- Email: [email protected]
The 2016 revised ACR criteria for diagnosis of giant cell arteritis – Our case series: Can this avoid unnecessary temporal artery biopsies?
Accepted Manuscript The 2016 revised ACR criteria for diagnosis of giant cell arteritis – Our case series: Can this avoid unnecessary temporal artery biopsies? Mohamed R. Sait, Mario Lepore, Richard Kwasnicki, Jonathan Allington, Rajesh Balasubramanian, Santosh K. Somasundaram, Rajiv Vashisht, Musa Barkeji PII:
S2405-8572(17)30065-7
DOI:
10.1016/j.ijso.2017.09.003
Reference:
IJSO 65
To appear in:
International Journal of Surgery Open
Received Date: 26 August 2017 Revised Date:
11 September 2017
Accepted Date: 15 September 2017
Please cite this article as: Sait MR, Lepore M, Kwasnicki R, Allington J, Balasubramanian R, Somasundaram SK, Vashisht R, Barkeji M, The 2016 revised ACR criteria for diagnosis of giant cell arteritis – Our case series: Can this avoid unnecessary temporal artery biopsies?, International Journal of Surgery Open (2017), doi: 10.1016/j.ijso.2017.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT THE 2016 REVISED ACR CRITERIA FOR DIAGNOSIS OF GIANT CELL ARTERITIS - OUR CASE SERIES: CAN THIS AVOID UNNECESSARY TEMPORAL ARTERY BIOPSIES?
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Mohamed R Sait , Mario Lepore , Richard Kwasnicki, Jonathan Allington , Rajesh Balasubramanian, Santosh K Somasundaram , Rajiv Vashisht, Musa Barkeji
Affiliation of all authors:
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Department of General Surgery West Middlesex University Hospital Twickenham road, Isleworth TW7 6AF
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Mr. Mohamed R Sait Department of General Surgery West Middlesex University Hospital Twickenham road, Isleworth TW7 6AF Email: [email protected]
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Corresponding Author:
ACCEPTED MANUSCRIPT Abstract Background
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Temporal artery biopsy (TAB) is considered the gold standard for diagnosing Giant Cell Arteritis (GCA). The aim of this study was to compare the functional utility of the 2016 revised ACR (rACR) criteria against the original ACR criteria with a view to avoiding TABs in select groups. We also aimed to investigate the temporal relationship of positive biopsies. Methods
Results and Discussion
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A retrospective study was conducted of patients undergoing TAB from August 2014 to August 2016, at a DGH. Data collected included patient demographics, history, biochemistry, time to TAB from commencement of steroids and histology. The ACR and the rACR scores and the relative TAB results were analysed using ROC to determine statistical measures of performance. Different score thresholds were applied to propose a clinical tool to be used as an adjunct in the management of suspected GCA.
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Forty two TABs were performed during this period of which 10 were males and 32 females. ROC analysis showed significant relationships between both ACR and rACR to TAB result. The AUC for rACR was 0.880 (p<0.001) and for ACR was 0.737 (p=0.023). The median time to TAB from referral was 10 days (IQR 6-13). The diagnostic yield was highest within 8 days (41%) of all positive biopsies. Conclusion
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This study demonstrates the potential value of the rACR criteria and a simple clinical tool is proposed to stratify relevant patients with a view to avoiding unnecessary TAB. Prolonged wait between referral to TAB is also likely to reduce its validity. Key words:
Temporal arteritis; Temporal artery biopsy; giant cell arteritis; ACR criteria; 2016 revised ACR criteria
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ACCEPTED MANUSCRIPT Introduction Giant Cell Arteritis (GCA) is a systemic vasculitis of the medium and large sized vessels with a tendency to involve extracranial branches of the carotid arteries[1]. GCA is 2 to 3 times more common in females than males and occurs in over 50 years of age. It is much more prevalent in the Northern European population with an
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annual incidence rate of above 20 per 100,000 population at risk and is less common amongst the Mediterranean population[1]. Clinical features of GCA typically include headache, temporal artery tenderness, acute vision loss in 5-15% or strokes in 37%, jaw claudication during mastication, Polymyalgia Rheumatica (PMR) or low
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grade fever[1].
Diagnosis of GCA is based on clinical and laboratory tests and application of the
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1990 ACR criteria (Table 1). Three of 5 points are required for clinical diagnosis of GCA from other forms of vasculitis with a sensitivity of 93.5% and specificity of 91.2%[2]. Temporal artery biopsy (TAB) however, remains the gold standard for diagnosis of GCA with a sensitivity of 15-40% and specificity of 100% [3].
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A revised ACR (rACR) has recently been proposed which includes a more extensive set of criteria (Table 2). It has been suggested that in the presence of 3 points or more out of 11, with at least 1 point belonging to Domain 1, the diagnosis of GCA
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can be established, however this is yet to be evaluated.[4]
Both versions require TAB results and therefore an invasive intervention for the
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patient. Our aim was to investigate the value of the non-biopsy criteria to predict GCA, and investigate the use of such scores to avoid biopsy when a very high, or very low likelihood of a positive TAB was predicted. An evaluation of the diagnostic yield of TAB over time from clinical presentation was conducted secondarily.
Methods This was a retrospective study of a consecutive cohort of patients who underwent TAB between August 2014 to August 2016 at a district general hospital. Patients were referred for TAB following commencement of steroids by the Rheumatology and Medical teams with a clinical suspicion of GCA. Local ethical approval was
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ACCEPTED MANUSCRIPT granted by the the Chelsea and Westminster NHS Trust clinical governance team. Patient data including demographics, clinical data, ESR, time to biopsy from referral, length of biopsy specimen and final histology were collected from electronic and paper health records. Patients without full clinical details were excluded except
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for analysing the temporal relationship of positive biopsies.
The ACR and rACR scores were calculated for each patient from clinical records. The elements of these scores related to biopsy were excluded resulting in an ACR score out of 4, and rACR out of 9. The relationship between ACR and rACR scores
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and biopsy results were investigated using Receiver Operating Characteristics
(ROC) analysis[5]. The performance of ACR and rACR to predict biopsy results was measured using the area under the curve (AUC) where 1.0 = perfect, 0.9 = excellent,
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0.8 = good, 0.7 = fair, 0.6 = poor and <0.5 = useless[6]. Next, threshold scores were individually assessed against biopsy results to calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A clinical tool for the intepretation of score and implications of further management was developed. Spearmans rank correlation coefficients were calculated to determine any
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relationship between ACR scores and time to biopsy. IBM SPSS statistics v.24 (IBM corp.) was used for data analysis. This work has been reported in line with the PROCESS criteria[7].
