AB0976 PLASMA PROTEIN INTER-ALPHA-TRYPSIN INHIBITOR HEAVY CHAIN 4 (ITIH4) LEVELS IN PATIENTS WITH axSpA AND RESPONSE TO TNF-INHIBITOR THERAPY
Authors: C. E. Mistegaard, A. Troldborg, A. G. Hansen, A. G. Jurik, R. M. Kiil, A. A. Christiansen, B. Schiøttz-Christensen, O. Hendricks, S. Juhl Pedersen, I. J. Sørensen, M. Østergaard, A. G. Loft, S. Thiel
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterized by inflammation of the axial skeleton. The pathogenesis of axSpA remains largely unclear, although recent evidence substantiates an involvement of the innate immune system. The complement system is a cornerstone of innate immunity and plays pivotal roles in host defense, homeostasis, and cell development. Previous studies comparing patients with axSpA and chronic low back pain (cLBP) have shown elevated levels of complement activating protein L-ficolin and complement activation in axSpA [1,2]. The plasma protein inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a newly described enzyme inhibitor, recently shown to inhibit serine proteases such as the complement enzymes MASP-1 and MASP-2 and tissue modulators matrix metalloproteinases (MMP) 7 and 13 [3]. Consequently, ITIH4 serves as a direct modulator of activities within the innate immune system and a regulator of extracellular matrix remodeling, i.e. related to bone formation. <h3>Objectives:</h3> This study aimed to investigate ITIH4 in axSpA patients compared with cLBP patients±SpA features. Furthermore, to explore ITIH4 levels in a longitudinal randomized controlled trial (RCT) cohort of axSpA patients initiating TNF-inhibitor (TNFi) therapy. <h3>Methods:</h3> EDTA plasma samples were obtained from a cross-sectional cohort (MICSA) of patients suffering from cLBP, encompassing I) 23 axSpA patients, II) 55 cLBP patients + SpA features and III) 64 cLBP patients - SpA features. Additionally, EDTA plasma samples from 49 axSpA patients from a longitudinal RCT cohort (DANISH) were included. Patients in DANISH were randomized to TNFi or placebo for 12 weeks, and hereafter TNFi until week 48. When ITIH4 acts as an inhibitor, it is cleaved in two. We employed two assays, one assay only detecting intact ITIH4 and one assay detecting both cleaved and intact ITIH4 (total ITIH4), and subsequently determined the ratio between intact and total ITIH4 (ITIH4 ratio) [4]. <h3>Results:</h3> No significant differences in plasma levels of total ITIH4 or intact ITIH4 were observed in the cross-sectional cohort, encompassing axSpA patients compared with cLBP patients ± SpA features (<b>Figure 1</b>). In the longitudinal RCT cohort, plasma levels of both total and intact ITIH4 decreased significantly after initiation of TNFi (<i>p</i> &lt; 0.001), and plasma levels of intact ITIH4 differed significantly according to treatment at week 12 (<i>p</i> = 0.011) (<b>Figure 2 a – b</b>). No significant differences were observed in ITIH4 ratio during the study period (<b>Figure 2 c</b>). <h3>Conclusion:</h3> We present the first investigations of the enzyme inhibitor ITIH4 in axSpA, involving both cross-sectional and longitudinal cohorts. Our study revealed no significant variations in plasma levels of total ITIH4 and intact ITIH4 among axSpA patients when compared to cLBP patients ± SpA features. Nevertheless, following the initiation of TNFi, plasma levels of both total and intact ITIH4 decreased in axSpA patients compared to the placebo group. The biological explanation for how TNFi treatment exerts these effects, such as whether it directly impacts the synthesis of ITIH4 or if it influences the catabolism of ITH4, remains to be elucidated. Additionally, there might be a feedback mechanism that reduces ITIH4 production in the presence of decreased inflammation in the body. We posit that the changes in ITIH4 levels reflect bone remodeling and that assessing ITIH4 could be advantageous in gauging treatment response and predicting prognosis, i.e. risk of radiographic progression, in axSpA. <h3>REFERENCES:</h3> [1] Mistegaard CE et al. J Rheumatol 2023 [2] Mistegaard CE et al. EULAR 2023 AB0093 [3] Pihl et al. Sci Adv 2021 [4] Laursen TL et al. J Clin Transl Hep 2022 <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>