The Crohnie

The abstracts from the Ninth International Colloquium on Paratuberculosis (9ICP), which I attended in Tsukuba, Japan, have been published online.

As with previous ICP, the number of papers presented on the relationship between Crohn’s Disease and Mycobacterium Paratuberculosis has grown, as knowledge of this complex organism and its potential to cause disease in humans, has grown.

The list of 9ICP presentations in the “Public Health” segment of the Colloquium are listed here

http://www.paratuberculosis.org/pubs/proc9/section6.htm

As acceptance of the relationship between MAP and CD grows, related papers are now being presented outside of the dedicated “Public Health” segment. The following paper discusses how the pathogenetic mechanisms of paratuberculosis in Johnes Disease and Crohn’s Disease can be compared in order to increase understanding of both; it was presented in the “Pathogenesis and Immunology” segment.

Role of Mycobacterium avium subsp. paratuberculosis in the pathogenesis of Crohn’s disease
http://www.paratuberculosis.org/pubs/proc9/abst4a.htm

Also of interest is the growing evidence that Mycobacterium avium subsp paratuberculosis may be a cause of Type-1 diabetes.

Association of Mycobacterium avium subsp. paratuberculosis with Type-1 diabetes, a possible trigger
http://www.paratuberculosis.org/pubs/proc9/abst181f_o3.htm

Paratuberculosis and Type I Diabetes -Mapping the TRIGR-
http://www.paratuberculosis.org/pubs/proc8/abst3b_o20.htm

An interesting new piece of research about the genetics of Crohn’s Disease Diabetes and other diseases.
http://www.nature.com/nature/journal/v447/n7145/pdf/nature05911.pdf

I note that one of the gene patterns associated with Crohn’s relates to “autophagy”, an innate immunity mechanism which the body uses to defend itself against intracellular bacterial pathogens.

http://en.wikipedia.org/wiki/Autophagy

“”"
The study has also confirmed the importance of a process known as autophagy in the development of Crohn’s disease. Autophagy, or “self eating”, is responsible for clearing unwanted material, such as bacteria, from within cells. The may be key to the interaction of gut bacteria in health and in inflammatory bowel disease and could have clinical significance in the future.
“”"

http://www.medicalnewstoday.com/medicalnews.php?newsid=73420

“”"
One of the newly identified genes, called ATG16L1, has been thought to be required for autophagy, a process that leads to programmed cell death and is involved in the process of inflammation. When the research team used RNA interference to suppress the gene’s activity in bacterially infected cells, decreased molecular action associated with autophagy confirmed that the process depends on ATG16L1 activity.
“”"

http://www.sciencedaily.com/releases/2007/04/070415160159.htm

Autophagy is one of the most important defenses against the class of intracellular bacterial pathogens known as mycobacteria. One of the most studied organisms in relation to autophagy is mycobacterium tuberculosis

Autophagy in Immune Defense Against Mycobacterium tuberculosis
http://www.landesbioscience.com/journals/autophagy/article/2830

Mycobacterium avium subspecies paratuberculosis (MAP) is another intracellular obligate pathogen with which autophagy would be a key defense mechanism.

So it is no surprise to me that recent results indicate a defective autophagy process in Crohn’s Disease; this lends further weight to the theory that Mycobacerium paratuberculosis is a cause of Crohn’s Disease.

Leprosy is caused a member of genus Mycobacteria, M. leprae, and some forms of leprosy are treated by “tamping down the immune system” with anti-TNF agents, such as thalidomide. Steroids are also used for the treatment of leprosy[1].

FDA approves Thalidomide for Hansen’s disease side effect, imposes unprecedented restrictions on distribution.
http://www.fda.gov/bbs/topics/ANSWERS/ANS00887.html

Redeeming thalidomide
http://pubs.acs.org/hotartcl/mdd/00/jun/mddkling.html

Remicade’s anti-TNF activity might also be useful for leprosy (a known mycobacterial disease), but there haven’t been any trials of remicade/infliximab for Leprosy (Hansen’s Disease), presumably because the manufacturers know that the average third-world leper can’t afford $30K+ a year to be maintained on remicade, and thus won’t spend the huge money necessary for the relevant clinical trials.

But Thalidomide, the poor man’s anti-TNF drug, is long out of patent, and is cheap, and so gets used for the poor lepers. But there is a fightback in the leprosy medical community, primarily because of the nasty birth defects that Thalidomide causes.

No Role for Thalidomide in Leprosy
http://www.paho.org/English/AD/DPC/CD/thalidomide.htm

Thalidomide has been trialled for Crohn’s Disease.

