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BMC - Gca
Abstract
Background: To compare the utility of ESR, CRP and platelets for the diagnosis of GCA.
Method: A clinical diagnosis of GCA was determined by case-note review of 270 individuals (68% female, mean age
72 years) referred to a central pathology service for a temporal artery biopsy between 2011 and 2014. The highest
levels of ESR, CRP and platelets (within 2 weeks of diagnosis) were documented. Evaluation of ESR, CRP and platelets
for the diagnosis of GCA were compared using Receiver Operating Characteristic Area Under the Curve (ROC-AUC),
and sensitivity/specificity at optimum cut-off values.
Results: GCA was clinically diagnosed in 139 (67%) patients, with 81 TAB positive. The AUC estimates for ESR, CRP and
platelets were comparable (0.65 vs 0.72 vs 0.72, p = 0.08). The estimated optimal cut-off levels were confirmed at 50
mm/hour for ESR, and determined as 20 mg/L for CRP and 300 × 109/L for platelets. Sensitivity estimates for these three
tests were comparable (p = 0.45) and ranged between 66% for ESR and 71% for platelets. Specificity estimates were also
comparable (p = 0.11) and ranged between 57% for ESR and 68% for CRP. There was only moderate agreement
between the three positive tests (agreement 67%, kappa: 0.34), and when considered collectively, CRP and platelet
positive tests were independent predictors of GCA (p < 0.001), but the ESR was not (p = 0.76).
Conclusion: ESR, CRP and platelets are moderate, equivalent diagnostic tests for GCA, but may yield disparate results in
individual patients. A combination of CRP and platelet tests may provide the best diagnostic utility for GCA.
Keywords: Giant cell arteritis, Inflammatory markers, Diagnosis, Vasculitis
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
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Chan et al. BMC Rheumatology (2019) 3:14 Page 2 of 7
CRP and platelet results may the most informative for a exclude the diagnosis of GCA [9]. This sensitivity rates
diagnosis of GCA. If a positive test is considered as ei- may be even lower in the large-vessel phenotype of
ther CRP > = 20 or platelets > = 300, then this test has GCA with reported rates being as low as 52%. [10] Skip
high sensitivity for GCA (87, 95% CI 80, 92, Table 3). lesions may contribute to a negative TAB in the pres-
Alternatively, if a positive test is considered as both ence of GCA; as well in patients with predominant
CRP > = 20 and platelets > = 300, then this test has a large vessel disease [11]. Therefore, there has been a
high specificity for GCA (84, 95% CI 77, 90, Table 3). If longstanding interest in the search for serological
both CRP and platelet values are below these thresh- markers to better aid the diagnosis of GCA with a focus
olds, then this may be a useful test for the exclusion of on inflammatory markers [11–21]. In this study we
GCA (negative predictive value 77, 95% CI 66, 86). have confirmed that ESR, CRP and platelet counts each
Conversely, if both CRP and Platelet tests are positive, have moderate diagnostic utility for a subsequent clin-
then this may be a useful test for the diagnosis of GCA ical diagnosis of GCA in the most relevant context,
(positive predictive value 77, 95% CI 67, 85). which is all patients referred for a TAB. Further, we
have estimated cut-off values for the interpretation of
Discussion test results. These cut-off values were estimated at 50
While a positive TAB is the gold standard for a diagno- mm/hr. for ESR, 20 mg/L for CRP and 300 × 109/L for
sis of GCA, its sensitivity ranges from ~ 70 to > 90%, platelet counts. Importantly, we found no difference in
which underscores that a negative biopsy does not these optimum cut-off values between TAB positive
Chan et al. BMC Rheumatology (2019) 3:14 Page 4 of 7
Table 1 Receiver Operating Characteristic (ROC) Area under the Curve (AUC) estimates, cut-off estimates to define a positive test,
