CRP an acute phase protein is synthesized by hepatocytes in response to proinflammatory cytokines in

particular IL-6. It has been shown to be of great value as an inflammatory marker in RA and has been
suggested to mediate part of the complement activation in RA [8].
8. Molenaar TH,. Voskuyl AE, FamilianA, Mierlo GJ, Dijkmans BA, and Hack CE. Complement
Activation in Patients with Rheumatoid Arthritis Mediated in Part by C - reactive protein. Arthritis &
Rheumatism, 2001; 44(5): 997-1002
C-reactive protein and ESR are nonspecific tests for acute phase inflammation and are widely used for
monitoring disease activity in rheumatoid arthritis (RA).4
4. Matsui T, Kuga Y, Kaneko A, et al. Disease Activity Score 28(DAS28) using C-reactive protein
underestimates disease activity and overestimates EULAR response criteria compared with DAS28
using erythrocyte sedimentation rate in a large observational cohort of rheumatoid arthritis patients
in Japan. Ann Rheum Dis. 2007;66(9):12211226
C- Reactive protein (CRP) was identified by Tilet and Francis (1930) in the plasma of patients with
pneumonia, and was named for its ability to bind and precipitate the C-polysaccharide of
pneumococcus.1,2 It is an alpha globulin with a molecular mass of approximately 110,000 to 140,000
daltons, and is composed of five identical subunits, which are noncovalently assembled as a cyclic
pentamer.3
1. Schultz, D.R., and Arnold P.I.: Properties of four acute phaseproteins: C-reactive protein, serum
amyloid A protein,glycoprotein, and fibrinogen. Seminars in Arthritis andRheumatism 20: 129-147,
1990.
2. Kindmark, C.O.: The Concentration of C-reactive protein in Serafrom Healthy Individuals. Scand J
Clin Lab Invest, 29: 407- 411,1972.
3. Dowling, P., and Cook, S.: Immune events in demyelinatingdisease. In Wolfgang, F., Ellison, G.W.,
Stevens J.G., andAndrew, J.M. (eds.): Multiple sclerosis. Academic Press Inc.,New York, 269-277,
1972.
CRP is synthesized in the liver and is normally present as a trace constituent of serum or plasma at
levels less than 0.3 mg/dl.2,4,5,6 Its physiological roles are numerous and varied, but with several
functions similar to those of immunoglobulins, CRP appears to function in host defense.
1. Schultz, D.R., and Arnold P.I.: Properties of four acute phaseproteins: C-reactive protein, serum
amyloid A protein,glycoprotein, and fibrinogen. Seminars in Arthritis andRheumatism 20: 129-147,
1990
2. Kindmark, C.O.: The Concentration of C-reactive protein in Sera from Healthy Individuals. Scand
J Clin Lab Invest, 29: 407- 411,1972.
4. Yudkin, J.S., et. al.: C-Reactive Protein in Healthy Subjects: Association with Obesity, Insulin
Resistance, and endothelial dysfunction. A potential role for cytokines originating from adipose
tissue? Arterioscler Thromb Vasc Biol 19:972-8, 1999.
5. Kushner, I., Rzewnicki, D.L.: The acute phase response: General aspects. Baillieres Clinical
Rheumatology 8: 513-530, 1994.
6. Macy, E.M., Hayes, T.E., and Tracy, R.P.: Variability in the measurement of C-reactive protein in
healthy subjects:implications for reference interval and epidemiological
applications. Clin Chem, 43;1:52-58, 1997
CRP is one of the acute-phase proteins, the serum or plasmalevels of which rise during general,
nonspecific response to a widevariety of diseases. This include infections by gram-positive andgram-

