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. 2022 Jul 12:9:933872.
doi: 10.3389/fmed.2022.933872. eCollection 2022.

Serological Biomarkers of Intestinal Collagen Turnover Identify Early Response to Infliximab Therapy in Patients With Crohn's Disease

Marta S Alexdottir  1   2 , Arno R Bourgonje  3 , Morten A Karsdal  1 , Martin Pehrsson  1 , Roberta Loveikyte  3 , Hendrik M van Dullemen  3 , Marijn C Visschedijk  3 , Eleonora A M Festen  3 , Rinse K Weersma  3 , Klaas Nico Faber  3 , Gerard Dijkstra  3 , Joachim H Mortensen  1
Affiliations

Serological Biomarkers of Intestinal Collagen Turnover Identify Early Response to Infliximab Therapy in Patients With Crohn's Disease

Marta S Alexdottir et al. Front Med (Lausanne). .

Abstract

Background: Crohn's disease (CD) is characterized by excessive protease activity and extracellular matrix (ECM) remodeling. To date, 30-50% of patients experience non-response to anti-TNF-α treatment. This study aimed to assess whether serological biomarkers of ECM turnover could monitor or predict response to infliximab (IFX) induction therapy in patients with and without a surgical history.

Methods: Serum biomarkers of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen degradation, type III (PRO-C3) and VI (PRO-C6) collagen formation, basement membrane turnover (PRO-C4), and T-cell activity (C4G), were measured at baseline and week 14, in 63 patients with CD undergoing IFX induction therapy. Patients were stratified according to surgical history.

Results: C4M was elevated at baseline in responders with a surgical history (n = 10) and associated with response at baseline (P < 0.05). Additionally, C6Ma3, PRO-C3, and PRO-C6 were elevated at week 14 in responders compared with non-responders (n = 8) and could differentiate between the two groups (P < 0.05). Two biomarker ratios (C4M/C4G and PRO-C4/C4G) were elevated at week 14 in non-responders (n = 5) without a surgical history compared with responders (n = 40) and could differentiate between the response groups (P < 0.05).

Conclusion: Baseline levels of a serological biomarker for type IV collagen degradation associated with response to IFX induction therapy, and biomarkers of type III and VI collagen formation may be used to monitor response at the end of induction therapy in patients with a surgical history. Biomarker ratios of type IV collagen turnover demonstrated promising results in monitoring treatment response in patients without a surgical history.

Keywords: Crohn’s disease; TNF-α antagonists; biomarkers; collagen; fibrosis; infliximab; surgery.

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Conflict of interest statement

MA, MP, MK, and JM are employees of Nordic Bioscience A/S. MK owns stocks in Nordic Bioscience A/S. GD received research grants from Royal DSM and speaker’s fees from Janssen Pharmaceuticals, Takeda, Pfizer, and Abbvie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Serum levels of C4M in CD patients with surgical history, stratified by response to IFX treatment. Baseline levels of type IV collagen degradation (C4M) were elevated in responders compared with non-responders (P < 0.05). (B) Receiver operating characteristic curve showing the discriminative power of C4M at baseline to differentiate between responders and non-responders at week 14 (P = 0.016). *P < 0.05.
FIGURE 2
FIGURE 2
(A) Serum biomarker levels in CD patients with surgical history, stratified by response to IFX treatment. Serum levels of collagen type III formation (PRO-C3), type VI degradation (C6Ma3), and type VI formation (PRO-C6) were elevated at week 14 in patients responding to treatment compared with non-responders (P = 0.004, P = 0.032, P = 0. 037). Data are shown as median + IQR. (B) Percent change from baseline of type III collagen formation, type VI collagen degradation and formation between responders and non-responders within CD patients with history of prior surgery. *P < 0.05; **P < 0.01.
FIGURE 3
FIGURE 3
(A) Serum biomarker levels in CD patients without surgical history, stratified by response to IFX treatment. Serum levels of type IV collagen ratios C4M/C4G and PRO-C4/C4G were elevated in non-responders at week 14 compared with responders (P = 0.035, P = 0.020). Significance was calculated using Mann–Whitney U-test. Data are shown as median + IQR. (B) Percent change from baseline of type IV collagen turnover between responders and non-responders, within CD patients with no history of prior surgery. Non-responders showed a 79 and 114% increase from baseline of type IV collagen turnover ratios C4M/C4G and PRO-C4/C4G, respectively. *P < 0.05.
FIGURE 4
FIGURE 4
Interaction plots displaying differing biomarker behavior depending on the history-of-surgery status. P-values are derived from likelihood-ratio tests depicting the significance of the interaction between the biomarkers and history of prior surgery. (A–C) Low baseline levels of C4M, and low levels of PRO-C3 and PRO-C6 at week 14 are indicative of non-response to treatment in patients with surgical history. (D–E) Low levels of C4M/C4G and PRO-C4/C4G at week 14 are indicative of response to treatment in patients without surgical history. The opposite can be seen within the group of patients with surgical history, where low levels of these ratios decrease the probability of responding to treatment.
FIGURE 5
FIGURE 5
Differing biomarker profiles based on prior history of surgery and disease behavior. Patients were stratified according to prior history of intestinal resection. Eighty-three percent of patients who have undergone prior surgery have stricturing/penetrating disease and thus a more fibrotic phenotype than patients without history of surgery, who mainly have a luminal disease phenotype. Responders within the yes-surgery group would theoretically have elevated levels of degradation markers, a possible result from the breakdown of fibrotic tissue and thus fibrosis resolution – while responders in the no-surgery group have decreased levels of aforementioned biomarkers, suggesting reduced inflammation and improved barrier integrity.
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