Shah A, Clair EWS. Rheumatoid Arthritis.

In editors: Fauci AS, Kasper DL,

Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons Principles of

Internal Medicine. 18 ed. New York 1 Mcgraw Hill; 2012; p 2738-2751.

Firestein GS. Etiology & Pathogenisis of Rheumatoid Arthritis. In editors:

Firestein GS, Budd RC, Harris ED, Mcinnes IB, Ruddy S, Sergent JS. Kellys

Textbook of Rheumatology, Vol-2, Sm ed. pl035-l079.

Malaviya AN, Kapoor SK, Singh RR, Kumar A. Prevalence of Rheumatoid

arthritis in adult Indian population. Rheumatology INT. 1993; l3:l3l-4.

Maddison P.J., David A. Isenberg, Patrica Woo, David N. Glass, Oxford Text

Book of Rheumatology 1 365 .

Klippel J .H, Dieppe P.A, Rheumatology. Londan, Mosby - year book Europe

Limited. l994;3:l3.3.

Bhatt G, Mathur DS, Saxena Gn, Bhandari S. Microalhuminuria in

Rheumatoid Arthritis A Correlation with Disease Activity. J Assoc Physicians

India.: 50: 2002:82.

Carotid Ultrasonography

The procedure was performed and interpreted by a single radiologist on the same ultrasound
machine as used above. Both carotid arteries were scanned, with the subject in supine position with
slight hyperextension of the neck, to identify atherosclerosis (plaque protruding into arterial lumen
_50%). Intima-media thickness was measured from end-diastolic M-mode images (minimum
distension) of the far wall of the distal common carotid artery in a location not containing the plaque.
The greatest distancebetween lumen-intima and media-adventitia interface was measured. Mean
value of 2 sides (right and left) was taken (41).

Cardio Risk CRP Test, Blood

C-reactive protein, serum
Main Medical Topics

Test Name Index Our April 2003 NewsPath letter to our doctors, about false positive problems

Costs, Billing &

Insurance If you use hs-CRP as a cardiac risk screening test, there is enough natural variab
day-to-day that one should never decide a risk status based upon just one result.
Finding Best Medical and average the results9. It is a stable molecule. Low-risk is less than 1.0 mg/L;
Care between 1.0-3.0; and high risk is greater than 3.09. Some consider 0.4 to be the u
"normal"10. The hr-CRP is reliable up to as high as 15 mg/L17.
About Pathology
Organ Donation
At LMC, the CRP became a 3 shifts per day, 7 days per week in March 2008. C-
Autopsy/Forensics (CRP) is the first of the "acute phase reactant" proteins to increase during states
inflammation. A high or increasing amount of CRP in your blood suggests that y
Related Sites infection or inflammation (to include inflammed, sterile tumor necrosis or gouty
[L08-12261]). That patients have high CRP during "attacks" of familial Mediter
Notice/Disclaimer
further assures that elevations do not implicate bacterial infections...they implica
Meaning Of Heading reactions that contain polys. If the CRP level in your blood drops, it means that
Images better and inflammation is being reduced. For uncertain reasons, CRP levels can
later stages of pregnancy as well as with use of birth control pills or hormone re
Faith & Health (i.e., estrogen). Higher levels of CRP have also been observed in the obese.
Contact Us
Sepsis & CRP vs. procalcitonin: CRP is said to take 12-24 hours to rise follow
assault, whereas procalcitonin (ProCT; PCT) is said to start rising within 2-4 hou
of CRP stays up about 3-7 days after the infection is cured before it normalizes,
normalizes quicker due to half life of only 24 hours15. Probably our support of n
sepsis management is already optimal. Our adult ID internists are not interested
the neonatologists are satisfied with our availability of STAT placenta exams (to
sections of formalin-fixed tissue, if truly needed). But, in early 2011, our emerg
rquested the test; and we will have begun this test for them March 7th, 2011.

