What Is the Optimal Therapy for Crohn's Disease: Step-up or Top-Down?
What Is the Optimal Therapy for Crohn's Disease: Step-up or Top-Down?
Crohn's disease (CD) is an idiopathic chronic inflammatory disorder of the digestive tract, which is incurable. Present therapeutic guidelines follow a sequential step-up approach that focuses on treating acute disease or 'inducing clinical remission' and subsequently aims to 'maintain clinical response'. In view of the chronic relapsing–remitting disabling disease course, new treatment approaches have been sought with the ultimate end point of disease course modification and mucosal healing. A recent preliminary study from D'Haens et al. has provided evidence suggesting that reversing the treatment paradigm from a 'step-up' to a 'top-down' approach may positively alter the natural course of this illness. Their findings indicate that early use of biologic therapy, in combination with immunomodulators, resulted in remission occuring more rapidly than the conventional 'step-up' treatment, with a longer time period to relapse, a decreased need for treatment with corticosteroids, a faster reduction in clinical symptoms, rapid decline in biochemical inflammatory markers (C-reactive protein) and improved endoscopic mucosal healing. These results, supported by previous studies on infliximab use, may hold a promising outcome of fewer stricturing complications, hospitalizations and surgeries for patients with CD. However, we need to better define the timing and candidates for the 'top-down' approach as we are still uncertain about the safety data and the long-term benefits if biologic agents are given as routine maintenance treatment, since most of the trials in CD have been short term, and approximately 30% of patients might have been overtreated. Future clinical trials will be crucial in answering these questions.
Crohn's disease (CD) is a chronic inflammatory disorder of the digestive tract with a wide spectrum of clinical presentations and an unpredictable disease course. The estimated annual prevalence and incidence of CD in the USA are 50 per 100,000 and five per 100,000, respectively. CD is more prevalent in Western countries, and although it was found to be a disease affecting all age groups, it is more commonly diagnosed in adults during the second and third decades of life. Despite the advancements made in understanding the etiology and pathogenesis of the disease, CD remains medically and surgically incurable. These patients are faced with a lifetime of recurrent disease flare-ups and remission and thus the management strategies for CD must be targeted towards lifelong management, taking into consideration both short- and long-term aspects of the disease.
The current standard medical practice is guided by the disease location, severity, associated complications and concurrent therapy taken by patients. It consists of a sequential ('step-up') approach to conservative use of immunomodulators and biological therapy with the ultimate goal of inducing and maintaining clinical remission. While the usage of the first-line agents (aminosalicylates [5-ASA], antibiotics and corticosteroids) and immunomodulators has, somewhat successfully, treated the acute disease and maintained remission, these agents have not been able to alter the long-term course of CD. The question of whether it is possible to alter the natural history of CD by an early introduction of therapies currently reserved for the 'top' of the treatment pyramid has been the subject of much discussion (i.e., 'top-down' approach).
In this review, we aim to provide an evidence-based discussion on the controversy and rationale for the use of 'top-down' versus 'step-up' therapy for the treatment of CD.
Abstract and Introduction
Abstract
Crohn's disease (CD) is an idiopathic chronic inflammatory disorder of the digestive tract, which is incurable. Present therapeutic guidelines follow a sequential step-up approach that focuses on treating acute disease or 'inducing clinical remission' and subsequently aims to 'maintain clinical response'. In view of the chronic relapsing–remitting disabling disease course, new treatment approaches have been sought with the ultimate end point of disease course modification and mucosal healing. A recent preliminary study from D'Haens et al. has provided evidence suggesting that reversing the treatment paradigm from a 'step-up' to a 'top-down' approach may positively alter the natural course of this illness. Their findings indicate that early use of biologic therapy, in combination with immunomodulators, resulted in remission occuring more rapidly than the conventional 'step-up' treatment, with a longer time period to relapse, a decreased need for treatment with corticosteroids, a faster reduction in clinical symptoms, rapid decline in biochemical inflammatory markers (C-reactive protein) and improved endoscopic mucosal healing. These results, supported by previous studies on infliximab use, may hold a promising outcome of fewer stricturing complications, hospitalizations and surgeries for patients with CD. However, we need to better define the timing and candidates for the 'top-down' approach as we are still uncertain about the safety data and the long-term benefits if biologic agents are given as routine maintenance treatment, since most of the trials in CD have been short term, and approximately 30% of patients might have been overtreated. Future clinical trials will be crucial in answering these questions.
Introduction
Crohn's disease (CD) is a chronic inflammatory disorder of the digestive tract with a wide spectrum of clinical presentations and an unpredictable disease course. The estimated annual prevalence and incidence of CD in the USA are 50 per 100,000 and five per 100,000, respectively. CD is more prevalent in Western countries, and although it was found to be a disease affecting all age groups, it is more commonly diagnosed in adults during the second and third decades of life. Despite the advancements made in understanding the etiology and pathogenesis of the disease, CD remains medically and surgically incurable. These patients are faced with a lifetime of recurrent disease flare-ups and remission and thus the management strategies for CD must be targeted towards lifelong management, taking into consideration both short- and long-term aspects of the disease.
The current standard medical practice is guided by the disease location, severity, associated complications and concurrent therapy taken by patients. It consists of a sequential ('step-up') approach to conservative use of immunomodulators and biological therapy with the ultimate goal of inducing and maintaining clinical remission. While the usage of the first-line agents (aminosalicylates [5-ASA], antibiotics and corticosteroids) and immunomodulators has, somewhat successfully, treated the acute disease and maintained remission, these agents have not been able to alter the long-term course of CD. The question of whether it is possible to alter the natural history of CD by an early introduction of therapies currently reserved for the 'top' of the treatment pyramid has been the subject of much discussion (i.e., 'top-down' approach).
In this review, we aim to provide an evidence-based discussion on the controversy and rationale for the use of 'top-down' versus 'step-up' therapy for the treatment of CD.
