Therapy of inflammatory bowel disease has changed: When will we?
(A plea for our patients)

Dr John P Wright

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Abstract

While inflammatory bowel disease has been know for over 100 years, the treatment commonly employed today harks back to the modalities of the 1970 – 80s. The advent of truly disease modifying agents capable of putting patients in full remission has not been fully accepted by the health care practitioners or funders.

The ongoing use of old, toxic and ineffective agents needs to end and the medications available for the past 26 years accepted as the standard care for these symptomatic patients.

In practice

The existence of inflammatory bowel disease (IBD), mainly ulcerative colitis and Crohn’s disease, has been known for over 100 years (1). Treatment had 2 arms, anti-inflammatories such as prednisone to dampen down the symptoms and inflammation, and surgery to remove it. These approaches are toxic and/or mutilating and neither addresses the underlying disease process which is immunological in origin and not well understood(2).

The first attempts to modify the disease process was with the use of immunosuppressants such as azathioprine in the 1980s. After a year of therapy one could expect 42 % of patients to remain in remission as compared to 7 % on placebo(3). Clearly azathioprine was better than placebo but 60% of patients did not benefit at all. Furthermore 6% could not tolerate the treatment either because of nausea and vomiting or pancreatitis and there was also a low cancer risk. Certainly the use of prednisone and surgery used to have a role to play but in reality were simply toxic blips on the patient’s progressive decline (4,5).

On 24 August 1998 our patient’s world changed. Infliximab (Remicade, Revellex) was marketed. This anti-TNF (Anti-Tumour Necrosis Factor) agent could miraculously turn the inflammatory process off and within days restore to patients a normal life in quality and duration. These anti-TNF agents and other newer drugs targeting different paths in the immune cascade have been shown to be similarly effective. Research on the best agent for each disease phenotype is ongoing but for the vast majority of patients complete disease control is now possible. What has become apparent is that one of the critical factors is getting the dose right. The measurement of blood levels from the beginning of therapy maximises the effectiveness of these agents. Normally one can expect a patient on an adequate dose to be substantially better within days of starting therapy. If the patient remains ill as determined clinically, endoscopically and biochemically, blood drug levels need to measured and optimised. If the levels are already optimum a different agent is probably indicated. Most of the biologicals have been shown to need a specific level for maximum effectiveness but for the small molecules such as Tofacitinib the data is not yet convincing(6).

The question needs to be asked why after 24 years of experience and the ever-increasing variety of powerful agents available why do not all patients have access to these agents? Initially the price of R20 000 a month was an obvious deterrent. Real and perceived side effects further complicated the decision making and delayed the use of these agents. Fortunately the price for the cheapest agent has now reduced to R3 500 a month. Although still expensive, for a life modifying agent this is more affordable.

So again why are patients with inflammatory bowel disease not started on modern therapy on the day of diagnosis? These are chronic diseases with a very small chance of spontaneous remission. In the pre-biological era 20% of patients had relapses every year after 20 years of disease(7). Studies have shown that the earlier the treatment is started the better the outcome(8).

There are a number of reasons for the non-use of these agents:

1. While the cost of the cheapest agent may be manageable most of new agents are still costing R 5 000 and R 7 500 a month.
2. The main side effect remains an increased susceptibility to tuberculosis. In South Africa with our prevalence of tuberculosis this remains a factor. Nevertheless with the use of initial serological tests, chest x-rays and clinical judgement, the risk can be mitigated. Fortunately the newer agents have a much lower or no risk of tuberculous infection(9).
3. In a strange twist of logic there remains a belief that patients need to earn the new therapies. This means they need to have been treated with largely ineffective therapy for 3 months prior to commencing modern medicine. This dictum is attractive to conservative risk averse doctors and cost averse funders. To the patient with abdominal cramps, diarrhoea and sometimes faecal incontinence this delay is impossible to justify.
4. The final factor to consider is the long-term life modifying benefit of these agents. The risk of colon cancer is related to the amount of inflammation in the bowel and the extent of disease. Patients with on biologics with normal mucosa have a reduced risk of colon cancer(10). Similarly patients with normal bowel walls do not get the strictures, fistulas and surgical complications that previous patients had to endure. When one reviews older patients treated over the years with prednisone, immunosuppression and surgery it is a tragedy that they did not have access to modern medical therapy. Even more bizarre, many patients in South Africa continue to be treated in this unacceptable fashion

So how should patients with possible IBD be managed in 2023. There are two groups of patient:

The first is the acutely ill patient with cramps, diarrhoea and possible pyrexia. The first factor to consider is an infective process which, if viral, usually settles down in a few days without treatment. When bacteria are suspected after investigation, antibiotics may be required. In either case the symptoms will usually resolve in 5 to 7 days. When symptoms continue after this, further investigation is usually required. Endoscopy of the colon is normally the next step which with the assistance of histology should diagnose IBD. If the disease activity indices indicate severe disease (a Mayo score >8 or a CDAI > 250) it is time to start a modern biological agent with careful attention to drug blood levels. Conversely if the disease is mild local therapy or even a short course of systemic prednisone may suffice(11).

The second group is the patient with months or years of intermittent cramps and diarrhoea. A faecal calprotectin may separate organic from functional disease but inevitably colonoscopy will be needed. Once again a visual diagnosis of inflammatory bowel disease with assistance of histology should finalise the diagnosis. If IBD is confirmed modern biologics need to be commenced along with the normal monitoring of drug levels.

It would seem that all patients with established inflammatory bowel disease need to be started on modern therapy at diagnosis. Interestingly the University of Chicago website states that “Biological drugs have become the standard of care for people with moderate to severe Crohn’s disease or ulcerative colitis” (12). The use of old agents such as prednisone, mesalamine, azathioprine and methotrexate are counterproductive. They have little or no effect on the underlying disease and have numerous side effects. Similarly routine endoscopy in asymptomatic patients has been replaced with faecal calprotectin done every few years. More expensive imaging with CAT scans and MRI are seldom needed and generally indicate a failure of medical therapy.

The new disease management is very different from that of the past with less surgery, endoscopy and hospital admissions. In summary these diseases are now totally manageable with little risk of serious complications so why do we resist? As Winston Churchill said, “When the facts change, I change my mind. What do you do…..?”. In conclusion all our patients deserve to be treated with modern agents. They have already been available for 26 years.

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