Thalidomide reduces tumour necrosis factor {alpha} and interleukin 12 production in patients with chronic active Crohn’s disease
http://gut.bmjjournals.com/cgi/content/abstract/50/2/196

Thalidomide: New uses for notorious drug
http://www.mayoclinic.com/health/thalidomide/HQ01507

So the relative success of treatment of Crohn’s Disease with Remicade is NOT an argument against a mycobacterial cause. In fact, if the Crohn’s Disease to Leprosy analogy that has been made by some researchers[2,3] is true, then Remicade treatment in Crohn’s could be an argument FOR a mycobacterial cause.

1. Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial.
http://bmj.bmjjournals.com/cgi/content/abstract/328/7454/1459

2. Comparisons with leprosy, tuberculosis and Johne’s disease: is Crohn’s disease caused by a mycobacterium?
http://www.paratuberculosis.org/proc7/abst6_p6.htm

3. Mycobacterium avium subspecies paratuberculosis in the causation of Crohn’s disease
http://www.wjgnet.com/1007-9327/6/630.asp

I want to draw your attention to a recent paper in The Lancet, by a group of researchers from McGill University, Montreal, Canada.

Crohn’s disease, Mycobacteria, and NOD2
http://infection.thelancet.com/journal/vol4/iss3/full/laid.4.3.reflection_and_reaction.28813.1

The researchers describe the case of a man who was diagnosed as having Crohn’s Disease. He tested positive (by PCR) for mycobacterium avium paratuberculosis (MAP) infection, was treated with an anti-paratuberculosis antibiotic regimen, and his health improved (after a period of suffering from a “flu-like syndrome”, a common problem in CD when treated with anti-paratuberculosis antibiotics).

More interestingly, he also tested positive for NOD2, an identified “IBD susceptibility gene”, which relates to host defences against bacterial infection. As the researchers note: ” …. this man has evidence of typically defined Crohn’s disease with a Crohn’s disease susceptibility mutation, but also has evidence of human MAP disease. Applying the principle of Occam’s razor, the most parsimonious explanation in a patient without other illness is that MAP infection in a genetically susceptible host resulted in the Crohn’s disease phenotype.”

The researchers conclude their paper with this statement: “We believe that this case illustrates a potential conceptual approach to Crohn’s disease aetiology, which involves a tandem search for bacterial trigger and host susceptibility. The proportion of Crohn’s disease cases potentially attributable to MAP and the clinical/epidemiological consequence of MAP exposure among human beings are the focus of continuing studies.”

More research needs to take this approach. Seeking genetic susceptibilities or genetic flaws, in isolation from the actual agent which exploits the susceptibility or flaw, is a tragic waste of vital research resources, time and money.

[Psyche0]
> I thought this treatment took 2 years — have they found
> a way of shortening it?

Actually no, no way has yet been found of shortening the duration of RMAT.

Prof John Hermon-Taylor, as reported in his “Two year outcomes analysis…” treated patients for between 6 and 35 months, with a median of around 18 months. It is only a small percentage of patients that are treated for as little as six months.

Dr. T.J. Borody in Australia treats *all* of his patients for a minimum of 24 months, and adds Clofazimine (Lamprene) to the basic regime. This is the protocol upon which the Australian clinical trial is based.

Dr. Shafran is attempting to lower both the dosages and the duration of treatment, with good reason, because these drugs can be difficult to tolerate, especially for such long periods of time, not to mention the expense (approx US$500/month), a vital consideration if you have very little/very poor medical insurance. However, one must be very careful when treating bacterial infections with antibiotics at too low a dosage, because resistance can develop. Dr. Shafran is also adding probiotics to his regime, I believe to improve tolerance and assist in the reduction of inflammation.

There are other conceivable ways to reduce the duration of treatment.

1. By vaccination with a harmless mycobacterium, e.g. M. phlei or M. vaccae. Such a vaccination would assist in antigen uptake by the immune system, which would hopefully increase the efficacy of any antibiotic treatment. More on this interesting approach at

http://crohn.ie/archive/research/vaccine/m_vaccae.htm

Prof. JHT is also pursuing the possibility of a subunit vaccine, using raw DNA vaccination.

2. Hyperbaric Oxygen Therapy. Although no one is following up this possibility, I firmly believe that it could be of enormous benefit. If I ever hear of any work in this area, I’ll report on it.

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

You may be interested in the following paper, which describes inducing clinical remission in 93.5% of patients by treating them with clarithromycin and rifabutin in combination for between 6 months and 3 years.

http://crohn.ie/archive/htout.htm

The treatment was conducted based on the theory that Crohn’s disease is caused by the bacterium mycobacterium paratuberculosis. Reams of info from

http://crohn.ie/archive/welcome.htm

In a recent study, 43 out of 52 Crohn’s patients went into remission (i.e. relief from symptoms) when treated with wide spectrum antibiotics. Follow this link to that paper

http://crohn.ie/archive/htout.htm

I have created a web page that contains a large amount of information about this topic. Follow this link for a summary of that information.

http://crohn.ie/archive/summary.htm

Follow this link to the main page:

http://crohn.ie/archive/welcome.htm

Please feel free to visit the site.