Use of biomarkers in clinical diagnosis and prognosis of RA

1. Use of biomarkers in clinical diagnosis and prognosis of RA Dr Eugen Feist Department of Rheumatology and Clinical Immunology Charité – Universitätsmedizin, Berlin, Germany

2. Goal: Early diagnosis and stratification Clinical Examination Novel Markers Improved Imaging Ubiquitous ACPA Profiling Nienhuis et al., ARD 1964; Young et al., Br Med. J 1979; Schellekens et al., JCI 1998

3. Anti-CCP antibodies precede disease onset Half of patients were IgM-RF and/or anti-CCP+ 4.5 years (median) before the onset of disease (0.1–13.8 years) 50 IgM-RF Anti-CCP IgM-RF or anti-CCP 40 30 Sensitivity (percentage positivity) 20 10 0 Nielen et al. Arthritis Rheum 2004;50:380-86 Anti-CCP, anti-cyclic citrullinated peptide

4. Half of patients with undifferentiated arthritis develop confirmed RA at 1 year Avouac et al. Ann Rheum Dis 2006;65:845–851

5. Structural comparison of CCP and mutated citrullinated vimentin (MCV) CCP synthetic peptides of app. 20 AA (1 - 2 potential epitopes) Human Vimentin = recombinant protein of 54 kD and app. 45 arginins = modified by enzymatic deimination and mutation e.g.: STRSVSSSSYXXMFR TYSLGSALRPSTSXSLYASSPXR GPGTASRPSSSR X: Citrullination (Arg-->Citr) R: g/c-Transversion (Gly-->Arg) X: g/c-Transversion (Gly-->Arg) and citrullination (Arg-->Citr) G,T: New tryptic cleavage site caused by g/c-Transversion Bang et al., Arthritis Rheum 2007

6. Comparison of autoantibodies against citrullinated antigens Bang et al., Arthritis Rheum 2007

7. 273 patients with early RA Anti-MCV Sensitivity = 70.7% Specificity = 95% Anti-CCP Sensitivity = 57.9% Specificity = 96% Anti-MCV predictive for high disease activity “Anti-MCV in early RA: Higher sensitivity and extended prognostic value” anti-MCV+ anti-MCV- 10 7.5 ** SJC 5 *** ** *** **p< 0.01; *** p < 0.001 *** 2.5 0 0 3 months 1 year 2 years 3 years 5 years Mathsson et al., Arthritis Rheum 2008

8. “Anti-MCV in early RA: Higher sensitivity and extended prognostic value” anti-MCV+ anti-MCV- TJC DAS28 10 8 6 6 5 4 4 * ** * * 3 2 2 0 1 0 3 months 1 year 2 years 3 years 5 years 0 3 months 1 year 2 years 3 years 5 years *P < 0.05; **P < 0.01 Mathsson et al. Arthritis Rheum 2008;58(1):36–45.

9. Anti-MCV appears to perform better than anti-CCP in identifying poor radiological prognosis in early RA *Mann-Whitney U test Mathsson et al., Arthritis Rheum 2008

10. Decrease in anti-CCP titres reported to be associated with treatment efficacy Evolution of anti-CCP titres in adalimumab-treated patients NS NS P=0.001 ND Anti-CCP titre Atzeni, et al. Arthritis Res Ther. 2006;8(1):R3.

11. Analytic precision and diagnostic performance of different anti-CCP assays Bizzaro et al., Clin Chem 2007

12. Novel rapid point of care tests Comparison of CCPoint® and standard CCP2-ELISA in 109 RA, 351 non-RA, 420 HD CCPoint® test was fast, valid and reliable (sensitivity & specificity 95%) Comparison of RheumaChec® and standard MCV-ELISA in 80 RA, 83 non-RA and 200 HD Sensitivity of MCV+ patients in whole blood 70.2% (serum 94.7%) and specificity 98.9% Snijders GF et al., Scand J Rheumatol 2008

13. Autoantibodies as prognostic markers in RA RF CCP/MCV App. 70% Erosive manifestation Seropositive App. 30% Seronegative Mild manifestation

14. Summary Anti-CCP antibodies precede RA occurrence Citrullination modifies potential autoantigens and likely plays an important role in the pathogenesis of RA Detection of anti-CCP significantly improves the diagnosis of early RA Anti-CCP and anti-MCV immunoassays provide a comparable diagnostic sensitivity and specificity

15. What does this mean for Ed’s patient? Anti-CCP provides a high diagnostic probability in an RF-negative patient with undifferentiated arthritis