Gastroenterology Associates of Big Bend, Tallahassee, Florida, USAUnited States
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I read with interest the open access, original article, by S.K. Murthy, et al, Introduction of anti-tumor necrosis factor (TNF) therapy has not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study appearing in Gut 12 June 2019.1 It must first be stated that the authors are to be congratulated for the magnificent demonstration of the benefits of the Canadian healthcare system in terms of collection of healthcare data.
OpenJournal Letter to the Editor Call Me Anything but Thoughtless or Misguided in IBD Management * Nicholas V. Costrini, MD, PhD, MBA* Gastroenterology Associates of Big Bend,Tallahassee, Florida, USA * *Corresponding author Nicholas V. Costrini, MD, PhD, MBA Gastroenterology Associates of Big Bend,Tallahassee, Florida, USA; E-mail: drcostn@gmail.com Article information th th th Received: September 7 , 2019; Accepted: September 19 , 2019; Published: September 26 , 2019 Cite this article Costrini NV. Call me anything but thoughtless or misguided in IBD management. Gastro Open J. 2019; 4(1): 4-6. doi: 10.17140/GOJ-4-129 read with interest the open access, original article, by S.K. Mur- with the physicians. I believe the authors are quite mistaken and I thy, et al, Introduction of anti-tumor necrosis factor (TNF) therapy has offer more likely explanations for consideration.
I not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study 2 3 The infliximab 2002 ACCENT I and 2004 ACCENT II appearing in Gut 12 June 2019.1 It must first be stated that the trials reported clinical remission rates of twenty-two percent. The authors are to be congratulated for the magnificent demonstra- adalimumab 2007 CHARM trial reported similarly less than spec- tion of the benefits of the Canadian healthcare system in terms tacular remission rates. For the first decade after anti-TNF entry of collection of healthcare data. That said, I take issue with their into the marketplace, practicing gastroenterologists were “guided” explanation and hypothesis: “misguided use and failure to optimize by the academic community to treat IBD patient with either “top- use of infliximab, particularly among patients with Crohn’s Disease down or the bottom-up” programs based upon clinical parameters. (CD), as well as possible underuse of infliximab among patients The 2015 REACT trial provided enough “real world” evidence with ulcerative colitis (CUC)….” In the follow-up press release, to support treating patients with early introduction of combined one summary recommendation was that “doctors should be more thou- immunomodulator plus biologic agent. While combined treatment ghtful in managing inflammatory bowel disease (IBD).” It is unfortunate, (i.e. top-down) did not offer a statistically significant improved indeed, that the term “misguided use” would appear and then be clinical remission rate compared to a conventional treatment pro- translated into perhaps a deeper, and unwarranted, criticism that gram (i.e. bottom-up), early combined treatment was associated doctors managing IBD have been “less than thoughtful or misgui- with a lower two-year aggregate rate of hospitalizations, surger- ded” in the use of biologics. I think the authors actually intended ies, and serious infections. We can extrapolate from the clinical to report that the academic community has collected clinical trial remission rates that the endoscopic remission rates would be in data and offered practicing clinicians a plan for use of biologics the twenty-five percent range. Hence, in clinical trials and in “real only to find in retrospect that those recommendations were not world” experience, the anti-TNF agents are rather weak in pro- likely to be effective given the general IBD patient population and viding endoscopic remission and by extension a weak tool in al- the less than complete effectiveness of the biologics. Nonetheless, tering the natural history of IBD. In fact, it was not until 2012, the message was certainly blurred.
the year the study ended, that the EXTEND trial was published. This was the first study to use endoscopic healing as the primary Beyond the social implications of the article and its in- endpoint in a CD treatment trial. Mucosal healing was recorded in terpretations, there are numerous clinical areas of concern in this only twenty-four percent of patients treated with adalimumab for publication. The basic premise of the conclusions is that since the two years. In patients with a less than a two-year history of CD, anti-TNF agent infliximab has been demonstrated to reduce hos- endoscopic remission reached thirty-three percent at two years. I pitalizations and surgeries in controlled trials and observational was very surprised by your explanation since it is agreed that while studies, one should expect, for the price and deep intrusion into these agents provide gratifying clinical relief for an interval, anti- the marketplace, similar effectiveness to be demonstrable in popu- TNF agents have the power to alter the natural history of CD in lation studies. Because such effectiveness was not demonstrated in only a small proportion of patient. That is why additional more this elegant study, the conclusion offered is that the fault must lay tightly designed trials have been completed. In 2018, the CALM cc Copyright 2019 by Costrini NV. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which Gastro Open J. 2019; 4(1): 4-6. doi: 10.17140/GOJ-4-129 trial7 was completed. In this trial patients with CD of less than one- for any incremental benefit would have been higher. Additionally, year duration and naïve to immunomodulators and biologics, were fifty to eighty percent of patients would have failed to benefit at entered into programs in which the treatments were escalated on all given the defined rate of remission with the conventional care the basis of regularly measured biomarkers and endoscopy as well practiced during 1995-2012 interval.
as clinical symptoms. In this highly selected, intensely investigated group of patients, endoscopic remission rates with adalimumab In closing, I offer my personal experience. I studied two reached its zenith of forty-six percent, well above the remission hundred CD patients in my private practice as a very early adopter rate of thirty percent in their patients managed conventionally. We of anti-TNF treatment. The incidences of surgery and steroid use have yet to learn if we have found a way to use anti-TNF agents in in the interval of 2000 to 2010 with and without exposure to anti- a manner that alters the natural history of the disease in the major- TNF agents were identical to those parameters in the decade of ity of patients and capable of deflecting adverse event curves. The 1990 to 2000. I was disappointed by the results to be sure. The pa- population of CD patients exposed to anti-TNF agents between tient demographics in my study group and in this publication were 2000 and 2012 were managed conventionally as directed by the identical. The explanation for the elegant study results and for my controlled trials of the time. Hence, remission occurred in only small office results rests in the fact that as far as anti-TNFs are con- a quarter of CD patients treated with infliximab (and for an un- cerned, IBD patient groups with long-standing disease (five years known duration). It is not surprising that the population curves or more), prior exposure to other agents (biologics and immuno- were not deflected. I offer that the fault lies not in “misguided” modulator), and managed principally by clinical measures cannot clinicians but in the fact that anti-TNF agents are only modestly be expected to generate a substantial proportion of patients with effective in promoting endoscopic healing when used as they were long-term endoscopic remissions. Without long-term endoscopic in the years of the study. Comment is made that drug trough levels remissions with mucosal healing, we cannot expect to change the were not used regularly. It was not until well after the study was natural history of IBD. As we consider new drugs in the pipeline completed that the academic community embraced such testing and aggressive management programs now being promoted, we as meritorious. The fact that we have spent a fortune on the drugs can hope for better directions and more appealing curves along for IBD and have so little to show for it, as you so vividly demon- the road leading to a cure for IBD. I thoughtfully offer my explana- strate, is evidence enough of the frailty of this class of drugs in tions for this data. The explanations, sir, resides in the potion and the mission of changing the natural history of the disease. This not in the physician.
limited anti-TNF impact on CD natural history is justification for the aggressive search for new drugs and the design of studies such