Medicine:Management of Crohn's disease

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Management of Crohn's disease
Specialtygastroenterology

Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections (generally antibiotics) and reduce inflammation (generally aminosalicylate anti-inflammatory drugs and corticosteroids). Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery.

Once remission is induced, the goal of treatment becomes maintenance of remission: avoiding the return of active disease, or "flares". Because of side effects, the prolonged use of corticosteroids is avoided. Although some people are able to maintain remission spontaneously, many require immunosuppressive drugs.[1]

Aminosalicylates

5-ASA compounds, such as mesalazine and sulfasalazine, have shown to be of very little efficacy in the treatment of Crohn's disease, either for induction or for maintenance of remission.[2] Current guidelines do not advise the use of 5-ASA compounds in Crohn's disease.[3]

Corticosteroids

Steroid enemas can be used for treatment of rectal disease symptoms

Corticosteroids are a class of anti-inflammatory drugs used to treat moderate to severe flares of Crohn's disease. However, they are used sparingly because they can cause serious side effects,[4] including Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. Corticosteroids should not be confused with the anabolic steroids used to enhance athletic performance.

The most commonly prescribed oral steroid is prednisone, which is typically dosed at 0.5 mg/kg for induction of remission in Crohn's disease.[5] Intravenous steroids, administered in a hospital setting, are used when oral steroids do not work or cannot be taken.[4] Because corticosteroids reduce the body's ability to fight infection, care must be taken to ensure that there is no active infection, particularly an intra-abdominal abscess, before the initiation of steroids.[citation needed]

Another oral corticosteroid, budesonide (trade name Entocort), has limited absorption and a high level of first-pass metabolism, meaning that lower quantities of the drug enter the bloodstream. It has been shown to be useful in the treatment of mild to moderate Crohn's disease,[6] and in maintaining remission.[7] It is also effective when used in combination with antibiotics to treat active Crohn's disease.[8] Budesonide is released in the ileum and right colon, and therefore has a topical effect against disease in that area.[6]

Steroid enemas can also be used to treat symptoms in the lower colon and rectum. Hydrocortisone and budesonide liquid and foam enemas are marketed for this purpose.[citation needed]

Mercaptopurine immunosuppressing drugs

Azathioprine, shown here in tablet form, is a first line steroid-sparing immunosuppressant

Azathioprine and 6-mercaptopurine (6-MP) are the most commonly used immunosuppressants for maintenance therapy of Crohn's disease. They are purine anti-metabolites, meaning that they interfere with the synthesis of purines required for inflammatory cells. They have a duration of action of months (slow-acting).[9] Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses.[10]

A Cochrane systematic review that included 13 randomized controlled trials, concluded that azathioprine and 6-mercaptopurine are not effective for inducing remission when a person has Crohn's Disease.[9]

Azathioprine and 6-MP may be useful for the following indications:

  • Maintenance therapy with azathioprine or 6-mercaptopurine may lead people with active Crohn's to take less steroid medication. This may lower side effects related to steroid treatments.[9]
  • Fistulizing disease[11]
  • Maintenance of remission after surgery for Crohn's disease[12]
  • A combination of azathioprine and infliximab treatment may be more effective than a single dose of infliximab to induce steroid-free remission for people with active Crohn's disease.[9]

Azathioprine treatment may lead to rare but life-threatening side effects. The rare side effects include leukopenia or pancreatitis.[9] There may also be an increased risk of lymphoma that is associated with azathioprine or 6-mercaptopurine treatment.[9]

Azathioprine is listed by the United States FDA as a human carcinogen.[13] However, it confers considerably less morbidity and mortality than corticosteroids.[citation needed]

Biologic therapies

Infliximab

Infliximab (trade name Remicade, among others) is a mouse-human chimeric antibody that targets tumor necrosis factor alpha (TNFα), a cytokine in the inflammatory response. It is a monoclonal antibody that inhibits the pro-inflammatory cytokine TNFα. It is administered intravenously and dosed per weight starting at 5 mg/kg and increasing according to character of disease.[citation needed]

