Combined therapy or precision medicine in inflammatory bowel disease, why? and how?

The treatment of inflammatory bowel diseases has evolved by leaps and bounds with the advent of biological therapy at the beginning of this century. Since the era of biologics, outcomes for patients with ulcerative colitis and Crohn’s disease have changed and improved such that complication rates and the need for surgery have dropped to a level that was unimaginable in the 90s, where the same drugs that had been the protagonists for more than 70 years were available: 5-aminosalicylates, steroids and immunomodulators (thiopurines and methotrexate).

In 2020, a major meta-analysis was published online that reviewed the contemporary risk of surgery in patients with inflammatory bowel disease, comparing the risk before 2000 and after 2000. Table 1 shows the results of this study in risk assessment of requiring surgery at one year, 5 years and 10 years of surgery in ulcerative colitis and Crohn’s disease, before and after 2000. Although this analysis does not directly attribute the reduction to biological therapy, the authors conclude that the important reduction in the need for surgical treatment and the improvement in the general outcomes of patients could be multifactorial, including earlier detection, the use of treatment algorithms, new strategies such as targeted therapy that lead to better disease control , early detection of neoplastic lesions, improvement in endoscopic technology, and finally the introduction and increasingly adopted use of biologics and small molecules.[1]

Table 1. Contemporary risk of surgery in patients with inflammatory bowel disease.[1]

inflammatory bowel disease

Risk of surgery at one year

Risk of surgery at 5 years

Risk of surgery at 10 years

Before 2000

after 2000

Before 2000

after 2000

Before 2000

after 2000

ulcerative colitis

4.8% (3.7 to 6.1)

2.8% (2.0 to 3.9)

9.5% (7.8 to 11.4)

7.0% (5.7 to 8.6)

15.2% (12.6 to 18.2)

9.6% (6.3 to 14.2)

Crohn’s disease

23.6% (18.3 to 29.9)

12.3 (10.8 to 14.0)

35.7% (29.2 to 42.9)

18.0% (15.4 to 21.0)

46.5% (36.7 to 56.6)

26.2% (23.4 to 29.4)

Despite the significant achievements of the last 20 years, the current number of available treatments, the constant discovery of new therapeutic targets, the development of new targeted molecules, and new clinical trials taking place around the world, the treatment continues to be “suboptimal” in the words of Dr. Colombel et al. in a commentary recently published in Gastroenterology in which these questions are asked: What should we do with the 50% of patients who behave as non-responders to initial therapy? How to optimize therapy in 50% of patients who will have a loss of secondary response to existing and future therapies? How do you get past the 45% maximum response ceiling that even the best-performing molecules can’t get past?[2]

The authors propose two ways to break the plateau that has now been reached with therapies for inflammatory bowel diseases. The first is a precision medicine approach. The second through combined therapies.

Precision medicine is one in which the objective is to adapt the therapy to the characteristics of each individual, but it goes far beyond personalized medicine; in precision medicine, it is proposed to classify all the possibilities of presentation of a disease through the identification of subpopulations and risk stratification, through knowledge of external factors interacting with internal ones: highlighting the importance of the so-called “omas” and the sciences that study them, in addition to all the complexity that a disease can involve. The term “interactome” refers to the combined study of several omas and how they are integrated, for inflammatory bowel disease we are still in the process of creating an interactome due to the biological complexity of the pathology, this in the future will allow us to create models molecular presentation of inflammatory bowel disease, replacing the current models based on the type of presentation of the disease.[3]

The second way proposed by the authors is “combined therapy”, which is not the first time that the term has been heard in inflammatory bowel disease, we even have extensive experience and good results of the use of combined therapy of infliximab and azathioprine, in which More than a synergistic effect, azathioprine allows infliximab to achieve better serum levels and a lower degree of immunogenicity.[4] This is the type of combinations that are expected to be created, in which there is no mixed activity in which the therapeutic effects overlap to a greater or lesser extent, reducing the meaning of the combination, or even that do not subject the patient to greater risk. of adverse effects.

There have been multiple reports and case series of patients treated with biologics combined with different molecular targets or biologics combined with small molecules, many of which resulted in patient benefit, with few adverse effects. However, the cases are anecdotal and there is currently no evidence to support the use of biologic combinations or even to prove that they have an adequate safety profile.[5]

However, the ideal combination will be one in which the therapies complement each other, increasing the opportunity to improve activity against the disease. The authors call this “rational use of combination therapy,” as it has been used in the field of neurology or infectology, such as with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) combination treatments.

It is even likely that the two suggested ways complement each other and when we reach that point, where both strategies come together, the therapies will be completely precise for each patient.

In the meantime, we must await the results of clinical trials of combinations of already known therapies with vitamin D, probiotics, antibiotics, and even microbiota transplantation; strategies that are currently applied, hoping that soon we will be able to start making that medicine aimed at the profile of each patient that brings the best results and overcomes that plateau that seems impossible to break.

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