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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


Comparison of autoantibodies against citrullinated antigens
Comparison of autoantibodies against citrullinated antigens vimentin (MCV)

Bang et al., Arthritis Rheum 2007


Anti mcv in early ra higher sensitivity and extended prognostic value

273 patients with early RA vimentin (MCV)

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.


Use of biomarkers in clinical diagnosis and prognosis of ra
Anti-MCV appears to perform better than prognostic value”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 anti-CCP assays

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 anti-CCP assays

RF

CCP/MCV

App. 70%

Erosive manifestation

Seropositive

App. 30%

Seronegative

Mild manifestation


Summary
Summary anti-CCP assays

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 assays

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