negative organisms, acute phase of rheumatoid arthritis,abdominal abscesses, and inflammation of the
bile duct.3
3. Dowling, P., and Cook, S.: Immune events in demyelinatingdisease. In Wolfgang, F., Ellison, G.W.,
Stevens J.G., andAndrew, J.M. (eds.): Multiple sclerosis. Academic Press Inc.,New York, 269-277,
1972.
Although the detection of elevated levels of CRP in the serum is not specific for any particular
disease, it is a useful indicator of inflammatory processes.9
9. Morley, J.J., Kushner, I.: Serum C-reactive Protein Levels. in: Kushner, I., Volanakis, J.E., and
Gerwutz, H., eds., C-Reactive Protein and the Plasma Protein Response to Tissue Injury. Annals of
N.Y. Acad Sci, 389: 406-417, 1982
CRP levels rise in serum or plasma within 24 to 48 hours following acute tissue damage, reach a peak
during the acute stage (approximately 1000x constitutive level) and decrease with the resolution of
inflammation or trauma.1,10,11
1. Schultz, D.R., and Arnold P.I.: Properties of four acute phaseproteins: C-reactive protein, serum
amyloid A protein,glycoprotein, and fibrinogen. Seminars in Arthritis andRheumatism 20: 129-147,
1990
10. Shine, B., de Beer, F.C., and Pepys, M.B.: Solid phase radiommunoassays for human C-reactive
protein. J Lab Clinica Chimica Acta 117:13-23, 1981.
11. Kushner, I.: C-reactive protein in rheumatology, Arthritis Rheum 34:1065-1068, 1991.
The concentration increase of CRP in human serum or plasma may last for several days before
decreasing to normal levels.10-12
10. Shine, B., de Beer, F.C., and Pepys, M.B.: Solid phase radiommunoassays for human C-reactive
protein. J Lab Clinica Chimica Acta 117:13-23, 1981.
11. Kushner, I.: C-reactive protein in rheumatology, Arthritis Rheum 34:1065-1068, 1991.
12. Dixon, J.S., et al.: C-reactive protein in the serial assessment of disease activity in rheumatoid
arthritis. Scand J Rheum, 13: 39-44, 1984.
The detection of CRP is a more reliable and sensitive indicatorof the inflammatory process than the
erythrocyte sedimentationrate13, which may also be influenced by physiological changes not
associated with an inflammatory process. Current testing methodsincluding latex agglutination,
nephelometry, and radial immunodiffusion (RID) have the general disadvantages of low sensitivity,
whereas enzyme-linked immunosorbent assays (ELISA) provide the highest sensitivity and
specificity.14-16
13. Hind, C.R.H., and Pepys, M.B.: The role of serum C-reactive (CRP) measurement in clinical
practice. Int Med. 5: 112-151,1984.
14. Van Leeuwen, M., and Van Rijswijk, M.H.: Acute phase proteins in monitoring inflammatory
disorders. Baillieres Clinical Rheumatology 8: 531-552, 1994.
15. Powell, L., Roantree, R.J., and Rantz, L.A.: C-reactive Protein. A review. Clinical experience with
the C-reactive protein test. Am JMed Technol, 87: 138-142, 1979.

16. Roberts, W. L., et. al.: Evaluation of Four Automated High-Sensitivity C-Reactive Protein
Methods: Implications for Clinical and Epidemiological Applications. Clin Chem 46:4, 461-468,2000.

As elevated CRP values are always associated with pathological changes, the CRP assay provides
useful information for the diagnosis, therapy and monitoring of inflammatory processes and
associated disease. 10-13
10. Shine, B., de Beer, F.C., and Pepys, M.B.: Solid phase radiommunoassays for human C-reactive
protein. J Lab Clinica Chimica Acta 117:13-23, 1981.
11. Kushner, I.: C-reactive protein in rheumatology, Arthritis Rheum 34:1065-1068, 1991.
12. Dixon, J.S., et al.: C-reactive protein in the serial assessment of disease activity in rheumatoid
arthritis. Scand J Rheum, 13: 39-44, 1984.
13. Hind, C.R.H., and Pepys, M.B.: The role of serum C-reactive (CRP) measurement in clinical
practice. Int Med. 5: 112-151,1984.
2. Molecular structure of CRP
Entrez Gene summary for CRP the protein encoded by this gene belongs to the pentaxin family. It is
involved in several host defense related functions based on its ability torecognize foreign pathogens
and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular
effector systems in the blood. Consequently, the level of this protein in plasma increases greatly
during acute phase response to tissue injury,infection, or other inflammatory ,stimuli It is induced by
IL1/interleukin-1 and IL6//interleukin-6 [12].
[12] http://www.genecards.org/cgi-bin/carddisp.pl?gene=CRP
Function: Displays several functions associated with host defense it promotes agglutination,bacterial
capsular swelling, phagocytosis (CRP initiates the activation of the complement cascade and binds Fc
gamma RI (CD64) and Fc gamma RIIA (CD32a) on phagocytes to activate phagocytic responses) and
complement fixation through its calcium-dependent binding to phosphorylcholine. It can interact with
DNA and histones and may scavenge nuclear material released from damaged circulating cells [13].
[13] A C-reactive protein promoter polymorphism is associated with type 2 diabetes
mellitus in Pima Indians. (PubMed id 12618085)1, 4, 5 Wolford J.K....Hanson R.L. (2003)
CRP is a 224-residue protein with a monomer molar mass of 25106 Da. The protein is an
annular pentameric disc in shape [14][15].
[14] http://www.genecards.org/cgi-bin/carddisp.pl?gene=CRP
[15] A C-reactive protein promoter polymorphism is associated with type 2 diabetes
mellitus in Pima Indians. (PubMed id 12618085)1, 4, 5 Wolford J.K....Hanson R.L. (2003)

