C-Reactive%20Protein:%20New%20Applications

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

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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

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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

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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

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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?

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CRP vs ESR

• ESR
• Non-specific index of inflammation primarily
  reflecting the concentration of fibrinogen and
  immunoglobulins in plasma
• CRP
• Acute phase protein

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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
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CRP vs ESR
Paulus et al J Rheumatol 1999 26 p2324-31
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CRP vs ESR Septic arthritis
Data from Kallio et al Ped. Inf. Disease J.
1997 16 411-13
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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
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CRP vs ESR RA

• Results
• CRP and ESR correlated r 0.60
• Relation to other serum proteins

Protein Variation explained CRP Variation explained ESR
IgA 1.1 9.7
IgG 0.6 7.3
IgM 0.3 3.1
RF 1.2 7.7
F Wolfe J Rheumatol 1997 24 1477-85
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CRP vs ESR RA

• Results
• CRP and ESR correlated r 0.60
• Relation to clinical parameters

Parameter Variation explained CRP Variation explained ESR
Disease Activity 11.1 9.8
Grip strength 9.2 6.5
Joint Count 7.8 4.8
Depression 4.1 2.8
F Wolfe J Rheumatol 1997 24 1477-85
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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
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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

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CRP vs hs-CRP

• Standard CRP tests measure serum CRP
  concentrations reliably gt 10 µg/L
• Hs-CRP measure CRP reliably within the normal
  range

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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

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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

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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
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hsCRP Predictive role in RA?

• Results

Quintile Cases (n) Controls (n) Odds Ratio 95 CI
1 25 74 1.00
2 21 69 0.89 0.45-1.76
3 30 78 1.11 0.59-2.08
4 24 70 0.99 0.51-1.91
5 24 74 0.94 0.49-1.87
Aho et al J Rheumatol 2000 27 1136 - 8
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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
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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

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Intra-individual variation of CRP
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Intra-individual variation of hsCRP(Healthy
individuals followed for 6 months)
De Maat et al Arterioscler. Thromb. Vasc. Biol.
1996 16 1156-62
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Intra-individual variation of hsCRP(Stable
angina pectoris patients followed for 6 months)
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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

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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

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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

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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

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SAA in assessment of early inflammatory arthritis
G Cunnane et al J Rheumatol 2000 2758-63
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SAA in assessment of early inflammatory arthritis
Measure of disease activity Variation () in clinical expression explained by Variation () in clinical expression explained by Variation () in clinical expression explained by
Measure of disease activity SAA CRP ESR
Ritchie Index 21.1 10.9 4.0
Swollen joint count 17.6 11.6 4.0
G Cunnane et al J Rheumatol 2000 2758-63
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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 2758-63
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