and diagnostic accuracy of positive tests for ESR, CRP and Platelets for a diagnosis of GCA. Numbers in brackets represent 95%
confidence intervals
ESR (mm/hr) CRP (mg/L) Platelets (109/L)
AUC 0.65 (0.57, 0.72) 0.72 (0.65, 0.79) 0.72 (0.65, 0.79)
Estimated cut-offa
Bx- GCA vs non-GCA 44 (21, 66) 23 (12, 35) 319 (291, 347)
Bx + GCA vs non-GCA 47 (28, 65) 23 (16, 32) 297 (263, 330)
All GCA vs non-GCA 47 (28–65) 23 (19, 28) 297 (272, 321)
Selected cut-off 50 20 300
Proportion positive at cut-off (%)
non-GCA (n = 131) 56 (43%) 42 (32%) 49 (37%)
GCA (n = 139) 91 (65%) 93 (67%) 99 (71%)
All (n = 270) 147 (54%) 135 (50%) 148 (55%)
Diagnostic accuracy of positive tests
Sensitivity (%) 65.5 (56.9, 73.3) 66.9 (58.4, 74.6) 71.2 (62.9, 78.6)
Specificity (%) 57.3 (48.3, 65.9) 67.9 (59.2, 75.8) 62.6 (53.7, 70.9)
Positive Predictive Value (%) 61.9 (53.5. 69.8) 68.9 (60.4, 76.6) 66.9 (58.7, 74.4)
Negative Predictive Value (%) 61.0 (51.8, 69.6) 65.9 (57.3, 73.9) 67.2 (58.1, 75.4)
Correct (%) 61.4 67.4 67.0
a
Cut-off values were determined at the maximum of the product of the sensitivity and specificity (Liu’s method)
Chan et al. BMC Rheumatology (2019) 3:14 Page 5 of 7
Fig. 3 Sensitivity and Specificity curves for different cut-off values of a ESR, b CRP and c Platelet counts for the diagnosis of GCA
to one previous study [15], was higher than in two other diagnostic tests in predicting positive biopsy is decreased
previous studies, 0.63 [17] and 0.61 [21] respectively. Simi- for patients who have been initiated on glucocorticoids at
larly, our AUC estimate for platelets, 0.72 (95% CI 0.65, the time of referral for biopsy.
0.79) was virtually identical to the point estimate from Discordance between positive ESR and CRP results is
three previous studies [15, 17, 19], but higher than a a recognised phenomenon and an evaluation of discord-
fourth (0.63) [21]. An important caveat for the comparison ant ESR/CRP laboratory tests in adults indicated clinical
of these studies to ours is that these previous studies all differences, with infections, myocardial infarction and
compared the TAB positive patients to TAB negative pa- venous thrombosis more prevalent in the high CRP/low
tients, which most likely included some TAB negative ESR group, and connective tissue disease, ischemic
GCA patients. Regardless, all studies suggest that ESR, strokes and transient ischemic attacks more prevalent in
CRP and platelets have, at best, moderate ability to distin- the high ESR/low CRP group [22]. This discordance is
guish between GCA and non-GCA patients, and as dem- also observed in GCA, with one study reporting that the
onstrated by Toren et al [21], the utility of these three CRP has a significantly better sensitivity for GCA com-
pared to the ESR [13]. In our study, this discordance also
Table 2 Logistic regression analysis for the association between extended to positive platelet count results, with a kappa
positive ESR (mm/hr), CRP (mg/L) and Platelets (109/L) tests and agreement between the three tests of only 67%. Al-
GCA. Each predictor is highly significant in individual, univariable though there was a trend for a lower AUC and lower
regression. However, in the multivariable regression with all three
specificity for the ESR test compared to the CRP and
predictors, both CRP and Platelets are independent predictors of
GCA (p < 0.001), whereas the ESR is not (p = 0.76)
platelet tests in our study, this did not reach statistical
significance, and we conclude that the tests are in fact
ESR > =50 CRP > =20 Platelets> = 300 Odds Ratio (95% CI) P-value
comparable at the cut-off values used. It is also quite
Univariable analysis
possible that discordant results may reflect underlying
Pos 2.6 (1.6, 4.2) < 0.001 meaningful clinical differences between GCA patients,
Pos 4.3 (2.6, 7.1) < 0.001 although this remains to be properly evaluated.
