Urinary Biomarkers as Indicators of RA Disease Activity

Rheumatoid arthritis (RA) is an inflammatory symmetric arthritis arising from alterations in immune tolerance, resulting in synovial inflammation. Tight control of RA involves reassessment of disease activity on a regular basis, using quantitative composite measures to guide adjustment of treatment regimens.  The current treat-to-target strategy aims to maintain a minimum level of residual disease activity, as evaluated at regular intervals by the disease activity score 28 (DAS28).

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are common biomarkers used to guide reassessments of disease activity in RA.  Disease exacerbations can cause elevations in ESR, and the duration of ESR elevation may continue well after the acute inflammatory phase has subsided.  Additionally, ESR and CRP may both remain normal despite increased disease activity as evidenced by increases in DAS28, which is scored by counts of tender and swollen joints.

Anti-cyclic citrullinated peptide antibodies (ACPAs) have been investigated as diagnostic markers for RA disease activity because of their ability to predict radiographic progression of joint damage in RA. However, despite the prognostic utility of ACPAs in RA, they do not appear to correlate with current disease activity, thus their roles in reassessing RA treatment regimens have been limited.

Ideally, a diagnostic marker for disease activity should be available for frequent retesting, so that treatments can be modified as soon as changes in disease activity are found. If a monitoring test can be easily performed by patients at home, results can be reported to physicians at regular intervals and adjustments can be made towards the treat-to-target goal in RA.  

To investigate the prognostic utility of 4 previously identified urinary biomarkers of RA disease activity, Yune-Jung Park, MD, and colleagues from the Division of Rheumatology  at the Catholic University of Korea School of Medicine, studied 264 patients with RA in a 3-year, single center, prospective study with matched controls.¹

The urinary biomarkers measured were gelsolin (GSN), orosomucoid (ORM)1, ORM2, and soluble CD14 (sCD14), initially identified in RA patients through transcriptomics and proteomics studies. These urinary biomarkers were positively correlated with RA disease activity.²  ORM2 specifically was shown to be mainly produced by synoviocytes in RA joints.²

Disease activity was measured by DAS28 scores, and radiographic severity of RA was assessed with yearly x-rays of the hands and feet. Urinary concentrations of sCD14, GSN, ORM1, and ORM2 were assayed by ELISA.

Patients with RA were found to have elevated urinary levels of ORM1, ORM2, and sCD14, and their levels were increased in proportion to the measured DAS28 score.  Over 3 years, patients with RA and higher levels of urinary ORM2 had rapid radiographic progression of RA joint destruction.  Additionally, the predictive ability of urinary ORM2 to gauge radiographic disease progression was increased when serum CRP was combined with levels of ORM2. The combination of 2 urinary biomarkers demonstrated an increased diagnostic sensitivity and specificity to predict DAS28>5.1 RA disease severity, as compared to the use of any single biomarker.

Summary and Clinical Applicability

“Urine tests using [ORM1, ORM2, sCD14] could better discriminate active RA from inactive RA without the need for blood tests, such as those for ESR and CRP….provid(ing) a rationale to develop urinary kits that can be utilized at home for self-assessment of RA activity,” the authors stated.

Tests for urinary levels of ORM1, ORM2 and sCD14 may in the future serve as new diagnostic targets for chronic, inflammatory arthritis.

“We are currently developing a new diagnostic kit and portable machine (FREND System at http://www.nanoentek.com) to accurately measure concentrations of ORM1, ORM2 and sCD14 in a drop of urine within 10 min,” the authors added.

Reference

1.       Park YJ, Yoo SA, Hwang D, Cho CS, Kim WU. Identification of Novel Urinary Biomarkers for Assessing Disease Activity and Prognosis of Rheumatoid Arthritis. Exp Mol Med. 2016;48:e211.

Kim WU, Park YJ, Yoo SA, Hong BK, Kim GM, Choi S, Lee S, Cho CS. A Paradigm Shift in the Disease Assessment of Rheumatoid Arthritis : From Blood to Urine Testing [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). Accessed March 1, 2016.