions of biologics. Instead there are
295:(= abnormal connections to the bowel) were treated with surgery. Patients with ulcerative colitis who do not respond to medications are still treated with
515:
Vedolizumab is very similar to natalizumab in that it is a humanized IgG monoclonal antibody, but vedolizumab is an IgG1 that specifically blocks the
817:"A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate"
49:
that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly
1985:
186:
The advancements in biological therapy greatly changed how IBD is treated. Patients with Crohn's disease and ulcerative colitis show an increase in
2254:
172:
632:
New biologic therapies that target both existing cellular targets (including IL-12 and IL-23) and new cellular targets are being developed.
2228:
740:
723:
2275:
1978:
1343:
270:
Prior to the development of biological therapy as a modality to treat IBD, other medications that modulate the immune system—including
1100:
1042:
667:
207:
2023:
582:
characterized with current analytical techniques. Also, the cell-based manufacturing process of biologics results in undefinable
2036:
662:
583:
1970:
2213:
2223:
1755:
Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P (February 2006).
815:
Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (January 1999).
1058:
533:
180:
1186:
Köhler G, Milstein C (August 1975). "Continuous cultures of fused cells secreting antibody of predefined specificity".
2280:
315:
21:
2147:
2099:
2001:
72:
107:, which consists of large bowel inflammation that shows elements of both Crohn's disease and ulcerative colitis.
1708:"The current state of the art for biological therapies and new small molecules in inflammatory bowel disease \"
427:
187:
1422:
Yanai H, Hanauer SB (April 2011). "Assessing response and loss of response to biological therapies in IBD".
310:
were elevated in both Crohn's disease and ulcerative colitis. Crohn's disease cytokines are of the type 1 (
160:
1757:"Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial"
2157:
1797:
474:
386:
352:
283:
100:
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1366:"Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives"
1137:"Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives"
2162:
1288:"The history of monoclonal antibody development - Progress, remaining challenges and future innovations"
470:
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2152:
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as well, but there have been concerns due to reports of progressive multifocal leukoencephalopathy.
537:
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374:
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135:. It wasn't until the 1900s that the newly emerging class of naturally derived medications such as
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493:
1083:
Smythe ML (2017). "Orally
Delivered Peptides for Treatment of Inflammatory Bowel Disease".
599:
administration results in blockading the same pathway in both healthy and diseased tissue,
1925:
Yu H, MacIsaac D, Wong JJ, Sellers ZM, Wren AA, Bensen R, Kin C, Park KT (February 2018).
545:
516:
439:
300:
92:
69:, and diseases of unknown cause that result in symptoms due to immune related mechanisms.
722:
Talpaz M, Kantarjian H, McCredie K, Trujillo J, Keating M, Gutterman JU (February 1987).
1927:"Market share and costs of biologic therapies for inflammatory bowel disease in the USA"
1527:
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substances like vaccines. Today, biological therapy most commonly refers to the use of
1638:"Optimizing the use of biological therapy in patients with inflammatory bowel disease"
1514:
Pallone F, Monteleone G (1996). "Regulatory cytokines in inflammatory bowel disease".
992:
876:
687:
Staren ED, Essner R, Economou JS (1989). "Overview of biological response modifiers".
127:
to treat diseases can be traced all the way back to the late 1800s with the advent of
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Integrin receptor antagonists are different than TNF inhibitors because they block
279:
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1035:
Biologics, A History of Agents Made From Living
Organisms in the Twentieth Century
1878:
1773:
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1821:
Veronese FM, Mero A (2008). "The impact of PEGylation on biological therapies".
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244:
240:
236:
1336:"Monoclonal Antibodies Approved by the EMA and FDA for Therapeutic Use – ACTIP"
1303:
741:
10.1002/1097-0142(19870201)59:3+<664::AID-CNCR2820591316>3.0.CO;2-Y
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Personalized medicine is already being used in practice in the oncology field.
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Interleukins are a cytokine that play a major role in the immune system.
326:γ. Ulcerative colitis was less conclusively linked to the production of
307:
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171:. They started the field of monoclonal antibody development and won the
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Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF (June 2018).
341:
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development of anti-drug antibodies, and the cost of treatment.
563:
the greatest effect on the therapeutic benefits of ustekinumab.
