Die Einführung von Biologika in der Therapie von chronisch entzündlichen Darmerkrankungen hat die Behandlungsstrategien revolutioniert. Nicht desto trotz ist unser Verständnis über richtigen Zeitpunkt, Auswahl von in Frage kommenden Patienten, optimale Dosierung und Kombination mit anderen Medikamenten einem permanenten Wandel unterworfen. Professor Jean-Frédéric Colombel aus Lille hat in anschaulicher Weise Entwicklung und Trends in praxisgerechter Form dargestellt. Seine zur Verfügung gestellten Unterlagen sollen uns helfen, Biologica optimal einzusetzen.
Ihr Wolfgang Petritsch.
There have been numerous trials that have proven the effect of anti TNF therapy in inflammatory bowel disease.
Today we are facing the following questions and changes:
Change in timing
when to start? (Fig. 1)
when to stop?
Change in therapeutic modalities
Change in therapeutic goals
In order to address some of these questions, the SONIC trial was performed. 508 patients naïve to immunomodulators were randomized to: 1) Azathioprine (AZA) 2.5 mg/kg capsules + placebo (PBO) infusions, 2) IFX 5 mg/kg infusions + PBO capsules, or 3) IFX 5 mg/kg infusions + AZA 2.5 mg/kg capsules through week 30. Infusions were administered at weeks 0, 2, and 6 followed by q8 week infusions. The trial results showed that the proportion of patients in steroid-free remission at week 26 (the primary endpoint) was 56.8% with IFX + AZA, 44.4% with IFX, 30.6% with AZA (p ≤ 0.001 IFX+AZA vs. AZA; p = 0.009 IFX monotherapy vs AZA monotherapy; p = 0.022 IFX + AZA vs. IFX monotherapy). The proportion of patients with complete mucosal healing at week 26 was 43.9% with IFX + AZA, 30.1% with IFX, and 16.5% with AZA (p ≤ 0.001 IFX + AZA vs. AZA; p = 0.023 IFX vs AZA; p = 0.055 IFX + AZA vs. IFX). When comparing the AZA monotherapy and IFX + AZA combination therapy, patients with elevated baseline CRP or mucosal lesions were twice as likely to achieve steroid-free remission than patients with normal CRP or no lesions. Importantly, in patients with normal CRP or no endoscopic lesions, no significant differences were observed among treatments. The results of the extension study at week 50 confirmed the superiority of IFX over AZA and of combination therapy over IFX alone to achieve long-term steroid-free clinical remission. Safety, including the proportion of patients with serious infections, was similar in all treatment groups.
The results of this trial are of extreme importance for the clinicians. First, they provide the best evidence so far that positioning biologics early in the IBD treatment algorithm (“top-down” strategy) results in superior outcomes compared with the current step-up strategy, in which biologics are used only in patients failing conventional therapies or who are steroid dependent. Second, they support the use of combination dual therapy with IFX and AZA in patients naïve to immunomodulators. Third, they demonstrate that measurement of CRP and endoscopy may serve as predictors of patients who are most likely to respond to IFX or combination therapy.
The data from this study should be used to make informed decisions for individual patients, recognizing that SONIC as all clinical trials is limited in duration and extrapolating beyond the length of the study must be done with caution. The concern that remains with the long term top-down dual approach is an increased risk of toxicity with infectious complications as well as an increased risk of lymphoma. Crohn’s disease is a heterogeneous disease and ultimately, we must weigh the safety and efficacy of the therapies with the risks of the disease itself in each patient.
One of the most interesting points for the clinician is the question when to stop treatment and in which patients. If the “bridge strategy” does not work (Fig. 2–3), is there a place for a longer bridge? The STORI trial gives some answers (Fig. 4–6).
Another way to optimize treatment could be the strategy of “tight control” with rapid step up based on objective parameters in addition to symptom scores. This strategy is going to be tested in the CALM-study.
New goals have emerged:
Goals of treatment are evolving in CD from mere control of symptoms to modification of natural history.
“Deep remission” as an emerging concept (Fig. 7,8).
New strategies have emerged:
There is a window of opportunity for the introduction of anti-TNFs and earlier treatment may provide better control of disease.
Combo therapy is the most effective strategy.
In a certain group of patients, discontinuing anti-TNFs therapy may be possible.
New studies are needed.
Prof. Jean-Frédéric Colombel
Professor of Hepatogastroenterology
Service des maladies de l’appareil digestif
Hôpital Claude Huriez and Centre Hospitalier Universitaire de Lille
59037 Lille Cedex
Fax: ++33/3/20 44 47 13