Chan et al.

BMC Rheumatology (2019) 3:14

https://doi.org/10.1186/s41927-019-0061-z
BMC Rheumatology

RESEARCH ARTICLE Open Access

The utility of ESR, CRP and platelets in the

diagnosis of GCA
Fiona Li Ying Chan, Susan Lester, Samuel Lawrence Whittle and Catherine Louise Hill*

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

Background biopsy or an erythrocyte sedimentation rate (ESR) of 50

Giant cell arteritis (GCA) is a vasculitis of large and mm/h or more. However, in recent years alternative acute
medium-sized vessels and is considered he most common phase reactants such as C-reactive protein (CRP) and plate-
form of vasculitis in the white population over the age of lets have been proposed as more sensitive markers in the
50 [1] with official descriptions present since 1932 [2]. diagnosis of GCA. The postulated mechanism of thrombo-
Temporal artery biopsy remains the gold standard for diag- cytosis in promoting inflammation stems from their early
nosis [3, 4] but has limited sensitivity due to the segmental interaction with the endothelium in inflammatory states
nature of this disease. The sensitivity rates also vary ac- during which they provide adhesion molecules and chemo-
cording to the cranial or large-vessel phenotypes of GCA. tactic stimulation to aid in the recruitment of leukocytes
Rapid diagnosis and management is paramount in GCA and enhance the release of different proinflammatory me-
due to its potential to cause irreversible vision loss [5]. diators [7]. Despite advances in our understanding, there
The American College of Rheumatology research classifi- continues to be a lack of specific diagnostic markers in the
cation criteria for GCA requires three or more of the fol- diagnosis of GCA, which pose a significant challenge,
lowing five criteria [6]: Age 50 years and older, new onset especially when there is a discrepancy between inflamma-
of localized headache, temporal artery tenderness on palpa- tory markers.
tion or decreased pulsation, an abnormal temporal artery Hence, the purpose of this study was to review the util-
ity of ESR, CRP and platelet count in the initial diagnostic
process for GCA to aid in clinical situations where there is
* Correspondence: [email protected]
The Rheumatology Department, The Queen Elizabeth Hospital, 28 Woodville a discordance between the laboratory results.
Road, Woodville, SA 5011, Australia

© 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
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Chan et al. BMC Rheumatology (2019) 3:14 Page 2 of 7

Methods 49 excluded due to incomplete laboratory data (Fig. 1).

