Steroids as a last resort?

A trial reported in The Lancet (full article by subscription) found that people treated by more aggressive medications earlier achieved better outcomes than those treated in the traditional manner.

Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

As explained by The Globe and Mail:

Traditionally, patients diagnosed with the devastating inflammatory bowel disease are treated with a "step-up" approach, a series of drugs given sequentially as their health deteriorates.

First, they get corticosteroids to control symptoms like abdominal pain and bloody diarrhea. They are then prescribed a powerful immune-suppressing drug, which prepares them for a third medication, an antibody that curbs the inflammation at the root of the disease.

This study shows that reversing the conventional order, using infliximab as the initial treatment, could provide better long-term results. Coincidentally, the more aggressive medications are typically much more expensive, though the improved results could outweigh this with lower overall medical costs.

I don't see this report as leading to any treatment changes in the near future. The inertia of conventional treatment requires larger, longer-term trials to be overturned. However, after the positive results of this report, I'm sure just such trials are being planned.

Updated 21 March 2008: The (Canadian) National Review of Medicine mentions that there is a larger study already in progress.

Still waiting for a magic pill

A few years ago it looked like antibiotics treating MAP would be effective in attacking the cause of Crohn's disease. Early trials had been very effective in producing and maintaining remission. However, not much was heard about later, larger trials.

Giaconda, the company which now owns the rights to this therapy, have published a summary of the details so far.

The results of a Phase II clinical trial of Myoconda®, conducted at the Centre for Digestive Diseases (CDD), were published in 2002. This was followed up with a full retrospective analysis of all CDD Crohn’s patients treated for at least six months with anti-MAP therapy. This analysis of 52 patients demonstrated a remission rate of 65% with a clinical response of almost 95%. These results exceed those of any Crohn’s therapy on the market by major margins.
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[A Phase III] trial was completed in September 2004. Overall results of the Phase IIIa trial demonstrated a statistically significant improvement in achieving remission at 16 weeks when using Myoconda® compared with conventional therapy. However, Myoconda® did not achieve statistically significant results in maintaining remission after therapy was complete in this trial.

They do not say whether the lack of remission was due to the antibiotics failing to prevent MAP, or whether the MAP was successfully eliminated but the Crohn's remained. However, since they are continuing their testing of variants of this treatment, it appears that it is the former, which means that the theory of MAP being a cause of Crohn's is still alive.

(CC-licensed image by Rodrigo Senna)

Gene therapy moves closer

A report from the Royal Society of Chemistry describes a potential new treatment for Crohn's that has shown promise in mice. RNA interference, a recently developed method of gene therapy, was used to suppress a gene that causes inflammation in the intestine, thus reducing the related symptoms.

RNA interference involves introducing into cells a double strand of RNA corresponding to the nucleic acid sequence of the target gene. This causes the destruction of the equivalent messenger RNA so 'silencing' the gene and preventing expression of the relevant protein.

Its discovery in 1998 by Andrew Fire and Craig Mello earned them the 2006 Nobel prize for medicine. But although their discovery has become a vital technique for molecular biology research it has not yet fulfilled its potential as a therapeutic method.
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When RNA was injected into mouse with colitis there was a dramatic reduction in intestinal tissue damage and suppression of leukocytes cells invading the gut wall. The mice were also able to absorb food through their gut wall again and started to regain weight. The team found that their results were due to a drop in the level of two cell signalling molecules (cytokines), TNF-alpha and IL-12, that normally drive inflammation and are produced as a result of cyclin D1 synthesis. They also found that the mice were making more of a protective cytokine called IL-10.

There is a long way to go until this research leads to a safe treatment in humans. For example, at this time not all of the genes involved in Crohn's have been identified. I'm sure that gene therapy would want to be as specific as possible to reduce unintended side-effects.

Tysabri approved for Crohn's in USA

Bloomberg.com reports that the Food and Drug Administration has approved Tysabri (Natalizumab) for treating Crohn's disease in some cases. Tysabri is already being used for the treatment of Multiple Sclerosis, but was briefly withdrawn after some serious side effects. European regulators refused to approve it for Crohn's disease.

Boston.com has further information:

European regulators recently rejected a similar request to use the drug as a Crohn's treatment, arguing the risk of infection outweighed the relatively modest benefit of Tysabri.

Biogen Idec temporarily shelved the drug three years ago after it was linked to a rare brain disease. The company says there have not been any additional cases of the disease since sales resumed in 2006, with new guidance on how it should be used. But some doctors remain wary of the treatment, even though it has been shown to be highly effective in some patients.

The Wikipedia has more comprehensive background on the drug.