3. Methodology and clinical applications

The hsCRP ELISA is based on the principle of a solidphase enzyme-linked immunosorbent assay.The
assaysystem utilizes a unique monoclonal antibody directed against a distinct antigenic determinant
on the on the CRPmolecule. This mouse monoclonal anti-CRP antibody isused for solid phase
immobilization (on the microtiter wells).A goat anti-CRP antibody is in the antibodyenzyme(horseradish peroxidase) conjugate solution. The test sampleis allowed to react
simultaneously with the two antibodies,resulting in the CRP molecules being sandwiched betweenthe
solid phase and enzyme-linked antibodies. After a 45-minute incubation at room temperature, the
wells are washedwith water to remove unbound labeled antibodies. A tetramethylbenzidine (TMB)
reagent is added and incubatedfor 20 minutes, resulting in the development of blue color.The color
development is stopped with the addition of 1NHCl changing the color to yellow. The concentration of
CRPis directly proportional the color intensity of the test sample.Absorbance is measured
spectrophotometrically at 450 nm. 24
24. Votila, M., et. el.: Immunol Methods, 42: 11, 1981.
Plasma CRP production occurs via the stimulation of IL-6 in the liver. It assists in the recognition of
damaged host cells and foreign pathogens, and their removal. When CRP binds to its ligand, it
activates the complement system via the classical pathway and increases phagocytosis [11].
[11] Pepys MB, Gideon MH. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-11
is present in minute quantities in the plasma, after an acute inflammatory stimulation, it rises within a
few hours. It peaks within 2-3 days. Its half-life is 19 hours [12].

[12] Pepys, MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and
related proteins and serum amyloid A proteins. Adv Immunol 1983; 34: 141-2.
The increase in CRP levels is proportional to the inflammatory stimulus. With a greater stimulus, a
higher and longer lasting level of CRP will be measured. After the inflammatory stimulus is removed,
the CRP levels will quickly decrease [4, 11, 12]
[4] Yasavul . Romatolojik hastalklarda laboratuar testlerinin kullanm. Hacettepe Hastalklar
Kitab 2003: 1470.
[11] Pepys MB, Gideon MH. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-11.
[12] Pepys, MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and
related proteins and serum
amyloid A proteins. Adv Immunol 1983; 34: 141-2.
In healthy individuals the CRP level is generally below 0.2 mg/dl. Due to micro-traumas that occur
during the day, this level can increase up to 1 mg/dl. After a single stimulus it can increase up to 5
mg/dl within 6 hours, and can reach a peak value. within 48 hours. While a value between 1-10 mg/dl
is considered as mild, and any value above 10 mg/dl is considered a very high increase , CRP is
mainly useful for following the response to treatment, hence the decrease in inflammation in organic
disorders accompanied by mainlyinflammation [3, 4, 11-13].
[3] Doanavargil E, Gmdi G. Romatolojik hastalklarn tansnda labaratuar yntemleri. Klinik
Romatoloji El Kitab 2003: 117 -8.
[4] Yasavul . Romatolojik hastalklarda laboratuar testlerinin kullanm. Hacettepe Hastalklar
Kitab 2003: 1470.
[11] Pepys MB, Gideon MH. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-11.
[12] Pepys, MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and
related proteins and serum amyloid A proteins. Adv Immunol 1983; 34: 141-2.
[13] Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated
human C-reavtive protein in health and disease. J Clin Invest 1983; 91: 1351-7.
In RA, high CRP values are almost always seen, and its titer correlates with the disease activity index
[15].A high CRP value at the initial presentation implies thata progressive erosive course is possible,
and hence, guides the treatment selection [15]. In RA, CRP levels do not decrease with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and only decreases with drugs that provide remission
[3].
[3] Doanavargil E, Gmdi G. Romatolojik hastalklarn tansnda labaratuar yntemleri. Klinik
Romatoloji El Kitab 2003: 117 -8.
[15] Rhodes B, Frnrohr BG, Vyse TJ. C-reactive protein in rheumatology:biology and genetics.
Nat Rev Rheumatol 2011; 7:282.

