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Circulating levels of frizzled-related protein (FRZB) are increased in patients with early rheumatoid arthritis and decrease in response to disease-modifying antirheumatic drugs
  1. Federica Corallini1,
  2. Paola Secchiero1,
  3. Gabriella Castellino2,
  4. Maurizio Montecucco3,
  5. Francesco Trotta2,
  6. Giorgio Zauli1,4
  1. 1Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy
  2. 2Rheumatology Section, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy
  3. 3Department of Rheumatology, IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
  4. 4IRCCS, Burlo Garofolo Hospital, Trieste, Italy
  1. Correspondence to Professor Giorgio Zauli, Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy; giorgio.zauli{at}

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Products of the secreted frizzled-related protein (FRZB) families have crucial roles in the development and maintenance of bone, cartilage and joints, mainly by inhibiting the wnt and/β catenin pathway.1 In particular, while several important studies have associated FRZB (also known as sFRP3) with an increased susceptibility to the development of osteoarthritis,2,,4 no information is available on the potential role of circulating FRZB in early rheumatoid arthritis (ERA).

We have measured the serum levels of FRZB by ELISA (R&D Systems, Minneapolis, Minnesota, USA) in a cohort of patients presenting with ERA, defined as previously described.5 Serological signs of inflammation (raised erythrocyte sedimentation rate or C reactive protein) or rheumatoid factor (RF) positivity and anti-citrullinated protein antibodies and a symptom duration of no more than 12 weeks were inclusion criteria. Clinical assessment of the patients included calculation of the disease activity score in 28 joints (DAS28) and the Health Assessment Questionnaire (HAQ). Serum samples were available for each patient at baseline and after 1 year of treatment with disease-modifying antirheumatic drugs (DMARDs). At baseline, before starting DMARD therapy, the patient group was characterised by 71.4% positivity of C reactive protein, mean±SD DAS28 score of 3.97±1.04, HAQ score of 1.33±0.75 and swollen and tender joint counts of 11.7±6.3 and 11.2±8.7, respectively. The serum levels of FRZB in patients with ERA at baseline (n=42, median 3890 pg/ml; mean±SD 5956±7823 pg/ml) were higher (p<0.05, Student t test for unpaired data) than those measured in sex- and age-matched normal controls (n=21, median 1817 pg/ml; mean±SD 3288±3645 pg/ml), returning to levels comparable to normal controls after 1 year of treatment with DMARDs (median 1894 pg/ml; mean±SD 3191±3252 pg/ml; figure 1A). In addition, baseline FRZB levels were significantly higher (p<0.01, Student t test for unpaired data) in patients positive for RF (n=16, median 5084 pg/ml; mean±SD 9940±11214 pg/ml) than in those negative for RF (n=26, median 2830 pg/ml; mean±SD 3505±2920 pg/ml; figure 1B). Interestingly, when the patients with ERA were subdivided into responders (n=30, median 1568 pg/ml; mean±SD 2796±3231 pg/ml) and non-responders (n=12, median 2926 pg/ml; mean±SD 4531±3015 pg/ml) on the basis of differences in the DAS28 score (decrease in DAS28 >1.2) after 1 year of treatment, patients showing a good response to treatment had significantly (p<0.05, Student t test for unpaired data) lower serum levels of FRZB than patients with a minimal change (<1.2) or no change in DAS28 after treatment (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.

Figure 1

Analysis of the circulating levels of frizzled-related protein (FRZB, also known as sFRP3) in patients with early rheumatoid arthritis (ERA) and healthy control subjects. Serum levels of FRZB were determined by ELISA in 42 patients with ERA and 21 healthy controls. (A) Serum samples were collected from patients with ERA at baseline (before starting treatment) and after 1 year of treatment with disease-modifying antirheumatic drugs (DMARDs). (B) Circulating levels of FRZB at baseline were analysed in patients with ERA in relationship to their positivity or negativity for rheumatoid factor (RF). (C) The circulating levels of FRZB determined in patients with ERA after 1 year of DMARD treatment were analysed by subdividing the patients into responders and non-responders on the basis of a change in DAS28 score of <1.2 and >1.2. Horizontal bars are medians, upper and lower edges of the boxes are 75th and 25th percentiles and lines extending from the boxes are 10th and 90th percentiles.

The major findings of this study are that patients with ERA have high serum levels of FRZB at baseline, which return to normal levels after 1 year of treatment with DMARDs. The potential pathogenetic role of FRZB is underscored by the fact that the levels of circulating FRZB after 1 year of treatment were significantly (p<0.05) higher in patients with a poor response to DMARDs.



  • Ethics approval This study was conducted with the approval of the ethics commitee of the Universities of Pavia and Ferrara and written consent for all procedures was obtained from all subjects in accordance with the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Competing interests None.