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.

Infliximab subsidised in Australia

The Sydney Morning Herald reports, as predicted, that Infliximab will be available on the Pharmaceutical Benefits Scheme (PBS) from October for the treatment of Crohn's disease. Prior to this patients would have to pay the thousands of dollars themselves, or be one of the lucky few paid for by a hospital.

Humira approved for Australia

The Daily Telegraph reports that Humira has been approved for the treatment of Crohn's disease in Australia. However, until it is listed on the Pharmaceutical Benefits Scheme (if it ever is), its cost of $16,000 per month will be prohibitive for many people.

Traditional Chinese medicine

From the unlikely source of a new player in pharmaceuticals, Asia's largest company Hutchison, comes news of an alternative to the usual Crohn's medicines. The Independent reports that initial trials of a compound found in traditional Chinese medicine have found it to be as effective as the more common treatments in Ulcerative Colitis, and is expected to be similarly effective in Crohn's. The story is in their business section, so it's a bit sparse on details, but it's definitely an area to keep an eye on. (Image from PoYang)

Long term effects of anti-TNF

A great editorial in the Annals of Internal Medicine discusses how the the two current anti-TNF treatments, infliximab and adalimumab, are not living up to their initial promise.

The article examines the latest research into the effectiveness of these antibodies, and notes that responses to infliximab lessen over time. It adds that people who have stopped responding to infliximab will then not respond as well as other people to adalimumab, and they ponder whether the infliximab has changed the underlying nature of the Crohn's disease.

I thoroughly recommend this as required reading for Crohn's patients who are considering starting on an anti-TNF regime.

Fewer Colonscopies

A Belgian study has found that PET/CT is 100% successful in diagnosing active Crohn's disease. PET, or Positron emission tomography, involves injecting the patient with a radioisotope, and watching for its decay. CT, Computed Tomography, is where multiple x-rays are taken in quick succession, and a computer combines them to form a 3D image. When referred to as PET/CT it indicates that the two procedures are done at the same time, using one integrated machine, which allows the results from each to be correlated.

Regarding the use of PET/CT for Crohn's investigation, the researcher noted:

"The big advantage of PET/CT is that it is noninvasive, simple, fast and without any side effects. There was no preparation for the patients, except that they fasted for six hours. Each study took less than 20 minutes," said Hustinx. "If the PET/CT is positive, the doctor should confirm the results using endoscopy. If the PET/CT is negative, there would be no need for the endoscopy—given the high negative predictive value of the technique," he added.

This compares very favourably with a colonoscopy, where the patient undertakes a day of strict diet, a day of fasting, and then fasting on the day of the procedure. There are also some minor risks with a colonoscopy, such as bowel perforation.

The only problem I can see with PET/CT is the exposure to radiation, which is about 3 times the annual background radiation for PET and 4 times background for CT.

Major new genetic discoveries

When the results of research are reported in three separate BBC reports you can tell it's important. Firstly, the BBC reported an overview:

A major advance in understanding the genetics behind several of the world's most common diseases has been reported.

The landmark Wellcome Trust study analysed DNA from the blood of 17,000 people to find genetic differences.

...

One of the most exciting finds was a previously unknown gene common to type 1 diabetes and Crohn's disease, a type of inflammatory bowel disorder, suggesting that they share similar biological pathways.

The team also unexpectedly found a process known as autophagy - a process of clearing bacteria from within cells - is important in the development of Crohn's disease.

The BBC then gave more details for each disease involved, including this promising quote:

Dr Miles Parkes, consultant gastroenterologist at Addenbrooke's Hospital and the University of Cambridge said: "The study has substantially advanced our understanding of what causes Crohn's disease.

"There is a lot of follow-up work required to fully understand the impact of the genetic associations that we have identified. However they have already provided some major leads regarding possible new treatment options."

Finally, the BBC did a great easy to read description of how the research came about, how it was performed, and what it means to afflicted people:

For example in Crohn's disease, the team did not expect to find that autophagy - a process of removing unwanted bacteria from within cells - was an important factor.

They now plan to study this further to find out if it is associated with specific bacteria and there are treatments available which effect autophagy that researchers can investigate for use in Crohn's disease.

You can look at the nitty gritty by going directly to Nature, where they note the interesting finding:

An emerging theme from molecular genetic studies of CD is the importance of defects in autophagy and the processing of phagocytosed bacteria. A number of other specific components within innate and adaptive immune pathways are also highlighted.

Amongst their technical details is that there seems to be some relation to

...IRGM (immunity-related guanosine triphosphatase; the human homologue of the mouse Irgm/Lrg47), the strongest signal being at rs1000113 (P = 5.1 times 10-8). IRGM encodes a GTP-binding protein which induces autophagy and is involved in elimination of intracellular bacteria, including Mycobacterium tuberculosis67. Reduced function and/or activity of this gene would be expected to lead to persistence of intracellular bacteria, consistent with existing models of CD pathogenesis57 and the recent ATG16L1 association64 (see above).

This is extremely interesting when you review my earlier blog entry about a possible Crohn's vaccine, which operated on exactly that bacteria.