1974:
156:, to regulate the immune system in the treatment of disease.
87:, includes two (or three) diseases of unknown causation:
1037:. London WC1A 2TH: Pickering & Chatto. pp. 3–19.
219:
in 1998. Infliximab as well as other TNF inhibitors like
167:
generated the first monoclonal antibodies using their own
1902:"Biosimilars - Biosimilar and Interchangeable Products"
953:
Hanauer SB (March 1996). "Inflammatory bowel disease".
2237:
2201:
2176:
2140:
2133:
2047:
2016:
306:However, basic science research showed that many
32:biological therapy for inflammatory bowel disease
2250:List of people diagnosed with ulcerative colitis
2219:National Society for Colitis and Crohn's Disease
1802:GEN - Genetic Engineering and Biotechnology News
536:help with the activation and differentiation of
1557:Romagnani S (November 1999). "Th1/Th2 cells".
2245:List of people diagnosed with Crohn's disease
1986:
115:and oral delivery to address these concerns.
8:
346:Schematic demonstrating infliximab structure
2137:
1993:
1979:
1971:
1931:Alimentary Pharmacology & Therapeutics
1900:Research, Center for Drug Evaluation and.
1516:Alimentary Pharmacology & Therapeutics
986:
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548:that is found on both of these cytokines.
434:. The addition of polyethylene glycol, or
2209:Crohn's and Colitis Foundation of America
1950:
1772:
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1661:
1490:
1467:"The place of surgery in Crohn's disease"
1391:
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724:"Therapy of chronic myelogenous leukemia"
577:When the patent period of a drug ends, a
210:. In 1988, a monoclonal antibody called
1595:The American Journal of Gastroenterology
1424:The American Journal of Gastroenterology
859:Hanauer SB, Feagan BG, Lichtenstein GR,
1798:"The Top 15 Best-Selling Drugs of 2017"
1364:Rawla P, Sunkara T, Raj JP (May 2018).
679:
61:has found a niche in the management of
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1078:
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1072:
1070:
1068:
904:
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430:antibody that is attached to a 40kDa
175:in 1984 for their work. Soon after,
7:
2229:World Inflammatory Bowel Disease Day
1239:"Biologic therapies: what and when?"
1028:
1026:
774:Expert Opinion on Biological Therapy
426:Certolizumab pegol is a recombinant
1528:10.1046/j.1365-2036.1996.22164024.x
1135:Rawla P, Sunkara T, Raj JP (2018).
997:The New England Journal of Medicine
955:The New England Journal of Medicine
915:The New England Journal of Medicine
821:The New England Journal of Medicine
286:—were primarily used in treatment.
1093:10.1016/b978-0-12-409547-2.12417-5
14:
668:Essential fatty acid interactions
1835:10.2165/00063030-200822050-00004
1796:Philippidis, Alex (2018-03-12).
1607:10.1111/j.1572-0241.1999.01372.x
1522:(Suppl 2): 75–9, discussion 80.
1370:Journal of Inflammation Research
1141:Journal of Inflammation Research
1033:von Schwerin, Alexander (2013).
645:multifocal leukoencephalopathy.
584:post-translational modifications
255:Rationale for biological therapy
75:(IBD), a collection of systemic
53:, are directly involved in the
2214:Digestive Disorders Foundation
2024:Crohn's Disease Activity Index
1465:Williams JA (September 1971).
1292:Annals of Medicine and Surgery
1087:. Elsevier. pp. 157–170.
446:, and ankylosing spondylitis.
99:, which can affect the entire
40:the use of medications called
1:
1243:Journal of Clinical Pathology
877:10.1016/S0140-6736(02)08512-4
689:Seminars in Surgical Oncology
465:Integrin receptor antagonists
235:receptor antagonists such as
1879:10.1053/j.gastro.2005.06.064
1774:10.1053/j.gastro.2005.11.030
1237:Johnston SL (January 2007).
993:"Inflammatory bowel disease"
663:Treatment of Crohn's disease
2255:Deaths from Crohn's disease
1559:Inflammatory Bowel Diseases
991:Podolsky DK (August 2002).