Infliximab has found utility as follows:

  • Induction and maintenance of remission for people with Crohn's disease[14]
  • Maintenance for fistulizing Crohn's disease[15]

Side effects of infliximab, like other immunosuppressants of the TNF class, can be serious and potentially fatal, and infliximab carries an FDA black-box warning on the label. Listed side effects include hypersensitivity and allergic reactions, risk of re-activation of tuberculosis, serum sickness, and risk of multiple sclerosis.[16] Serious side effect also include lymphoma and severe infections.[17]

Adalimumab

Adalimumab, like infliximab, is an antibody that targets tumor necrosis factor.[18] It has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn's disease in adults who have not responded well to conventional treatments and who have lost response to or are unable to tolerate infliximab.[19]

Adalimumab also has a number of serious, potentially fatal, safety concerns characteristic of the anti-TNFα drugs. It, too, has a black-box warning on its FDA label. Listed potential side effects include serious and sometimes fatal blood disorders; serious infections including tuberculosis and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure.[citation needed]

Natalizumab

Natalizumab is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease.[20] Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha, such as infliximab.[21]

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease.[22]

A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission[23] and maintaining symptom-free status[24] in patients with Crohn's disease.

Natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a).[25][26] The label also recommends monitoring of liver enzymes due to concerns over possible damage or failure.[27]

Also associated with a rare but serious risk of multifocal leukoencephalopathy (brain infection leading to death or severe disability). Therefore, a specific program exists in which prescribers must be enrolled, CD-TOUCH (Crohn's Disease-Tysabri Outreach Unified Commitment to Health) Prescribing Program.[citation needed]

Ustekinumab

Ustekinumab (CNTO 1275) is a monoclonal antibody that suppresses cytokines IL-12 and IL-23. Originally designed to treat psoriasis, Ustekinumab was FDA approved for the treatment of Crohn's Disease in 2016.[28] Evidence from four quality randomized control trials suggest that Ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's Disease.[29] Based on these studies, Ustekinumab appears to be safe, but the implications of longer-term drug administration needs to be studied.

Vedolizumab

Vedolizumab is a gut-selective, Alpha-4 Beta-7 anti-integrin, monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) to treat Crohn's disease in 2014. It is indicated for management of moderate-to-severe, active Crohn's disease patients and it works by inhibiting the trafficking of pro-inflammatory immune cells to the site of inflammation. Evidence from three randomized control trials, including an international, multi-center, randomized, parallel-group, double-blind clinical trial, GEMINI 2 (NCT00783692), demonstrated that Vedolizumab is effective for induction and maintenance of remission in patients with active Crohn's disease.

Surgery

Resected ileum for Crohn's disease.

Surgery is normally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed.[30] Surgery is often used to manage complications of Crohn's disease, including fistulae, small bowel obstruction, colon cancer, small intestine cancer and fibrostenotic strictures, when strictureplasty (expansion of the stricture) is sometimes performed. Otherwise, and for other complications, resection and anastomosis – the removal of the affected section of intestine and the rejoining of the healthy sections – is the surgery usually performed for Crohn's disease (e.g., ileocolonic resection). None of these surgeries cure or eliminate Crohn's disease, as the disease eventually comes back in healthy segments of the intestine, although when Crohn's disease recurs after surgery, it usually comes back at the site of the surgery.[31]

Small intestine transplants are becoming less experimental, but are still mainly performed in response to short bowel syndrome due to a high rate of transplant rejection.[32]

Diet and lifestyle

Many diets have been proposed for the management of Crohn's disease, and many do improve symptoms, but none have been proven to cure the disease.[33] The specific carbohydrate diet usually requires adjustments by patients; if a patient finds that certain foods increase or decrease symptoms, they may adjust their diet accordingly. A food diary is recommended to see what positive or negative effects particular foods have. A low residue diet may be used to reduce the volume of stools excreted daily. People with lactose intolerance due to small bowel disease may benefit from avoiding lactose-containing foods. Patients who cannot eat may be given total parenteral nutrition (TPN), a source of vitamins and nutrients.