CRP is exclusively produced in the liver. In this context of "rule in or rule out in
8 mg/L is considered "normal". CRP elevation is thought to correlate with endo
dysfunction6. The plasma level can double every 8 hours, peaking in 50 hours; u
stimulus, CRP drops rapidly, having a 5-7 hour half life1. In the post-shock (trau
period, the body swings into a catabolic phase and makes acute phase reactants
such proteins as prealbumin and albumin7. A sarcoidosis study normal control g
CRP levels from 3.7-5.9 mg/L13.

More recently, related to theories that CRP is a surrogate reflector of the inflamm
of the pathogenesis of coronary artery obstructive/stenotic lesions, it has been no
risk of future initial acute myocardial infarction (AMI) is increased in persons w
of CRP above 2.0 mg/L. This "cardio-CRP" screen (CRP-H...high-sensitivity CR
down to about 0.1 mg/L) should, like lipid profiles, be done only during periods
free from any recent minor or major illnesses. NOTE: tests at different times in
person may vary by about 30%4 or more10; so, as with cholesterol screening, it is
hs-CRP no less than on two, separate healthy occasions. Aspirin, although havin
inflammatory properties, does not lower hs-CRP10.

Some (clinical chemist, Nader Rifai, of Harvard) feel that hs-CRP is the single b
future cardiovascular disease risk (those with CRP levels in the upper 25% are 3
suffer a heart attack6). Sustained elevations are also predictive of increased strok
vascular disease risk; and increased levels may predict increased risk of hip frac
women14. Post-stroke elevations should decrease to baseline within 3-6 months f
cerebral infarct & the inflammatory organization of the infarcted brain matter; fa
suggests an underlying inflammatory process18. In healthy adults, 75% of hs-CR
mg/L3. The mediannormal concentration of CRP is 0.8 mg/L, with 90% of appa
individuals having a value less than 3 mg/L and 99% less than 12 mg/L1. Our la
<0.2 mg/dl (2 mg/L), but there is significant personal day-to-day variation (and
paragraph, above).

And, different methodology in different labs will likely not relate exactly to pub
quartile information6...therefore, hs-CRP risk categorization should be viewed so
loosely. AHA/CDC 2003 state divides into tertiles & says <1 mg/L is "low risk"
"moderate risk", and >3 mg/L is "high risk"9; these are the ranges reported in ou

In situations (such as colonic diverticulosis) which have had a pyogenic complic

& conservatively managed, one can determine that patient's baseline CRP when
well. Then if suspect symptoms begin, a significantly elevated CRP would sugg
institution of conservative management, again.

CRP level below normal: consider protein calorie malnutrion (

Situations with CRP Within Normal Range:

lowest cardio-risk quintile (quintile #1) is < 0.55 mg/L (or 0.1-0.6)...(low

low-mid (low) cardio-risk (quintile #2) is 0.55-0.99 mg/L (or 0.7-1.1)...(

mid-high (moderate) cardio-risk (quintile#3) is 1.0-2.1 (or 1.2-1.9) mg/L

risk)

is recommended as an additional screening test for CVD in those at inte

20% risk of attack of CVD in the next 10 years [calculate by clicking on
then "risk assessment"]) to decide additional diagnostic assessment (ima
testing) or therapeutic intervention (lipid-lowering, antiplatelet, cardiopr

even such smoldering important but non-acutely threatening active chron

gingivitis, periodontitis, or localized peri-apical bone inflammation can c
into one of the higher quintiles.

a normal CRP is highly unlikely in the face of a significantly acutely thre

infection1.

in evaluating a patient with "fever and night sweats", the signs and symp
certainly NOT due to hidden infection when CRP is in normal range (the
& signs could be due to malignant lymphoma).

may be normal in both temporal arteritis and polymyalgia rheumatica11.

detecting supervening infection after "clean" surgery: a potentially valua

serially follow after surgery...in search of early detection of postoperativ
(hidden) infection. Clean CRP pattern: begin increase from baseline in 4
peaks at (usually to intermediate elevations) 48-72 hours, begins to decre
 and back near baseline by 5th-7th postop day5.

if serum CRP is not elevated, a failed joint prothesis is unlikely due to se

stable or even progressing, mild sarcoidosis can have CRP less than 8...b
above 5...and sarcoidosis unlikely if below 5 mg/L13.