967:10.1056/NEJM199603283341307
834:10.1056/NEJM199901283400401
492:Natalizumab is a humanized
314:) cytokines, which include
2297:
2276:Inflammatory bowel disease
2224:Crohn's and Colitis Canada
2148:Giovanni Battista Morgagni
2100:Protein losing enteropathy
2002:Inflammatory bowel disease
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570:
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73:Inflammatory bowel disease
1724:10.1038/s41385-018-0050-3
1636:Moss AC (February 2015).
594:Side effects and concerns
188:proinflammatory cytokines
91:, which affects only the
1286:Liu JK (December 2014).
1057:: CS1 maint: location (
786:10.1517/14712598.6.6.631
428:antigen-binding fragment
173:Nobel Prize for Medicine
2120:Small bowel obstruction
1767:(2): 323–33, quiz 591.
1642:Gastroenterology Report
1255:10.1136/jcp.2005.032300
524:Interleukin antagonists
517:alpha 4 beta 7 integrin
475:cell adhesion molecules
471:transmembrane receptors
2158:Thomas Kennedy Dalziel
1571:10.1002/ibd.3780050410
701:10.1002/ssu.2980050603
387:ankylosing spondylitis
347:
267:
101:gastrointestinal tract
85:gastrointestinal tract
34:
2163:Burrill Bernard Crohn
1654:10.1093/gastro/gou087
444:psoriatic arthropathy
345:
262:
154:monoclonal antibodies
131:for the treatment of
105:indeterminate colitis
19:
2115:Short bowel syndrome
2105:Pyoderma gangrenosum
1483:10.1136/gut.12.9.739
1436:10.1038/ajg.2011.103
1009:10.1056/NEJMra020831
928:10.1056/NEJMoa050516
614:anti-drug antibodies
538:natural killer cells
383:rheumatoid arthritis
169:hybridoma technology
161:Georges J. F. Köhler
129:diphtheria antitoxin
1383:10.2147/jir.s165330
1200:1975Natur.256..495K
1154:10.2147/jir.s165330
432:polyethylene glycol
391:psoriatic arthritis
375:monoclonal antibody
67:autoimmune diseases
38:Biological therapy,
25:monoclonal antibody
2281:Medical treatments
2189:William Hale-White
2032:Biological therapy
2010:ulcerative colitis
1712:Mucosal Immunology
734:(3 Suppl): 664–7.
624:) in combination.
499:multiple sclerosis
422:Certolizumab pegol
416:Certolizumab pegol
348:
299:(= removal of the
284:immunosuppressants
272:5-aminosalicylates
268:
89:ulcerative colitis
59:Biological therapy
42:biopharmaceuticals
35:
2263:
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2197:
2196:
2153:Antoni Leśniowski
1943:10.1111/apt.14430
542:CD4+ T lymphocyte
247:antagonists like
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1718:(6): 1558–1570.
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2287:
2286:
2285:
2266:
2265:
2264:
2259:
2233:
2193:
2172:
2129:
2043:
2037:Crohn's disease
2012:
2006:Crohn's disease
1999:
1969:
1968:
1924:
1923:
1919:
1910:
1908:
1899:
1898:
1894:
1863:
1862:
1858:
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1333:
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1194:(5517): 495–7.
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1184:
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1110:
1103:
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1066:
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1032:
1031:
1024:
990:
989:
982:
952:
951:
944:
921:(23): 2462–76.
908:
907:
900:
858:
857:
850:
814:
813:
809:
770:
769:
765:
721:
720:
716:
686:
685:
681:
676:
659:
630:
596:
575:
569:
560:
554:
546:protein subunit
526:
513:
507:
490:
484:
478:disease sites.
467:
458:
452:
440:bioavailability
424:
418:
409:
403:
371:
365:
340:
288:Corticosteroids
266:involved in IBD
257:
121:
97:Crohn's disease
12:
11:
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2292:
2284:
2283:
2278:
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2112:
2107:
2102:
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2092:
2087:
2082:
2077:
2072:
2067:
2062:
2057:
2055:Abdominal pain
2051:
2049:
2045:
2044:
2042:
2041:
2040:
2039:
2034:
2026:
2020:
2018:
2014:
2013:
2000:
1998:
1997:
1990:
1983:
1975:
1967:
1966:
1937:(3): 364–370.