In rheumatologic diseases other than RA and SLE, CRP can be a good indicator of disease activity [3,
4].

[3] Doanavargil E, Gmdi G. Romatolojik hastalklarn tansnda labaratuar yntemleri. Klinik

Romatoloji El Kitab 2003: 117 -8.
[4] Yasavul . Romatolojik hastalklarda laboratuar testlerinin kullanm. Hacettepe Hastalklar
Kitab 2003: 1470.

Munford R. C-Reactive Protein and Cardiovascular Risk: The Eyes of the Hippopotamus. Internal
Medicine Grand Rounds, Louisiana State University Medical Center, October 19, 2000.
(http://homepage.mac.com/juliofigueroa/docs/GRdocs/BobMunford2000/RobertMunford.html)
(Assesed 23 May 2005).

CRP is an acute phase reactant that was discovered over 70 years ago to be a blood protein that binds
to the C-polysaccharide of pneumococci. CRP is a pentamer of 23 kDa subunits; its level is usually
low in normal individuals but can rise 100- to 200-fold or higher with acute systemic inflammation.4

4. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J
Med. 1999;340:448454.

In healthy young adult volunteer blood donors, the median concentration of CRP is 0.8 mg/L (2),
2. Shine, B., de Beer, F.C., and Pepys, M.B. 1981. Solid phase radioimmunoassays for C-reactive
protein. Clin. Chim. Acta. 117:1323.\
Plasma CRP is produced only by hepatocytes, predominantly under transcriptional control by the
cytokine IL-6,
3. Vigushin, D.M., Pepys, M.B., and Hawkins, P.N. 1993. Metabolic andscintigraphic studies of
radioiodinated human C-reactive protein in health and disease. J. Clin. Invest. 91:13511357

1. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol 2003;3:292303.

