Biological therapy for inflammatory bowel disease

Biological therapy refers to the use of medication that is tailored to specifically target an immune or genetic mediator of disease. cite journal | author = Staren E, Essner R, Economou J | title = Overview of biological response modifiers. | journal = Semin Surg Oncol | volume = 5 | issue = 6 | pages = 379–84 | year = 1989 | pmid = 2480627 | doi = 10.1002/ssu.2980050603] Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy; many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, cite journal | author = Talpaz M, Kantarjian H, McCredie K, Trujillo J, Keating M, Gutterman J | title = Therapy of chronic myelogenous leukemia. | journal = Cancer | volume = 59 | issue = 3 Suppl | pages = 664–7 | year = 1987 | pmid = 10822467 | doi = 10.1002/1097-0142(19870201)59:3+<664::AID-CNCR2820591316>3.0.CO;2-Y | doilabel = 10.1002/1097-0142(19870201)59:3+664::AID-CNCR28205913163.0.CO;2-Y] cite journal | author = Kalinski P, Mapara M | title = 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. | journal = Expert Opin Biol Ther | volume = 6 | issue = 6 | pages = 631–3 | year = 2006 | pmid = 16706609 | doi = 10.1517/14712598.6.6.631] autoimmune diseases, cite journal | author = Weinblatt M, Kremer J, Bankhurst A, Bulpitt K, Fleischmann R, Fox R, Jackson C, Lange M, Burge D | title = A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. | journal = N Engl J Med | volume = 340 | issue = 4 | pages = 253–9 | year = 1999 | pmid = 9920948 | doi = 10.1056/NEJM199901283400401] and diseases of unknown cause that result in symptoms due to immune related mechanisms. cite journal | author = Hanauer S, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J, Rachmilewitz D, Wolf D, Olson A, Bao W, Rutgeerts P | title = Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. | journal = Lancet | volume = 359 | issue = 9317 | pages = 1541–9 | year = 2002 | pmid = 12047962 | doi = 10.1016/S0140-6736(02)08512-4 ] cite journal | author = Rutgeerts P, Sandborn W, Feagan B, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer S, Lichtenstein G, de Villiers W, Present D, Sands B, Colombel J | title = Infliximab for induction and maintenance therapy for ulcerative colitis. | journal = N Engl J Med | volume = 353 | issue = 23 | pages = 2462–76 | year = 2005 | pmid = 16339095 | doi = 10.1056/NEJMoa050516]

Inflammatory bowel disease, or IBD, is a collection of systemic diseases involving inflammation of the gastrointestinal tract. cite journal | last = Hanauer | first = Stephen B. | year = 1996 | month = March | title = Inflammatory bowel disease | journal = New England Journal of Medicine | volume = 334 | issue = 13 | pages = 841–848 | pmid = 8596552 | url = http://content.nejm.org/cgi/content/extract/334/13/841 | | doi = 10.1056/NEJM199603283341307 ] IBD includes two (or three) diseases of unknown causation: ulcerative colitis, which affects only the large bowel; Crohn's disease, which can affect the entire gastrointestinal tract; and, indeterminate colitis, which consists of large bowel inflammation that shows elements of both Crohn's disease and ulcerative colitis. Cite journal|last=Podolsky|first= Daniel K.|title=Inflammatory bowel disease|journal=New England Journal of Medicine|month=August|year=2002|volume=346|issue=6|pages=417–29
url=http://content.nejm.org/cgi/content/extract/347/6/417|pmid=12167685|doi=10.1056/NEJMra020831] 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 have been developed for the treatment of these diseases. These have changed the way physicians treat Crohn's disease and ulcerative colitis.

Rationale for biological therapy

Prior to the development of biological therapy as a modality to treat IBD, other medications that modulate the immune system -- including 5-aminosalicylates, steroids, azathioprine, and other immunosuppressants -- were primarily used in treatment.. Patients with Crohn's disease that developed complications, including fistulae (= abnormal connections to the bowel) were treated with surgery. cite journal | author = Williams J | title = The place of surgery in Crohn's disease. | journal = Gut | volume = 12 | issue = 9 | pages = 739–49 | year = 1971 | pmid = 4938523 | doi = 10.1136/gut.12.9.739] Patients with ulcerative colitis who do not respond to medications are still treated with colectomy (= removal of the colon).

