4 Questions About Inhibitor of DNA Binding 1 Protein in Rheumatoid Arthritis

Inhibitor of DNA binding 1 (ID-1) is a nuclear transcription factor that controls transcriptional activation of target genes. Previous research indicates that ID-1 may contribute to angiogenesis and vasculogenesis via independent mechanisms and interact with other inflammatory cells within the rheumatoid arthritis (RA) synovium.

The authors of a new study¹ sought to evaluate the role of ID-1 in RA fibroblast‐like synoviocytes (FLS) and determine whether serum ID-1 levels are citrullinated and autoantigenic in RA. Results showed a positive correlation between serum ID-1 levels and several RA disease parameters.

Rheumatology Consultant caught up with Jeffrey Ruth, PhD, an associate research scientist at the University of Michigan Medical School, and coauthor on the study, about the research.

Rheumatology Consultant: What prompted you to conduct your study?

Jeffrey Ruth: Anti-cyclic citrullinated antibodies (anti-CCPs) are very specific and have become key diagnostic markers for RA. They are found among less than 2% of individuals with other diseases but are present in approximately 75% of individuals with RA.² One study found that the antibodies present a mean of 4.5 years before disease onset.³ Additionally, a genetic association between the peptidyl arginine deiminase 4 gene and RA has been found in the Asian population. This gene encodes peptidyl arginine deiminase, the enzyme responsible for citrullination. We wanted to examine whether ID-1, a citrullinated protein, may play an important role in RA and can serve as a target for anti-CCPs.

RHEUM CON: What were the most important findings from the study?

JR: Analyses revealed that soluble ID-1 is present and up-regulated in the serum of individuals with RA and shows a significant positive correlation with a number of disease parameters, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, matrix metalloproteinase-3 level, Simple Disease Activity Index score, Clinical Disease Activity Index score, Disease Activity Score 28-CRP, and Disease Activity Score 28-ESR. This indicates that circulating ID-1 levels could be a potential biomarker for RA severity. Since serum ID-1 concentration does not correlate with rheumatoid factor (RF) titer, it is possible to identify individuals with RF-negative RA whose disease will be severe, by measurement of elevated ID-1. After 12 weeks of infliximab, serum levels of ID-1 showed significant reductions. We found that a majority of individuals responded to infliximab and that reduced ID-1 levels significantly correlated with reduction in disease activity in the responders. The ID-1 levels were highly correlated with RA disease severity, and this finding is in complete agreement with our previous studies showing that ID-1 is an active angiogenic mediator in RA.^4,5 Because of the elevated circulating concentrations of ID-1, we surmised that citrullinated ID-1 (cit-ID-1) could be present and immunogenic among individuals with RA.

RHEUM CON: How can the findings impact clinical practice?

JR: The molecules targeted by anti-CCPs are poorly defined. We present evidence that individuals with RA uniquely express cit-ID-1 and form antibodies that bind to it, possibly years before disease onset. Antibodies to cit-ID-1 called anti-citrullinated protein antibodies (ACPAs) could potentially play an important role not just later in the course of disease, but also closer to the initiation phase of RA. These studies should give novel insight into the role of cit-ID-1 in the pathogenesis of RA, likely identifying a new therapeutic target and autoantigen in this disease.

RHEUM CON: What are the next steps of your research?

JR: Further investigation is needed to determine whether and how citrullination of ID-1 may alter its functions. ID-1, cit-ID-1, and ACPAs to cit-ID-1 may serve as promising therapeutic targets or biomarkers in RA. Our data support the idea that a specific immunoassay that can accurately measure serum and synovial fluid for cit-ID-1 may be a valuable diagnostic tool that could identify potential individuals with RA well before disease onset.

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References:

1. Ohara RA, Edhayan G, Rasmussen SM, et al. Citrullinated inhibitor of DNA binding 1 is a novel autoantigen in rheumatoid arthritis [published online March 12, 2019]. Arthritis Rheumatol. doi:10.1002/art.40886.
2. Clavel C, Nogueira L, Laurent L, et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis–specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 2008;58(3):678-688. doi:10.1002/art.23284.
3. Uysal H, Bockermann R, Nandakumar KS, et al. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J Exp Med. 2009; 206(2):449-462. doi:10.1084/jem.20081862.
4. Edhayan G, Ohara RA, Stinson WA, et al. Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis. Arthritis Res Ther. 2016;18:87. doi:10.1186/s13075-016-0984-3.
5. Isozaki T, Amin MA, Arbab AS, et al. Inhibitor of DNA Binding 1 as a secreted angiogenic transcription factor in rheumatoid arthritis. Arthritis Res Ther. 2014;16(2):R68. doi:10.1186/ar4507.