Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

Abstract

Objective Inter‐alpha‐trypsin inhibitor heavy chain 4 (ITIH4) regulates immunity and inflammation, but its clinical role in rheumatoid arthritis (RA) patients remains unclear. Hence, this study was conducted to explore the association of circulating ITIH4 with disease risk, clinical features, inflammatory cytokines, and treatment outcomes of RA. Methods After the enrollment of 93 active RA patients and 50 health controls (HCs), their serum ITIH4 level was analyzed by enzyme‐linked immunosorbent assay (ELISA). For RA patients only, serum ITIH4 level at week (W) 6 and W12 after treatment was also analyzed. Besides, serum tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1β, IL‐6, and IL‐17A at baseline of RA patients were also detected by ELISA. Results ITIH4 was downregulated in RA patients (151.1 (interquartile range (IQR): 106.2–213.5) ng/mL) than in HCs (306.8 (IQR: 238.9–435.1) ng/mL) (p < 0.001). Furthermore, ITIH4 was negatively related to C‐reactive protein (CRP) (rs = −0.358, p < 0.001) and 28‐joint disease activity score using erythrocyte sedimentation rate (DAS28‐ESR) (rs = −0.253, p = 0.014) in RA patients, but not correlated with other clinical features (all p > 0.05). Besides, ITIH4 was negatively linked with TNF‐α (rs = −0.337, p = 0.001), IL‐6 (rs = −0.221, p = 0.033), and IL‐17A (rs = −0.368, p < 0.001) in RA patients, but not correlated with IL‐1β (rs = −0.195, p = 0.061). Moreover, ITIH4 was gradually elevated in RA patients from baseline to W12 after treatment (p < 0.001). Additionally, the increment of ITIH4 at W6 and W12 was linked with treatment response and remission in RA patients (all p < 0.05). Conclusion Circulating ITIH4 possesses clinical utility in monitoring disease risk, inflammation, disease activity, and treatment outcomes of RA.

Longitudinal change of serum inter‐alpha‐trypsin inhibitor heavy chain H4, and its correlation with inflammation, multiorgan injury, and death risk in sepsis

“…As a novel anti‐inflammatory factor, the dysregulation of ITIH4 has been revealed in various diseases, such as autoimmune, cardiovascular, and cerebrovascular diseases 17,23–26 . For instance, serum ITIH4 is reduced in inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) patients compared to HCs 23,24 .…”

“…Regarding the association between ITIH4 with clinical characteristics and inflammatory cytokines, several studies have explored this aspect in patients with autoimmune diseases 23,24 . Whereas the correlation between ITIH4 with clinical properties and inflammation in sepsis patients still should be investigated.…”

“…As a novel anti‐inflammatory factor, the dysregulation of ITIH4 has been revealed in various diseases, such as autoimmune, cardiovascular, and cerebrovascular diseases. 17 , 23 , 24 , 25 , 26 For instance, serum ITIH4 is reduced in inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) patients compared to HCs. 23 , 24 Meanwhile, a previous study claims that serum ITIH4 may be a potential biomarker for coronary heart disease (CHD) patients since it is decreased in patients with acute cardiovascular events compared to patients without those events.…”

“… 17 , 23 , 24 , 25 , 26 For instance, serum ITIH4 is reduced in inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) patients compared to HCs. 23 , 24 Meanwhile, a previous study claims that serum ITIH4 may be a potential biomarker for coronary heart disease (CHD) patients since it is decreased in patients with acute cardiovascular events compared to patients without those events. 25 In addition, serum ITIH4 is also reduced in acute ischemic stroke patients compared to HCs.…”

“…Regarding the association between ITIH4 with clinical characteristics and inflammatory cytokines, several studies have explored this aspect in patients with autoimmune diseases. 23 , 24 Whereas the correlation between ITIH4 with clinical properties and inflammation in sepsis patients still should be investigated. Firstly, it was discovered that serum ITIH4 was related to the absence of cardiovascular and cerebrovascular disease history in sepsis patients.…”