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All TABs were performed under local anaesthesia as day case procedures by senior registrars or consultants. Biopsy specimens were submitted for
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pathological examination in formalin and examined histologically in paraffinembedded sections with serial transverse sections through the entire length of the artery. A minimum of six sections were cut transversely. Hematoxylin and Eosin (H&E) stains were accompanied by Elastic Van Gieson (EVG) histochemistry staining to highlight the internal and external elastic lamina. The diagnosis required identification of a vasculitis characterised by predominance of mononuclear cells or granulomatous inflammation.
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ACCEPTED MANUSCRIPT Results Forty two patients with suspected GCA underwent TABs during the 2 year study period between August 2014 and August 2016. There was a female preponderance with 32 females and 10 males. The age range was between 48 to 91 years with a median age of 63 years. The median time from commencement of steroids to TAB
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was 10 days (IQR – 6 to 13 days). The average length of biopsy specimen was 10.1mm. Four patients were excluded from ROC analysis due to incomplete clinical data availability for ACR and rACR scoring.
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There were a total of 11 (28.9%) positive biopsies. The average overall ACR score was 2.53 (SD = 0.716), with 3.00 (0.603) for positive biopsies and 2.33 (0.667) for negative biopsies. The average overall rACR score was 2.63 (SD =1.49), with 4.18
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(1.34) for positive biopsies and 2.00 (1.02) for negative biopsies. The AUC calculated by ROC analysis was 0.737 (p = 0.023) for ACR and 0.880 (p < 0.001) for rACR.
A clinical management tool is proposed using rACR scores (Table 5). In this study
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cohort, rACR of 3 has high sensitivity (90.9%) which means 90% of GCA cases are identified using the score alone (i.e. 9.1% of GCA cases would score less than 3 and would be missed). However as the PPV is only 55.6% there still should be a biopsy
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to confirm GCA as otherwise 45% of patients are being treated unnecessarily. The patients that score rACR of 5 or more are extremely likely to have GCA (PPV is 100%), so arguably these patients should just be treated and avoid biopsy. Twelve
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patients scored 3 – 4 in rACR and of these, 3 patients (25%) had positive biopsy. Six patients scored 5 or more and all had positive biopsies.
Utilising a similar tool for ACR, using a score of 2 as criteria to detect GCA has good sensitivity of 100%, so would pick up all cases. But, as the PPV is only 31% there would be almost 70% of patients treated unnecessarily and so would need a biopsy. Using an ACR of 4, the PPV is 100% and so these patients could avoid biopsy and be treated with steroids as all are likely to have GCA. Thirty-three patients scored 2–
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ACCEPTED MANUSCRIPT 3. Out of these, 9 patients (27%) had a positive biopsy. Two in this group scored 4 and both had positive biopsies.
Comparing the two models (Table 6), the classic ACR would mean 33/38 patients
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would have had a biopsy of which 24 would be negative. With the revised ACR score of 3-4 there would only be 12/38 patients having biopsies of which 9 were
negative. The number of biopsies required using ACR is almost 3 times the number needed using rACR (33 vs 12) which would generate similar outcomes with this
dataset. Furthermore, patients scoring greater than 5 on the rACR (n=6) could have
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avoided biopsies and have a very high likelihood of GCA, compared to only 2
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patients scoring 4 using normal ACR who would avoid biopsies.
Temporality of test
The median time taken from referral to biopsy was 10 days. The diagnostic yield from the test showed a bell shaped curve (Figure 2) with a peak at 8 days (41%). Within the first 8 days, 41% (7 out of 17) of biopsies were positive. Between day 8
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and day 16, 16% (4 out of 25) of biopsies were positive. There was no correlation between ACR or rACR scores with time to biopsy (Spearmans rank R = -1.32 and -
Discussion
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0.057 respectively, p >0.05).
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This study demonstrates the statistical performance of the ACR criteria in relation to TAB results. Furthermore, the more extensive rACR has been shown to have similar, if not more value than ACR particularly considering the functional relevance of TAB in high or low risk patient groups. The diagnosis of GCA is traditionally based on the patients’ clinical and biochemical findings summated using the ACR scoring system. Biopsy provides confirmation of the diagnosis and steroids are stopped if it is negative in the absence of strong clinical suspicion. Removing the biopsy element of the ACR score leaves only 4 criteria, which is difficult to begin to use to justify avoiding biopsy for low or high-risk patients. The revised ACR however has 9 non-biopsy criteria which allows for greater differentiation of patient likelihood
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ACCEPTED MANUSCRIPT of a positive TAB result and GCA diagnosis. In this study a score of 3/9 on the rACR criteria would detect 91% of cases which would have avoided 20 biopsies. It has to be weighed-up whether potentially missing 1-2 cases of GCA with TAB equates to the morbidity (haematoma, scalp necrosis, infection and nerve damage[8]’[9]) and cost associated with 20 biopsies. Similarly, 100% of patients scoring 5 or more had
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positive biopsy results and so were potentially avoidable. The middle group of patients scoring 3-4/9 are the key cases to be performing TAB as they could be
equivocal. The original ACR has a much poorer utility for preventing unnecessary
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biopsies due to fewer criteria for assessment of risk.
Some studies have examined the ACR criteria individually with the aim of reducing
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the number of negative biopsies and conclude that the presence of certain individual criteria such as jaw claudication and double vision have a stronger positive predictive value of GCA and thereby help in commencement of steroid therapy[10]. In a retrospective audit involving 55 TAB’s in order to reduce total true negative biopsies, the authors suggested implementing ACR scoring system to objectify decision for TAB[11]. However, this could often result in unnecessary biopsies in low ACR
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scores. In a study by Toren et al, clinical features most predictive of a positive biopsy were jaw claudication and abnormal temporal artery pulse[12]. Apart from ESR, C reactive protein (CRP) values and sex of the patient, addition of platelet count and age, when fully used to generate a post-test probability, could influence a clinician’s
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decision to perform a biopsy[13].
