The association between systemic inflammation as measured by calprotectin and autoantibody load in rheumatoid arthritis

BACKGROUND: Plasma calprotectin is a marker of neutrophil activity. Its relation to the clinical phenotype and autoantibodies in rheumatoid arthritis (RA) is only partly understood. We therefore aimed to investigate the association between calprotectin and clinical parameters, CRP, ESR, anti-CCP2 and other anti-modified protein autoantibodies (AMPAs) in patients with RA. METHODS: Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (CCP2) isotypes and plasma calprotectin were centrally measured in a cross-sectional cohort of 4521 Scandinavian RA patients using fluoroenzyme immunoassays. IgG to 15 citrullinated (Cit) and four carbamylated or acetylated (Carb/Acet) peptides were measured by multiplex solid-phase array. CRP and ESR values were obtained from clinical measurements at the time of blood sampling. RESULTS: Calprotectin levels correlated with ESR (ρ=0.53), CRP (ρ=0.47), VAS pain (ρ=0.24), SJC28 (ρ=0.39), and TJC28 (ρ=0.26; p<0.0001 for all). Patients with both elevated CRP (>10mg/L) and calprotectin (>15 AU/ml) (14%, N=613) had significantly higher VAS pain, SJC28, and TJC28 than patients with only elevated CRP (p<0.0001), in early and established disease. Patients with elevated calprotectin, independent of CRP levels, had significantly higher proportions of AMPA positivity including anti-CCP2. When patients were divided into six groups based on increasing number of Cit/Carb/Acet-reactivities and anti-CCP2 IgG levels, elevated calprotectin was associated with increasing AMPA load, particularly in the presence of RF IgM. The differences between AMPA load groups remained after adjusting for sex, age, RF IgM, and disease duration. CONCLUSIONS: Plasma calprotectin is positively associated with seropositivity and AMPA load by autoantibody levels and the breadth of the autoantibody response.

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Journal
Arthritis & Rheumatology
Published
2026-10-03
DOI
https://doi.org/10.1002/art.70357
Primary Topic
S100 Proteins and Annexins
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article
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article

The association between systemic inflammation as measured by calprotectin and autoantibody load in rheumatoid arthritis

Espen Andre Haavardsholm, Søren Jacobsen, Isabel Gehring, Martina Johannesson et al.
Arthritis & Rheumatology
S100 Proteins and Annexins
article

The association between systemic inflammation as measured by calprotectin and autoantibody load in rheumatoid arthritis

Espen Andre Haavardsholm, Søren Jacobsen, Isabel Gehring, Martina Johannesson, Niels Steen Krogh, S Rantapää Dahlqvist, Salome Kristensen, Hilde Berner Hammer, Johan Askling, Anne Gitte Loft, Torkell Ellingsen, Tore Kristian Kvien, Alf Kastbom, Asta Linauskas, Nasim Ghasemzadeh, Oliver Hendricks, Siri Lillegraven, Carl Turesson, Merete Lund Hetland, Lena I Björkman, Caroline Grönwall, Heidi Lausten Munk, Tue Wenzel Kragstrup, Dorte Vendelbo Jensen, Linda Mathsson Alm, Bente Glintborg, Helga Westerlind, Johan Rönnelid, Eva Baecklund, Jens Kristian Pedersen, Lene Dreyer, Swedish Rheumatology Quality Register Biobank Study Group(SRQb) The Danish Rheumatologic Biobank Study Group, Ellen‐Margrethe Hauge, Estrid Høgdall
article en

Abstract

BACKGROUND: Plasma calprotectin is a marker of neutrophil activity. Its relation to the clinical phenotype and autoantibodies in rheumatoid arthritis (RA) is only partly understood. We therefore aimed to investigate the association between calprotectin and clinical parameters, CRP, ESR, anti-CCP2 and other anti-modified protein autoantibodies (AMPAs) in patients with RA. METHODS: Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (CCP2) isotypes and plasma calprotectin were centrally measured in a cross-sectional cohort of 4521 Scandinavian RA patients using fluoroenzyme immunoassays. IgG to 15 citrullinated (Cit) and four carbamylated or acetylated (Carb/Acet) peptides were measured by multiplex solid-phase array. CRP and ESR values were obtained from clinical measurements at the time of blood sampling. RESULTS: Calprotectin levels correlated with ESR (ρ=0.53), CRP (ρ=0.47), VAS pain (ρ=0.24), SJC28 (ρ=0.39), and TJC28 (ρ=0.26; p<0.0001 for all). Patients with both elevated CRP (>10mg/L) and calprotectin (>15 AU/ml) (14%, N=613) had significantly higher VAS pain, SJC28, and TJC28 than patients with only elevated CRP (p<0.0001), in early and established disease. Patients with elevated calprotectin, independent of CRP levels, had significantly higher proportions of AMPA positivity including anti-CCP2. When patients were divided into six groups based on increasing number of Cit/Carb/Acet-reactivities and anti-CCP2 IgG levels, elevated calprotectin was associated with increasing AMPA load, particularly in the presence of RF IgM. The differences between AMPA load groups remained after adjusting for sex, age, RF IgM, and disease duration. CONCLUSIONS: Plasma calprotectin is positively associated with seropositivity and AMPA load by autoantibody levels and the breadth of the autoantibody response.

Arthritis & Rheumatology
Uppsala University (SE), University of Copenhagen (DK), Karolinska University Hospital (SE), University of Oslo (NO), Aarhus University (DK), Glostrup Hospital (DK), Aarhus University Hospital (DK), Rigshospitalet (DK), Karolinska Institutet (SE), Thermo Fisher Scientific (Sweden) (SE), Regionshospitalet Silkeborg (DK), Diakonhjemmet Hospital (NO), Thermo Fisher Scientific (Germany) (DE)
Openalex Percentile: Top 19%
S100 Proteins and Annexins
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