However, basic science research showed that there were many cytokines that were elevated in both Crohn's disease and ulcerative colitis. cite journal | author = Pallone F, Monteleone G | title = Regulatory cytokines in inflammatory bowel disease. | journal = Aliment Pharmacol Ther | volume = 10 Suppl 2 | issue = | pages = 75–9; discussion 80 | year = | pmid = 8899105] Crohn's disease cytokines, are of the type 1 ("Th1") cytokines which include TNF-α, interleukin-2, and interferon γ. cite journal | author = Romagnani S | title = Th1/Th2 cells. | journal = Inflamm Bowel Dis | volume = 5 | issue = 4 | pages = 285–94 | year = 1999 | pmid = 10579123] Ulcerative colitis was less conclusively linked to the production of "Th2" cytokines.cite journal | author = Inoue S, Matsumoto T, Iida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M | title = Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. | journal = Am J Gastroenterol | volume = 94 | issue = 9 | pages = 2441–6 | year = 1999 | pmid = 10484006 | doi = 10.1111/j.1572-0241.1999.01372.x]

Infliximab

The monoclonal antibody infliximab is a mouse-human chimeric antibody to TNF-α. It first was used in the treatment of rheumatoid arthritis, cite journal | author = Elliott M, Maini R, Feldmann M, Kalden J, Antoni C, Smolen J, Leeb B, Breedveld F, Macfarlane J, Bijl H | title = Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. | journal = Lancet | volume = 344 | issue = 8930 | pages = 1105–10 | year = 1994 | pmid = 7934491 | doi = 10.1016/S0140-6736(94)90628-9] and was the first biological agent used in the treatment of IBD. It is also used in the treatment of psoriasis and ankylosing spondylitis. cite journal | author = Chaudhari U, Romano P, Mulcahy L, Dooley L, Baker D, Gottlieb A | title = Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. | journal = Lancet | volume = 357 | issue = 9271 | pages = 1842–7 | year = 2001 | pmid = 11410193 | doi = 10.1016/S0140-6736(00)04954-0] cite journal | author = Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sörensen H, Zeidler H, Thriene W, Sieper J | title = Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. | journal = Lancet | volume = 359 | issue = 9313 | pages = 1187–93 | year = 2002 | pmid = 11955536 | doi = 10.1016/S0140-6736(02)08215-6] Infliximab has shown significant success in treating Crohn's disease.

Other monoclonal antibodies

Other biological therapy agents and monoclonal antibodies have not showed as much efficacy in the treatment of IBD. These include etanercept (which is the soluble receptor for TNF. cite journal | author = Sandborn W, Hanauer S, Katz S, Safdi M, Wolf D, Baerg R, Tremaine W, Johnson T, Diehl N, Zinsmeister A | title = Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. | journal = Gastroenterology | volume = 121 | issue = 5 | pages = 1088–94 | year = 2001 | pmid = 11677200 | doi = 10.1053/gast.2001.28674 ] Adalimumab (which is a humanized recombinant antibody to TNF) showed effectiveness in patients with moderate-to-severe Crohn's disease, but less than that of infliximab. cite journal | author = Hanauer S, Sandborn W, Rutgeerts P, Fedorak R, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P | title = Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. | journal = Gastroenterology | volume = 130 | issue = 2 | pages = 323–33; quiz 591 | year = 2006 | pmid = 16472588 | doi = 10.1053/j.gastro.2005.11.030] It however conveys an advantage in that it is given by subcutaneous injection as opposed to infliximab, which is given by intravenous infusion.

In 2005, two other recombinant medications were reported to have benefit in moderate to severe Crohn's disease. Certolizumab is a Fab fragment of a humanized anti-TNF alpha monoclonal antibody that is attached to polyethylene glycol to increase its half-life in circulation. 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. [cite journal | author = Schreiber S, Rutgeerts P, Fedorak R, Khaliq-Kareemi M, Kamm M, Boivin M, Bernstein C, Staun M, Thomsen O, Innes A | title = A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. | journal = Gastroenterology | volume = 129 | issue = 3 | pages = 807–18 | year = 2005 | pmid = 16143120 | doi = 10.1053/j.gastro.2005.06.064] Natalizumab is an anti-integrin monoclonal antibody that shown utility as induction and maintenance treatment for moderate to severe Crohn's disease. [cite journal | author = Sandborn W, Colombel J, Enns R, Feagan B, Hanauer S, Lawrance I, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge G, Rutgeerts P | title = Natalizumab induction and maintenance therapy for Crohn's disease. | journal = N Engl J Med | volume = 353 | issue = 18 | pages = 1912–25 | year = 2005 | pmid = 16267322 | doi = 10.1056/NEJMoa043335] However, it has been associated with progressive multifocal leukoencephalopathy, a usually fatal viral infection of the brain, that may limit its use. [cite journal | author = Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P | title = Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. | journal = N Engl J Med | volume = 353 | issue = 4 | pages = 362–8 | year = 2005 | pmid = 15947080 | doi = 10.1056/NEJMoa051586]