Suspicion falls on milk

Researchers at The University of Liverpool have got one step closer to linking Crohn's disease to milk consumption.

The team found that a bacterium called Mycobacterium paratuberculosis releases a molecule that prevents a type of white blood cell from killing E.coli bacteria found in the body. E.coli is known to be present within Crohn’s disease tissue in increased numbers.

It is thought that the Mycobacteria make their way into the body’s system via cows’ milk and other dairy products. In cattle it can cause an illness called Johne's disease - a wasting, diarrhoeal condition. Until now, however, it has been unclear how this bacterium could trigger intestinal inflammation in humans.

The Daily Mail has further details, including a comment from the dairy industry:

The Dairy Council, which speaks for milk producers, said a number of studies had failed to show a causal link between MAP in milk and Crohn's.

Its director, Dr Judith Bryans, said: "While the findings of the study are interesting, it is important to stress that not all Crohn's patients have MAP in their intestines.

"This would suggest that there are additional factors which may cause Crohn's disease."

She added: "There is no need for anyone to alter their consumption of milk based on current scientific knowledge."

Wouldn't it be nice if most Crohn's was found to be caused by MAP in milk, and that it could be cured with a brief cause of antibiotics. I am certain we'll be hearing more on this subject during 2008.

Stem cells to reboot Crohn's?

There's some interesting research being done at the University of Nottingham into using stem cell therapy to "cure" Crohn's disease. Their trial hasn't started yet, but it is intriguing.

Crohn's sufferers are genetically predisposed to the disease, which is first triggered in their body when they come into contact with a particular environmental stimulus. Once this happens, the immune system responds — leading to symptoms that blight the lives of sufferers.

Stem cells hold a potential solution to this problem. As the body's 'master' cells, which can be directed to form any type of tissue, they will be extracted from patients and then re-established in their bone marrow to 're-boot' the immune system, taking it back to a state before Crohn's symptoms were triggered.

There is also a brief mention of their other current investigation into the use of hookworms to control mild Crohn's disease, but unfortunately they don't say whether the trial is going well.

Biologic in a pill

Can-Fite(pdf) have stated that they believe their new biologic medication CF101 will be effective in improving the symptoms of Crohn's sufferers.

Can-Fite reports that pre-clinical studies show that the A3 adenosine receptor, which is targeted by CF101, is over-expressed in bowel tissue and peripheral blood mononuclear cells derived from patients with Crohn's disease. These findings are in line with previous data showing the efficacy of CF101 as an anti-inflammatory agent in pre-clinical models of inflammatory bowel diseases.

The presence of this receptor on the surface of the affected cells of patients with Crohn’s disease strongly suggests that this patient population may benefit from CF101 which binds to the receptor and leads to apoptosis of the inflammatory cells. It should also be underlined that, similar to other indications under development, the drug exerts a differential effect on inflammatory normal cells.

All things being equal, if CF101 is as effective as infliximab (Remicade) and adalimumab (Humira), then being able to take it as a pill will offer a great benefit to patients compared to the injections required for the current biologics.

Crohn's comic

Artist Tom Humberstone has created an engaging personal account of the Crohn's experience in his comic Everything You Never Wanted to Know About Crohn's Disease. It's a great resource to explain the effects of Crohn's to family and friends, instead of the dry list of medical symptoms from most medical sites.

Better results from capsule endocopies

A small trial has found that capsule endoscopies after surgery are better tolerated and produce better results than regular colonscopies. This was reported in Gastrointestinal Endoscopy (full article for subscribers only), with more details freely viewable at Medpage Today.

Given that patients preferred the preparation and procedure surrounding swallowing a small camera, and that the results were significantly more accurate than with the traditional camera on the end of a flexible tube, I expect to see further progress on making this standard soon.

How do Tysabri and Cimzia work?

The Los Angeles Times has a good description of how two of the latest Crohn's medications operate:

Cimzia is also a TNF blocker, but unlike the others it contains only part of the antibody -- the portion that recognizes TNF. The rest of the antibody -- the part that can induce its own immune response -- is replaced with a compound called PEG.

This PEG tail stabilizes the drug, allowing it to stay in the patient's body much longer[...].

That means patients would only require treatment every other month, as opposed to every other week with Humira.

During inflammation, infection-fighting white blood cells of the immune system cruise through capillaries, searching for infection. When tissues are infected, they put out signals to slow down the blood cells and coax them to enter the tissue. [...]

Tysabri binds to those exit signs -- blocking them from recognition by the immune cells that are causing the Crohn's. So the white blood cells keep on moving, and the course of inflammation is stopped.

It'll be exciting to see how well these drugs operate on a wider variety of Crohn's patients, if and when they are approved.