Monoclonal Antibody Decoder

I've created a simple online tool, the MAB Decoder (see the top right of this page) to decode the generic name of any monoclonal antibody. For example, type in the common Crohn's medication infliximab to find from which animal species it is derived, and what part of the body it acts upon. This can be important because human-sourced antibodies are often better tolerated than those from other animals, which may influence your choice of medications. New monoclonal antibodies are being generated all the time, and often you'll see some new ones mentioned in passing. With this tool you simply enter their names to be able to learn more about them.

The MAB Decoder works with generic rather than brand names. Humira, for example, should be entered as adalimumab (the generic name of monoclonal antibodies always end in -mab). Incidentally, it is useful to be familiar with generic names because brand names may vary from country to country.

You can read more about monoclonal antibody naming at Wikipedia.

Although I created this tool to investigate Crohn's drugs, it will decipher monoclonal antibody names for all conditions. You can also try creating your own names, like humungofungomab!

October summary of biologics

Medscape [direct link requires subscription] has released a new summary of the latest findings in biologic therapy for Crohn's disease. Their previous summary on recent anti-TNF research was in June. Although that's still well worth reading, there have been much activity in this area since then.

This article discusses combination therapies, first-line therapy (i.e. should biologics be used earlier in the treatment regime), switching biologics if they become ineffective, safety and newer biologics which have only recently been approved for use. Most of these have been reported in detail previously, but it's handy to have them summarised in one place.

A missing bacterium?

According to the BBC French researchers suspect that a low level of Faecalibacterium prausnitzii bacteria in the intestine could be the cause of Crohn's disease.

The researchers, from the Institut National de la Recherche Agronomique, had already shown that patients with Crohn's disease have a marked deficiency in bacteria from the Clostridium leptum group.

Their latest work shows that F. prausnitzii - a major component of this group - accounts for a large part of the deficit.

If this is true, then treatment would be a simple course of specific probiotics to boost the levels of the bacteria. However, this research is only at the level of cells in test tube. It still has the difficult hurdles of animal and human trials to come.

It's interesting to note that probiotics and antibiotics are both being proposed as possible cures for Crohn's. Although this sounds contradictory, they could both be successful. The probiotic may encourage the growth of certain "good" bacteria which work against "bad" bacteria, whereas the antibiotic works solely on eliminating the "bad" bacteria.

Infliximab more effective than Azathioprine

The Associated Press reports on research that shows Infliximab (Remicade), used alone or in combination with Azathioprine (Imuran) is significantly more effective, and no less safe, than a treatment of just Azathioprine.

Currently, doctors usually prescribe Azathioprine first, and only progress to Infliximab when that fails. This study indicates that Infliximab should be considered earlier. (Note that this study was financed and run by the producer of Infliximab.)

There is more coverage at MedPage Today.

The anti-Crohn's diet

There have been plenty of anecdotal reports of people who have successfully controlled their Crohn's by following specific diets. The Daily Mail mentions the success of a thousand patient trial in a UK hospital.

(...) At Addenbrooke's Hospital, gastroenterologist Professor John Hunter and his team identify foods that act as a 'trigger' for symptoms, eliminate them from a patient's diet and 'switch off' the disease.

Now 90 per cent of his patients are symptom-free and 56 per cent can resume a normal diet after five years.

During the first phase of treatment, patients consume only specially formulated drinks.

'They contain all the nutrients a patient needs, already broken down into their most simple constituent elements so the body does not have to do any work digesting them,' explains Professor Hunter.

'By taking the gut out of action, we effectively switch off the disease. After two to three weeks, 90 per cent of patients find their symptoms have disappeared.'

They then gradually reintroduce different foods to determine which will cause flare-ups in the individual.

This is the first reasonably large trial of using diet alone to control Crohn's that I've heard of. However, it really needs to be expanded into a much larger scientifically-controlled trial to truly ascertain its effectiveness. Unfortunately, most trials are funded by drug companies, and a diet solution to Crohn's wouldn't offer any profit for them. On the other hand, I'm sure there would be no shortage of volunteers for the trials, and doctors willing to assist.

Comprehensive look at MAP

I've always been fond of the idea that Crohn's is caused by MAP, and that it will be easily cured by a short course of antibiotics. A comprehensive look into how this proposition stands today is made by the American Society for Microbiology in their report "Mycobacterium avium paratuberculosis: Infrequent Human Pathogen or Public Health Threat?".

One acknowledged potential microbial agent of CD is Mycobacterium avium subspecies paratuberculosis (MAP), a microorganism that causes a gastrointestinal disease similar to CD in ruminants, including dairy cattle, called Johne’s disease (or paratuberculosis). People with CD have 7:1 odds of having a documented presence of MAP in blood or gut tissues than those who do not have CD, thus the association of MAP and CD is no longer in question (see Figure 1, page 11). The critical issue today is not whether MAP is associated with CD, but whether MAP causes CD or is only incidentally present, not an inciter or participant in the disease process.

They include a table of virtually all current Crohn's medications, their dosage and costs. This is very handy information that I haven't seem summarised anywhere before.