new classification criteria for RA including ESR and CRP measurements allow early aggressive
treatment of RA [4,5].
CRP level correlates with morning stiffness, pain, fatigue, grip strength, articular index, and disability
[7].Moreover, CRP level is not affected by age,gender, and abnormalities in erythrocytes and serum
proteins. Hence, among various parameters, CRP is the most reliable and objective measure and a
useful prognostic factor for disease progression to joint damage and functional outcome [11-13].
CRP is a member of the pentraxin protein family, which is composed of five 23-kDa subunits and it
can increase by 1,000-fold or more with infection, inflammation, andtissue injury [14,15]. Interleukin
(IL)-6, IL-1, and tumor necrosis factor (TNF)- promote the synthesis of CRP inhepatocytes [15,16].
While hepatocytes are main sources of CRP, monocytes, lymphocytes, adipocytes, neurons, and
vascular smooth muscle cells are the extrahepatic sources of CRP [17-19]. To eliminate infectious
microorganisms and damaged or dead cells, CRP activates the classical complement cascade and
stimulates the influx and phagocytic activity of neutrophils [20,21]
Interaction of CRP with Fcgamma receptor (FcR)I and FcRIIA also promotes the production of
proinflammatory cytokines, resulting in the amplification loop of inflammatory reaction
However, it is possible that CRP is one of the proinflammatoryand bone destruction molecules in the
pathogenesis of RA. In this study, we hypothesized that CRP not only results from the inflammation
process, but also triggers proinflammatory responses and bone destruction. These processes are
initiated through the induction of the receptor activator of nuclear factor-B ligand (RANKL) protein
and direct stimulation of osteoclastogenesis, causing a vicious loop between inflammation and bone
destruction in RA. In the treatment of RA, the reduction of CRP level reflects not only the control of
disease activity, but also the prevention of bone destruction. [25]
Measurement of CRP
High-sensitivity CRP was measured by an immunoturbidimetric method (CRP II Latex X2, Denka
Seiken Co.
Ltd., Tokyo, Japan) using an autoanalyzer (Toshiba,Tokyo, Japan). Measurement range of this assay is
0.01
to 32 mg/dL.
In RA, high CRP levels correlate to rapid and severe progression of joint damage in one year, and
persistently
high CRP levels are associated with substantial progression in radiological joint damage [12].
4. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 3rd CO, et al. 2010 Rheumatoid
arthritis classification criteria: an American College of Rheumatology/European League Against
Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:256981.
5. Jung YO, Kim HA. Recent paradigm shifts in the diagnosis and treatment of rheumatoid arthritis.
Korean J Intern Med. 2012;27:37887.
7. Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in
patients with rheumatoid arthritis. J Rheumatol.1997;24:147785.
11. Rhodes B, Furnrohr BG, Vyse TJ. C-reactive protein in rheumatology: biologyand genetics. Nat
Rev Rheumatol. 2011;7:2829.
12. Jansen LM, van der Horst-Bruinsma IE, van Schaardenburg D, Bezemer PD,Dijkmans BA.
Predictors of radiographic joint damage in patients with earlyrheumatoid arthritis. Ann Rheum Dis.
2001;60:9247.
13. Devlin J, Gough A, Huissoon A, Perkins P, Holder R, Reece R, et al. The acutephase and function
in early rheumatoid arthritis, C-reactive protein levelscorrelate with functional outcome. J Rheumatol.
1997;24:913.

14. Shrive AK, Holden D, Myles DA, Greenhough TJ. Structure solution ofC-reactive proteins:
molecular replacement with a twist. Acta Crystallogr DBiol Crystallogr. 1996;52:104957.
15. Baumann H, Gauldie J. The acute phase response. Immunol Today.1994;15:7480.
16. Zhang D, Sun M, Samols D, Kushner I. STAT3 participates in transcriptionalactivation of the Creactive protein gene by interleukin-6. J Biol Chem.1996;271:95039.
17. Kuta AE, Baum LL. C-reactive protein is produced by a small number ofnormal human peripheral
blood lymphocytes. J Exp Med. 1986;164:3216.
18. Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated Creactiveprotein production
by human coronary artery smooth muscle cells.Circulation. 2003;108:19302.
19. Calabro P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein inresponse to
inflammatory cytokines by human adipocytes: linking obesityto vascular inflammation. J Am Coll
Cardiol. 2005;46:11123.
20. Siegel J, Osmand AP, Wilson MF, Gewurz H. Interactions of C-reactiveprotein with the
complement system. II. C-reactive protein-mediatedconsumption of complement by poly-L-lysine
polymers and otherpolycations. J Exp Med. 1975;142:70921.
21. Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein.
Immunopharmacology. 1999;42:2330.
25. Lu J, Marnell LL, Marjon KD, Mold C, Du Clos TW, Sun PD. Structural recognition and
functional activation of FcgammaR by innate pentraxins.Nature. 2008;456:98992.
The role of CRP itself is complex and not fully understood. On one hand, it seems to have proinflammatory effects, such as activating the classic complement pathway and decreasing IL-6 receptor
concentrations in areas where IL-6 has anti-inflammatory effects.2 On the other hand, it also has antiinflammatory properties,such as reducing neutrophil adhesion to endothelium.3
2.Jones SA, Novick D, Horiuchi S, et al. C-reactive protein: a physiologicactivator of interleukin 6
receptor shedding. J Exp Med 1999;189:599604.
3. Zouki C, Beauchamp M, Baron C, et al. Prevention of in vitro neutrophil adhesion to endothelial
cells through shedding of L-selectin by C-reactive protein and peptides derived from C-reactive
protein. J Clin Invest 1997;100:522529.