Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations.
OBJECTIVE
Phagocytes are extensively involved in the synovial inflammation associated with chronic arthritis. The aim of our study was to determine neutrophil activation in juvenile rheumatoid arthritis (JRA) by analyzing S100A12 (EN-RAGE; calgranulin C), a proinflammatory protein secreted by human neutrophils.


METHODS
S100A12 serum concentrations were determined in 124 patients with chronic active polyarticular-, oligoarticular-, or systemic-onset JRA. S100A12 was also analyzed in synovial fluid obtained from 22 patients. Changes in S100A12 levels in response to anti-tumor necrosis factor alpha (anti-TNF alpha) therapy, intraarticular injections of corticosteroids, and methotrexate (MTX) treatment were analyzed. Forty-five patients were followed up after successful antiinflammatory treatment, for a mean period of 2.8 years.


RESULTS
The mean serum level of S100A12 was 395 ng/ml in patients with active polyarticular JRA and 325 ng/ml in patients with active oligoarticular JRA (normal <120 ng/ml). The level of S100A12 was approximately 10-fold higher in synovial fluid than in serum, indicating release at sites of local inflammation. In patients with systemic-onset JRA, the mean level of S100A12 was 3,700 ng/ml. Moreover, serum levels decreased in response to different antiinflammatory therapies (i.e., intraarticular injections of corticosteroids, MTX, or etanercept). S100A12 levels were elevated in 20 patients who experienced disease flares after the initial induction of remission, even weeks before the relapses became clinically apparent.


CONCLUSIONS
S100A12 serum concentrations indicate neutrophil activation in JRA and correlate with disease activity. S100A12 may indicate synovial inflammation even when other signs of arthritis are absent. Its function as a proinflammatory factor secreted by activated neutrophils makes this protein a potential target for future therapies.
Foell
Dirk
D
Institute of Experimental Dermatology and Department of Pediatrics, University of Muenster, Muenster, Germany. dfoell@uni-muenster.de
Wittkowski
Helmut
H
Hammerschmidt
Inga
I
Wulffraat
Nico
N
Schmeling
Heinrike
H
Frosch
Michael
M
Horneff
Gerd
G
Kuis
Wietse
W
Sorg
Clemens
C
Roth
Johannes
J
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001171:Arthritis, Juvenile / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology*; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007223:Infant; D007270:Injections, Intra-Articular; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D018375:Neutrophil Activation / Q000276:immunology*; D011237:Predictive Value of Tests; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D012008:Recurrence; D012307:Risk Factors; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D015415:Biomarkers; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept; D008727:Methotrexate