Circulating levels of frizzled-related protein (FRZB) are increased in patients with early rheumatoid arthritis and decrease in response to disease-modifying antirheumatic drugs.

Products of the secreted Frizzled-related protein families have crucial roles in the development and maintenance of bone, cartilage and joints, mainly by inhibiting the wnt and/beta-catenin pathway. In particular, while several important studies have associated FRZB, also known as sFRP3, with an increased susceptibility to the development of osteoartritis (OA), no information are available on the potential role of circulating FRZB in early rheumatoid arthritis (ERA). Therefore, we have measured the serum levels of FRZB by ELISA (R&D Systems, Minneapolis, MN) in a cohort of patients presenting with early rheumatoid arthritis (ERA), defined as previously described. In addition, serological signs of inflammation [elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)] or rheumatoid factor (RF) positivity and anti-citrullinated protein antibodies (a-CCP) and a symptom duration of no longer than 12 weeks were inclusion criteria. Clinical assessment of the patients included the calculation of a disease activity score in 28 joints (DAS 28) and the health assessment questionnaire (HAQ). Serum sample were available for each patient at baseline and after 1 year treatment with disease-modifying antirheumatic drugs (DMARD). At baseline, before starting DMARD therapy, this patient group was characterized by 71.4% positivity of CRP, DAS28 score of 3.97±1.04 (mean±SD), HAQ score of 1.33±0.75 (mean±SD), swollen and tender joint count of 11.7±6.3 and 11.2±8.7 (mean±SD), respectively. The levels of serum FRZB in ERA patients at baseline (n=42, median of 3890 pg/ml; mean+SD 5956+7823 pg/ml) were higher (p<0.01, Student’s t test for unpaired data) than those measured in sex- and age-matched normal controls (n=21, median of 1817; mean+SD: 3288+3645), returning to levels comparable to normal controls after 1 year of DMARD therapy (median of 1894; mean+SD: 3191+3252; In addition, baseline FRZB levels were significantly (p<0.05, Student’s t test for unpaired data) higher in patients positive (n=16, median of 5084; mean+SD: 9940+11214) than in patients negative (n=26, median of 2830; mean+SD: 3505+2920) for rheumatoid factor (Figure 1B). Interestingly, when ERA patients were subdivided into responder (n=30, median of 1568; mean+SD: 2796+3231) and non-responder (n=12, median of 2926; mean+SD: 4531+3015) on the basis of differences in the DAS28 score (decrease in DAS28>1.2) after 1 year of therapy ERA patients showing a good response to therapy displayed significantly (p<0.05, Student’s t test for unpaired data) lower levels of serum FRZB compared to patients whose delta DAS28 showed minimal (<1.2) or absent variation after therapy (Figure 1C). Currently, it is still difficult to predict who among the patients with ERA will have progression of their disease and optimal management of RA is needed within 3-6 months after the onset of disease. The major findings of this study are that ERA patients show high serum levels of FRZB at baseline, which return to normal levels after 1 year of DMARD therapy. The potential pathogenetic role of FRZB is underscored by the fact that the levels of circulating FRZB after one year of therapy were significantly (p<0.01) more elevated in patients with a poor response to DMARD.