Circulating calprotectin in JIA & Still’s disease

Juvenile idiopathic arthritis (JIA) is the most common occurring paediatric chronic rheumatic disease, defined as arthritis of unknown origin that starts before the age of 16.¹ Systemic juvenile idiopathic arthritis (sJIA) on the other hand is the paediatric form of Still’s disease, a systemic autoinflammatory disease characterised by prominent symptoms of systemic inflammation such as spiking fever. Adult form of Still’s is called adult-onset Still’s disease (AOSD).^1-3 The neutrophilic protein calprotectin has been described as valuable biomarker in several rheumatic conditions, including rheumatoid arthritis (RA)^4-7 and JIA,^8,9 where the highest levels have been reported in sJIA,⁸ as well as AOSD.¹⁰

Calprotectin in treatment monitoring of Rheumatic patients

Calprotectin serum and plasma levels are strongly correlated with the degree of inflammation,^8,9,11 hence it can provide important assessment of disease activity, treatment response and relapse. Rheumatic patients are often treated with a wide range of medications, some of which indirectly lower downstream levels of C-reactive protein (CRP). Calprotectin can therefore be a useful biomarker when CRP is normal or difficult to interpret, reported in RA patients treated with therapies that suppress interleukin-6 (IL-6) or tumour necrosis factor (TNF),^12-15 as well as methotrexate (MTX).¹⁶

Calprotectin as guide for treatment decisions in JIA

In patient management of JIA, circulating calprotectin has proven great value in assessment and prediction of treatment response, remission and flares.

High calprotectin concentrations at baseline has been shown as good predictor of positive response to several treatment forms (biological DMARDs (Disease-modifying antirheumatic drugs), MTX, anti-TNF),^11,17-19 and notably the patient groups do not differ in regards to any other clinical or laboratory parameters.^11,17 After the discontinuation of treatment and in stable clinically inactive remission, low levels of calprotectin were associated with decreased risk of subsequent flares.^18,20,21

In a long-term follow up study of MTX treated JIA patients in a routine clinical setting, clinicians reported that calprotectin was ordered for assessment and guidance of medication. Low calprotectin levels were interpreted favourably for stopping, notably no patients with a low calprotectin result flared within 12 months. In clinical routine, high calprotectin levels can therefore guide decision towards the continuation of treatment even in clinical inactive disease.²²

Calprotectin in diagnosis and patient monitoring of Still’s disease (sJIA and AOSD)

The innate immune system plays a pivotal role in Still’s pathogenesis and immunocytes are heavily activated, including neutrophils. As neutrophil activation marker, plasma and serum calprotectin has been implicated in diagnosis, prediction of relapse, and evaluation of disease activity in both paediatric and adult Still's disease.^1-3

Diagnosis of sJIA and AOSD is heavily depended on exclusion due to the non-specificity of clinical presentation. Differentiating from other inflammatory conditions, infections and fever of unknown origin (FUO) is particularly challenging, where calprotectin can allow the crucial early differentiation. Circulating calprotectin has been shown to differentiate sJIA of FUO more effectively than CRP,^23-25 as well as distinguishing both sJIA and AOSD from other rheumatic diseases.^8,10,26-28

In patient monitoring, calprotectin has been described as a predictive biomarker for relapse in sJIA, surpassing the performance of erythrocytes sedimentation rate (ESR) and CRP.²⁹ Furthermore, it correlates with treatment response in both sJIA^23,29 and AOSD,²⁶ providing clinicians with the ability to track the progression of the disease.

GCAL® - Gentian's plasma and serum calprotectin assay

Gentian’s calprotectin immunoassay GCAL^® is the first turbidimetric assay for the quantitative measurement of calprotectin in plasma and serum intended as an aid in the detection and assessment of inflammation and inflammatory response to infection.

GCAL® on clinical chemistry systems – TAT 10 min

The assay can be applied on a wide range of automated clinical chemistry analysers. GCAL^® is CE-marked and IVDR certified. It is not cleared for use in the USA (Research Use Only).

