Background: Anti-TNFα agents such as Infliximab (IFX) are effective in inducing and maintaining remission in Crohn's Disease (CD). However, approximately 40% do not reach clinical remission and there are no serological biomarkers available that can predict adequate response. Inadequate response to IFX has been associated with increased submucosal fibrosis. Therefore, we investigated if serological collagen formation and degradation markers could predict for response to IFX.
Methods: Markers for matrix metalloproteinase degraded collagens III and IV (C3M, C4M) and formation of collagens III, IV and V (Pro-C3, P4NP, Pro-C5) were measured using competitive ELISAs in serum from 60 CD patients with active disease, drawn before starting 5mg/kg IFX (week 0), and after 2, 6 and 14 weeks. Clinical disease activity was classified by physician's global assessment (PGA, 0: disease in remission, 1: mild disease, 2: moderate disease, 3: severe disease) and the Harvey Bradshaw Index (HBI). Clinical response was defined as a reduction of >1 in PGA and thereby induction of remission according to PGA and HBI during follow-up due to IFX. Clinical non-response was defined as <2 PGA decrease and IFX failing to induce clinical remission (in PGA and HBI) during follow-up. Patients with clinical response, who stopped IFX due to pregnancy or side effects, were defined as responder.
Results: Sixty patients started IFX after median disease duration of 9.3 years. Forty-four (73%) patients responded, whereas 16 (27%) patients did not respond (median follow-up 3.9 years). None of these patients had primary non-response before week 14. Levels of P4NP and C3M were lower after 2, 6 and 14 weeks in responders.
C4M (p: 0.012) levels were higher in non-responders at week 14. Pro-C3 levels increased in responders after week 2 and 6 (p: 0.010, 0.002 respectively) whether non-responder levels remained stable. P4NP levels at week 2 were able to predict responders (AUC: 0.715). C3M, P4NP and Pro-C5 levels at week 14 were also able to predict responders (AUCs: 0.758, 0.827, 0.730 respectively).
Conclusions: Serological markers for collagen type IV formation (P4NP) and collagen type III degradation (C3M) can identify CD patients responding to IFX within the first 14 weeks of treatment. These markers could be used as early biomarkers for response to IFX and aid in early therapy decision-making.