All of this news leads me to think that it won't be too long before we get a treatment for the cause, rather than the symptoms, of Crohn's.

Encouraging results of photopheresis

Tests on a new form of treatment called extracorporeal photopheresis have been announced.

Results from an international multi-center Phase II clinical trial suggest that extracorporeal photopheresis (ECP) may be effective in treating patients with clinically active (OR symptomatic) Crohn's disease who cannot tolerate or are refractory to immunosuppressants and/or anti-TNF agents.

A 50% response rate after 3 months of ECP treatment was noted in the study, using standard disease activity criteria, as presented this afternoon at a scientific research session of Digestive Disease Week (DDW). The majority of patients who responded to ECP therapy had a notable improvement in their disease symptoms and signs after only six weeks of treatment.

You can read more about photopheresis at the Wikipedia and in layman's terms at aidsmap. Essentially, it involves exposing the patient's blood to ultraviolet radiation. The term extracorporeal means outside the body, so the blood is drawn out, exposed to UV, then returned. It is a recommended treatment for some diseases, but is being tested on many others.

Infliximab may soon be subsidised in Australia

The Australian Pharmaceutical Benefits Advisory Committee has recommended that Infliximab (Remicade) be subsidised for the treatment of Crohn's disease (it's already subsidised for other conditions):

The PBAC recommended the listing of infliximab for the treatment of patients with severe Crohn’s disease (Crohn’s Disease Activity Index ≥ 300) or patients with an ileostomy or colectomy due to Crohn’s disease on the basis of a high but acceptable cost-effectiveness ratio compared to placebo. Acceptable cost-effectiveness was demonstrated at a dose of 5 mg/kg infliximab for three doses (weeks 0, 2 and 6) and when continuation of treatment beyond three doses was determined by remission (CDAI ≤ 150) at approximately 12 weeks from the commencement of treatment.

As noted by the Sydney Morning Herald it still has to be approved by the government. If they do so, then the cost per injection will be reduced from $4000 to a much more manageable $30.

Genome discoveries

Hot on the heels of the US and Canadian gene findings is another genome-led research article, this time from Belgium. You can read the very technical article online in full at PLoS Genetics. I present the author summary in full here, because the article itself is too complicated for me to summarise:

Individual susceptibility to many common diseases is determined by a combination of environmental and genetic factors. Identifying these genetic risk factors is one of the most important objectives of modern medical genetics, as it paves the way towards personalized medicine and drug target identification. Recent advances in SNP genotyping technology allows systematic association scanning of the entire genome for the detection of novel susceptibility loci. We herein apply this approach to Crohn disease, which afflicts an estimated 0.15% of the people in the developed world and identify a novel susceptibility locus on Chromosome 5. A unique feature of the novel 5p13.1 locus is that it coincides with a 1.25-Mb gene desert. We present evidence that genetic variants at this locus influence the expression levels of the closest gene, PTGER4, located 270 kb away, in the direction of the centromere. PTGER4 encodes the prostaglandin receptor EP4 and is a strong candidate susceptibility gene for Crohn disease as PTGER4 knock-out mice have increased susceptibility to colitis.

More Crohn's genes found

It has now been conclusively shown that genetics plays a role in the development of Crohn's disease, with the release of a study in Nature Genetics (full article available for purchase for US$30). Data from the Human Genome Project was used to compare the genes of people with and without the disease. The ABC mention:

Scientists previously had some indications of a genetic component to Crohn's disease. It tends to run in families and is more common in certain ethnic groups, especially people of central and eastern European Jewish descent.

Pinpointing the genes that predispose people to Crohn's disease could help lead to new ways to treat it, say the researchers.

Amongst all the other areas of research into Crohn's, we shall now have to keep an eye on developments in gene therapy.

Possible trigger found

Sometimes it can be difficult to interpret press releases to decide whether they're really announcing something revolutionary. From the European Molecular Biology Laboratory, and published in Nature, is such a case.

Our gut is home to an enormous number of bacteria, which live in harmony with us and help in food digestion. If they penetrate the wall of the intestine, however, these bacteria can become harmful and cause diseases. This is why a thin, continuous layer of interconnected cells, called an epithelium, lines the intestinal surface creating a barrier that prevents bacteria from crossing that border. The mechanisms that control the integrity of the epithelium and contribute to maintaining a healthy gut have remained unknown.

Arianna Nenci from the group of Manolis Pasparakis at the University of Cologne and Christoph Becker, a member of Markus Neurath's group in Mainz, investigated the role of NF-κB, a signaling molecule that helps cells cope with stress, in the intestinal epithelium. Using sophisticated genetic methods, they generated a mouse model that does not express NEMO, a protein needed to activate NF-κB, in intestinal epithelial cells. As a result, these mice developed severe chronic intestinal inflammation very similar to Colitis in humans.

...

The finding that defective NF-κB signaling in the gut epithelium initiates the outbreak of inflammation in the intestine provides a new paradigm for the pathogenesis of inflammatory bowel disease. Since the immune systems of mice and humans are very similar, the insights gained through the mouse model are steps towards a better understanding of the mechanisms causing human inflammatory bowel diseases and may pave the way for novel therapeutic approaches.