Situations with CRP Elevations:

with cardio-risk screening in mind, values greater than 15 mg/L suggest

effort is confounded by false positive situations (see link above) or recen
inflammatory disease beyond what could be expected related to coronary
post-shock (trauma, sepsis) catabolic phase can highly elevate CRP7

those with troponin-normal cardiac events who have hs-CRP >3 mg/L at
increased risk of major event within the next 3 months and, if >5 mg/L o
increased risk of a major event on out for 6 months6

hi-risk cardio-risk (quintile #4) is 2.0-3.8 mg/L...(high risk if greater tha

highest cardio-risk zone (quintile #5), is from 3.9-15 mg/L...(high risk9)

reflect 4-7x normal risk10.

even such smoldering important but non-acutely threatening active chron

gingivitis/periodontitis, chronic prostatitis , chronic gastritis, chronic bro
urinary tract infections can cause elevations into one of the higher quinti

hs-CRP predicts a future stroke, AMI, or PVD event in males & females
nonsmokers, when in the highest quartile at a relative risk over "normals
and 4-fold, respectively.

usually elevated in temporal arteritis

hs-CRP joined with TC:HDL-C ratio gives strongest predictive informat

estrogen replacement therapy (HRT or ERT) increases CRP level6; vitam

will cause CRP "elevations" (probably meaning as to cardio-risk quintile
pressure, elevated BMI (obesity)[calculate your BMI], cigarette smoking
syndrome12" (see below), diabetes mellitus, low HDL/high triglyceride li
estrogen/progesterone hormone use, and chronic inflammatory condition
rheumatoid arthritis) all can innately cause elevations of hs-CRP in the a
inflammation9.

minor elevations1: SLE, scleroderma (systemic sclerosis), dermatomyosi

 colitis, leukemia, GVHD (graft vs. host disease)

major serum/plasma elevations:1

false positive due to RF, HAMA, etc.

CSF CRP reported to increas

Infections
viral5
rheumatic fever
hypersensitivity complications of infections
erythema nodosum

rheumatoid arthritis
juvenile chronic arthritis
ankylosing spondylitis
psoriatic arthritis
systemic vasculitis syndrom
inflammatory disease polymyalgia rheumatica
Reiter's disease
Crohn's disease
familial Mediterranean feve
urate pyarthrosis [L08-12261
necrotizing glial tumor [L08-

allograft rejection kidney & marrow (not heart)5

carcinoma (breast, lung, GI)5
5
malignant but not benign tumors lymphoma
sarcoma
acute myocardial infarction (A
Necrosis tumor embolization
acute pancreatitis
burns
Trauma
fractures

bacterial vs. viral infection: a very high level (>100 mg/L) more likely b
while intermediate levels (10-50 mg/L) can be either viral or bacterial

postoperative elevations, especially when they can be concretely related

reasonably low-elevated preoperative CRP baseline test value, tend to be
infection and not just organizing resolution of clean-surgical tissue dama
42. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med .2000;51:207
29.

43. Bresnihan B, Alvaro-Gracia JM, Cobby M. Treatment of rheumatoid arthritis with recombinant
human interleukin-l receptor antagonist. Arthritis Rheum 1998;41:2196-204.

44.Weinblatt ME, Kremer JM, Bankhurst AD. A trial of etanercept, a recombinant tumor necrosis
factor receptor fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J
Med 1999;340:253-9.

45.Bathon JM, Martin RW, Fleischmann RM. A comparison of etanercept and methotrexate in
patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93.

46.Maini R, St. Clair EW, Breedveld F. lnfliximab (chimeric anti-tumour necrosis factor alfa
monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant
methotrexate: a randomized phase Ill trial. Lancet 1999;354:1932-9.