Fish oil may be effective in reducing the chance of relapse in less severe cases.[34]

Because the terminal ileum is the most common site of involvement and is the site for vitamin B12 absorption, people with Crohn's disease are at risk for B12 deficiency and may need supplementation. In cases with extensive small intestine involvement, the fat-soluble vitamins A, D, E and K may be deficient. Folate deficiency is a risk for patients treated with methotrexate who do not simultaneously receive folate supplementation.

Stress can influence the course of Crohn's disease. Smoking has also been associated with the disease, and smokers with Crohn's are encouraged to explore smoking cessation programs. Smoking can not only make Crohn's disease worse in people who do it, but also increase the risk of recurrence after surgery. If a Crohn's disease patient who undergoes surgery does not quit smoking, the disease is likely to recur more aggressively.

Microbiome Modification

The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched recently to understand whether it may help to improve remission rate in people with Crohn's disease. However only 2 controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation.[35]

Helminthic therapy

In an experimental idea called helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts who have diseases linked to overactive immune systems. This may be explained by the hygiene hypothesis.[36] Hookworm therapy is currently in the trial stage at the University of Nottingham. Due to the unconventional nature of this therapy, it is not widely used.

Alternative medicine

More than half of people with Crohn's disease have tried complementary or alternative therapy.[37] These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit, if any, and risks of these therapies is uncertain.

Acupuncture

Acupuncture is used to treat inflammatory bowel disease in China , and is being used more frequently in Western society.[38] Evidence has been put forth suggesting that acupuncture can have benefits beyond the placebo effect, improving quality of life, general well-being and a small decrease in blood-bound inflammatory markers.[38] This study however had a very small test set and did not reach the threshold for benefit.

Herbal

  • Boswellia is an ayurvedic (Indian traditional medicine) herb, used as a natural alternative to drugs. One study has found that the effectiveness of H-15 extract is not inferior to mesalazine: "Considering both safety and efficacy of Boswellia serrata extract H15, it appears to be superior over mesalazine in terms of a benefit-risk-evaluation."[39]
  • Yunnan Baiyao[40]

Other medications

  • Methotrexate is a folate anti-metabolite drug that is also used for chemotherapy. It is useful in maintenance of remission for those no longer taking corticosteroids.[41]
  • The antibiotics Metronidazole and ciprofloxacin may be used to treat Crohn's disease with colonic or perianal involvement, although this usage has not been approved by the Food and Drug Administration.[42] They are also used to treat complications, including abscesses and other infections.[4]
  • Thalidomide has shown efficacy in reversing endoscopic evidence of disease.[43]
  • Cannabis may be used to treat Crohn's disease because of its anti-inflammatory properties. Cannabis and cannabis-derived drugs may also help to heal the gut lining,[44] and may reduce the need for surgery and other medications.[45]

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can cause flares of inflammatory bowel disease in approximately 25% of patients.[46] These flares tend to occur within one week after starting regular use of the NSAID. In contrast, acetaminophen (paracetamol) and aspirin appear to be safe.[46] Celecoxib (Celebrex), a cox-2 inhibitor, also appears to be safe, at least in short-term studies of patients in remission and on medication for their Crohn's disease.[46]

Research

File:Trichuris trichiura egg (01).tif

Many clinical trials have been recently completed or are ongoing for new therapies for Crohn's disease. They include the following:

