Crohnology: A tale of time and times and inflammatory bowel diseases

Abstract

Time, times and timing are key words in inflammatory bowel diseases (IBD). The leitmotif of this issue or World Journal of Gastroenterology is time. We have asked experts to review on the epidemiology of these diseases over time, the changes in innate immunity that could be present in the first time, and then the timing of key treatments. The correct time of using azathioprine, mercaptopurine, infliximab, cyclosporine and surgery are reviewed. We have chosen experts with not only great clinical expertise but also personal interest in clinical and basic investigation. Our goal in this monograph is to get an idea not only of the present but of the immediate future in some of the key management issues in IBD. To this end, we think that the authors are the most adequate.

Key Words: Inflammatory bowel diseases; Epidemiology; Innate immunity; Treatment

TEXT

Life and time are concepts that can not be apart[1]. In fact, from a medical point of view, life, time and disease are inseparable concepts. The importance of time in life is being clarified by basic scientists and chronobiology is an area of knowledge steadily growing[2]. As we are writing on inflammatory bowel diseases (IBDs) we have misspelled on purpose the word crohnology, as new additional tribute to Burrill Bernard Crohn[3]. In fact, we borrowed the fundamental idea from another great expert, not only on Beethoven’s piano sonatas, but on IBDs: David Sachar. He wrote some years ago an excellent editorial on this subject[4], and although he thinks that, at the end, no one reads his articles, he was wrong this time: we do. David Sachar wrote (sic): …“time course of disease progression should enter into our phenotyping schemes as elements in their own right” and also: “to understand the time course of Crohn’s disease …, we have to figure out when and where to start the clock”. Time is the leitmotif of this monographic issue of the World Journal of Gastroenterology.

First, IBDs are diseases of our times. Diseases affecting human beings have greatly changed over time[5]. In Spain, Crohn’s disease could not to be found in most standard textbooks as late in the twentieth century as 1975. Now the Spanish working group on IBD (GETECCU, http://www.geteccu.org) has more than 300 gastroenterologists as active members. Of course, this can not be taken as an epidemiological figure, but it may be an idea about the quick changes in some of the health needs in our current world. Whatever the complex reasons for these dramatic changes, environmental factors must be a prominent influence, because the time taken to these changes is too short to blame genetics to explain them (at least in full). It is difficult to forget the similarities with cigarette smoking. “The IBDs’ century “could be a very adequate title for a book on Crohn’s disease (CD) and Ulcerative Colitis (UC)[6].

Second, we take a look to a very interesting hypothesis: “the first precursors of recognizable Crohn’s disease”[3]. Professor Eduard Stange and co-workers, from Germany, suggests that IBDs are in fact the final consequence of a defective innate immunity against bacteria. Their data on defensins have been the matter of controversy in most recent meetings on IBDs. He has written a short review on the topic. The disturbances of adaptative immunology in advanced IBDs were first recognized; however, innate immunity errors are emerging as key clues to chronic inflammation[7]. The “defensins hyphothesis” is not unique, but it is very attractive and gives a refreshing point of view to the pathogenesis of IBD. In fact, human brain is more adapted to see what it is there, but has serious difficulties to think of absent things[8]. Could it be possible that the lack of adequate defense mechanisms being the primary phenomenon, explain the final excess of inflammation? Certainly this seems an interesting and attractive way to explore.

Most of the chapters in this issue are directly related to the real life situations for a clinician in care of IBDs’ patients. Clinicians have to take, or at least help to take, many decisions. Ideally, these decisions should be taken on time and always trying to avoid delays; that is, the time elapsed to take these decisions has to be the correct and needed time. Time is important for us, but much more for our patients. In certain occasions taking decisions on time it is not easy at all and we make errors[9]. These mistakes have sometimes very undesirable consequences to our patients. Timing of decisions is a key factor in our practice. In this issue the answer to some critical questions has been addressed.

In the very difficult clinical scenario of severe ulcerative colitis, there are two crucial questions: how long, if no response is obtained, should steroids be maintained to define resistance? and if steroids do not work: it is time for cyclosporine or for infliximab? These points are often discussed in meetings, but we do want the best answers. Therefore, we have asked these questions to real experts. Dr. María Esteve has been working for years both in basic and clinic research and at the same time she has great clinical experience; she is a real translational physician. She can approach steroid resistance from both points of view, and this was exactly our aim. The same can be said from Drs Gert van Asche and Severine Vermeire. Of course we know that currently there is not a formal clinical trial comparing cyclosporine and infliximab in severe UC, but patients are there and we have to help them just on time; today, not tomorrow. We expect that these two experts help us to understand the pros and cons for using these drugs at the proper time and for how long.

Azathioprine and mercaptopurine are the most important drugs in the maintenance treatment of IBDs[10]. Much has been written on these very useful old friends. However, do we start these treatments at the proper time or do delay theis use too much? This is a common and important clinical question, not very easy to answer. It is about prediction, a rather difficult science. Can we predict clinical course and therefore select the adequate timing for starting treatment? In any case, many patients are finally on immunomodulators, and many do stay quite well during years: so, is it a time to withdraw them?

Biologics are newer therapies[11], but are here to stay. There are, at least, two very different points of view. Many clinicians, as well as regulatory agencies[12], do think that these drugs should be used at later stages in therapy, after the failure of conventional treatments; high cost and high risks are the main arguments for this position. However, this way if thinking it seems rather intuitive (intuition is of course not sort of scientific proof) that administering treatment earlier could beneficially modify the natural history of disease. So many clinicians, as well as pharmaceutical companies, think that the earlier biological are administered, clearly the better. In fact there is some recent evidence supporting this argument[13]. The timing of this treatment seems critical. We think that giving both points of views would be interesting and useful for the clinician.

Finally, few decisions are as difficult as timing surgery in IBDs. Sometimes we decide too late (don’t you have at least one patient telling you: Hey doc, why did we go through surgery so late?), perhaps sometimes the decision was taken too early (some refractory pouchitis could comment on this side). Few tips may help in those difficult clinical nodes. In addition, after surgery it is also time to act: you need to prevent recurrence. How is not easy to say, but we also need to know when.

Words are almost living beings. We have chosen times, time and timing, to think over IBDs. But, it is time to finish. It is time to continue working to help our IBDs’ patients.