Research Finds MRP8/14 May Be a Biomarker of Systemic Juvenile Idiopathic Arthritis

Investigation into myeloid-related protein 8/14 (MRP8/14) serves as an important next step of translational research to discovering a diagnostic biomarker for systemic juvenile idiopathic arthritis.

An editorial published in Rheumatology described a study’s findings regarding myeloid-related protein 8/14 (MRP8/14) as an important and potentially conclusive next step of translational research to discovering a diagnostic biomarker for systemic juvenile idiopathic arthritis (sJIA).1

The editorial focused on a study that provided data that validated the usefulness of MRP8/14 measurements in the diagnostic workup to treat sJIA.2

SJIA is a rare childhood polygenic autoinflammatory disease that often presents with nonspecific signs and symptoms, such as fever, rash, arthralgia, and elevation of inflammatory markers. Differential diagnosis in children with these symptoms is challenging and must include bacterial or viral infections, malignancy, and other inflammatory diseases.

“MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children,” the study investigators concluded. “The results could be confirmed with commercial ELISA and LFIA [lateral flow immunoassay] enabling a rapid diagnostic point-of-care screening test.”

As explained in the editorial, overt arthritis can be absent at onset and potentially result in a diagnostic delay, further resulting in a delay of targeted treatment.

“It is therefore evident that biomarkers that allow for distinguishing sJIA from its differential diagnoses are highly warranted,” the editorial authors wrote. “Such a biomarker should be stable, easily measurable with high reproducibility and show high sensitivity and specificity, ideally with a clear association with disease pathogenesis.”

In one cohort of 940 pediatric patients, MRP8/14 was elevated in sJIA compared with other diagnoses, including infections and autoinflammatory diseases, regardless of fever and anti-inflammatory treatment. The other cohort of 195 participants showed even higher MRP8/14 levels in sJIA compared with other diagnoses.

MRP8 and MRP14 are both cytosolic proteins secreted from myeloid cells as proinflammatory mediators and are expressed in granulocytes, monocytes, and macrophages, with MRP8/14 secreted via the alternative pathway and binding to TLR4, a transmembrane protein. This elicits pro-inflammatory effects, with a positive feedback loop with interleukin (IL) 1b.

The editorial authors also wrote that future studies may lead to evaluating a combination of laboratory biomarkers in the diagnostic workup of patients with sJIA, crediting the study’s findings that combining MRP8/14 levels with levels of ferritin, IL-18, and/or erythrocyte sedimentation rate may lead to a sJIA diagnosis specificity greater than 90%.

“Serum IL-18 levels have previously been proposed as a diagnostic biomarker for sJIA, given its longer half-life and stable expression, supported by a clear link to the pathogenesis of sJIA and macrophage activation syndrome,” they wrote. “However, validation studies for IL-18 in differential diagnoses are still needed and therefore the discriminative value of IL-8 in sJIA diagnosis remains to be investigated.”

According to the authors of the editorial, translating laboratory research into clinically useful biomarkers is complex, requiring both patience and perseverance.

“Park and coworkers have provided solid data to start the final phase of this translation, giving evidence for the use of MRP8/14, measured by commercially available assays, as a diagnostic biomarker for sJIA and paving the way to optimal exploitation of the "window of opportunity" by starting early targeted treatment,” the editorial concluded.

References

1. Pardeo M, Vastert SJ, De Benedetti F. It is about time: the first validated biomarker for early diagnosis of sJIA. Rheumatology. Published online December 31, 2021. doi:10.1093/rheumatology/keab948

2. Park C, Miranda-Garcia M, Berendes R, et al. MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever. Rheumatology. Published online September 24, 2021. doi:10.1093/rheumatology/keab729