Is ESR the Preferable Measure of the Acute Phase Response in RA?

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Journal of Rheumatology

May 2004

Editorial

Is Erythrocyte Sedimentation Rate the Preferable Measure of the Acute

Phase Response in Rheumatoid Arthritis?

HAROLD E. PAULUS, MD;

ERNEST BRAHN, MD,

Department of Medicine,

Division of Rheumatology,

UCLA School of Medicine,

Room 32-59 Rehabilitation Center,

1000 Veteran Avenue,

Los Angeles, California 90095, USA

In this issue, Ward1 compares the acute phase reactants

erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for

their ability to detect change during studies of disease modifying

antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA).

In a metaanalysis of 63 clinical trials or observational studies of RA

treatment, 89 treatment arms with DMARD therapy included sufficient

paired data of both ESR and CRP at baseline and at 4 to 24 weeks to

determine the treatment effect sizes for both measures of acute phase

reactant changes. Recent studies with minocycline, leflunomide,

etanercept, infliximab, and anakinra (but not adalimumab) were included,

along with studies of traditional DMARD and DMARD combinations. Only 6

of the studies were published before 1988, and most were published

within the past 10 years.

Placebo treatment arms were not included in this analysis, and one study

of prednisolone was excluded as an outlier because it reported very

large effect sizes after only 4 weeks of treatment. Effect sizes for the

89 treatment arms ranged widely from -0.22 to 3.89 for ESR, and 0.02 to

1.46 for CRP. Pooled effect sizes for values at 4, 8, 12, 16, and 24

weeks after baseline were determined by weighting the number of subjects

in each arm by its effect size at that time point, and ranged from 0.29

to 0.65 for ESR, and 0.39 to 0.59 for CRP. Differences between pooled

weighted effect sizes for ESR and CRP were calculated for each of these

time points, although the amount of available data varied at the

different time points. At 12, 16, and 24 weeks the pooled effect sizes

for ESR were 0.09 to 0.11 units greater than those for CRP. Effect size

for CRP was 0.05 greater than that for ESR at week 4 and 0.06 greater at

week 8, but these differences were not statistically significant because

of fewer subjects at these time points. The authors concluded that ESR

is more sensitive to change than CRP and may be the preferred measure of

the acute phase response in RA.

These interesting findings are derived from a large number of clinical

trials and appear to reflect real differences in the sensitivity to

change of the 2 measures. The clinical significance of an effect size

difference of 0.09 or 0.11, however, is not clear. Standing alone, these

values would be considered to be " small " effect sizes, but they may be

sufficient to influence the statistical significance of a composite

outcome measure in a large clinical trial, and may influence trial

design.

Effect size is a statistical representation of change over time in a

measure that is standardized by dividing the change value by the

standard deviation of its baseline values for the cohort being

considered. If there is great variability among the baseline values of

the cohort, the standard deviation will be large and the effect size

relatively smaller, whereas if there is little variability among

baseline values, the standard deviation will be small and the effect

size relatively larger if the average change value is the same. Effect

size is a unitless expression of change and is widely used in

metaanalyses to compare or pool the results of multiple studies,

increasing the statistical power of studies that have been too small to

individually demonstrate statistical significance. Effect size can also

be used to compare the sensitivity to change of various outcome

measures, as was done in the report by Ward.

The ESR has been part of the tool kit of physicians since before there

were rheumatologists. Measuring the distance that erythrocytes in

anticoagulated whole blood fall during 1 hour in a standardized tube is

simple and easily done in a doctor's office or local laboratory, and

does not require any chemical reagents or complex calculations by a

computer. When promptly done with freshly drawn blood, the ESR is

reliable and reproducible, and has been useful in the differential

diagnosis of inflammatory disorders and to monitor responses to therapy.

However, ESR is sensitive to various conditions; it decreases with

increases in the time and storage temperatures between drawing the

specimen and performing the assay. It increases if the tube is not

vertical or if it is subject to vibration, e.g., by a centrifuge on the

same laboratory bench. Values are also affected by red blood cell size,

shape, and hematocrit2,3, as well as the age and sex of the patients.

Two methods have been commonly used to assay the ESR. The Westergren

method is preferred because it is relatively linear, although it

requires a special citrate tube. The Wintrobe method can be performed on

blood from an EDTA tube commonly used to measure complete blood cell

count, is slightly more sensitive than the Westergren method at modest

ESR levels, but has a major drawback in that it tends to plateau at

about 50-55 mm/h. In the metaanalysis by Ward1, only 51% of the studies

specified that the Westergren method was employed; the remaining studies

did not report the method. ESR increases with moderate increases in

fibrinogen (an acute phase protein) and with major increases in

immunoglobulin concentrations2,3 that increase rouleaux formation and

the subsequent surface-to-volume ratio that favors erythrocyte

sedimentation. It is estimated that about 60-70% of an increase in ESR

is attributable to fibrinogen because of its neutralizing effects on red

blood cell (RBC) sialic acid residues that typically inhibit RBC

aggregation and rouleaux. Fibrinogen is among the acute phase proteins

produced by the liver in response to inflammation and is upregulated

primarily by interleukin 6 (IL-6), tumor necrosis factor (TNF), and

IL-1. Consequently, biologic response modifiers, such as anti-TNF

interventions, may directly interfere with cytokines controlling the

level of putative markers of disease activity. Plasma concentrations of

fibrinogen slowly increase by 2- to 3-fold, and peak levels are seen 7

to 10 days after an appropriate stimulus3,4. ESR is a component of the

remission criteria for RA5, and was an essential element in the original

Disease Activity Score (DAS)6.

