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P039. Serum MMPs 7–9 and their inhibitors during glucocorticoid and anti-TNF-alpha therapy in IBD

L. Mäkitalo1, T. Sipponen2, H. Rintamäki1, T. Tervahartiala3, T. Sorsa3, K.‑L. Kolho1

1Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland; 2Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland; 3Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Background: Matrix metalloproteinases (MMP) take part in both destructive and regenerative processes in inflammatory bowel diseases (IBD). They are inhibited by tissue inhibitors of matrix metalloproteinases (TIMP), and by plasma inhibitor, alpha-2-macrogobulin (alpha-2M). We examined serum levels of MMPs, their inhibitors and markers of neutrophil activity, myeloperoxidase (MPO) and human neutrophil elastase (HNE), before and after treatment with either glucocorticoid (GC) or anti-TNF-alpha agent, to find possible markers of response to therapy.

Methods: Serum samples were collected before and within two to three weeks after beginning either anti-TNF-alpha (n = 15) or oral glucocorticoid therapy (n = 17), and from IBD patients with inactive disease (n = 14). We analyzed serum level of MMP‑8 with immunofluorometric assay (IFMA), and levels MMP‑7, MMP‑9, TIMP‑1, TIMP‑2, HNE, alpha-2M and MPO using enzyme-linked immunoabsorbent assays (ELISA). Disease activity was assessed with fecal calprotectin, erythrocyte sedimentation rate (ESR), C‑reactive protein (CRP) and Crohn's disease endoscopic index of severity (CDEIS).

Results: Samples from inactive IBD had higher levels of alpha-2M than serum from patients assigned to receive therapy (p < 0.000). Levels of MMP‑8 and MMP‑9 were lower in the pre-treatment anti-TNF-alpha group (p = 0.007 and p = 0.007, respectively) compared to pre-treatment GC samples, while TIMP‑1 was elevated (p = 0.006). Fecal and serum markers of inflammation (CRP, ESR, calprotectin) decreased with treatment, but did not markedly correlate with MMPs or their inhibitors. During anti-TNF-alpha therapy, levels of MMP‑8 and TIMP‑1 decreased (p = 0.017 and p = 0.011, respectively), but levels of TIMP‑1 remained elevated compared to post-treatment GC samples. During GC therapy, levels of MMP‑7 decreased during therapy (p = 0.001) but there was no change in TIMP‑1.

Conclusions: In IBD, serum MMP‑7 may reflect response to glucocorticoid therapy, while MMP‑8 and TIMP‑1 present as important mediators in the anti-TNF-alpha effect. Alpha-2M may be an important inhibitor in controlling inflammation in IBD.