47. Ljipsky PE, van der Heijde DM, St. Clair EW. Infliximab and methotrexate in the treatment of
rheumatoid arthritis. N Engl J Med 2000;343:1594-602.

48.Jamal OS, Conaghan PG, Cunningham AM. Increased expression of human type lla secretory
phospholipase A2; antigen in arthritic synovium. Ann Rheum Dis 1998;57:550-8.

49.Siegle l, Klein T, Backman JT, Saal JG, Nusing RM, Fritz P. Expression of cyclooxygenase l and
cyclooxygenase 2 in human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory
joint diseases. Arthritis Rheum 1998;41:122-9.

50.Stichtenoth DO, Thoren S, Bian H, Peters-Golden M, Jakobsson PJ, Crofford LJ. Microsomal
prostaglandin E synthase is regulated by proinflammatory Cytokines and glucocorticoids in primary
rheumatoid synovial cells. J Immunol. 2001;167:469-74.

53. Schiff MH, Bulpitt K, Weaver AA. Safety of combination therapy with anakinra and etanercept in
patients with RA [abstract] Arthritis Rheum. 2001;44 Suppl:S79.

those without the disease. CHF risk precedes the diagnosis of RA and cannot be explained by an
increased incidence of traditional CV risk factors(13). RA is associated with increased left ventricular
mass which is independently related to disease duration, while systolic function is typically preserved
(14). Both the clinical presentation and the outcome of CHF differ significantly between RA and
control individuals. In the former, CHF presentation may be more subtle but mortality from this
complication is significantly higher(15). Even after adjusting for CV risk factors and ischemic heart
disease, RA patients have almost twice the risk of developing CHF than patients without arthritis.
Again, this increase has been seen primarily in patients who are seropositive for the RF(16). In
addition, patients with RA are at increased risk for death in the period immediately after CHF
develops and this risk remains elevated for 6 months after(17).
Further, preliminary evidence indicates that patients with RA who are positive for anti-cyclic
citrullinated peptide antibodies (anti-CCP) have higher subclinical atherosclerosis than those who
are not (36).

A study of Atherosclerosis in rheumatoid arthritis: the role of high-resolution B mode ultrasound

in the measurement of the arterial intima-media thickness by Carotti M et al revealed accelerated
atherosclerosis, as shown by increased common carotid IMT, in patients with RA and High-resolution
B-mode ultrasound may be considered a promising, sensitive and non-invasive tool for assessing the
existence of subclinical atherosclerosis in RA patients. 81

A study of Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis Compared
with Healthy Subjects: A Case-Control Study by Alper M.Van Sijl et al. showed RA is associated with
maladaptive outward carotid arterial remodeling. 82

Atherosclerotic cardiovascular disease is the major cause of mortality in Rheumatoid arthritis.

Dyslipidaemia is an important risk factor for cardiovascular disease and is influenced by disease
activity of Rheumatoid arthritis, which is the combined effect of these inflammatory mediators 85.

9. Del RI, Freeman G, Hass R et al. A escalante abstract 1901. Effects of carotid atherosclerosis on
the incidence of acute coronary syndromes in rheumatoid arthritis. Arthritis Rheum 2005; 52: 3413
23.

13. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid
arthritis: a population-based study over 46 years. Arthritis Rheum Feb;2005 52(2):412420.

14. Rudominer RL, Roman MJ, Devereux RB, et al. Independent association of rheumatoid arthritis
with increased left ventricular mass but not with reduced ejection fraction. Arthritis Rheum Jan;2009
60 (1):2229.

15. Davis JM 3rd, Roger VL, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. The presentation

and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general

population. Arthritis Rheum Sep;2008 58(9):26032611.

16. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid
arthritis: a population-based study over 46 years. Arthritis Rheum Feb;2005 52(2):412420.

