The Crohnie

There is a small amount of research going on in the veterinary world on this topic, although lack of funding has hampered the effort.

“Role of Nramp 1 in Johne’s Disease.”
http://www.paratuberculosis.org/proc6/abst7_9.htm

“Genetic influence on the susceptibility of cattle to paratuberculosis”
http://www.paratuberculosis.org/proc6/abst2_35.htm

Excerpt from “An interview with Dr T.J. Borody”

————————————————-

Question: Why do you think there were some failures with this treatment [anti-paratuberculosis antibiotic treatment]?

Dr Borody: We could probably spend a long time in this area. Firstly, let us reflect on Crohn’s Disease, which has a wide variety of manifestations, the symptoms of which are different in every patient. It is quite possible, and there is growing support for this view, that Crohn’s Disease may have more than one underlying cause, with MAP infection as one of those causes. If Crohn’s Disease is a collection of disorders, a proportion of which is caused by Mycobacterium avium subspecies paratuberculosis, then we aren’t going to be successful in 100% of patients by treating them with anti-MAP treatment.

Secondly, Mycobacterium avium subspecies paratuberculosis is a difficult infection to eradicate. Experience in Mycobacterium Avium Complex disease in patients with AIDS, where multiple drugs have to be used simultaneously and for a very long period of time, has shown that the success rate for clearance of infection is disappointingly low. Even with culturable Mycobacterium tuberculosis, we do not always achieve cure with multiple antibiotics given for a long time. In fact, there is a known increase in resistance of Mycobacterium tuberculosis to antibiotics. Hence we can expect that with the even more slowly growing and more antibiotic-resistant Mycobacterium avium subspecies paratuberculosis, we are going to get treatment failures.

Furthermore, we believe that pre-treatment with drugs used in these combinations, in particular the macrolide antibiotics Clarithromycin and Azithromycin, may increase the likelihood of ending up with antibiotic resistant Mycobacterium avium subspecies paratuberculosis in the patient. If we had the capability to culture Mycobacterium avium subspecies paratuberculosis and do sensitivity studies beforehand, we would be more likely to overcome treatment failure due to resistance. Unfortunately, reliable isolation of Mycobacterium avium subspecies paratuberculosis from Crohn’s Disease, and thus susceptibility testing of isolates, is not widely available.

————————————————-

Dr Tom Borody (Center for Digestive Diseases, Sydney, Australia) is a Gastroenterologist of over two decades experience, who has been treating Crohn’s patients with anti-paratuberculosis antibiotics for the last three years.

Full text of this interview available at

http://www.crohns.org/treatment/borody.htm

Is it possible that Crohn’s disease is more than one disease, i.e. it is really Crohn’s syndrome, a collection of symptoms caused by a variety of different underlying diseases?

Firstly, it has been estimated that up to 20% of people diagnosed with Crohn’s disease don’t actually have Crohn’s disease(1). Secondly, there are various disease syndromes that have a wide range of symptoms, and which are sometimes misdiagnosed as Crohn’s disease. For example, Behcet’s Syndrome(2,3,4), Reiter’s Syndrome(5), Sweet’s Syndrome(6,7,8), Melkersson-Rosenthal Syndrome(9,10,11), Orofacial Granulomatosis(12,13,14), Granulomatous Cheilitis (15,16,17), Hidradenitis Suppurativa (18,19,20), Erythema Nodosum (21), Sarcoidosis (22,23,24) and of course Ulcerative Colitis and intestinal tuberculosis have all been confused with Crohn’s disease. Note that many of these diseases are looking more and more like infectious diseases, e.g. Klebsiella infection in Ankylosing spondylitis(25,26,27,28), Campylobacter jejuni in Reiter’s Syndrome(29,30).

So it is quite possible that the people who have Crohn’s disease may share the same symptoms, but not for the same reasons. How many different diseases Crohn’s disease actually is is unknown, and won’t be until we start studying these diseases individually, e.g. MAP infection, etc.

What is the effect of that on research? Well, the way that all existing Crohn’s disease research is conducted is based on statistical significance. When testing a new drug treatment, you must show that a statistically significant proportion of patients on active treatment improve, compared to patients on placebo.

BUT, if Crohn’s disease is several different diseases, in unknown proportions, then statistical significance may be *impossible* to achieve.

In relation to genetics, if there is a genetic susceptibility for Crohn’s disease, then there is probably a *different* genetic susceptibility for every underlying disease condition that gives rise to the symptoms of Crohn’s Disease (Crohn’s Syndrome is probably a far better description). Say, for discussion purposes, that Crohn’s is 5 different diseases, each suffered by 20% of the Crohn’s disease patient population. So you isolate a genetic abnormality in 20% of Crohn’s disease patients, which predisposes them to developing disease when exposed to a particular bacterium, virus, or environmental toxin. Current research methodologies would discard this finding, because 20% of patients is not a statistically significant proportion of the Crohn’s disease patient population.