  • Certolizumab is a PEGylated Fab fragment of a humanized anti-TNFα monoclonal antibody that was found to have efficacy over placebo in one large trial.[47]
  • Traficet-EN/CCX282/GSK'786/vercirnon is a CCR9 chemokine receptor antagonist intended to modulate immune response. It failed in Phase III clinical trials, showing no improvement over a placebo.[48][49]
  • ABT-874 is a human anti-IL-12 monoclonal antibody being developed by Abbott Laboratories in conjunction with Cambridge Antibody Technology for the treatment of multiple autoimmune diseases, including Crohn's disease. Phase II trials showed promising results,[50]
  • Sargramostim, or granulocyte-monocyte colony stimulating factor (GM-CSF), has been shown to substantially improve health-related quality of life in pilot studies, measured by an increase in score on a 32-item IBD questionnaire.[51] A recent Phase II trial showed that Sargramostim significantly decreased CD severity (48%, compared with 26% in the placebo group) and improved quality of life (40%, versus 19% for placebo).[52]
  • Trichuris suis is a pig whipworm that been shown in one study to improve Crohn's disease symptoms.[53]
  • Autologous stem cell transplants have also been evaluated.[54]
  • Rifabutin, clarithromycin and clofazimine are antibiotics designed to attack mycobacterium avium subsp. paratuberculosis, which may be a cause of Crohn's disease. This treatment, called Myoconda, is being tested by Giaconda.
  • A pilot study found that Low-dose naltrexone, a very inexpensive drug, helped patients with active Crohn's disease. In the study, 89% of patients exhibited a response to therapy, and 67% achieved remission within four weeks.[55]

