Management of Crohn's disease

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 disease, 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 or abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease by any means - it involves removing the diseased part of the intestine and rejoining the healthy ends, as Crohn's 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 spontaneously, many require immunosuppressive drugs.[1]

Aminosalicylate

5-ASA compounds (Mesalazine, Sulfasalazine, etc.) have shown to be of very little efficacy in the treatment of Crohn's disease both for induction and for maintenance of remission.[2] Current guidelines do not advise the use of 5-ASA compounds for the treatment of Crohn's disease.

Corticosteroid

Steroid enemas can be used for treatment of rectal disease symptoms

Corticosteroids are a class of anti-inflammatory drug that are used primarily for treatment of moderate to severe flares of Crohn's disease. They are used more sparingly due to the availability of effective treatments with fewer side-effects.[3] The side effects of corticosteroids include Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. These 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.[4] Intravenous steroids are used when oral steroids do not work, or where oral steroids cannot be taken.[3] These are administered in the hospital setting. Because corticosteroids reduce the ability to fight infection, care must be used to ensure that there is no active infection, particularly an intra-abdominal abscess before the initiation of steroids.

Budesonide is an oral corticosteroid with limited absorption and high level of first-pass metabolism, meaning that less quantities of steroid enter into the bloodstream. It has been shown to be useful in the treatment of mild-to-moderate Crohn's disease[5] and for maintenance of remission in Crohn's disease.[6] Formulated as Entocort, budesonide is released in the ileum and right colon, and is therefore has a topical effect against disease in that area.[5]

Budesonide is also useful when used in combination with antibiotics for active Crohn's disease.[7]

Steroid enemas can also be used for disease of the lower colon and rectum, in order to treat symptoms. Hydrocortisone and budesonide liquid and foam enemas are being marketed for these reasons.

Corticosteroids however have a host of side effects, some very serious, and it is desirable to curtail their use whenever possible.

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 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, making it unwieldy to use them for induction of remission. Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses.[8]

Azathioprine and 6-MP have been found to be useful for the following indications:

Azathioprine is however a particularly dangerous drug, with great potential for inviting a host of potentially fatal infections, and is also listed by the FDA as a human carcinogen; however, it confers considerably less morbidity and mortality than corticosteroids.

Biologic therapies

Infliximab

Infliximab, is a mouse-human chimeric antibody that targets tumour necrosis factor, a cytokine in the inflammatory response. It is a monoclonal antibody that inhibits the pro-inflammatory cytokine tumour necrosis factor alpha. It is administered intravenously and dosed per weight starting at 5 mg/kg and increasing according to character of disease.

Infliximab has found utility as follows:

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.[15] Serious side effect also include lymphoma and severe infections.[16]

Adalimumab

Adalimumab like infliximab is an antibody that targets tumour necrosis factor.[17] Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn's disease (CD) in adults who have not responded well to conventional treatments and who have lost response to, or are unable to tolerate infliximab.[18]

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 TB (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.

Natalizumab

Natalizumab is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease.[19] Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab.[20]

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease.[21]

A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission[22] and maintaining symptom-free status[23] in patients with Crohn's disease.

Natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a).[24][25] The label also recommends monitoring of liver enzymes due to concerns over possible damage or failure.[26]

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.

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.[27] 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.[28]

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.[29]

Diet and lifestyle

Many diets have been proposed for treatment of Crohn's disease, and many do improve symptoms, but none have been proven to actually cure Crohn's disease.[30] Specific Carbohydrate Diet usually needs adjustments for patients so that they can handle the diet. If a patient finds that certain foods increase or decrease the symptoms, then 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 are recommended to take total parenteral nutrition (TPN) - a source of vitamins and nutrients.

Fish oil has been found to be effective in reducing the chance of relapse in less severe cases.[31]

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 can 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. Conversely, stress is likely to be caused by the flaring up of the disease and this would make day-to-day life more difficult.

Smoking has also been noted to have an association with Crohn's, and smokers with Crohn's are encouraged to explore smoking cessation programs.

Not only can smoking make Crohn's disease worse in people who do it, it also means that the risk of their disease recurring after surgery increases, and if a Crohn's disease sufferer who is having surgery does not quit smoking, their Crohn's will inevitably recur more aggressively.

Helminthic therapy

In an experimental idea called Helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts suffering from diseases linked to overactive immune systems. This is possibly explained by the hygiene hypothesis. Helminthic therapy may help sufferers of Crohn's Disease[32] 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.[33] These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit of these medications is uncertain.

Acupuncture

Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society.[34] 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.[34] This study however had a very small test set and did not reach the threshold for benefit.

