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Use of biomarkers in clinical diagnosis and prognosis of RA. Dr Eugen Feist Department of Rheumatology and Clinical Immunology Charité – Universitätsmedizin, Berlin, Germany. Goal: Early diagnosis and stratification . Clinical Examination. Novel Markers. Improved Imaging. Ubiquitous. ACPA.

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use of biomarkers in clinical diagnosis and prognosis of ra

Use of biomarkers in clinical diagnosis and prognosis of RA

Dr Eugen Feist

Department of Rheumatology and Clinical Immunology Charité – Universitätsmedizin, Berlin, Germany

goal early diagnosis and stratification
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

anti ccp antibodies precede disease onset
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

half of patients with undifferentiated arthritis develop confirmed ra at 1 year
Half of patients with undifferentiated arthritis develop confirmed RA at 1 year

Avouac et al. Ann Rheum Dis 2006;65:845–851

structural comparison of ccp and mutated citrullinated vimentin mcv
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

anti mcv in early ra higher sensitivity and extended prognostic value
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

anti mcv in early ra higher sensitivity and extended prognostic value1
“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.

slide9
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

decrease in anti ccp titres reported to be associated with treatment efficacy
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.

analytic precision and diagnostic performance of different anti ccp assays
Analytic precision and diagnostic performance of different anti-CCP assays

Bizzaro et al., Clin Chem 2007

novel rapid point of care tests
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

autoantibodies as prognostic markers in ra
Autoantibodies as prognostic markers in RA

RF

CCP/MCV

App. 70%

Erosive manifestation

Seropositive

App. 30%

Seronegative

Mild manifestation

summary
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

what does this mean for ed s patient
What does this mean for Ed’s patient?

Anti-CCP provides a high diagnostic probability in an RF-negative patient with undifferentiated arthritis

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