See also

References

  1. ↑ Hanauer, Stephen B.; Sandborn, William; Practice Parameters Committee of the American College of Gastroenterology (2001). "Management of Crohn's disease in adults". The American Journal of Gastroenterology 96 (3): 635–43. doi:10.1111/j.1572-0241.2001.3671_c.x. PMID 11280528. 
  2. ↑ Lim, Wee-Chian; Wang, Y (2016). "Aminosalicylates for induction of remission or response in Crohn's disease". Cochrane Database of Systematic Reviews 7 (12): CD008870. doi:10.1002/14651858.CD008870.pub2. PMID 27372735. 
  3. ↑ Feuerstein, Joseph D.; Ho, Edith Y.; Shmidt, Eugenia; Singh, Harminder; Falck-Ytter, Yngve; Sultan, Shanaz; Terdiman, Jonathan P.; American Gastroenterological Association Institute Clinical Guidelines Committee (June 2021). "AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease". Gastroenterology 160 (7): 2496–2508. doi:10.1053/j.gastro.2021.04.022. ISSN 1528-0012. PMID 34051983. 
  4. ↑ 4.0 4.1 4.2 Gopal, Latha; Nachimuthu, Senthil (June 16, 2011). "Crohn Disease". in Katz, Julian. WebMD. http://www.emedicine.com/MED/topic477.htm. 
  5. ↑ Hanauer, SB (1991). "Sulfasalazine vs. Steroids in Crohn's disease: David vs. Goliath?". Gastroenterology 101 (4): 1130–1. doi:10.1016/0016-5085(91)90746-8. PMID 1679735. 
  6. ↑ 6.0 6.1 Greenberg, Gordon R.; Feagan, Brian G.; Martin, Francois; Sutherland, Lloyd R.; Thomson, Alan; Williams, C. Noel; Nilsson, Lars-Goran; Persson, Tore (1994). "Oral Budesonide for Active Crohn's Disease". New England Journal of Medicine 331 (13): 836–41. doi:10.1056/NEJM199409293311303. PMID 8078529. 
  7. ↑ Sandborn, William J.; Lofberg, Robert; Feagan, Brian G.; Hanauer, Stephen B.; Campieri, Massimo; Greenberg, Gordon R. (2005). "Budesonide for Maintenance of Remission in Patients with Crohn's Disease in Medically Induced Remission: A Predetermined Pooled Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials". The American Journal of Gastroenterology 100 (8): 1780–7. doi:10.1111/j.1572-0241.2005.41992.x. PMID 16086715. 
  8. ↑ Steinhart, A; Feagan, BG; Wong, CJ; Vandervoort, M; Mikolainis, S; Croitoru, K; Seidman, E; Leddin, DJ et al. (2002). "Combined budesonide and antibiotic therapy for active Crohn's disease: A randomized controlled trial". Gastroenterology 123 (1): 33–40. doi:10.1053/gast.2002.34225. PMID 12105831. .
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Chande, Nilesh; Townsend, Cassandra M; Parker, Claire E; MacDonald, John K; Chande, Nilesh (2016). "Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease". Cochrane Database of Systematic Reviews 10 (10): CD000545. doi:10.1002/14651858.CD000545.pub5. PMID 27783843. 
  10. ↑ Podolsky, Daniel K. (2002). "Inflammatory Bowel Disease". New England Journal of Medicine 347 (6): 417–29. doi:10.1056/NEJMra020831. PMID 12167685. http://gut.bmj.com/cgi/content/short/39/Suppl_1/A15. 
  11. ↑ Dejaco, C.; Harrer, M.; Waldhoer, T.; Miehsler, W.; Vogelsang, H.; Reinisch, W. (2003). "Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease". Alimentary Pharmacology and Therapeutics 18 (11–12): 1113–20. doi:10.1046/j.1365-2036.2003.01793.x. PMID 14653831. 
  12. ↑ Hanauer, Stephen B.; Korelitz, Burton I.; Rutgeerts, Paul; Peppercorn, Mark A.; Thisted, Ronald A.; Cohen, Russell D.; Present, Daniel H. (2004). "Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: A 2-year trial". Gastroenterology 127 (3): 723–9. doi:10.1053/j.gastro.2004.06.002. PMID 15362027. 
  13. ↑ National Toxicology Program, United States Department of Health and Human Services. "Azathioprine. Report on Carcinogens, Fourteenth Edition" (in en-us). https://ntp.niehs.nih.gov/ntp/roc/content/profiles/azathioprine.pdf. 