In addition, they cover:

• possible causes of Crohn's
• where MAP comes from and whether it can affect humans
• treatment of MAP in humans
• whether MAP causes Crohn's
• where future MAP research should be headed

On a hopeful note, they mention the success that anti-MAP treatments have had against Crohn's:

Treatment of some CD patients with antibiotics that have activity on certain other Mycobacteria, although not specifically selected for their activity against MAP, provides short-term or long-term relief or remission of symptoms.

Everything is written in a medical-jargon-free manner, so it's easy to understand. In addition, a brief summary is also available at Medical News Today.

Post AntiTNF biologics

The most recent successfully-introduced medications for the treatment of Crohn's disease, infliximab and adalimumab, have targeted tumor necrosis factor (TNF). However, they are ineffective for some people, and become ineffective in others over time. The Lancet(free registration required) reports some of the different directions that researchers have been examining for further biologic agents, their safety and effectiveness in trials.

Investigators have long sought to identify a micro-organism that causes inflammatory bowel disease. The present theory suggests a breakdown in the balance
between putative species of protective versus harmful bacteria—a notion that has been termed dysbiosis.

Whilst many current drugs reduce the symptoms of Crohn's by suppressing the immune system, research is continuing into drugs that act as immune stimulators.

As a result of decades of intensive research, treatment for inflammatory bowel disease is undergoing a transition from the era of TNF antagonists to an era of novelbiological agents, including those that are able to stimulate the innate immune system.

As you might expect for a medical journal it's quite a technical article, but well worth the effort to see what possible treatments are just around the corner. For easier reading there's a summary at Medical News Today.

Adalimumab subsidised in Australia

The Age reports that adalimumab (marketed as Humira) will be listed on the Pharmaceutical Benefits Scheme from next week. This means that Australian Crohn's patients will be able to purchase the drug for a nominal fee.

Previously, the drug's high cost would have kept it out of reach of many people. Although the government is now picking up the tab, there is a net economic benefit to Australia. More Crohn's patients will be able to remain productive members of the workforce instead of relying on disability pensions.

For a behind-the-scenes look at a similar decision I found it interesting to read an advisory note from the Western Australian Therapeutic Advisory Group indicating their economic reasons for recommending subsidising adalimumab.

32 genes for Crohn's - so far

New research featured in Nature Genetics [full article via subscription] has found many more genes which increase the likelihood of a person developing Crohn's. Each gene helps scientists understand the mechanism of Crohn's better, and offers the potential for new targets of therapies.

The Boston Globe reports further:

The genome research has helped produce a "fundamentally new concept" of Crohn's, said Dr. R. Balfour Sartor, chief medical adviser of the Crohn's and Colitis Foundation of America.

The idea, he said, is that in Crohn's disease, cells in the intestine have trouble using the weapons of the innate immune system - such as autophagy - to get rid of bacteria, so the immune system's second line of defense, big-gun T-cells, get called in, causing inflammation.

Reuters has more:

Significantly, three of the individual genes that have been implicated in Crohn's have previously been shown to influence risk of type 1 diabetes and asthma, suggesting a possible common genetic mechanism underlying these disorders.

As we come closer to identifying the cause of Crohn's we will have medications that attack the cause, rather than the symptoms, of the disease. The identification of related genes will no doubt play an important role in this.

Summary of latest anti-TNF research

Medscape (free subscription, or go via Google) has a great in-depth interview with David A. Schwartz, Director of the IBD Center at Vanderbilt University Medical Center, about the latest developments in anti-TNF medications for the treatment of Crohn's Disease. He manages to translate medical-journalese into language that non-medical professionals can understand. It includes important information regarding safety and effectiveness of newer therapies.

Towards the end of the interview he indicates the method of delivery is one important factor in patients' preference for newer biologics over the original infliximab (noting that infliximab must be delivered intravenously by a medical professional, whereas other drugs can be administered by the patient themself at home):

100% of patients who had received both intravenous and subcutaneous anti-TNF therapy preferred the subcutaneous route. The main reasons given for this preference included that the infusions were painful as well as the autonomy that subcutaneous administration provided.

Methotrexate no aid to infliximab

Medpage Today reports the preliminary results of a study which indicated that the common combination of infliximab plus methotrexate is no more effective than infliximab alone. The drugs have very different methods of operation, and are both effective in controlling the symptoms of Crohn's Disease in some people. Until now, it has been commonly believed that the effectiveness of infliximab is improved by concurrent use of methotrexate. However, this report states:

Patients receiving the combination had the same treatment success rate as others treated with infliximab alone in a 50-week, placebo-controlled trial, reported Brian Feagan, M.D., of the Robarts Research Institute in London, Ontario, at Digestive Disease Week.

If further research backs up this finding then there'll be a lot of happy patients who'll be able to reduce the number of injections they need to take. In addition, fewer medications should lead to fewer side-effects.

Low levels of JAM-A protein associated with Crohn's

UPI have a very brief article that includes researchers definitively stating that Crohn's disease is "linked to low levels of a protein that helps bind the stomach lining". They go on:

The scientists say that the stomach lining helps keep out bacteria that cause Crohn's, an inflammation that can involve any part of the digestive tract from the mouth to the anus. They found that patients with Crohn's and similar diseases have low levels of a protein known as JAM-A in their stomach linings.

This is the limit of technical details in the article. The full research should appear shortly in the journal Gastroenterology.

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.
...
[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.
...
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.