17. Davis JM 3rd, Roger VL, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. The presentation
and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general
population. Arthritis Rheum Sep;2008 58(9):26032611.
36.Lopez-Longo FJ, Oliver-Minarro D, de la Torre I, et al. Association between anti-cyclic citrullinated
peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthritis Rheum
Apr 15;2009 61(4):419424.

75. Tyrrell PN,Beyene J,Feldman BM,McCrindle BW,Silverman ED, Bradley TJ.et al.Rheumatic disease
and carotid intima-media thickness: A systematic review and meta-analysis. Arterioscler Thromb Vasc
Biol 2010;30:101426.

79. H Singh, Mukesh Goyal, J Sen, Harish Kumar, Rahul Handa, Susheel Garg.Correlation of Intima
Media Thickness(as a Marker of Atherosclerosis) with Activity and Duration of Rheumatoid Arthritis
using Carotid Ultrasound:JIACM 2011; 12(1): 15-20.

81. Carotti M, Salaffi F, Mangiacotti M, Cerioni A, Geusepetti GM, Grassi W. et al. Atherosclerosis in
rheumatoid arthritis: the role of high-resolution B mode ultrasound in the measurement of the
arterial intima-media thickness;Rheumatismo; 2007 Jan-Mar;59(1):38-49.

82. Alper M.Van Sijl et al. Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis
Compared with Healthy Subjects: A Case-Control Study; The Journal of Rheumatology December 1,
2012 vol. 39 no. 12 2261-2266.

83. Corrales A, Parra JA, Gonzalez-Juanetey C.et al. Cardiovascular risk stratification in
rheumatic diseases: carotid ultrasound is more sensitive than Coronary ArteryCalcification Score to
detect subclinical atherosclerosis in patients with rheumatoid arthritis;Ann Rheum Dis; 2013 Jul 13.

85. Sattar N, McCarey DW, Capell H, et al. Circulation 2003; 108: 2957-63.

18.Girasole G, Passeri G, Jilka RL, Manolagas SC. Interleukin-11: a new cytokine critical for osteoclast
development. J Clin Invest 1994;93:1516-1524.

28. van RIEL PLCM, REEKERS P, van de PUTTE LBA, GRIBNAU FWJ: Association of HLA antigens, toxic
reactions and therapeutic response to auranofin and aurothioglucose in patients with rheumatoid
arthritis. Tissue Antigens 1983; 22: 194-9.
75. Tyrrell PN,Beyene J,Feldman BM,McCrindle BW,Silverman ED, Bradley TJ.et al.Rheumatic disease
and carotid intima-media thickness: A systematic review and meta-analysis. Arterioscler Thromb Vasc
Biol 2010;30:101426.

79. H Singh, Mukesh Goyal, J Sen, Harish Kumar, Rahul Handa, Susheel Garg.Correlation of Intima
Media Thickness(as a Marker of Atherosclerosis) with Activity and Duration of Rheumatoid Arthritis
using Carotid Ultrasound:JIACM 2011; 12(1): 15-20.

81. Carotti M, Salaffi F, Mangiacotti M, Cerioni A, Geusepetti GM, Grassi W. et al. Atherosclerosis in
rheumatoid arthritis: the role of high-resolution B mode ultrasound in the measurement of the
arterial intima-media thickness;Rheumatismo; 2007 Jan-Mar;59(1):38-49.

82. Alper M.Van Sijl et al. Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis
Compared with Healthy Subjects: A Case-Control Study; The Journal of Rheumatology December 1,
2012 vol. 39 no. 12 2261-2266.

83. Corrales A, Parra JA, Gonzalez-Juanetey C.et al. Cardiovascular risk stratification in
rheumatic diseases: carotid ultrasound is more sensitive than Coronary ArteryCalcification Score to
detect subclinical atherosclerosis in patients with rheumatoid arthritis;Ann Rheum Dis; 2013 Jul 13.

85. Sattar N, McCarey DW, Capell H, et al. Circulation 2003; 108: 2957-63.