FAQ: How do calprotectin and CRP compare in rheumatology?

Written by Kristin Hart | Apr 29, 2026 8:00:17 AM

Calprotectin and CRP – Two inflammatory biomarkers

Calprotectin and C-reactive protein (CRP) are both widely used biomarkers of inflammation, yet they reflect different aspects of the inflammatory response. While CRP represents a downstream, liver-derived acute-phase reaction, calprotectin is directly released from activated immune cells at the site of inflammation.

Understanding how these two markers differ, and how they complement each other, is increasingly important for accurate disease assessment, particularly in conditions such as rheumatic diseases.

Circulating calprotectin

Calprotectin is a key alarmin directly released by myeloid cells during the inflammatory response. The protein is a heterodimer of S100A8/A9 and is constitutively expressed in large quantities in neutrophils (accounts up to 40-60% of cytosolic content). Elevated levels of extracellular calprotectin are present in diverse inflammatory disorders, making the protein a strong candite as reliable circulating biomarker for inflammation.^1,2

C‑reactive protein (CRP)

CRP is a classic acute‑phase marker, primarily synthesized by hepatocytes in the liver in response to pro-inflammatory cytokines, with IL‑6 being the main inducer of CRP gene expression and IL‑1 enhancing its effect. Transcriptional induction of the CRP gene leads to a rise of levels in circulation in response to injury, infection, and inflammation. Because of its pronounced and quantifiable increase, ease of measurement, CRP has become well established in clinical practice as a systemic biomarker across a wide range of infectious and inflammatory conditions.^3,4

Similar considerations apply to erythrocyte sedimentation rate (ESR), another traditional systemic marker reflecting hepatic acute-phase protein changes, though with slower kinetics and lower specificity.

Calprotectin – The better inflammatory marker in rheumatology?

CRP continues to anchor composite disease activity scores like DAS28, SDAI, and CDAI, yet it primarily captures systemic inflammation rather than localised joint damage. After decades of routine use, these conventional markers still have clear shortcomings. Key issues include clinical-serological discordance, where many patients show persistent joint inflammation despite normal CRP levels, and direct treatment interference, as biologics like IL-6 inhibitors suppress hepatic CRP synthesis and undermine its value as a true measure of disease activity.

Calprotectin’s key advantage over CRP lies in its direct release at the site of inflammation (from activated neutrophils), followed by diffusion into circulation due to its low molecular weight (~36.5 kDa). Unlike CRP, which depends on hepatic synthesis driven by cytokines like IL-6, calprotectin is cytokine-independent and thus unaffected by biologics (e.g., IL-6 or TNF inhibitors) that suppress CRP production. This makes it a more sensitive marker of local disease activity (including patients with low CRP levels^5-7), better reflecting joint-specific pathology while enabling reliable, therapy-independent monitoring.^8-11

CRP – Acute-phase marker	Calprotectin – Neutrophil activation marker
General systemic inflammation marker reflecting downstream hepatic response (to inflammatory cytokines like IL-6)	Direct marker of immune cell activity and local joint inflammation
May remain low despite active disease	Can detect low-level inflammation, even in remission
Suppressed by certain medications (e.g. IL-6 or TNF blockers)	Reflects inflammation independently of cytokine suppression

GCAL® - Plasma & serum calprotectin: Easy implementation in routine

The Gentian Calprotectin GCAL® assay is designed for the quantitative determination of calprotectin in plasma and serum, intended as an aid in detection and assessment of inflammation and inflammatory response to infections. As the first turbidimetric assay available since 2019, GCAL^® offers distinct advantages:

Advanced technology: PETIA assay on clinical chemistry platforms using avian antibodies, which minimises interference from rheumatoid factor and HAMA antibodies
Versatility: Compatible with a wide range of automated clinical chemistry analysers
Regulatory compliance: CE-marked in compliance with IVDR 2017/746 (CE 0123) and registered in multiple regions*
Ready-to-use format: Complete kit components - including calibrators and dedicated controls - are available in two sizes to meet the needs of both small and high-volume laboratories

Let’s talk about GCAL®

Interested in how GCAL® calprotectin can support your clinical, research, or laboratory needs? Get in touch with our team to explore applications, discuss implementation, or request more information. Send us an email marketing@gentian.com or fill out the form below.

References:

Wang Q. et al. S100A8/A9: An emerging player in sepsis and sepsis-induced organ injury. Biomed Pharmacother, 2023
Pruenster M. et al. S100A8/A9: From basic science to clinical application. Pharmacol Ther, 2016
Sproston NR. and JJ. Ashworth. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol, 2018
Zhou H-H. et al. C-reactive protein: structure, function, regulation, and role in clinical diseases. Frontiers in Immunology, 2024
Hurnakova J. et al. Serum calprotectin may reflect inflammatory activity in patients with active rheumatoid arthritis despite normal to low C-reactive protein. Clin Rheumatol, 2018
Torgutalp M. et al. Serum Calprotectin is Indicating Clinical and Ultrasonographic Disease Activity in Rheumatoid Arthritis, even with Normal C-Reactive Protein Levels. Mediterr J Rheumatol, 2021
Wang Y. and Y. Liang. Clinical significance of serum calprotectin level for the disease activity in active rheumatoid arthritis with normal C-reactive protein. Int J Clin Exp Pathol, 2019
Frade-Sosa B. et al. Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors. Ther Adv Musculoskelet Dis, 2022
Gernert M. et al. Calprotectin (S100A8/S100A9) detects inflammatory activity in rheumatoid arthritis patients receiving tocilizumab therapy. Arthritis Res Ther, 2022
Inciarte-Mundo J. et al. Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants. Rheumatology (Oxford), 2015
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
Jarlborg M. et al. Serum calprotectin: a promising biomarker in rheumatoid arthritis and axial spondyloarthritis. Arthritis research & therapy, 2020
Hurnakova J. et al. Relationship between serum calprotectin (S100A8/9) and clinical, laboratory and ultrasound parameters of disease activity in rheumatoid arthritis: A large cohort study. PloS one, 2017
Inciarte-Mundo, JB. Frade-Sosa and R. Sanmartí. From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis. Front Immunol, 2022
Hurnakova J. et al. Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis. Arthritis research & therapy, 2015

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