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Davies et al suggested TAB should be reserved for scores of 2 (borderline) of the ACR criteria for diagnosis of GCA. In those with scores of 3 pre-biopsy, performing a TAB adds little to management, as treatment will still be continued based on clinical suspicion[14]. In a retrospective review of 185 patients with suspected GCA, TAB was of benefit in patients who scored 2 or 3 on the ACR criteria without biopsy[15]. In a study by Hussain et al involving 100 patients referred for TAB, 53% of patients had already fulfilled the ACR criteria for a clinical diagnosis of GCA and biopsy therefore had no impact on management[16]. They also demonstrated a linear correlation of high ACR scores with positive biopsies and recommended that biopsies were most beneficial when there was diagnostic uncertainty such as ACR
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ACCEPTED MANUSCRIPT scores of 1 or 2, an atypical presentation or in whom steroids were relatively contraindicated such as those with diabetes or osteoporosis[16]. Our study also confirms that ACR score of 4 had a sensitivity of 18.2% and a PPV of 100% thereby implying that patients with such scores could avoid biopsy and be treated with
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steroids as they are likely to have GCA.
Other technological methods have been proposed in place of TAB, including Ultrasound Scan (USS)[3]. Colour Duplex Ultrasound can reveal vessel
wall oedema, typically known as halo, through its length thereby potentially
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overcoming the problem of skip lesions. However the poor intra-operator reliability and high skill requirements are barriers to widespread implementation[8]. MRI is useful where echosonography and/or vascular biopsy for histopathological analyses
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are not possible. It is also used to assess and follow up cases with large vessel involvement[17]. Other imaging modalities such as PET-CT has a 85% sensitivity and a 95% specificity in detecting large vessel vasculitis[18].
Within the related scientific literature, this study contributes by asking the same
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questions regarding the avoidance of biopsy yet using the revised ACR criteria. The results are promising and even within a relatively small dataset suggest significant functional value in the rACR in the management of suspected GCA.
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A simple graduated management plan is proposed whereby rACR scores of ≤2 may not need a biopsy as they are very unlikely to have GCA. In patients with rACR
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scores of ≥5 a TAB will not be necessary as they are highly likely to have GCA and should continue steroid therapy. Biopsy will be required in those with rACR scores 3 and 4 as it is these patients who are most variable in TAB result.
Regarding time to TAB, the diagnostic yield in this study cohort appears to wane, 8 days following commencement of steroids. This observation was not associated with lower ACR or rACR scores. The difference of 41% (prior to 8 days) to 16% (after 8 days), whilst not statistically confirmed is likely to be of some clinical significance and raises the question whether TAB has a beneficial role after around 8 days of commencement of steroids. There are however reports of positive biopsies even after 4 weeks of commencement of steroids[19]. 8
ACCEPTED MANUSCRIPT The results of the study must be considered in the context of the limitations in sample size. The work is aimed to pilot the use of the revised criteria in determining the value of TAB in the diagnosis of GCA and a larger prospective study would be necessary to validate and further define these findings. We also did not examine a
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specific clinical symptom or sign such as jaw claudication or visual disturbances of the revised ACR criteria driving the sensitivity and positive predictive values high due to smaller sample size. Despite these limitations, revised ACR score stratification offers an opportunity to revisit ACR criteria for the diagnosis of GCA which were not
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designed for this purpose[20] and meant to distinguish GCA from other form of vasculitis.
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Conclusion
Stratification of patients based on ACR and revised ACR criteria has not been applied to in literature for diagnosis of GCA. This study demonstrates the potential value of the rACR score as a more extensive criteria in selecting patients for TAB in the management of suspected GCA. A simple clinical tool has been proposed to
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stratify relevant patients with a view to avoiding unnecessary TAB. It is also noted that prolonged wait between commencement of steroids and TAB is likely to reduce the validity of the investigation. Future work ideally across multiple centres with strict inclusion criteria should be carried out prior to the potential application of a biopsy-
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avoiding algorithm in GCA management.
Additional Information
There is no conflict of interest or any source of funding related to this work.
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ACCEPTED MANUSCRIPT REFERENCES:
Nesher G, Breuer GS, Giant Cell Arteritis and Polymyalgia Rheumatica: 2016 Update, Rambam Maimonides Med. J. 7 (2016) e0035. doi:10.5041/RMMJ.1.
[2]
K. Le, L.M. Bools, A.B. Lynn, T. V. Clancy, W.B. Hooks, W.W. Hope, The effect of temporal artery biopsy on the treatment of temporal arteritis, Am. J. Surg. 209 (2015) 338–341. doi:10.1016/j.amjsurg.2014.07.007.
[3]
A.T. Cristaudo, R. Mizumoto, R. Hendahewa, The impact of temporal artery biopsy on surgical practice, Ann. Med. Surg. 11 (2016) 47–51. doi:10.1016/j.amsu.2016.09.004.
[4]
I. Salehi-Abari, 2016 ACR Revised Criteria for Early Diagnosis of Giant Cell (Temporal) Arteritis, 3 (2016) 1–4. http://aperito.org/uploads/pdf/ADTAOA-3119.pdf.
[5]
M.H. Zweig, G. Campbell, Receiver-operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine, Clin. Chem. 39 (1993) 561– 577. doi:ROC; Receiver-Operating Characteristic; SDT; Signal Detection Theory.
[6]
M.S. Pepe, The Statistical Evaluation of Medical Tests for Classification and Prediction, 2003. http://www.amazon.com/dp/0198565828.
[7]
R.A. Agha, A.J. Fowler, S. Rajmohan, I. Barai, D.P. Orgill, Preferred reporting of case series in surgery; the PROCESS guidelines, Int. J. Surg. 36 (2016) 319–323. doi:10.1016/j.ijsu.2016.10.025.
[8]
S. Monti, A. Floris, C. Ponte, W.A. Schmidt, A.P. Diamantopoulos, C. Pereira, J. Piper, R. Luqmani, The use of ultrasound to assess giant cell arteritis: review of the current evidence and practical guide for the rheumatologist, Rheumatology. (2017) 1–9. doi:10.1093/rheumatology/kex173.
[9]
A. Gunawardene, H. Chant, Facial nerve injury during temporal artery biopsy, Ann. R. Coll. Surg. Engl. 96 (2014) 257–260. doi:10.1308/003588414X13814021679438.
