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C-Reactive Protein: New Applications Dr Job Ubbink, D.Sc (Pret), MRCPath (Lond) Consultant: Chemical Pathology

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C-Reactive Protein: New Applications Dr Job Ubbink, D.Sc (Pret), MRCPath (Lond) Consultant: Chemical Pathology. Presentation Outline. Physiological function of CRP CRP and ESR: Applications in Rheumatoid Arthritis High sensitivity CRP measurements in chronic disease risk assessment

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slide1

C-Reactive Protein: New Applications

Dr Job Ubbink, D.Sc (Pret), MRCPath (Lond)

Consultant: Chemical Pathology

presentation outline
Presentation Outline
  • Physiological function of CRP
  • CRP and ESR: Applications in Rheumatoid Arthritis
  • High sensitivity CRP measurements in chronic disease risk assessment
    • Coronary heart disease
    • Rheumatoid Arthritis
  • Serum Amyloid A: New inflammatory marker
crp physiological function
CRP: Physiological Function
  • Structure
  • Binds to repeating bacterial polysaccharides and activates classical complement pathway.
  • C4 and C3 fragments deposit on bacteria
  • Adherence and phagocytosis by leucocytes
presentation outline8
Presentation Outline
  • Physiological function of CRP
  • CRP and ESR: Applications in Rheumatoid Arthritis
  • High sensitivity CRP measurements in chronic disease risk assessment
    • Coronary heart disease
    • Rheumathoid Arthritis
  • Serum Amyloid A: New inflammatory marker
crp and rheumatoid arthritis
CRP and Rheumatoid Arthritis
  • CRP used to:
    • Establish if inflammation is present
    • Monitor course of disease in patients with a known disease process
  • New suggested applications:
    • Determine risk of future disease
crp a fundamental role in ra
CRP: A fundamental role in RA?
  • Complement activation
  • CRP binds also to:
    • Phosphatidylcholine
    • Chromatin
    • Small nuclear RNP particles
  • Scavenger function: cutaneous lesions
  • Detrimental in ischaemia or autoimmunity?
crp vs esr
CRP vs ESR
  • ESR
    • Non-specific index of inflammation primarily reflecting the concentration of fibrinogen and immunoglobulins in plasma
  • CRP
    • Acute phase protein
crp vs esr12
CRP vs ESR
  • ESR used in
    • Disease Activity Score (DAS) (DAS = 0.54 (RI)½ + 0.065(swollen joint count) + 0.33 (lognESR) + 0.024)
    • American College of Rheumatology 20% improvement score
  • CRP considered equally acceptable by ACR
  • Nomogram relating CRP to ESR

Paulus et al: J Rheumatol; 1999: 26: p2324-31

crp vs esr13
CRP vs ESR

Paulus et al: J Rheumatol; 1999: 26: p2324-31

crp vs esr septic arthritis
CRP vs ESR: Septic arthritis

Data from: Kallio et al: Ped. Inf. Disease J. 1997; 16: 411-13

crp vs esr ra
CRP vs ESR: RA

Study Outline

  • Arthritis Centre: Kansas – Retrospective study
  • Demographic, clinical ESR, CRP, other protein measurements on 774 patients with RA.
  • Stepwise multiple regression to determine relationships between variables

F Wolfe: J Rheumatol 1997; 24: 1477-85

crp vs esr ra16
CRP vs ESR: RA
  • Results
    • CRP and ESR correlated: r = 0.60
    • Relation to other serum proteins:

F Wolfe: J Rheumatol 1997; 24: 1477-85

crp vs esr ra17
CRP vs ESR: RA
  • Results
    • CRP and ESR correlated: r = 0.60
    • Relation to clinical parameters:

F Wolfe: J Rheumatol 1997; 24: 1477-85

crp vs esr ra18
CRP vs ESR: RA
  • Conclusion
    • Acute phase is better monitored by CRP
    • ESR measures acute phase less well, but also measures elements of chronicity and severity that is not measured by CRP.