Pos 4.1 (2.5, 6.9) < 0.001 The discordance between ESR, CRP and platelet re-
Multivariable analysis sults in GCA suggest the possibility that a combination
Neg Neg Neg 1
of tests may provide the best utility for the diagnosis of
GCA. In our study, a multivariable analysis indicated
Pos Neg Neg 0.8 (0.2, 2.8) 0.73
that, given CRP and platelet results, the ESR was essen-
Neg Pos Neg 2.4 (0.7, 8.1) 0.16 tially redundant, and that specific combinations of CRP
Neg Neg Pos 2.9 (1.2, 7) 0.020 and platelet results resulted in high sensitivity and speci-
Pos Pos Neg 4.0 (1.5, 10.2) 0.004 ficity for GCA. Of the three previous studies which eval-
Pos Neg Pos 3.9 (1.4, 11.4) 0.012 uated ESR, CRP and platelets by multivariable
Neg Pos Pos 11.8 (2.9, 48.3) 0.001
regression, two concluded, as in our study, that CRP and
platelets were the best predictors of GCA [15, 20],
Pos Pos Pos 10.7 (4.8, 23.8) < 0.001
whereas the other concluded that ESR and platelets were
Chan et al. BMC Rheumatology (2019) 3:14 Page 6 of 7
Table 3 Diagnostic performance of a combination of CRP (mg/L) and Platelet (109/L) tests for GCA
Diagnostic Test Criteria
Performance
CRP > = 20 or Platelets > = 300 CRP > = 20 and Platelets > = 300
Sensitivity% 87.1 (80.3, 92.1) 51.1 (42.5, 59.6)
Specificity% 46.6 (37.8, 55.5) 84.0 (76.5, 89.8)
PPV% 63.4 (56.1, 70.2) 77.2 (67.2, 85.3)
NPV% 77.2 (66.4, 85.9) 61.8 (54.2, 69.0)
% Correct 67.4 67.4
the best predictors [17]. This latter study also included Authors’ contributions
other blood count markers such as neutrophil: lympho- FC: Responsible for data collection, initial analysis and major contributor to the
writing of the manuscript. SL: Significant contributions in in-depth data analysis
cyte ratio, and monocyte: lymphocyte ratio which, in with major contribution to the writing of the manuscript. SW: Contribution to
addition to CRP, which did not reach statistical signifi- concept and design of manuscript with analysis of dataset. Critical revision of
cance in multivariable regression. article. CH: Significant contribution to concept and design of manuscript with
analysis of dataset. Critical revision of article. All authors have read and ap-
A strength of our study was that it consisted of a proved final manuscript.
state-wide cohort of patients from 5 tertiary referral and
peripheral centres hence capturing the full spectrum of Ethics approval and consent to participate
patients. Our study included not only patients with a This study has obtained appropriate ethics approval for data collection, storage
and publication via Southern Adelaide Clinical Human Research Ethics Committee
positive TAB but included patients with a clinical diag- (South Australia, Australia) with the approval number of 354.09. The need for
nosis of GCA, despite having a negative TAB. This is informed consent was waived by the aforementioned ethics committee.
crucial as studies have shown TAB results do not affect
the management of patients with suspected GCA [14] Consent for publication
Not applicable.
and as the ACR Classification criteria were not designed
as diagnostic criteria, patients may still be diagnosed Competing interests
with GCA on clinical grounds, especially if there is a The authors declare that they have no competing interests.
good response to glucocorticoid therapy. Hence, we be-
lieve our findings more accurately reflect real-world clin- Publisher’s Note
ical practice. Limitations of this study were that a third Springer Nature remains neutral with regard to jurisdictional claims in
of the study population was excluded due to missing published maps and institutional affiliations.
data, however the excluded patients had similar age and Received: 31 October 2018 Accepted: 25 March 2019
gender distribution to the included cohort. Further data
on concomitant steroid treatment was not available.
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