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[1]
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[10] O. Article, Initiation of Glucocorticoid Therapy : Before or After, 79 (2004) 483– 491. doi:10.1016/S0025-6196(11)62765-1. [11] A. Pieri, R. Milligan, V. Hegde, C. Hennessy, Temporal artery biopsy: are we doing it right?, Int. J. Health Care Qual. Assur. 26 (2013) 559–563. doi:10.1108/IJHCQA-06-2012-0055. [12] A. Toren, E. Weis, V. Patel, B. Monteith, S. Gilberg, D. Jordan, Clinical predictors of positive temporal artery biopsy, Can. J. Ophthalmol. 51 (2016) 476–481. doi:10.1016/j.jcjo.2016.05.021. [13] S. Pathogens, HHS Public Access, 1848 (2016) 3047–3054. doi:10.1016/j.bbamem.2015.02.010.Cationic. [14] C.G. Davies, D.J. May, The role of temporal artery biopsies in giant cell arteritis, Ann. R. Coll. Surg. Engl. 93 (2011) 4–5.
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ACCEPTED MANUSCRIPT doi:10.1308/003588411X12851639107476. [15] E.M. Quinn, D.E. Kearney, J. Kelly, C. Keohane, H.P. Redmond, Temporal artery biopsy is not required in all cases of suspected giant cell arteritis, Ann. Vasc. Surg. 26 (2012) 649–654. doi:10.1016/j.avsg.2011.10.009.
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[16] O. Hussain, A. McKay, K. Fairburn, P. Doyle, R. Orr, Diagnosis of giant cell arteritis: When should we biopsy the temporal artery?, Br. J. Oral Maxillofac. Surg. 54 (2016) 327–330. doi:10.1016/j.bjoms.2015.12.013. [17] A. Gudelj Gračanin, J. Ćurić, J. Lončarević, J. Morović- Vergles, Magnetic resonance imaging in the diagnosis and follow-up of giant cell arteritis: case report and review of literature, Eur. J. Rheumatol. 2 (2015) 125–128. doi:10.5152/eurjrheum.2015.0080.
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[18] F. Kesten, M. Aschwanden, P. Gubser, K. Glatz, T. Daikeler, C. Hess, Giant cell arteritis--a changing entity., Swiss Med. Wkly. 141 (2011). doi:10.4414/smw.2011.13272.
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[19] J. Narváez, B. Bernad, D. Roig-Vilaseca, C. García-Gómez, C. GómezVaquero, X. Juanola, J. Rodriguez-Moreno, J.M. Nolla, J. Valverde, Influence of Previous Corticosteroid Therapy on Temporal Artery Biopsy Yield in Giant Cell Arteritis, Semin. Arthritis Rheum. 37 (2007) 13–19. doi:10.1016/j.semarthrit.2006.12.005.
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[20] B. Seeliger, J. Sznajd, J.C. Robson, A. Judge, A. Craven, P.C. Grayson, R.S. Suppiah, R.A. Watts, P.A. Merkel, R.A. Luqmani, Are the 1990 American College of Rheumatology vasculitis classification criteria still valid?, Rheumatology. (2017) 1–8. doi:10.1093/rheumatology/kex075.
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ACCEPTED MANUSCRIPT Score Criteria Age at onset ≥50 years
2
A new headache
3
Temporal artery abnormality such as tenderness to palpation or decreased pulsation
4
Erythrocyte sedimentation rate ≥50 mm/h
5
Abnormal artery biopsy showing vasculitis with mononuclear cell or granulomatous inflammation, usually with giant cell infiltrates
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1
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Table 1: The American College of Rheumatology 1990 GCA Classification Criteria
ACCEPTED MANUSCRIPT Score Entry: N/A
Age at onset ≥ 50 years old Absence of exclusion criteria(b) Domain I New onset localized headache(c) 1p
1
Sudden onset of visual disturbances(c) 1p
2
Polymyalgia Rheumatica (PMR) 2p
1
Jaw Claudication(c) 1p
2
Abnormal temporal artery (d) up to 2p
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Domain II
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1
1
Unexplained fever and/or anaemia 1p
1
ESR ≥ 50 mm/hour (e)
2
Compatible pathology (f) up to 2p
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1p
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Table 2: Revised ACR criteria (rACR) for diagnosis of GCA(a)
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a. In the presence of 3 points or more out of 11 with at least one point belonging to domain I along with all entry criteria, the diagnosis of Giant cell arteritis can be established; b. Exclusion criteria are including : ENT and eye inflammation, kidney, skin and peripheral nervous system involvement, lung infiltration, lymphadenopathies, stiff neck and digital gangrene or ulceration; c. No other aetiologies can better explain any one of the criteria; d. Enlarged and/or pulseless temporal artery : 1.p. / tender temporal artery: 1.p; e. It must be ignored in the presence of PMR; f. Vascular and/or perivascular fibrinoid necrosis along with leucocyte infiltration: 1.p. /and granuloma: 1.p
ACCEPTED MANUSCRIPT Sensitivity(
Specificity(
PPV(% NPV(
(x/4)
%)
%)
)
%)
2
100%
11.1%
31.4%
100%
3
81.8%
55.6%
42.9%
88.2%
4
18.2%
100%
100%
75%
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ACR Score
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Table 3: Performance scores for ACR and TAB
rACR Score
Sensitivity(
Specificity(
(x/9)
%)
%)
4
70.4
55.6
95
72.7
88.9
72.7
88.9
54.5
100
100
84.4
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5
%)
90.9
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3
PPV(%) NPV(
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Table 4: Performance scores for rACR and TAB
ACCEPTED MANUSCRIPT rACR score
Comments
Management
≤2
Unlikely GCA
No TAB or steroids
3 and 4
Requires
Perform TAB
(x/9)
≥5
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confirmation Likely GCA
No TAB, continue steroids
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Table 5 – Proposed clinical management tool
rACR Score 3-4
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ACR Score 2-3 33
12
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Table 6: Comparative groups with borderline scores
ACCEPTED MANUSCRIPT ACR
rACR
AUC = 0.880
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AUC = 0.737
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Figure 1 – Receiver operating characteristics analysis curves for ACR and rACR scores and TAB results
0.45
0.40
0.30
0.25
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DIAGNOSTIC YIELD
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0.35
0.20 0.15
0.10 0.05 0.00 1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 DAY OF BIOPSY
Figure 2. Graph showing change in diagnostic yield of TAB over time
ACCEPTED MANUSCRIPT HIGHLIGHTS
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•
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•
Risk stratification of the 2016 revised ACR (rACR) criteria is a simple clinical tool proposed for the diagnosis of GCA This could help avoid unnecessary Temporal artery biopsies in select group of patients Temporal artery biopsies should be performed early on from commencement of steroids
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•
S2405-8572(17)30065-7
DOI:
10.1016/j.ijso.2017.09.003
Reference:
IJSO 65
To appear in:
International Journal of Surgery Open
Received Date: 26 August 2017 Revised Date:
11 September 2017
Accepted Date: 15 September 2017
Please cite this article as: Sait MR, Lepore M, Kwasnicki R, Allington J, Balasubramanian R, Somasundaram SK, Vashisht R, Barkeji M, The 2016 revised ACR criteria for diagnosis of giant cell arteritis – Our case series: Can this avoid unnecessary temporal artery biopsies?, International Journal of Surgery Open (2017), doi: 10.1016/j.ijso.2017.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT THE 2016 REVISED ACR CRITERIA FOR DIAGNOSIS OF GIANT CELL ARTERITIS - OUR CASE SERIES: CAN THIS AVOID UNNECESSARY TEMPORAL ARTERY BIOPSIES?
