Surrogate markers have an important role in the disease management of IBD. Researchers found evidence that microbial butyrate synthesis may predict therapeutic efficacy and thus play an important role in personalized treatment decision-making. In another study, fecal lipocalin-2 emerged as a sensitive biomarker for assessing inflammatory burden and may be another relevant parameter in the future alongside fecal calprotectin in measuring the course of IBD.
The incidence of Crohn’s disease (M. Crohn) and ulcerative colitis (C. ulcerosa) has risen sharply in recent years. With regard to the optimization of targeted IBD therapies, the identification of biomarkers is of particular importance. Among other things, they allow prediction of treatment response and play an important role in the assessment of progression. Recently, two very interesting papers were published in the Journal of Crohn’s and Colitis on this topic [1,2].
Butyrate as a possible predictor of treatment response
Research into the biological mechanisms of inflammatory processes in the intestinal mucosa and the development of new predictors of therapeutic efficacy are highly relevant. Dr. Maria Effenberger from the Medical University of Innsbruck (A), in collaboration with microbiome specialists from Kiel University, searched for predictive metabolites. Several established therapies are available today for the treatment of inflammatory bowel disease, including azathioprine (AZA) in tablet form with a response rate of about 50% and infusion therapy with anti-TNF antibodies [1,3]. “Using stool and blood samples from 65 IBD patients, we were able to analyze specific changes in the microbiome and clinical remission. We found that patients in whose microbiome a lot of butyrate – this short-chain fatty acid is the end product in the degradation of complex carbohydrates – is produced respond well to AZA therapy, an effect that was not found to the same extent with anti-TNF therapy,” explains Dr. Effenberger [3].
AZA is among the most commonly used immunosuppressants in the long-term treatment of IBD and is mainly used for remission maintenance or in chronic active IBD. A clinically relevant effect usually occurs only after a delay of about two to six months. Therefore, treatment is considered ineffective only if no significant effect can be detected after this period, which is often reflected in the fact that the corticosteroid used concomitantly to treat the acute episode cannot be completely discontinued [4].
The use of TNF blockers, the first biologics approved for the indication of IBD, has been tried and tested for almost two decades. The mechanism of action is neutralization of the inflammatory mediator tumor necrosis factor-α (TNF-α), which is produced in very large quantities in Crohn’s disease and C. ulcerosa [4]. TNF-α blockers approved for both C.ulcerosa and M. Crohn’s disease in Switzerland are currently adalimumab (Humira®) and infliximab (Remicade®). Certolizumab pegol (Cimzia®) is also available for the indication Crohn’s disease and golimumab (Simponi®) for ulcerative C. ulcerosa [5].
Fecal lipocalin-2 (FLCN2) as a progression parameter.
Endoscopic remission is associated with a reduction in recurrence and is therefore an important treatment goal. Surrogate markers that correlate well with endoscopic findings are required for individual monitoring. To date, fecal calprotectin (FCAL) in particular has been considered the gold standard for assessing the inflammatory burden of chronic bowel disease. An increase above a certain level is an important prognostic marker for recurrence of inflammation in the intestine [6]. Thus, although FCAL is an excellent biomarker in IBD, it is produced almost exclusively by neutrophils and there is some uncertainty, particularly in the presence of low-level or chronic inflammatory activity [7]. Lipocalin 2 (LCN2), unlike calprotectin, is also expressed by the intestinal epithelium. In a research study led by Assistant Professor PD Dr. Alexander Moschen, PhD, the scientists investigated the diagnostic potential of the infection-defending protein LCN2, to which the Innsbruck researchers were able to attribute a protective function in the development of intestinal inflammation and intestinal tumors several years ago [2]. In the recent study, fecal lipocalin-2 (FLCN2) now emerges as a particularly sensitive biomarker. “In two large comparative studies, we were able to demonstrate that FLCN2 is an equal fecal biomarker for assessing the actual disease burden. However, for patients with low inflammation, it has the particular advantage that – in contrast to FCAL – it can be detected in the intestine even in the presence of clinically undetectable inflammation. The protein LCN2, which is expressed among others by epithelial cells of the inner wall of the intestine, is thus suitable as a precise marker for molecular inflammation,” explains Prof. Moschen [3].
Literature:
- Effenberger M, et al: Microbial butyrate synthesis indicates therapeutic efficacy of azathioprine in IBD patients. J Crohns Colitis 2020 ;jjaa152. doi: 10.1093/ecco-jcc/jjaa152. Online ahead of print.
- Zollner A, et al: Fecal biomarkers in inflammatory bowel diseases: calprotectin versus lipocalin-2 – a comparative study. J Crohns Colitis 2020; jjaa124. doi: 10.1093/ecco-jcc/jjaa124. Online ahead of print.
- “Novel biomarkers for targeted therapy of inflammatory bowel disease,” Medical University of Innsbruck, Sept. 22, 2020. www.i-med.ac.at/mypoint/news/748284.html
- Ibdnet.ch: Chronic inflammatory bowel disease: Therapy of CED today and tomorrow, Patient Information: 3rd edition, www.ibdnet.ch, last accessed Jan. 11, 2021.
- Swiss Drug Compendium: https://compendium.ch
- De Vos M, et al: Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy. Inflamm Bowel Disease 2013; 19(10): 2111-2117.
- Zollner A, et al: Calprotectin versus lipocalin 2 in inflammatory bowel disease. Z Gastroenterol 2019; 57(05): e138.
HAUSARZT PRAXIS 2021; 16(1): 28