CRP was discovered and named in 1930 because it bound to the

C-polysaccharide of the pneumococcal cell wall, resulting in

calcium-dependent precipitation. It is a cyclic pentameric molecule of 5

protomers, each consisting of 206 amino acids. CRP binds to the

phosphocholine binding sites of foreign pathogens and damaged host

cells, and also contains Clq and Fc-gamma receptor-binding sites, thus

providing a mechanism to eliminate foreign pathogens and damaged host

tissue4. It is stable in frozen plasma or serum and can be accurately

assayed from these stored frozen specimens. CRP concentrations increase

within 4 hours after an appropriate stimulus, peak within 24 to 72

hours, and may increase as much as 1000-fold4. They promptly return to

normal when the underlying inflammation resolves. Thus CRP values can

accurately reflect current clinical activity of inflammation/tissue

injury found in RA. Many methods have been utilized to assay circulating

levels of CRP, and even the reporting units can vary (internationally as

mg/l, but in the United States as mg/dl, a log difference). In the Ward

report1 the measurement methods for CRP were reported in only 23% of the

studies. Consequently, it is unclear how much widening of the standard

deviation and subsequent impact on effect size is influenced by these

differences in laboratory techniques for not only CRP, but also ESR.

Wolfe7 has suggested that CRP measures the acute phase response, but

that ESR measures elements of chronicity and severity of RA in addition

to the acute phase response. He found that ESR correlates better than

CRP with measures that are not acute phase proteins, such as

immunoglobulins, rheumatoid factor, and anemia. He concluded that CRP

appears to be a better test for acute phase responses, but ESR may

measure aspects of general severity of RA better than CRP, even though

it is a poorer measure of inflammation7. These observations are

supported by the findings of the metaanalysis by Ward1, in that the

effect sizes for changes in CRP were slightly greater than those for ESR

when assayed 4 or 8 weeks after the initiation of treatment, whereas

effect sizes for changes in ESR were greater than those for CRP 12, 16,

and 24 weeks after starting treatment, when the slower changes in

fibrinogen levels have stabilized and non-acute phase changes in

immunoglobulins, rheumatoid factors, and hematocrit are occurring.

Are composite outcome measures affected differently by the use of ESR or

CRP? When we used either CRP or ESR to calculate the American College of

Rheumatology response measure (ACR20) responders in an observational

cohort of patients with early RA, the differences in ACR20 responder

rates were 0.4% at 6 months, 0.2% at 12 months, and 2.0% at 24 months.

The mean Disease Activity Score value calculated using actual ESR values

was 4.043 ± 1.52 (SD), compared to 4.045 ± 1.51 when ESR was imputed

from actual CRP values using a nomogram8, suggesting similarity of the 2

measures when used in these composite outcome measures.

Is it helpful to measure both CRP and ESR? Wolfe7 found discordance

between CRP and ESR in 28% of 774 patients with RA. High ESR (³ 20 mm/h)

and low CRP (< 0.75 mg/dl) were noted in 20%, and high CRP (³ 0.75

mg/dl) with low ESR (< 20 mm/h) was present in 8%. High CRP/high ESR was

associated with worse clinical status, followed by high CRP/low ESR,

high ESR/low CRP, and low ESR/low CRP in that order, when assessed by

clinical variables such as joint counts, grip strength, Health

Assessment Questionnaire disability index, pain, and global severity7.

Despite the slight advantage of ESR for later time points, as noted in

the metaanalysis1, CRP is probably a better measure for use in large

multi-investigator clinical trials because it is stable and can be

performed on frozen specimens by a central laboratory. The report by

Ward1, across a varied spectrum of individual therapeutic studies,

measures reductions in acute phase proteins as a function of time. It

assumes that responses to traditional DMARD and the newer biologic

response modifiers are reasonable to group together for analysis based

on their rate and level of impact on disease. It should be noted that

this study does not claim to address the more critical question of which

surrogate marker correlates best with actual improvement in clinical,

functional, or structural outcome with a given therapy. It only measures

the change over time after initiation of therapy compared to baseline.

In the 9 treatment arms that used a TNF inhibitor, the effect size of

CRP was modestly better than that of ESR at 4 weeks (2 of 2 studies), 16

weeks (one of one study), and 24 weeks (7 of 9 studies). ESR may be

preferable for single-investigator studies if specimen collection and

handling can be closely controlled. In view of substantial evidence that

treatments that control CRP and ESR reduce radiographic joint

damage9,10, it is worthwhile for clinicians to follow the ESR or CRP

when treating individual RA patients. If they can do ESR in their office

or a reliable local laboratory that can report the results within one or

2 hours, ESR may have advantages for monitoring individual responses to

DMARD therapy.

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