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Mohamed R Sait , Mario Lepore , Richard Kwasnicki, Jonathan Allington , Rajesh Balasubramanian, Santosh K Somasundaram , Rajiv Vashisht, Musa Barkeji
Affiliation of all authors:
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Department of General Surgery West Middlesex University Hospital Twickenham road, Isleworth TW7 6AF
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Mr. Mohamed R Sait Department of General Surgery West Middlesex University Hospital Twickenham road, Isleworth TW7 6AF Email: [email protected]
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Corresponding Author:
ACCEPTED MANUSCRIPT Abstract Background
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Temporal artery biopsy (TAB) is considered the gold standard for diagnosing Giant Cell Arteritis (GCA). The aim of this study was to compare the functional utility of the 2016 revised ACR (rACR) criteria against the original ACR criteria with a view to avoiding TABs in select groups. We also aimed to investigate the temporal relationship of positive biopsies. Methods
Results and Discussion
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A retrospective study was conducted of patients undergoing TAB from August 2014 to August 2016, at a DGH. Data collected included patient demographics, history, biochemistry, time to TAB from commencement of steroids and histology. The ACR and the rACR scores and the relative TAB results were analysed using ROC to determine statistical measures of performance. Different score thresholds were applied to propose a clinical tool to be used as an adjunct in the management of suspected GCA.
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Forty two TABs were performed during this period of which 10 were males and 32 females. ROC analysis showed significant relationships between both ACR and rACR to TAB result. The AUC for rACR was 0.880 (p<0.001) and for ACR was 0.737 (p=0.023). The median time to TAB from referral was 10 days (IQR 6-13). The diagnostic yield was highest within 8 days (41%) of all positive biopsies. Conclusion
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This study demonstrates the potential value of the rACR criteria and a simple clinical tool is proposed to stratify relevant patients with a view to avoiding unnecessary TAB. Prolonged wait between referral to TAB is also likely to reduce its validity. Key words:
Temporal arteritis; Temporal artery biopsy; giant cell arteritis; ACR criteria; 2016 revised ACR criteria
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ACCEPTED MANUSCRIPT Introduction Giant Cell Arteritis (GCA) is a systemic vasculitis of the medium and large sized vessels with a tendency to involve extracranial branches of the carotid arteries[1]. GCA is 2 to 3 times more common in females than males and occurs in over 50 years of age. It is much more prevalent in the Northern European population with an
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annual incidence rate of above 20 per 100,000 population at risk and is less common amongst the Mediterranean population[1]. Clinical features of GCA typically include headache, temporal artery tenderness, acute vision loss in 5-15% or strokes in 37%, jaw claudication during mastication, Polymyalgia Rheumatica (PMR) or low
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grade fever[1].
Diagnosis of GCA is based on clinical and laboratory tests and application of the
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1990 ACR criteria (Table 1). Three of 5 points are required for clinical diagnosis of GCA from other forms of vasculitis with a sensitivity of 93.5% and specificity of 91.2%[2]. Temporal artery biopsy (TAB) however, remains the gold standard for diagnosis of GCA with a sensitivity of 15-40% and specificity of 100% [3].
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A revised ACR (rACR) has recently been proposed which includes a more extensive set of criteria (Table 2). It has been suggested that in the presence of 3 points or more out of 11, with at least 1 point belonging to Domain 1, the diagnosis of GCA
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can be established, however this is yet to be evaluated.[4]
Both versions require TAB results and therefore an invasive intervention for the
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patient. Our aim was to investigate the value of the non-biopsy criteria to predict GCA, and investigate the use of such scores to avoid biopsy when a very high, or very low likelihood of a positive TAB was predicted. An evaluation of the diagnostic yield of TAB over time from clinical presentation was conducted secondarily.
Methods This was a retrospective study of a consecutive cohort of patients who underwent TAB between August 2014 to August 2016 at a district general hospital. Patients were referred for TAB following commencement of steroids by the Rheumatology and Medical teams with a clinical suspicion of GCA. Local ethical approval was
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ACCEPTED MANUSCRIPT granted by the the Chelsea and Westminster NHS Trust clinical governance team. Patient data including demographics, clinical data, ESR, time to biopsy from referral, length of biopsy specimen and final histology were collected from electronic and paper health records. Patients without full clinical details were excluded except
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for analysing the temporal relationship of positive biopsies.
The ACR and rACR scores were calculated for each patient from clinical records. The elements of these scores related to biopsy were excluded resulting in an ACR score out of 4, and rACR out of 9. The relationship between ACR and rACR scores
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and biopsy results were investigated using Receiver Operating Characteristics
(ROC) analysis[5]. The performance of ACR and rACR to predict biopsy results was measured using the area under the curve (AUC) where 1.0 = perfect, 0.9 = excellent,
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0.8 = good, 0.7 = fair, 0.6 = poor and <0.5 = useless[6]. Next, threshold scores were individually assessed against biopsy results to calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A clinical tool for the intepretation of score and implications of further management was developed. Spearmans rank correlation coefficients were calculated to determine any
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relationship between ACR scores and time to biopsy. IBM SPSS statistics v.24 (IBM corp.) was used for data analysis. This work has been reported in line with the PROCESS criteria[7].