We performed a retrospective audit of all temporal ar- Therefore, a total of 270 patients were included in the
tery biopsies reviewed at South Australian teaching hos- analysis. There was no difference in age or gender be-
pitals from January 1st, 2011 to December 31st, 2014. A tween patients who were included (n = 270) or excluded
structured case note review was undertaken of both (n = 150) (Fig. 1).
electronic and paper medical records. The highest re- Of the 270 included patients, 139 (51%) received a
corded values for ESR, CRP and platelet count within a physician diagnosis of GCA, with a positive TAB re-
two-week period prior to biopsy were recorded from ported for 81/139 (58%). A negative TAB result was re-
Oacis (South Australian state-wide electronic medical ported for 57 GCA patients and one TAB result was
record system) and from physician documentation in inconclusive.
paper medical records. The two-week period was deter- ROC curves (Fig. 2) were used to compare the diag-
mined to be optimal by taking into account the adminis- nostic utility of ESR, CRP and platelet counts for GCA,
trative and clinical delays associated with the and area under the curve (AUC) estimates are reported
organisation of a temporal artery biopsy. TAB results, in Table 1. While the AUC estimate for the ESR (0.65) is
with no review of actual specimens and a final clinical slightly less than for CRP (0.72) or platelet counts (0.72),
diagnosis (irrespective of biopsy results) were also noted. indicating a slightly lower utility of the ESR, the three
Final clinical diagnosis was at the discretion of the treat- ROC curves are in fact comparable (p = 0.08), and AUC
ing physician and in biopsy negative cases these were values in this range indicate only moderate, or border-
made based upon suggestive clinical features and clinical line acceptable performance as diagnostic tests [8].
response to glucocorticoid therapy. The diagnosis was Cut-off values, which maximized both the sensitivity
reviewed after treatment and follow up period of at least and specificity of a positive test, were defined from
3 months. sensitivity-specificity curves over the range of observed
Patients were excluded when one or more laboratory values (Fig. 3). The cut-off values for each test were
data (ESR, CRP or platelet count) could not be collected comparable whether determined for biopsy negative
due to either results being inaccessible (due to alternative GCA, biopsy positive GCA or all GCA diagnoses (Table
laboratories in rural or private healthcare referrals), or not 1). Accordingly, cut-off values to define a positive test
being performed due to physician preference. Patients were determined as 50 mm/hour for ESR, which is
with no record of a final clinical diagnosis due to a lack of identical to the recommended cut-off in the ACR 1990
follow up data were also excluded. Reasons for lack of fol- Classification Criteria for GCA [6], 20 mg/L for CRP
low up data included departure of non-domestic patients, and 300 × 109/L for platelet counts. Based on these
alternative non-rheumatological diagnosis and limited ac- cut-off values, the three tests identified a similar pro-
cess to private and rural healthcare medical records where portion of positive results (between 50 and 54%, Table
patients were subsequently reviewed. 1, p = 0.30). Sensitivity estimates for these three tests
Statistical analysis was performed in Stata v14 (Stata- were comparable (p = 0.45) and ranged between 66%
Corp LLC, Texas, USA). The performance of ESR, CRP for ESR and 71% for platelets (Table 1). Specificity esti-
and platelet counts as diagnostic tests for GCA was ana- mates were also comparable (p = 0.11) and ranged be-
lysed using Receiver Operating Characteristic (ROC) tween 57% for ESR and 68% for CRP (Table 1).
analysis, performed using non-parametric ROC regres- While both the ROC-AUC analysis and sensitivity/
sion, with 5000 bootstrap replicates. Optimum cut-off specificity analysis at optimum cut-off values deter-
values to define a positive test were estimated at the mined that ESR, CRP and platelet counts are equivalent
maximum of the product of the sensitivity and specifi- tests with moderate utility for the diagnosis of GCA,
city (Liu’s method). Generalized McNemar tests were there was in fact, only moderate agreement between
used to compare positive/negative results for ESR, CRP the three tests in terms of the individual positive/nega-
and platelet tests matched within each individual, and tive classifications (agreement: 67 95% CI 63, 71; preva-
prevalence and bias adjusted kappa was used to quantify lence and bias adjusted kappa: 0.34, 95%CI 0.26, 0.42).
agreement between the three test results. The three-way Therefore, the three-way relationships between ESR,
relationship between ESR, CRP and platelet positive tests CRP and platelet positive tests for the prediction of
for the prediction of GCA were evaluated by multi-vari- GCA were evaluated by logistic regression (Table 2).
able logistic regression. While each test is significant in individual univariable
regression, the multivariable regression demonstrates
Results that both CRP and platelet count are independent pre-
A total of 420 medical records of patients referred for a dictors of GCA (p < 0.001), whereas the ESR is not
temporal artery biopsy (TAB) were reviewed with 101 (p = 0.76). In other words, given CRP and platelet re-
excluded due to incomplete follow-up data and further sults, the ESR is not informative, and a combination of
Chan et al. BMC Rheumatology (2019) 3:14 Page 3 of 7

Fig. 1 Study Flowchart

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

define a positive test. Our study identified a cut-off of

50 mm/hr. for the ESR, which is the same as that used
in the ACR Classification Criteria for GCA [6], and
which has been utilised by a number of similar studies
[14, 16, 17]. In comparison, other studies have utilized
the upper limit of the normal laboratory range [12, 19],
which is substantially lower than either CRP or ESR
levels generally seen in GCA. Overall, there has been
limited research on appropriate cut-off criteria for inter-
pretation of a positive test for GCA. Importantly, the
cut-off values derived from our study for ESR and CRP
are comparable to those derived by Heyreh et al [18]
who identified a cut-off of 47 mm/hr. for ESR and 24.5
mg/L for CRP, and also similar to those derived by Ker-
mani et al [12] who identified a cut-off of 56 mm/hr. for
ESR and 26.9 mg/L for CRP. Studies evaluating platelet
count for the diagnosis of GCA have generally utilized a
value of 400 × 109/L, derived from laboratory estimates
of the normal range [15, 17, 19], whereas, in contrast to
Fig. 2 Receiver operating curves (ROC) analysis to compare the ESR and CRP, our estimated cut-off for platelets was
diagnostic utility of ESR, CRP and platelet counts for the diagnosis of
within the normal laboratory range.
GCA. The three ROC curves are not significantly different (p = 0.08)
Studies which report AUC estimates for ESR, CRP and
platelets can be directly compared to our study because
and negative GCA patients, as these tests are likely to these are independent of the cut-off values used. We re-
be the most useful in TAB negative patients. ported an AUC for the ESR of 0.65 (95% CI 0.57, 0.72),
The findings of our study are broadly consistent with and previous point estimates of 0.62 [15], 0.67 [17], 0.59
findings of multiple previous studies, yet direct compari- [19] and 0.71 [21] from four previous studies are within
sons are complicated by differences in patients and con- the confidence intervals of our estimate. Our AUC esti-
trol definition, and particularly, cut-off values used to mate for CRP, 0.72 (95% CI 0.65, 0.79), although identical

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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