The same applies to antibiotic treatment. There is a long history of controlled trials of anti-mycobacterial treatment for Crohn’s disease. In every trial, a proportion of the patients got fundamentally better, although a majority did not. But instead of investigating why the small subset of patients got better, the investigators invariably concluded that "treatment with a combination of anti-mycobacterial drugs A + B +C is of no value in the treatment of Crohn’s disease".

To date, "promising linkages" have been found on 9 different chromosomes in Crohn’s disease. Every time a new linkage is found, much excitement is generated, but then enthusiasm wanes as it turns out that the finding has no statistical significance. What these researchers are missing is that they are asking the wrong question!

They should be asking themselves "Why do a subset of Crohn’s patients get better when we treat them with anti-mycobacterials, and how can identify and separate those patients from the rest of the patients?"

Until these we start asking and answering these questions, we may never find a cure for Crohn’s disease.

Update: 18th May 2009: Since this post was written, a genetic marker for Crohn’s Disease, NOD2, has been discovered. This protein is a prt of the immune system, and is involved in the recognition of microbes in the intestine. However, a mutated version of NOD2 is present in only 25% to 30% of people with "Crohn’s Disease" in western populations. The percentage is noticably lower in Asian patients(31).

References

1. Trends in the incidence rates of Ulcerative Colitis and Crohn’s Disease.
Calkins BM, Lilienfield AM, Garland CF, Medeloff AI.
Dig. Dis. Sci. 1984;29:913-20.

http://www.ncbi.nlm.nih.gov/pubmed/85003090

2. Behcet’s colitis: a differential diagnosis in inflammations of the large intestine.
Kyle SM, Yeong ML, Isbister WH, Clark SP.
Aust N Z J Surg 1991 Jul;61(7):547-50

http://www.ncbi.nlm.nih.gov/pubmed/91315342

3. A case of Behcet’s disease with intestinal involvement due to Crohn’s disease.
Tolia V, Abdullah A, Thirumoorthi MC, Chang CH.
Am J Gastroenterol 1989 Mar;84(3):322-5

http://www.ncbi.nlm.nih.gov/pubmed/89148179

4. Behcet’s syndrome in a family with inflammatory bowel disease.
Yim CW, White RH.
Arch Intern Med 1985 Jun;145(6):1047-50

http://www.ncbi.nlm.nih.gov/pubmed/85224646

5. Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy.
Lyons JL, Rosenbaum JT.
Arch Ophthalmol 1997 Jan;115(1):61-4

http://www.ncbi.nlm.nih.gov/pubmed/97159085

6. Sweet’s syndrome: an unusual cutaneous feature of Crohn’s disease or ulcerative colitis. The South West Gastroenterology Group.
Travis S, Innes N, Davies MG, Daneshmend T, Hughes S.
Eur J Gastroenterol Hepatol 1997 Jul;9(7):715-20:

http://www.ncbi.nlm.nih.gov/pubmed/97408464

7. Intestinal involvement in Sweet’s syndrome.
Fain O, Mathieu E, Feton N, Sibony M, Sitbon M, Lejeune F, Thomas M.
J Am Acad Dermatol 1996 Dec;35(6):989-90

http://www.ncbi.nlm.nih.gov/pubmed/97119140

8. Recurrent Sweet’s syndrome in reactivated Crohn’s disease.
Actis GC, Lagget M, Ciancio A, Rocca G, Tomasini C, Puiatti P, Verme G.
J Clin Gastroenterol 1995 Dec;21(4):317-9

http://www.ncbi.nlm.nih.gov/pubmed/96159680

9. Magnetic resonance imaging of the facial nerve in a case of Melkerson-Rosenthal syndrome
Ferriby D, Pertuzon B, Clarisse J, Vermersch P.
Rev Neurol (Paris) 1998 Jun;154(5):426-8

http://www.ncbi.nlm.nih.gov/pubmed/98446254

10. Complete Melkersson-Rosenthal syndrome in a patient with Crohn’s disease
De Aloe G, Rubegni P, Mazzatenta C, Fimiani M.
Dermatology 1997;195(2):182

http://www.ncbi.nlm.nih.gov/pubmed/97456777

11. Melkersson-Rosenthal syndrome and Crohn’s disease: one disease or two? Report of a case and discussion of the literature.
Lloyd DA, Payton KB, Guenther L, Frydman W.
J Clin Gastroenterol 1994 Apr;18(3):213-7

http://www.ncbi.nlm.nih.gov/pubmed/94308477

12. Oro-facial granulomatosis and oral Crohns disease: are they specific diseases and do they predict systemic Crohns disease? [editorial]
Challacombe SJ.
Oral Dis 1997 Sep;3(3):127-9

http://www.ncbi.nlm.nih.gov/pubmed/98128460

13. Orofacial lesions in Crohn’s disease.
Misra S, Ament ME.
Am J Gastroenterol 1996 Aug;91(8):1651-3

http://www.ncbi.nlm.nih.gov/pubmed/96322192

14. Orofacial granulomatosis and Crohn’s disease.
Cleary KR, Batsakis JG.
Ann Otol Rhinol Laryngol 1996 Feb;105(2):166-7

http://www.ncbi.nlm.nih.gov/pubmed/96223593

15. Granulomatous cheilitis: a study of six cases.
Kolokotronis A, Antoniades D, Trigonidis G, Papanagiotou P.
Oral Dis 1997 Sep;3(3):188-92:

http://www.ncbi.nlm.nih.gov/pubmed/98128470

16. Diseases of the lips.
Rogers RS 3rd, Bekic M.
Semin Cutan Med Surg 1997 Dec;16(4):328-36

http://www.ncbi.nlm.nih.gov/pubmed/98081580

17. [Cheilitis granulomatosa as the first manifestation of Crohn's disease]
Jenss H, Plauth M, Hoffmann R, Weber P.
Dtsch Med Wochenschr 1989 Oct 6;114(40):1524-7

http://www.ncbi.nlm.nih.gov/pubmed/90004952

18. Hidradenitis suppurativa in Crohn’s disease. A further support to this association.
Tsianos EV, Dalekos GN, Tzermias C, Merkouropoulos M, Hatzis J
J Clin Gastroenterol 1995 Mar;20(2):151-3

http://www.ncbi.nlm.nih.gov/pubmed/95286940

19.Hidradenitis suppurativa in Crohn’s disease.
Ostlere LS, Langtry JA, Mortimer PS, Staughton RC
Br J Dermatol 1991 Oct;125(4):384-6

http://www.ncbi.nlm.nih.gov/pubmed/92062558

20. The differential diagnosis and comorbidity of hidradenitis suppurativa and perianal Crohn’s disease.
Church JM, Fazio VW, Lavery IC, Oakley JR, Milsom JW
Int J Colorectal Dis 1993 Sep;8(3):117-9

http://www.ncbi.nlm.nih.gov/pubmed/94065434

21: Sweet’s syndrome and erythema nodosum: the simultaneous occurrence of 2 reactive dermatoses.
Waltz KM, Long D, Marks JG Jr, Billingsley EM.
Arch Dermatol 1999 Jan;135(1):62-6

http://www.ncbi.nlm.nih.gov/pubmed/99120658

22.Sarcoidosis: association with small bowel disease and folate deficiency.
MacRury SM, McQuaker G, Morton R, Hume R
J Clin Pathol 1992 Sep;45(9):823-5

http://www.ncbi.nlm.nih.gov/pubmed/1401218

23. Gastrointestinal sarcoidosis resembling Crohn’s disease.
Bulger K, O’Riordan M, Purdy S, O’Brien M, Lennon J
Am J Gastroenterol 1988 Dec;83(12):1415-7

http://www.ncbi.nlm.nih.gov/pubmed/3195549

24. Granulomatous gastritis as a diagnostic problem between sarcoidosis and other granulomatous disorders.
Tukiainen H, Vaara J, Syrjanen K, Terho EO
Sarcoidosis 1988 Mar;5(1):66-7

http://www.ncbi.nlm.nih.gov/pubmed/3381022

25. Characterization of the humoral immune response to Klebsiella species in inflammatory bowel disease and ankylosing spondylitis.
Tiwana H, Walmsley RS, Wilson C, Yiannakou JY, Ciclitira PJ, Wakefield AJ, Ebringer A
Br J Rheumatol 1998 May;37(5):525-31

http://www.ncbi.nlm.nih.gov/pubmed/9651080

26. Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.
Tiwana H, Wilson C, Walmsley RS, Wakefield AJ, Smith MS, Cox NL, Hudson MJ, Ebringer A
Rheumatol Int 1997;17(1):11-6

http://www.ncbi.nlm.nih.gov/pubmed/9194209

27. Systemic and mucosal antibodies to Klebsiella in patients with ankylosing spondylitis and Crohn’s disease.
O’Mahony S, Anderson N, Nuki G, Ferguson A
Ann Rheum Dis 1992 Dec;51(12):1296-300

http://www.ncbi.nlm.nih.gov/pubmed/1485810

28. Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease.
Cooper R, Fraser SM, Sturrock RD, Gemmell CG
Br Med J (Clin Res Ed) 1988 May 21;296(6634):1432-4

http://www.ncbi.nlm.nih.gov/pubmed/3132277

29. Long-term sequelae to foodborne disease.
McDowell RM, McElvaine MD Rev
Sci Tech 1997 Aug;16(2):337-41

http://www.ncbi.nlm.nih.gov/pubmed/9501346

30. Clinical aspects of Campylobacter jejuni infections in adults.
Peterson MC
West J Med 1994 Aug;161(2):148-52

http://www.ncbi.nlm.nih.gov/pubmed/7941533

31. An update on the epidemiology of inflammatory bowel disease in Asia.
Thia KT, Loftus EV Jr, Sandborn WJ, Yang SK.
Am J Gastroenterol. 2008 Dec;103(12):3167-82.Click here to read Links

http://www.ncbi.nlm.nih.gov/pubmed/19086963