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All TABs were performed under local anaesthesia as day case procedures by senior registrars or consultants. Biopsy specimens were submitted for
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pathological examination in formalin and examined histologically in paraffinembedded sections with serial transverse sections through the entire length of the artery. A minimum of six sections were cut transversely. Hematoxylin and Eosin (H&E) stains were accompanied by Elastic Van Gieson (EVG) histochemistry staining to highlight the internal and external elastic lamina. The diagnosis required identification of a vasculitis characterised by predominance of mononuclear cells or granulomatous inflammation.
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ACCEPTED MANUSCRIPT Results Forty two patients with suspected GCA underwent TABs during the 2 year study period between August 2014 and August 2016. There was a female preponderance with 32 females and 10 males. The age range was between 48 to 91 years with a median age of 63 years. The median time from commencement of steroids to TAB
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was 10 days (IQR – 6 to 13 days). The average length of biopsy specimen was 10.1mm. Four patients were excluded from ROC analysis due to incomplete clinical data availability for ACR and rACR scoring.
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There were a total of 11 (28.9%) positive biopsies. The average overall ACR score was 2.53 (SD = 0.716), with 3.00 (0.603) for positive biopsies and 2.33 (0.667) for negative biopsies. The average overall rACR score was 2.63 (SD =1.49), with 4.18
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(1.34) for positive biopsies and 2.00 (1.02) for negative biopsies. The AUC calculated by ROC analysis was 0.737 (p = 0.023) for ACR and 0.880 (p < 0.001) for rACR.
A clinical management tool is proposed using rACR scores (Table 5). In this study
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cohort, rACR of 3 has high sensitivity (90.9%) which means 90% of GCA cases are identified using the score alone (i.e. 9.1% of GCA cases would score less than 3 and would be missed). However as the PPV is only 55.6% there still should be a biopsy
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to confirm GCA as otherwise 45% of patients are being treated unnecessarily. The patients that score rACR of 5 or more are extremely likely to have GCA (PPV is 100%), so arguably these patients should just be treated and avoid biopsy. Twelve
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patients scored 3 – 4 in rACR and of these, 3 patients (25%) had positive biopsy. Six patients scored 5 or more and all had positive biopsies.
Utilising a similar tool for ACR, using a score of 2 as criteria to detect GCA has good sensitivity of 100%, so would pick up all cases. But, as the PPV is only 31% there would be almost 70% of patients treated unnecessarily and so would need a biopsy. Using an ACR of 4, the PPV is 100% and so these patients could avoid biopsy and be treated with steroids as all are likely to have GCA. Thirty-three patients scored 2–
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ACCEPTED MANUSCRIPT 3. Out of these, 9 patients (27%) had a positive biopsy. Two in this group scored 4 and both had positive biopsies.
Comparing the two models (Table 6), the classic ACR would mean 33/38 patients
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would have had a biopsy of which 24 would be negative. With the revised ACR score of 3-4 there would only be 12/38 patients having biopsies of which 9 were
negative. The number of biopsies required using ACR is almost 3 times the number needed using rACR (33 vs 12) which would generate similar outcomes with this
dataset. Furthermore, patients scoring greater than 5 on the rACR (n=6) could have
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avoided biopsies and have a very high likelihood of GCA, compared to only 2
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patients scoring 4 using normal ACR who would avoid biopsies.
Temporality of test
The median time taken from referral to biopsy was 10 days. The diagnostic yield from the test showed a bell shaped curve (Figure 2) with a peak at 8 days (41%). Within the first 8 days, 41% (7 out of 17) of biopsies were positive. Between day 8
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and day 16, 16% (4 out of 25) of biopsies were positive. There was no correlation between ACR or rACR scores with time to biopsy (Spearmans rank R = -1.32 and -
Discussion
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0.057 respectively, p >0.05).
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This study demonstrates the statistical performance of the ACR criteria in relation to TAB results. Furthermore, the more extensive rACR has been shown to have similar, if not more value than ACR particularly considering the functional relevance of TAB in high or low risk patient groups. The diagnosis of GCA is traditionally based on the patients’ clinical and biochemical findings summated using the ACR scoring system. Biopsy provides confirmation of the diagnosis and steroids are stopped if it is negative in the absence of strong clinical suspicion. Removing the biopsy element of the ACR score leaves only 4 criteria, which is difficult to begin to use to justify avoiding biopsy for low or high-risk patients. The revised ACR however has 9 non-biopsy criteria which allows for greater differentiation of patient likelihood
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ACCEPTED MANUSCRIPT of a positive TAB result and GCA diagnosis. In this study a score of 3/9 on the rACR criteria would detect 91% of cases which would have avoided 20 biopsies. It has to be weighed-up whether potentially missing 1-2 cases of GCA with TAB equates to the morbidity (haematoma, scalp necrosis, infection and nerve damage[8]’[9]) and cost associated with 20 biopsies. Similarly, 100% of patients scoring 5 or more had
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positive biopsy results and so were potentially avoidable. The middle group of patients scoring 3-4/9 are the key cases to be performing TAB as they could be
equivocal. The original ACR has a much poorer utility for preventing unnecessary
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biopsies due to fewer criteria for assessment of risk.
Some studies have examined the ACR criteria individually with the aim of reducing
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the number of negative biopsies and conclude that the presence of certain individual criteria such as jaw claudication and double vision have a stronger positive predictive value of GCA and thereby help in commencement of steroid therapy[10]. In a retrospective audit involving 55 TAB’s in order to reduce total true negative biopsies, the authors suggested implementing ACR scoring system to objectify decision for TAB[11]. However, this could often result in unnecessary biopsies in low ACR
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scores. In a study by Toren et al, clinical features most predictive of a positive biopsy were jaw claudication and abnormal temporal artery pulse[12]. Apart from ESR, C reactive protein (CRP) values and sex of the patient, addition of platelet count and age, when fully used to generate a post-test probability, could influence a clinician’s
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decision to perform a biopsy[13].
