A Crystal Ball for Long-Term Poor Outcomes in RA?

A new Canadian study shows that measuring 14-3-3η protein serum levels, in combination with existing prognostic biomarkers, can more accurately identify patients with early polyarthritis (EPA) who are at risk for long-term poor outcomes.

Researchers found that the presence of elevated 14-3-3η protein levels were associated with a subset of patients who have a high risk of clinically refractory disease, and significant joint damage, over the next five years. In addition, these patients are at high risk for structural damage - even if they have achieved SDAI (Simple Disease Activity Score) remission.

The study, which appears in the Feb. 1 issue of Arthritis Research and Therapy, is based on the analysis of 331 patients (62 percent women, mean age 60 years) who were followed for five years. 

“We show that serum 14-3-3η protein levels can be used in addition to baseline RA-associated antibodies to facilitate early identification among EPA patients of RA patients likely to have poor outcomes - both clinically and radiographically,” wrote the authors of the study which was led by Gilles Boire, M.D., of the University of Sherbrooke in Quebec.

Researchers found that a combination of a high C-Reactive Protein (CRP) and an elevated 14-3-3η protein at baseline and during treatment was indicative of an “an adverse prognostic signature suggesting that a majority of these patients will deteriorate significantly, especially older individuals,” the researchers wrote.

Researchers found that the higher the 14-3-3η baseline levels, the stronger the association with radiographic progression (r approximately 0.19, p <0.001). Also, the higher the decrease in 14-3-3η titers between baseline and 18 months, the lesser the radiographic progression from 18 to 30 months (r = –0.14, p = 0.018).

14-3-3η protein is found at increased concentrations in the serum of rheumatoid arthritis patients, and even more so in their synovial fluid. It acts as a ligand that increases the production of inflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα), and osteoclast-activating factors, such as receptor activator of nuclear factor kappa-B ligand (RANKL). It is similar to CRP in that elevated or sustained high levels are associated with a worse long-term prognosis, particularly in older people.

“As older patients are particularly susceptible to joint damage in the presence of elevated 14-3-3η and CRP, this combination of unfavorable biomarkers might be used to identify those patients most likely to benefit from more targeted treatment strategies,” the authors wrote.

The authors suggest that a 14-3-3η protein positive test can assist primary care providers in whether to refer a patient to a rheumatologist.

The results as reported in Arthritis Research and Therapy:[[{"type":"media","view_mode":"media_crop","fid":"45609","attributes":{"alt":"@DeVisu/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_8065758910961","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5233","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"@DeVisu/Shutterstock.com","typeof":"foaf:Image"}}]]

• Baseline levels of 14-3-3η protein were ≥0.19 ng/ml (manufacturer recommended threshold) in 153 patients (46.2 %) and ≥0.50 ng/ml (the optimal prognostic threshold defined in our cohort) in 119 patients (36.0 %). (≥0.50 ng/ml appears superior in identifying patients most likely to progress rapidly).
• CRP was >8.0 mg/ml in 207 patients (62.5 %), and RF, anti-CCP2 and anti-Sa antibodies (Abs) were positive in 146 (44.1 %), 133 (40.2 %) and 73 (22.1 %) of patients, respectively.
• 170 patients (51.5 %) had at least one positive antibody.
• ROC curve analyses defined a decrease of <0.76 ng/ml as the best to predict definite radiographic progression (ΔSvH ≥5) over 5 years: 28.6 % vs 14.3 %, RR (95 % CI) = 2.00 (1.20–3.34), p = 0.01 (area under the curve (AUC) = 0.567, sensitivity = 0.844, specificity = 0.308).
• Of the 308 patients with complete radiographs, 84 (27.3 %) were 14-3-3η-positive (≥0.50) at both baseline and 18-month visits, and 23 patients (7.5 %), who were positive at baseline, reverted to negative and 11 patients (3.6 %), who were initially negative converted to positive at 18 months.

The study had a number of strengths such as the size and prospective nature of the study, but it also had a number of limitations:  only EPA patients were followed for five years, most patients were younger and more frequently positive for RF, but not anti-Sa/citrullinated vimentin positive, and high thresholds of measure were used. Most importantly, the authors wrote, positive 14-3-3η levels identified patients at higher risk of worse outcomes, but “it remains to be determined whether using the results of the assay to refine optimized treatment can prevent or delay the development of poor outcomes.”

The authors of the study suggest further study on the role that a 14-3-3η protein measures could have in diagnosing rheumatoid arthritis in early polyarthritis patients.

References:

Nathalie Carrier, Anthony Marotta, et. al.

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Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis," 

Arthritis Research & Therapy. 

DOI: 10.1186/s13075-016-0935-z Received: 29 October 2015Accepted: 18 January 2016Published: 1 February 2016