• Developed and manufactured by Gentian Diagnostics
• Manufactured according to ISO 13485:2016

Get in touch

For more details on GCAL^® products and prices please contact us at marketing@gentian.com 

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References:

1. Swart JF et al. Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype. Eur J Immunol, 2016
2. Jung JY et al. Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease. Front Immunol, 2020
3. Rao S et al. Adult-onset Still's disease: A disease at the crossroad of innate immunity and autoimmunity. Front Med (Lausanne), 2022
4. Ometto F et al. Calprotectin in rheumatic diseases. Exp Biol Med (Maywood), 2017
5. Pruenster M et al. S100A8/A9: From basic science to clinical application. Pharmacol Ther, 2016
6. Romand X et al. Systemic calprotectin and chronic inflammatory rheumatic diseases. Joint Bone Spine, 2019
7. Wang Q et al. The Role of Calprotectin in Rheumatoid Arthritis. J Transl Int Med, 2019
8. Altobelli E et al. Serum Calprotectin a Potential Biomarker in Juvenile Idiopathic Arthritis: A Meta-Analysis. J Clin Med, 2021
9. Keskitalo PL et al. Myeloid-related protein 8/14 in plasma and serum in patients with new-onset juvenile idiopathic arthritis in real-world setting in a single center. Pediatr Rheumatol Online J, 2022
10. Guo Q et al. Serum calprotectin--a promising diagnostic marker for adult-onset Still's disease. Clin Rheumatol, 2016
11. La C et al. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis. RMD Open, 2021
12. Andrés Cerezo, L et al. Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis research & therapy, 2011
13. Inciarte-Mundo J et al. Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity. Arthritis Res Ther, 2016
14. Hammer HB et al. The soluble biomarker calprotectin (an S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab. Arthritis Res Ther, 2011
15. Jarlborg M et al. Serum calprotectin: a promising biomarker in rheumatoid arthritis and axial spondyloarthritis. Arthritis research & therapy, 2020
16. Nielsen UB et al. Calprotectin in patients with chronic rheumatoid arthritis correlates with disease activity and responsiveness to methotrexate. Scand J Clin Lab Invest, 2018
17. Moncrieffe H et al. A subgroup of juvenile idiopathic arthritis patients who respond well to methotrexate are identified by the serum biomarker MRP8/14 protein. Rheumatology (Oxford), 2013
18. Anink J et al. MRP8/14 serum levels as a predictor of response to starting and stopping anti-TNF treatment in juvenile idiopathic arthritis. Arthritis Res Ther, 2015
19. Alberdi-Saugstrup M et al. Low pretreatment levels of myeloid-related protein-8/14 and C-reactive protein predict poor adherence to treatment with tumor necrosis factor inhibitors in juvenile idiopathic arthritis. Clin Rheumatol, 2017
20. Schulze zur Wiesch A et al. Myeloid related proteins MRP8/MRP14 may predict disease flares in juvenile idiopathic arthritis. Clin Exp Rheumatol, 2004
21. Foell D et al. Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop? Ann Rheum Dis, 2004
22. Sumner EJ et al. Use of MRP8/14 in clinical practice as a predictor of outcome after methotrexate withdrawal in patients with juvenile idiopathic arthritis. Clin Rheumatol, 2022
23. Frosch M et al. The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum, 2009
24. Shenoi S et al. Comparison of biomarkers for systemic juvenile idiopathic arthritis. Pediatr Res, 2015
25. Park C et al. MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever. Rheumatology (Oxford), 2021
26. Kim HA et al. Serum S100A8/A9, but not follistatin-like protein 1 and interleukin 18, may be a useful biomarker of disease activity in adult-onset Still's disease. J Rheumatol, 2012
27. Bojko J. Measurement of blood calprotectin (MRP-8/MRP-14) levels in patients with juvenile idiopathic arthritis. Reumatologia, 2017
28. Aljaberi N et al. The use of S100 proteins testing in juvenile idiopathic arthritis and autoinflammatory diseases in a pediatric clinical setting: a retrospective analysis. Pediatr Rheumatol Online J, 2020
29. Holzinger D et al. The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis. Ann Rheum Dis, 2012

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