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Davies et al suggested TAB should be reserved for scores of 2 (borderline) of the ACR criteria for diagnosis of GCA. In those with scores of 3 pre-biopsy, performing a TAB adds little to management, as treatment will still be continued based on clinical suspicion[14]. In a retrospective review of 185 patients with suspected GCA, TAB was of benefit in patients who scored 2 or 3 on the ACR criteria without biopsy[15]. In a study by Hussain et al involving 100 patients referred for TAB, 53% of patients had already fulfilled the ACR criteria for a clinical diagnosis of GCA and biopsy therefore had no impact on management[16]. They also demonstrated a linear correlation of high ACR scores with positive biopsies and recommended that biopsies were most beneficial when there was diagnostic uncertainty such as ACR
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ACCEPTED MANUSCRIPT scores of 1 or 2, an atypical presentation or in whom steroids were relatively contraindicated such as those with diabetes or osteoporosis[16]. Our study also confirms that ACR score of 4 had a sensitivity of 18.2% and a PPV of 100% thereby implying that patients with such scores could avoid biopsy and be treated with
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steroids as they are likely to have GCA.
Other technological methods have been proposed in place of TAB, including Ultrasound Scan (USS)[3]. Colour Duplex Ultrasound can reveal vessel
wall oedema, typically known as halo, through its length thereby potentially
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overcoming the problem of skip lesions. However the poor intra-operator reliability and high skill requirements are barriers to widespread implementation[8]. MRI is useful where echosonography and/or vascular biopsy for histopathological analyses
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are not possible. It is also used to assess and follow up cases with large vessel involvement[17]. Other imaging modalities such as PET-CT has a 85% sensitivity and a 95% specificity in detecting large vessel vasculitis[18].
Within the related scientific literature, this study contributes by asking the same
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questions regarding the avoidance of biopsy yet using the revised ACR criteria. The results are promising and even within a relatively small dataset suggest significant functional value in the rACR in the management of suspected GCA.
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A simple graduated management plan is proposed whereby rACR scores of ≤2 may not need a biopsy as they are very unlikely to have GCA. In patients with rACR
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scores of ≥5 a TAB will not be necessary as they are highly likely to have GCA and should continue steroid therapy. Biopsy will be required in those with rACR scores 3 and 4 as it is these patients who are most variable in TAB result.
Regarding time to TAB, the diagnostic yield in this study cohort appears to wane, 8 days following commencement of steroids. This observation was not associated with lower ACR or rACR scores. The difference of 41% (prior to 8 days) to 16% (after 8 days), whilst not statistically confirmed is likely to be of some clinical significance and raises the question whether TAB has a beneficial role after around 8 days of commencement of steroids. There are however reports of positive biopsies even after 4 weeks of commencement of steroids[19]. 8
ACCEPTED MANUSCRIPT The results of the study must be considered in the context of the limitations in sample size. The work is aimed to pilot the use of the revised criteria in determining the value of TAB in the diagnosis of GCA and a larger prospective study would be necessary to validate and further define these findings. We also did not examine a
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specific clinical symptom or sign such as jaw claudication or visual disturbances of the revised ACR criteria driving the sensitivity and positive predictive values high due to smaller sample size. Despite these limitations, revised ACR score stratification offers an opportunity to revisit ACR criteria for the diagnosis of GCA which were not
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designed for this purpose[20] and meant to distinguish GCA from other form of vasculitis.
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Conclusion
Stratification of patients based on ACR and revised ACR criteria has not been applied to in literature for diagnosis of GCA. This study demonstrates the potential value of the rACR score as a more extensive criteria in selecting patients for TAB in the management of suspected GCA. A simple clinical tool has been proposed to
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stratify relevant patients with a view to avoiding unnecessary TAB. It is also noted that prolonged wait between commencement of steroids and TAB is likely to reduce the validity of the investigation. Future work ideally across multiple centres with strict inclusion criteria should be carried out prior to the potential application of a biopsy-
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avoiding algorithm in GCA management.
Additional Information
There is no conflict of interest or any source of funding related to this work.
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ACCEPTED MANUSCRIPT REFERENCES:
Nesher G, Breuer GS, Giant Cell Arteritis and Polymyalgia Rheumatica: 2016 Update, Rambam Maimonides Med. J. 7 (2016) e0035. doi:10.5041/RMMJ.1.
[2]
K. Le, L.M. Bools, A.B. Lynn, T. V. Clancy, W.B. Hooks, W.W. Hope, The effect of temporal artery biopsy on the treatment of temporal arteritis, Am. J. Surg. 209 (2015) 338–341. doi:10.1016/j.amjsurg.2014.07.007.
[3]
A.T. Cristaudo, R. Mizumoto, R. Hendahewa, The impact of temporal artery biopsy on surgical practice, Ann. Med. Surg. 11 (2016) 47–51. doi:10.1016/j.amsu.2016.09.004.
[4]
I. Salehi-Abari, 2016 ACR Revised Criteria for Early Diagnosis of Giant Cell (Temporal) Arteritis, 3 (2016) 1–4. http://aperito.org/uploads/pdf/ADTAOA-3119.pdf.
[5]
M.H. Zweig, G. Campbell, Receiver-operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine, Clin. Chem. 39 (1993) 561– 577. doi:ROC; Receiver-Operating Characteristic; SDT; Signal Detection Theory.
[6]
M.S. Pepe, The Statistical Evaluation of Medical Tests for Classification and Prediction, 2003. http://www.amazon.com/dp/0198565828.
[7]
R.A. Agha, A.J. Fowler, S. Rajmohan, I. Barai, D.P. Orgill, Preferred reporting of case series in surgery; the PROCESS guidelines, Int. J. Surg. 36 (2016) 319–323. doi:10.1016/j.ijsu.2016.10.025.
[8]
S. Monti, A. Floris, C. Ponte, W.A. Schmidt, A.P. Diamantopoulos, C. Pereira, J. Piper, R. Luqmani, The use of ultrasound to assess giant cell arteritis: review of the current evidence and practical guide for the rheumatologist, Rheumatology. (2017) 1–9. doi:10.1093/rheumatology/kex173.
[9]
A. Gunawardene, H. Chant, Facial nerve injury during temporal artery biopsy, Ann. R. Coll. Surg. Engl. 96 (2014) 257–260. doi:10.1308/003588414X13814021679438.