  14. ↑ Hanauer, Stephen B; Feagan, Brian G; Lichtenstein, Gary R; Mayer, Lloyd F; Schreiber, S; Colombel, Jean Frederic; Rachmilewitz, Daniel; Wolf, Douglas C et al. (2002). "Maintenance infliximab for Crohn's disease: The ACCENT I randomised trial". The Lancet 359 (9317): 1541–9. doi:10.1016/S0140-6736(02)08512-4. PMID 12047962. 
  15. ↑ Sands, Bruce E.; Anderson, Frank H.; Bernstein, Charles N.; Chey, William Y.; Feagan, Brian G.; Fedorak, Richard N.; Kamm, Michael A.; Korzenik, Joshua R. et al. (2004). "Infliximab Maintenance Therapy for Fistulizing Crohn's Disease". New England Journal of Medicine 350 (9): 876–85. doi:10.1056/NEJMoa030815. PMID 14985485. 
  16. ↑ Rutgeerts, P.; Assche, G.; Vermeire, S. (2006). "Review article: Infliximab therapy for inflammatory bowel disease - seven years on". Alimentary Pharmacology and Therapeutics 23 (4): 451–63. doi:10.1111/j.1365-2036.2006.02786.x. PMID 16441465. 
  17. ↑ "Infliximab". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/infliximab.html. 
  18. ↑ Hanauer, Stephen B.; Sandborn, William J.; Rutgeerts, Paul; Fedorak, Richard N.; Lukas, Milan; MacIntosh, Donald; Panaccione, Remo; Wolf, Douglas et al. (2006). "Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn's Disease: The CLASSIC-I Trial". Gastroenterology 130 (2): 323–33; quiz 591. doi:10.1053/j.gastro.2005.11.030. PMID 16472588. 
  19. ↑ "Medication guide: Humira". Abbott Laboratories. 2008-02-01. http://www.rxabbott.com/pdf/humira_medguide.pdf. 
  20. ↑ Sandborn, William J.; Colombel, Jean Frédéric; Enns, Roberts; Feagan, Brian G.; Hanauer, Stephen B.; Lawrance, Ian C.; Panaccione, Remo; Sanders, Martin et al. (2005). "Natalizumab Induction and Maintenance Therapy for Crohn's Disease". New England Journal of Medicine 353 (18): 1912–25. doi:10.1056/NEJMoa043335. PMID 16267322. 
  21. ↑ Michetti, Pierre; Mottet, Christian; Juillerat, Pascal; Pittet, Valérie; Felley, Christian; Vader, John-Paul; Gonvers, Jean-Jacques; Froehlich, Florian (2007). "Severe and Steroid-Resistant Crohn's Disease". Digestion 76 (2): 99–108. doi:10.1159/000111023. PMID 18239400. 
  22. ↑ "FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease". Food and Drug Administration. 2008-01-14. https://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html. 
  23. ↑ Ghosh, Subrata; Goldin, Eran; Gordon, Fiona H.; Malchow, Helmut A.; Rask-Madsen, Jørgen; Rutgeerts, Paul; Vyhnálek, Petr; Zádorová, Zdena et al. (2003). "Natalizumab for Active Crohn's Disease". New England Journal of Medicine 348 (1): 24–32. doi:10.1056/NEJMoa020732. PMID 12510039. 
  24. ↑ Feagan, Brian G.; Sandborn, William J.; Hass, Steven; Niecko, Timothy; White, Jeffrey (2007). "Health-Related Quality of Life During Natalizumab Maintenance Therapy for Crohn's Disease". The American Journal of Gastroenterology 102 (12): 2737–46. doi:10.1111/j.1572-0241.2007.01508.x. PMID 18042106. 
  25. ↑ Kleinschmidt-Demasters, B.K.; Tyler, Kenneth L. (2005). "Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis". New England Journal of Medicine 353 (4): 369–74. doi:10.1056/NEJMoa051782. PMID 15947079. 
  26. ↑ Langer-Gould, Annette; Atlas, Scott W.; Green, Ari J.; Bollen, Andrew W.; Pelletier, Daniel (2005). "Progressive Multifocal Leukoencephalopathy in a Patient Treated with Natalizumab". New England Journal of Medicine 353 (4): 375–81. doi:10.1056/NEJMoa051847. PMID 15947078. 
  27. ↑ "Tysabri product information sheet". http://tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf. 