1917:
1892:
1856:
1813:
1788:
1747:
1677:
1628:
1584:
1549:
1506:
1457:
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1327:
1278:
1229:
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1101:
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980:
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678:
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675:
672:
671:
670:
665:
658:
655:
629:
626:
595:
592:
571:Main article:
568:
565:
556:Main article:
553:
550:
525:
522:
509:Main article:
506:
503:
486:Main article:
483:
480:
466:
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454:Main article:
451:
448:
420:Main article:
417:
414:
405:Main article:
402:
399:
367:Main article:
364:
361:
353:subcutaneously
339:
338:TNF inhibitors
336:
256:
253:
165:César Milstein
120:
117:
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2204:
2202:Organizations
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2187:
2185:
2182:
2181:
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2169:
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2166:
2164:
2161:
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2088:
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2076:
2073:
2071:
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2061:
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2048:Complications
2046:
2038:
2035:
2033:
2030:
2029:
2027:
2025:
2022:
2021:
2019:
2015:
2011:
2007:
2003:
1996:
1991:
1989:
1984:
1982:
1977:
1976:
1973:
1962:
1958:
1953:
1948:
1944:
1940:
1936:
1932:
1928:
1921:
1918:
1907:
1903:
1896:
1893:
1888:
1884:
1880:
1876:
1873:(3): 807–18.
1872:
1868:
1860:
1857:
1852:
1848:
1844:
1840:
1836:
1832:
1829:(5): 315–29.
1828:
1824:
1817:
1814:
1803:
1799:
1792:
1789:
1784:
1780:
1775:
1770:
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1477:(9): 739–49.
1476:
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1346:on 2020-12-20
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661:
660:
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360:
358:
357:intravenously
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242:
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230:
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222:
218:
217:TNF inhibitor
213:
209:
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189:
184:
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177:muromonab-CD3
174:
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130:
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55:immune system
52:
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2184:Samuel Wilks
2110:Sacroiliitis
2060:Anal abscess
2031:
1934:
1930:
1920:
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1905:
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1344:the original
1339:
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631:
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438:, increases
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282:, and other
280:azathioprine
269:
225:certolizumab
185:
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81:inflammation
71:
37:
36:
31:
1906:www.fda.gov
1648:(1): 63–8.
1376:: 215–226.
1249:(1): 8–17.
1147:: 215–226.
642:Etrolizumab
618:thiopurines
588:biosimilars
573:Biosimilars
567:Biosimilars
558:Ustekinumab
552:Ustekinumab
511:Vedolizumab
505:Vedolizumab
488:Natalizumab
482:Natalizumab
330:cytokines.
320:interleukin
249:ustekinumab
245:interleukin
241:natalizumab
237:vedolizumab
123:The use of
113:biosimilars
93:large bowel
30:is a major
2270:Categories
2028:Treatment
1911:2018-11-29
1807:2018-11-15
1350:2018-10-24
674:References
634:Brazikumab
436:PEGylation
407:Adalimumab
401:Adalimumab
378:infliximab
369:Infliximab
363:Infliximab
324:interferon
221:adalimumab
212:infliximab
152:, such as
145:antitoxins
133:diphtheria
125:antibodies
79:involving
28:infliximab
2095:Proctitis
2075:Granuloma
1053:cite book
456:Golimumab
450:Golimumab
308:cytokines
297:colectomy
264:Cytokines
229:golimumab
159:In 1975,
51:cytokines
47:molecules
20:The anti-
2125:Stenosis
1961:29164650
1887:16143120
1851:23901382
1843:18778113
1823:BioDrugs
1783:16472588
1742:29907872
1672:25567472
1623:23785163
1615:10484006
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861:Mayer LF
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758:29012197
750:10822467
657:See also
628:Research
322:-2, and
293:fistulae
276:steroids
233:integrin
190:such as
150:proteins
141:vaccines
77:diseases
2134:History
2085:Ileitis
2070:Fistula
1952:5760274
1733:6279599
1663:4324872
1536:8899105
1501:4938523
1492:1411802
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1196:Bibcode
1164:5961645
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579:generic
119:History
83:of the
2238:People
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798:S2CID
754:S2CID
534:IL-23
530:IL-12
316:TNF-α
301:colon
204:IL-23
22:TNF-α
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2008:and
1957:PMID
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