ide effects and concerns

There have been concerns about the side effects of monoclonal antibodies, and specifically of infliximab, but these are rare. Early side effects include the risk of allergic reactions (including anaphylaxis which may be life-threatening), and reactions to the infusion. These are often treated with medications given before treatment. Infliximab also carries a risk of worsening infection, and can cause reactivation of old infections, like tuberculosis. Over time, there is the risk of serum sickness, which is a delayed hypersensitivity response to the medication. Later complications may include multiple sclerosis and lymphoma. Finally, the medication is quite expensive, with treatment costs ranging from US$3000 to $8000 per infusion. cite journal | author = Blonski W, Lichtenstein G | title = Safety of biologics in inflammatory bowel disease. | journal = Curr Treat Options Gastroenterol | volume = 9 | issue = 3 | pages = 221–33 | year = 2006 | pmid = 16901386 | doi = 10.1007/s11938-006-0041-4] cite journal | author = Rutgeerts P, Van Assche G, Vermeire S | title = Review article: Infliximab therapy for inflammatory bowel disease--seven years on. | journal = Aliment Pharmacol Ther | volume = 23 | issue = 4 | pages = 451–63 | year = 2006 | pmid = 16441465 | doi = 10.1111/j.1365-2036.2006.02786.x] cite journal | author = Siegel C, Hur C, Korzenik J, Gazelle G, Sands B | title = Risks and benefits of infliximab for the treatment of Crohn's disease. | journal = Clin Gastroenterol Hepatol | volume = 4 | issue = 8 | pages = 1017–24; quiz 976 | year = 2006 | pmid = 16843733 | doi = 10.1016/j.cgh.2006.05.020]

Loss of response to infliximab over time is a concern, due to the development of antibodies to infliximab (termed human anti-chimeric antibodies, or HACA). This can be reduced by concurrent treatment with other immunosuppressant medications (including azathioprine and methotrexate), by maintaining a regular infusion schedule, and by giving patients a pre-treatment dose of steroid medication. cite journal | author = Sandborn W | title = Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease. | journal = Curr Gastroenterol Rep | volume = 5 | issue = 6 | pages = 501–5 | year = 2003 | pmid = 14602060 | doi = 10.1007/s11894-003-0040-8]

Helminthic Therapy

.cite journal |author=Summers RW, Elliott DE, Urban JF, Thompson RA, Weinstock JV |title=Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial |journal=Gastroenterology |volume=128 |issue=4 |pages=825–32 |year=2005 |pmid=15825065 |doi=]

The therapy involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely related treatments available, either inoculation with Necator americanus, commonly known as hookworms, or Trichuris Suis Ova, (TSO) commonly known as Pig Whipworm Eggs.

Helminthic therapy has emerged from the extensive research into why the incidence of autoimmune diseases and allergies is relatively low in less developed countries, while there has been a significant and sustained increase in autoimmune diseases in the industrialized countries.cite journal |author= P ZACCONE,* Z FEHERVARI,* J M PHILLIPS, D W DUNNE, and A COOKE |title= Parasitic worms and inflammatory diseases. |journal= Parasite Immunol |volume= 28 |issue= 10|pages=515–523 | year=2006 |pmid= |doi= 10.1111/j.1365-3024.2006.00879.x.] cite journal |author=Weinstock JV, Summers R, Elliott DE. |title= Helminths and harmony |journal=Gut |volume=53 |issue= |pages=7–9 |year=2004 |pmid= 14684567 |doi=] . Current research and available therapy is targeted at, or available for, the treatment of Crohn’s Disease, Ulcerative Colitis, Inflammatory Bowel Disease (IBD) as well as Multiple Sclerosis, Asthma, Eczema, Dermatitis, Hay fever and food allergies. Please see Helminthic therapy for information regarding those conditions.

ee also

*Nomenclature of monoclonal antibodies

References