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TE D
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SC
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[1]
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[10] O. Article, Initiation of Glucocorticoid Therapy : Before or After, 79 (2004) 483– 491. doi:10.1016/S0025-6196(11)62765-1. [11] A. Pieri, R. Milligan, V. Hegde, C. Hennessy, Temporal artery biopsy: are we doing it right?, Int. J. Health Care Qual. Assur. 26 (2013) 559–563. doi:10.1108/IJHCQA-06-2012-0055. [12] A. Toren, E. Weis, V. Patel, B. Monteith, S. Gilberg, D. Jordan, Clinical predictors of positive temporal artery biopsy, Can. J. Ophthalmol. 51 (2016) 476–481. doi:10.1016/j.jcjo.2016.05.021. [13] S. Pathogens, HHS Public Access, 1848 (2016) 3047–3054. doi:10.1016/j.bbamem.2015.02.010.Cationic. [14] C.G. Davies, D.J. May, The role of temporal artery biopsies in giant cell arteritis, Ann. R. Coll. Surg. Engl. 93 (2011) 4–5.
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ACCEPTED MANUSCRIPT doi:10.1308/003588411X12851639107476. [15] E.M. Quinn, D.E. Kearney, J. Kelly, C. Keohane, H.P. Redmond, Temporal artery biopsy is not required in all cases of suspected giant cell arteritis, Ann. Vasc. Surg. 26 (2012) 649–654. doi:10.1016/j.avsg.2011.10.009.
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[16] O. Hussain, A. McKay, K. Fairburn, P. Doyle, R. Orr, Diagnosis of giant cell arteritis: When should we biopsy the temporal artery?, Br. J. Oral Maxillofac. Surg. 54 (2016) 327–330. doi:10.1016/j.bjoms.2015.12.013. [17] A. Gudelj Gračanin, J. Ćurić, J. Lončarević, J. Morović- Vergles, Magnetic resonance imaging in the diagnosis and follow-up of giant cell arteritis: case report and review of literature, Eur. J. Rheumatol. 2 (2015) 125–128. doi:10.5152/eurjrheum.2015.0080.
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[18] F. Kesten, M. Aschwanden, P. Gubser, K. Glatz, T. Daikeler, C. Hess, Giant cell arteritis--a changing entity., Swiss Med. Wkly. 141 (2011). doi:10.4414/smw.2011.13272.
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[19] J. Narváez, B. Bernad, D. Roig-Vilaseca, C. García-Gómez, C. GómezVaquero, X. Juanola, J. Rodriguez-Moreno, J.M. Nolla, J. Valverde, Influence of Previous Corticosteroid Therapy on Temporal Artery Biopsy Yield in Giant Cell Arteritis, Semin. Arthritis Rheum. 37 (2007) 13–19. doi:10.1016/j.semarthrit.2006.12.005.
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[20] B. Seeliger, J. Sznajd, J.C. Robson, A. Judge, A. Craven, P.C. Grayson, R.S. Suppiah, R.A. Watts, P.A. Merkel, R.A. Luqmani, Are the 1990 American College of Rheumatology vasculitis classification criteria still valid?, Rheumatology. (2017) 1–8. doi:10.1093/rheumatology/kex075.
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ACCEPTED MANUSCRIPT Score Criteria Age at onset ≥50 years
2
A new headache
3
Temporal artery abnormality such as tenderness to palpation or decreased pulsation
4
Erythrocyte sedimentation rate ≥50 mm/h
5
Abnormal artery biopsy showing vasculitis with mononuclear cell or granulomatous inflammation, usually with giant cell infiltrates
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1
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Table 1: The American College of Rheumatology 1990 GCA Classification Criteria
ACCEPTED MANUSCRIPT Score Entry: N/A
Age at onset ≥ 50 years old Absence of exclusion criteria(b) Domain I New onset localized headache(c) 1p
1
Sudden onset of visual disturbances(c) 1p
2
Polymyalgia Rheumatica (PMR) 2p
1
Jaw Claudication(c) 1p
2
Abnormal temporal artery (d) up to 2p
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Domain II
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1
1
Unexplained fever and/or anaemia 1p
1
ESR ≥ 50 mm/hour (e)
2
Compatible pathology (f) up to 2p
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1p
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Table 2: Revised ACR criteria (rACR) for diagnosis of GCA(a)
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a. In the presence of 3 points or more out of 11 with at least one point belonging to domain I along with all entry criteria, the diagnosis of Giant cell arteritis can be established; b. Exclusion criteria are including : ENT and eye inflammation, kidney, skin and peripheral nervous system involvement, lung infiltration, lymphadenopathies, stiff neck and digital gangrene or ulceration; c. No other aetiologies can better explain any one of the criteria; d. Enlarged and/or pulseless temporal artery : 1.p. / tender temporal artery: 1.p; e. It must be ignored in the presence of PMR; f. Vascular and/or perivascular fibrinoid necrosis along with leucocyte infiltration: 1.p. /and granuloma: 1.p
ACCEPTED MANUSCRIPT Sensitivity(
Specificity(
PPV(% NPV(
(x/4)
%)
%)
)
%)
2
100%
11.1%
31.4%
100%
3
81.8%
55.6%
42.9%
88.2%
4
18.2%
100%
100%
75%
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ACR Score
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Table 3: Performance scores for ACR and TAB
rACR Score
Sensitivity(
Specificity(
(x/9)
%)
%)
4
70.4
55.6
95
72.7
88.9
72.7
88.9
54.5
100
100
84.4
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5
%)
90.9
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3
PPV(%) NPV(
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Table 4: Performance scores for rACR and TAB
ACCEPTED MANUSCRIPT rACR score
Comments
Management
≤2
Unlikely GCA
No TAB or steroids
3 and 4
Requires
Perform TAB
(x/9)
≥5
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confirmation Likely GCA
No TAB, continue steroids
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Table 5 – Proposed clinical management tool
rACR Score 3-4
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ACR Score 2-3 33
12
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Table 6: Comparative groups with borderline scores
ACCEPTED MANUSCRIPT ACR
rACR
AUC = 0.880
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AUC = 0.737
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Figure 1 – Receiver operating characteristics analysis curves for ACR and rACR scores and TAB results
0.45
0.40
0.30
0.25
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DIAGNOSTIC YIELD
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0.35
0.20 0.15
0.10 0.05 0.00 1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 DAY OF BIOPSY
Figure 2. Graph showing change in diagnostic yield of TAB over time
ACCEPTED MANUSCRIPT HIGHLIGHTS
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Risk stratification of the 2016 revised ACR (rACR) criteria is a simple clinical tool proposed for the diagnosis of GCA This could help avoid unnecessary Temporal artery biopsies in select group of patients Temporal artery biopsies should be performed early on from commencement of steroids
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