F Wolfe: J Rheumatol 1997; 24: 1477-85

presentation outline19
Presentation Outline
  • Physiological function of CRP
  • CRP and ESR: Applications in Rheumatoid Arthritis
  • High sensitivity CRP measurements in chronic disease risk assessment
    • Coronary heart disease
    • Rheumathoid Arthritis
  • Serum Amyloid A: New inflammatory marker
crp vs hs crp
CRP vs hs-CRP
  • Standard CRP tests measure serum CRP concentrations reliably > 10 μg/L
  • Hs-CRP measure CRP reliably within the normal range
presentation outline33
Presentation Outline
  • Physiological function of CRP
  • CRP and ESR: Applications in Rheumatoid Arthritis
  • High sensitivity CRP measurements in chronic disease risk assessment
    • Coronary heart disease
    • Rheumatoid Arthritis
  • Serum Amyloid A: New inflammatory marker
hscrp predictive role in ra
hsCRP: Predictive role in RA?

Background

  • Clinical rheumatoid arthritis is preceded by an immunological process
  • Rheumatoid factor and other marker antibodies of RA appear in serum before clinical symptoms develop
  • Serum CRP: possible inflammatory component in the pre-rheumatoid process?
  • Investigated by: Aho et al, J Rheumatol 2000; 27: 1136-1138
hscrp predictive role in ra35
hsCRP: Predictive role in RA?

Study Outline

  • Case control study nested within a Finnish cohort of 19 072 adults
  • Baseline examination: 1973 – 1977
  • Serum stored at -20○C
  • By 1989, 124 individuals had developed RA
  • Three controls, matched for age, sex and municipality, were selected for each case
  • CRP measured by sensitive immunoassay

Aho et al: J Rheumatol 2000; 27: 1136 - 8

hscrp predictive role in ra36
hsCRP: Predictive role in RA?

Results

Aho et al: J Rheumatol 2000; 27: 1136 - 8

hscrp predictive role in ra37
hsCRP: Predictive role in RA?

Comments

  • Mean time period between sampling and clinical expression of disease: 5y.
  • Putative asymptomatic synovitis preceding clinical disease too mild to be reflected in CRP? (authors)
  • Short duration of pre-clinical phase? (authors)
  • Sample storage conditions inappropriate? (Ubbink)
  • Type 2 statistical error due to inadequate sample sizes? (Ubbink)

Aho et al: J Rheumatol 2000; 27: 1136 - 8

hs crp clinical utility
Hs CRP: Clinical Utility

‘A single plasma CRP estimation in an individual subject has a high risk of misclassification and cannot accurately determine whether they are at future risk of atherosclerotic events”

Campbell et al: Ann Clin Biochem 2002; 39: 85 -88

intra individual variation of hscrp healthy individuals followed for 6 months
Intra-individual variation of hsCRP(Healthy individuals followed for 6 months)

De Maat et al: Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1156-62

hs crp clinical utility42
Hs CRP: Clinical Utility

‘In order to reduce the intra-individual variation sufficiently, each subject is likely to require blood samples collected on at least 10 occasions”

Campbell et al: Ann Clin Biochem 2002; 39: 85 -88

hs crp clinical utility43
Hs CRP: Clinical Utility

‘The task for researchers will be to find another marker for the same, presumably inflammatory, processes that are causing plasma CRP to be elevated. This marker must be capable of being measured with adequate analytical precision and should not have the large intra-individual variation as shown by plasma CRP.”

Campbell et al: Ann Clin Biochem 2002; 39: 85 -88

presentation outline44
Presentation Outline
  • Physiological function of CRP
  • CRP and ESR: Applications in Rheumatoid Arthritis
  • High sensitivity CRP measurements in chronic disease risk assessment
    • Coronary heart disease
    • Rheumatoid Arthritis
  • Serum Amyloid A: New inflammatory marker
serum amyloid a inflammatory marker to replace crp
Serum Amyloid A: Inflammatory marker to replace CRP?
  • 2 acute phase SAA genes in humans (SAA1, SAA2)
  • SAA normally carried as part of HDL-3
  • Circulating precursor of amyloid deposits in secondary amyloidosis
  • Studies suggest that SAA is a more sensitive marker of disease activity
saa in assessment of early inflammatory arthritis
SAA in assessment of early inflammatory arthritis

G Cunnane et al: J Rheumatol 2000; 27:58-63

saa in assessment of early inflammatory arthritis47
SAA in assessment of early inflammatory arthritis

G Cunnane et al: J Rheumatol 2000; 27:58-63

saa in assessment of early inflammatory arthritis48
SAA in assessment of early inflammatory arthritis

“Although SAA is a nonspecific marker of inflammation and must be interpreted in the context of the full clinical picture, our observations suggest that an early diagnosis of RA may be made in patients presenting with synovitis and very high SAA levels”

G Cunnane et al: J Rheumatol 2000; 27:58-63

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