  28. ↑ "FDA Approves STELARA® (Ustekinumab) for Treatment of Adults With Moderately to Severely Active Crohn's Disease | Johnson & Johnson" (in en-US). https://www.jnj.com/media-center/press-releases/fda-approves-stelara-ustekinumab-for-treatment-of-adults-with-moderately-to-severely-active-crohns-disease. 
  29. ↑ MacDonald, John K.; Nguyen, Tran M.; Khanna, Reena; Timmer, Antje (25 November 2016). "Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease". The Cochrane Database of Systematic Reviews 2016 (11): CD007572. doi:10.1002/14651858.CD007572.pub3. ISSN 1469-493X. PMID 27885650. 
  30. ↑ Wood, Alastair J.J.; Hanauer, Stephen B. (1996). "Inflammatory Bowel Disease". New England Journal of Medicine 334 (13): 841–8. doi:10.1056/NEJM199603283341307. PMID 8596552. http://gut.bmj.com/cgi/content/short/39/Suppl_1/A15. 
  31. ↑ "Surgery for Crohn's Disease". Crohn's and Colitis Foundation of America. March 2006. http://www.ccfa.org/info/surgery/surgerycd. 
  32. ↑ Garg M., Jones R. M., Vaughan R. B., Testro A. G. (2011). "Intestinal transplantation: Current status and future directions". Journal of Gastroenterology and Hepatology 26 (8): 1221–1228. doi:10.1111/j.1440-1746.2011.06783.x. PMID 21595748. 
  33. ↑ Gottschall, Elaine (1994). Breaking the Vicious Cycle: Intestinal Health Through Diet. Baltimore: Kirkton Press. ISBN 978-0-9692768-1-4. 
  34. ↑ Belluzzi, Andrea; Brignola, Corrado; Campieri, Massimo; Pera, Angelo; Boschi, Stefano; Miglioli, Mario (1996). "Effect of an Enteric-Coated Fish-Oil Preparation on Relapses in Crohn's Disease". New England Journal of Medicine 334 (24): 1557–60. doi:10.1056/NEJM199606133342401. PMID 8628335. 
  35. ↑ Limketkai, Berkeley N.; Akobeng, Anthony K.; Gordon, Morris; Adepoju, Akinlolu Adedayo (2020-07-17). "Probiotics for induction of remission in Crohn's disease". The Cochrane Database of Systematic Reviews 2020 (7): CD006634. doi:10.1002/14651858.CD006634.pub3. ISSN 1469-493X. PMID 32678465. 
  36. ↑ Croese, J; O'Neil, J; Masson, J; Cooke, S; Melrose, W; Pritchard, D; Speare, R (2006). "A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors". Gut 55 (1): 136–7. doi:10.1136/gut.2005.079129. PMID 16344586. 
  37. ↑ Caprilli, R; Gassull, MA; Escher, JC; Moser, G; Munkholm, P; Forbes, A; Hommes, DW; Lochs, H et al. (2006). "European evidence based consensus on the diagnosis and management of Crohn's disease: Special situations". Gut 55 (Suppl 1): i36–58. doi:10.1136/gut.2005.081950c. PMID 16481630. 
  38. ↑ 38.0 38.1 Joos, Stefanie; Brinkhaus, Benno; Maluche, Christa; Maupai, Nathalie; Kohnen, Ralf; Kraehmer, Nils; Hahn, Eckhart G.; Schuppan, Detlef (2004). "Acupuncture and Moxibustion in the Treatment of Active Crohn's Disease: A Randomized Controlled Study". Digestion 69 (3): 131–9. doi:10.1159/000078151. PMID 15114043. 
  39. ↑ Gerhardt, H; Seifert, F; Buvari, P; Vogelsang, H; Repges, R (2001). "Therapie des aktiven Morbus Crohn mit dem Boswellia-serrata-Extrakt H 15" (in de). Zeitschrift für Gastroenterologie 39 (1): 11–7. doi:10.1055/s-2001-10708. PMID 11215357. 
  40. ↑ Li, Richard; Alex, Philip; Ye, Mei; Zhang, Ting; Liu, Ling; Li, Xuhang (2011-10-29). "An old herbal medicine with a potentially new therapeutic application in inflammatory bowel disease". International Journal of Clinical and Experimental Medicine 4 (4): 309–319. ISSN 1940-5901. PMID 22140602. 
  41. ↑ Feagan, Brian G.; Fedorak, Richard N.; Irvine, E. Jan; Wild, Gary; Sutherland, Lloyd; Steinhart, A. Hillary; Greenberg, Gordon R.; Koval, John et al. (2000). "A Comparison of Methotrexate with Placebo for the Maintenance of Remission in Crohn's Disease". New England Journal of Medicine 342 (22): 1627–32. doi:10.1056/NEJM200006013422202. PMID 10833208. 