So, while the researchers managed to causes Crohn's-like symptoms in mice, the press-release does not elaborate on why they conclude that their method of causing these symptoms is of relevance. However, from the abstract of the Nature article, it is obvious that there is indeed more substantial evidence available to those with access to the full article.

Humira released in USA

As expected, the new biologic medicine Humira has been approved by the FDA for adult use. According to the Wikipedia it may come in preloaded pen devices , which do sound like an improvement on the old manual syringe.

The story appeared in the Chicago Tribune's business pages:

"Humira has been shown to reduce signs and symptoms, and to induce and maintain clinical remission of Crohn's disease in patients who have had an inadequate response to conventional therapy, and in those patients who did not benefit from treatment, or who were intolerant to previous treatment with Remicade therapy," said Dr. Douglas Throckmorton, deputy director of the FDA's Center for Drug Evaluation and Research.

Abbott's drug also could be more convenient, the company and analysts say. Unlike Remicade, which has to be infused by a physician in the doctor's office, Humira is the only new Crohn's treatment that can be injected by the patient on his own.

Better surgery for Crohn's

Newswise has an excerpt from an article in the Journal of Surgery which contains interesting research into the long-term success of surgery that avoids removing parts of the bowel.

Among other findings, the study supports the notion that strictureplasty -- a bowel-sparing surgical procedure commonly used to correct Crohn's-related strictures -- is less likely to lead to stricture recurrence later on, compared to surgical excision ("resection") of the stricture.

...

In decades past, Crohn's patients typically underwent surgical removal of the bowel at the point of stricture, although in recent years, corrective, bowel-sparing "strictureplasties" have become much more common. Dr. Michelassi has been a pioneer in developing new strictureplasty techniques. But he says that, up till now, surgeons lacked good information on the long-term consequences of these operations compared with resection.

...
The study also found that up to a third of recurrences occur away from the site of the original operation. Furthermore, the type and site of prior surgery appears to influence the pattern of recurrence, the researchers found. The study also provides new guidance on what surgeons call "prophylactic strictureplasty" -- procedures aimed at preventing stricture-related trouble.

"Sometimes we encounter a stricture that isn't giving the Crohn's patient any symptoms right now. We know, though, that these strictures can lead to trouble in about 25 percent of cases," Dr. Michelassi explains. "Based on our findings, we would now advise that if an asymptomatic stricture can be fixed using bowel-sparing strictureplasty, then the surgeon should go ahead and perform that type of prophylactic procedure," the NewYork-Presbyterian/Weill Cornell expert says. "However, if fixing the problem requires bowel resection, then we would advise leaving the stricture alone, because there's still a 75 percent chance it will not cause the patient any harm."

Humira nears US release for Crohn's

The Boston Globe has an update on new medication that is expected to be released to US consumers soon. Crohn's afflicted people outside the US will probably welcome this news, as it will introduce a large new population for the drugs to be tested on. It'll be interesting to see if Humira lives up to its promise of providing longer-term remission than infliximab (Remicade).

Within days, Illinois-based Abbott Laboratories expects to win federal approval to sell its drug, Humira , currently used to treat rheumatoid arthritis, psoriatic arthritis, and a disease that causes arthritis of the spine, to combat the intestinal disorder.

...

In clinical trials, 21 percent of patients who had stopped responding to Remicade were coaxed into remission by week four on Humira, compared with 7 percent who achieved remission on a placebo. Those results were impressive enough for the FDA to speed its handling of the drug -- trimming the review from 10 months to six months and indicating that an approval decision could come by the end of February.

Recent developments

Hidden behind the subscription wall of The Wall Street Journal is a nice summary of the current status of the various Crohn's treatment options. That article has now made its way into the free world via the naplesnews.com.

Amongst developments not yet reported in this blog is news of medicine which is potentially better than the highly-regarded anti-TNFs gaining popularity today. These include arthritis drug Orencia, interleukin-12 and interleukin-23 (interleukin has been mentioned previously), and a drug using adult stem cells.

Besides anti-TNFs, there is a rheumatoid arthritis drug from Bristol-Myers Squibb, called Orencia, that is being studied for Crohn's disease. The drug works on inflammation earlier in the process than do anti-TNFs. Bristol started the final phase of human testing of Orencia against Crohn's last month and is currently enrolling patients in a trial.
...
J&J and Abbott are working on drugs that inhibit two proteins called interleukin-12 and interleukin-23. Both companies are in the middle stages of human testing. Strober, of the National Institute of Allergy and Infectious Diseases, says the benefit could be tackling inflammation much earlier in its development than the anti-TNFs do, but that the drugs could carry an increased risk of infection.
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Osiris Therapeutics, based in Baltimore, just got approval from the FDA to go into the third and final phase of human testing on a Crohn's drug that uses adult stem cells. The company says the agency gave the drug fast-track status, which means it could come to market as early as 2008.

The drug is thought to work by correcting inflammation only where it's taking place — which could help avoid excessive immune suppression.