Herbal

Other medications

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can cause flares of inflammatory bowel disease in approximately 25% of patients.[41] 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.[41] Celecoxib (Celebrex), a cox-2 inhibitor, appears to be safe, at least in short-term studies of patients in remission and on medicine for their Crohn's disease.[41]

Research

Egg of Trichuris spp. whipworm. Trichuris suis or pig whipworm has been investigated for treatment of Crohn's disease.

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

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.1572-0241.2001.03671.x. PMID 11280528.
  2. ↑ Hanauer, S (2010). "Aminosalicylates for induction of remission or response in Crohn's disease". Cochrane Database Syst Rev. 2010 Dec 8;(12):CD008870. doi:10.1002/14651858.CD008870.
  3. 1 2 3 Gopal, Latha; Nachimuthu, Senthil (June 16, 2011). Katz, Julian, ed. "Crohn Disease". WebMD. Retrieved July 7, 2012.
  4. ↑ Hanauer, SB (1991). "Sulfasalazine vs. Steroids in Crohn's disease: David vs. Goliath?". Gastroenterology 101 (4): 1130–1. PMID 1679735.
  5. 1 2 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.
  6. ↑ 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.
  7. ↑ 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..
  8. ↑ Podolsky, Daniel K. (2002). "Inflammatory Bowel Disease". New England Journal of Medicine 347 (6): 417–29. doi:10.1056/NEJMra020831. PMID 12167685.
  9. ↑ Rosenberg, James L.; Levin, Bernard; Wall, Alfred J.; Kirsner, Joseph B. (1975). "A controlled trial of azathioprine in Crohn's disease". The American Journal of Digestive Diseases 20 (8): 721–6. doi:10.1007/BF01070829. PMID 1098449.
  10. ↑ 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.
  11. ↑ Sandborn, William J; Sutherland, Lloyd R; Pearson, David; May, Gary; Modigliani, Robert; Prantera, Cosimo; Sandborn, William J (1998). "Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease". Cochrane Database Syst Rev: CD000545. doi:10.1002/14651858.CD000545. PMID 10796557.
  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. 1 2 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ "Infliximab". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015.
  17. ↑ Hanauer, Stephen B.; Sandborn, William J.; Rutgeerts, Paul; Fedorak, Richard N.; Lukas, Milan; MacIntosh, Donald; Panaccione, Remo; Wolf, Douglas; Pollack, Paul (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.
  18. ↑ "Medication guide: Humira" (pdf). Abbott Laboratories. 2008-02-01. Retrieved 2008-03-25.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ "FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease". Food and Drug Administration. 2008-01-14. Retrieved 2008-03-09.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ "Tysabri product information sheet" (PDF). Archived from the original (PDF) on August 22, 2007. Retrieved 2008-03-13.
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  28. ↑ "Surgery for Crohn's Disease". Crohn's and Colitis Foundation of America. March 2006. Retrieved 2006-06-08.
  29. ↑ 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, 1221-1228
  30. ↑ Gottschall, Elaine (1994). Breaking the Vicious Cycle: Intestinal Health Through Diet. Baltimore: Kirkton Press. ISBN 0-9692768-1-8.
  31. ↑ 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.
  32. ↑ 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. PMC 1856386. PMID 16344586.
  33. ↑ 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: i36–58. doi:10.1136/gut.2005.081950c. PMC 1859996. PMID 16481630.
  34. 1 2 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.
  35. ↑ Gerhardt, H; Seifert, F; Buvari, P; Vogelsang, H; Repges, R (2001). "Therapie des aktiven Morbus Crohn mit dem Boswellia-serrata-Extrakt H 15" [Therapy of active Crohn disease with Boswellia serrata extract H 15]. Zeitschrift für Gastroenterologie (in German) 39 (1): 11–7. doi:10.1055/s-2001-10708. PMID 11215357.
  36. ↑ 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.
  37. ↑ 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. PMID 6124474.
  38. ↑ 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.
  39. ↑ "Cannabis-based drugs could offer new hope for inflammatory bowel disease patients"
  40. ↑ 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.
  41. 1 2 3 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
  42. ↑ 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.
  43. ↑ http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/41155
  44. ↑ http://www.reuters.com/article/2013/08/23/us-glaxosmithkline-idUSBRE97M0NY20130823
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ Dieckgraefe, Brian K (2006). "Improving Mucosal Barrier Function—A Novel Therapeutic Strategy for Crohn's Disease". US Gastroenterology & Hepatology Review (1): 19–22.
  48. ↑ 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. PMC 1774382. PMID 15591509.
  49. ↑ 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.
  50. ↑ 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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