  42. ↑ Ursing, B; Alm, T; Bárány, F; Bergelin, I; Ganrot-Norlin, K; Hoevels, J; Huitfeldt, B; Järnerot, G et al. (1982). "A comparative study of metronidazole and sulfasalazine for active Crohn's disease: The cooperative Crohn's disease study in Sweden. II. Result". Gastroenterology 83 (3): 550–62. doi:10.1016/S0016-5085(82)80189-3. PMID 6124474. 
  43. ↑ Cohen, LB (2004). "Re: Disappearance of Crohn's ulcers in the terminal ileum after thalidomide therapy. Can J Gastroenterol 2004; 18(2): 101-104". Canadian Journal of Gastroenterology 18 (6): 419; author reply 419. PMID 15230268. 
  44. ↑ ""Cannabis-based drugs could offer new hope for inflammatory bowel disease patients"". http://www.medicalnewstoday.com/articles/28584.php. 
  45. ↑ Naftali, T; Lev, LB; Yablecovitch, D; Half, E; Konikoff, FM (2011). "Treatment of Crohn's disease with cannabis: An observational study". The Israel Medical Association Journal 13 (8): 455–8. PMID 21910367. 
  46. ↑ 46.0 46.1 46.2 What should patients with Crohn's disease avoid?, from Inflammatory Bowel Disease Program at the Digestive Disease Center at Beth Israel Deaconess Medical Center. Retrieved March 2014
  47. ↑ Schreiber, Stefan; Rutgeerts, Paul; Fedorak, Richard N.; Khaliq–Kareemi, Munaa; Kamm, Michael A.; Boivin, Michel; Bernstein, Charles N.; Staun, Michael et al. (2005). "A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for Treatment of Crohn's Disease". Gastroenterology 129 (3): 807–18. doi:10.1053/j.gastro.2005.06.064. PMID 16143120. 
  48. ↑ "GSK IBD Drug Fails in Trial". 2013-08-23. http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/41155. 
  49. ↑ "GSK's Crohn's disease treatment fails in Phase III trial". Reuters. 2013-08-23. https://www.reuters.com/article/us-glaxosmithkline-idUSBRE97M0NY20130823. 
  50. ↑ Mannon, Peter J.; Fuss, Ivan J.; Mayer, Lloyd; Elson, Charles O.; Sandborn, William J.; Present, Daniel; Dolin, Ben; Goodman, Nancy et al. (2004). "Anti–Interleukin-12 Antibody for Active Crohn's Disease". New England Journal of Medicine 351 (20): 2069–79. doi:10.1056/NEJMoa033402. PMID 15537905. 
  51. ↑ Korzenik, Joshua R.; Dieckgraefe, Brian K.; Valentine, John F.; Hausman, Diana F.; Gilbert, Mark J.; Sargramostim in Crohn's Disease Study Group (2005). "Sargramostim for Active Crohn's Disease". New England Journal of Medicine 352 (21): 2193–201. doi:10.1056/NEJMoa041109. PMID 15917384. 
  52. ↑ Dieckgraefe, Brian K (2006). "Improving Mucosal Barrier Function—A Novel Therapeutic Strategy for Crohn's Disease". US Gastroenterology & Hepatology Review (1): 19–22. http://www.touchgastroenterology.com/articles/improving-mucosal-barrier-function-novel-therapeutic-strategy-crohns-disease. 
  53. ↑ Summers, R W; Elliott, DE; Urban Jr, JF; Thompson, R; Weinstock, JV (2005). "Trichuris suis therapy in Crohn's disease". Gut 54 (1): 87–90. doi:10.1136/gut.2004.041749. PMID 15591509. 
  54. ↑ Oyama, Yu; Craig, Robert M.; Traynor, Ann E.; Quigley, Kathleen; Statkute, Laisvyde; Halverson, Amy; Brush, Mary; Verda, Larissa et al. (2005). "Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease". Gastroenterology 128 (3): 552–63. doi:10.1053/j.gastro.2004.11.051. PMID 15765390. 
  55. ↑ Smith, Jill P.; Stock, Heather; Bingaman, Sandra; Mauger, David; Rogosnitzky, Moshe; Zagon, Ian S. (2007). "Low-Dose Naltrexone Therapy Improves Active Crohn's Disease". The American Journal of Gastroenterology 102 (4): 820–8. doi:10.1111/j.1572-0241.2007.01045.x. PMID 17222320. 



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