Calprotectin Discriminates Septic Arthritis From Pseudogout and Rheumatoid Arthritis

Athan Baillet; Candice Trocmé; Xavier Romand; Chuong M.V. Nguyen; Anais Courtier; Bertrand Toussaint; Philippe Gaudin; Olivier Epaulard


Rheumatology. 2019;58(9):1644-1648. 

In This Article

Abstract and Introduction


Objective: We aimed to determine whether calprotectin and α-defensins could discriminate septic from other inflammatory arthritides.

Methods: Synovial fluids with a predominance of neutrophils from patients with septic arthritis, pseudogout and RA were prospectively collected. Neutrophil-related proteins calprotectin and human neutrophil α-defensins levels were assessed in synovial fluids. Demographic parameters and biomarkers with P-value ≤0.05 for differentiating septic from non-septic arthritis were included in a multivariable model. Multivariable logistic regression with stepwise selection was performed to build the final combined model.

Results: A total of 74 patients were included: septic arthritis (n = 26), pseudogout (n = 28) and RA (n = 20). Patients with septic arthritis were more likely to be male and young, and to display higher synovial neutrophil count. Calprotectin was significantly increased in patients with septic arthritis. The multivariable model included calprotectin, synovial fluid neutrophil count and gender. Calprotectin was the only biomarker that discriminated septic arthritis from non-septic inflammatory arthritides, with 76% sensitivity, 94% specificity and a positive likelihood ratio = 12.2 at the threshold for calprotectin of 150 mg/l.

Conclusion: Synovial fluid calprotectin is a relevant biomarker to discriminate septic arthritis from other inflammatory arthritides. This biomarker should be tested in an independent cohort.


Acute bacterial septic arthritis is a severe disease with a lethality rate of 15%, and a high risk of persistent functional impairment.[1] The causative organisms are diverse, with Staphylococcus aureus infection being the most common.[2] The main differential criteria for the diagnosis septic arthritis are crystal-related arthritis and chronic inflammatory rheumatic diseases, which both display a predominance of neutrophils in the joint fluid. Early diagnosis is crucial, as early antibiotic therapy and debridement surgery are associated with better prognosis.[3] A significant increase in the incidence of septic arthritis has been reported.[2] A recent study evaluated that patient hospitalizations in the United States led to an increase in total hospital charges, reaching $759 million in 2012, despite the fact that average hospital stay and proportion discharged home remained stable over the past few years.

Clinical features and serum biomarkers such as CRP and procalcitonin levels display a limited diagnostic value.[4] Previous studies suggested that procalcitonin[5] and α-defensins (human neutrophil peptides 1–3, HNP1–3)[6] may help to diagnose prosthetic joint infections among patients who present with fever and pain in a prosthetic joint site. However, these surrogate markers offer a limited value to rule out septic arthritis in daily practice.[6] Hence early recognition of septic arthritis is often difficult when Gram-stained direct smear of joint fluid is negative.

Upon activation induced by bacterial contact, neutrophils release a huge amount of bactericidal proteins, which enhance neutrophil killing of bacteria.[7] Among these neutrophil-related bactericidal proteins, calprotectin (heterodimer S100A8/A9 proteins) and α-defensins, both of which are highly upregulated in RA,[8] could be used to discriminate infections from other joint disorders. While details of α-defensins bactericidal actions are still unclear, calprotectin chelates zinc and manganese[7] and thereby potentiates the bactericidal activity of reactive oxygen species by inhibiting the manganese-dependent superoxide dismutase activity.

Considering on one hand the burden of septic arthritis on medico-economic resources and on the other hand the limits of clinical features, such as currently available blood tests and imaging for the diagnosis of septic arthritis, we aimed to determine whether neutrophil-related calprotectin and α-defensins could discriminate septic from other inflammatory arthritides in daily practice.