RMD Open: first published as 10.1136/rmdopen-2022-002507 on 5 December 2022. Downloaded from http://rmdopen.bmj.com/ on July 18, 2023 at Sant Paul Hospital Consortia. Protected Vasculitis ORIGINAL RESEARCH Influence of the EULAR recommendations for the use of imaging in large vessel vasculitis in the diagnosis of giant cell arteritis: results of the ARTESER register Eugenio De Miguel ‍ ‍,1 Jesús T Sanchez-­Costa,2 Paula Estrada,3 Alejandro Muñoz,4 Cristina Valero Martínez,5 Patricia Moya Alvarado,6 María Jesús García-­Villanueva,7 Vanessa A Navarro Angeles,3 Carlos Galisteo Lencastre Da Veiga,8 Anne Riveros Frutos,9 Jose A Román Ivorra,10 Selena Labrada Arrabal,11 Margarida Vasques Rocha,12 Carlota L Iñiguez,13 María García-­Gonzalez,14 Clara Molina-­Almela,15 María Alcalde Villar,16 Antonio Juan Mas,17 Miguel A Gonzalez-­Gay ‍ ‍,18 Ricardo Blanco ‍ ‍18 To cite: De Miguel E, ABSTRACT Sanchez-­Costa JT, Estrada P, WHAT IS ALREADY KNOWN ON THIS TOPIC Objective The main study objective was to determine et al. Influence of the EULAR how giant cell arteritis (GCA) is diagnosed in our clinical ⇒ Temporal artery biopsy has been the gold standard for recommendations for the use confirming the diagnosis of giant cell arteritis (GCA), practice and whether the EULAR recommendations have of imaging in large vessel but its sensitivity is moderate. In recent years, various influenced the diagnostic procedures used. vasculitis in the diagnosis of imaging modalities, including vascular ultrasound, have by copyright. giant cell arteritis: results of theMethods ARTEritis of the Rheumatology Spanish Society ARTESER register. RMD Open -Sociedad Española de Reumatología (ARTESER) is a shown to have high sensitivity and specificity for GCA 2022;8:e002507. doi:10.1136/ multicentre observational retrospective study conducted diagnosis. rmdopen-2022-002507 in 26 hospitals with support from the Spanish Society of ⇒ Ultrasound is now recommended as a first-­line di- Rheumatology. All patients diagnosed with GCA between agnostic tool in current 2018 EULAR recommenda- ► Additional supplemental 1 June 2013 and 29 March 2019 were included. The gold tions on the use of imaging in GCA and biopsy or material is published online only. standard for the diagnosis of GCA was the judgement additional imaging tests are considered redundant, To view, please visit the journal of the physician in charge, according to clinical criteria, in patients with positive imaging and a high clinical online (http://​dx.d​ oi.​org/​10.​ supported by data available from laboratory tests, imaging probability of GCA or unnecessary when ultrasound 1136/​rmdopen-​2022-0​ 02507). studies (ultrasound, positron emission tomography (PET) is negative and the clinical pretest probability is low. and MRI/CT angiography) and temporal artery biopsy (TAB) when available. WHAT THIS STUDY ADDS Received 19 July 2022 Results We included 1675 patients with GCA (mean ⇒ The results show, as the diagnosis methods of GCA are Accepted 19 October 2022 age±SD (76.9±8.1) years, 1178 women (70.3%)). Of these, changing in the last years and how after the publica- 776 patients had a positive TAB (46.3%), 503 (30.0%) tion of the 2018 EULAR recommendations on the use positive ultrasound, 245 positive PET (14.6%) and 64 of imaging in large vessel vasculitis, ultrasound have positive MRI/CT angiography (3.8%). These percentages displaced the biopsy as main support in the diagnosis changed substantially over the study. From 2013 to 2019, of GCA and other image techniques are also increasing the use of ultrasound in diagnosis grew from 25.8% to their use. 52.9% and PET from 12.3% to 19.6%, while use of TAB decreased from 50.3% to 33.3%. HOW THIS STUDY MIGHT AFFECT RESEARCH, Conclusions Biopsy was the most widely used diagnostic PRACTICE OR POLICY test for confirming GCA, but use of imaging as a diagnostic ⇒ The use of ultrasound and other imaging techniques will tool has grown in recent years. Following publication of the expand the spectrum of GCA covering not only cranial © Author(s) (or their 2018 EULAR recommendations, ultrasound has displaced employer(s)) 2022. Re-­use involvement but also the large extracranial vessels. permitted under CC BY-­NC. No biopsy as the first-­line diagnostic test; TAB was performed ⇒ The use of ultrasound will improve accuracy and commercial re-­use. See rights in a third and PET in a fifth of cases. early diagnosis of GCA. Image training should be and permissions. Published enhanced in the coming years. by BMJ. For numbered affiliations see end of article. INTRODUCTION loss is common if initiation of treatment is Correspondence to Giant cell arteritis (GCA) is the most common delayed and stroke and constitutional symp- Dr Eugenio De Miguel; form of systemic vasculitis in adults.1 2 It is toms may occur. For decades, temporal artery ​eugenio.​demiguel@g​ mail.​com associated with considerable morbidity; vision biopsy (TAB) has been the gold standard De Miguel E, et al. RMD Open 2022;8:e002507. doi:10.1136/rmdopen-2022-002507    1 RMD Open: first published as 10.1136/rmdopen-2022-002507 on 5 December 2022. Downloaded from http://rmdopen.bmj.com/ on July 18, 2023 at Sant Paul Hospital Consortia. Protected RMD Open for confirming the diagnosis of GCA, but it has only a A list of patients with a diagnosis of GCA was obtained moderate sensitivity (of 40–60%), with false-­ negative during the recruitment period, by consulting the appro- results due to skip lesions and difficulties detecting priate databases according to the characteristics of each involvement of extracranial arteries.3 hospital, namely, those of the departments of pathology, In recent years, several studies have found various internal medicine, neurology or rheumatology, and imaging modalities, including vascular ultrasound, each patient’s full clinical record was obtained to allow MRI, CT and positron emission tomography (PET) to the collection of data required to meet the objectives of have high sensitivity and specificity for GCA.4 Evidence the study. These data were gathered over a period of 17 from imaging in the diagnosis of the disease has allowed months. widening of the concept from cranial disease diagnosed by TAB to isolated or associated involvement of large Variables extracranial vessels.5 6 Ultrasound is now recommended The types of data collected in this substudy were: (1) as a first-­line diagnostic tool in GCA in current Euro- social and demographic characteristics: age at inclu- pean guidelines, and TAB or additional imaging tests are sion, sex and race (Caucasian, Hispanic, African, Latin considered redundant in patients with positive imaging American, Others); (2) clinical characteristics at diag- and a high clinical probability of GCA. In patients with nosis: initial symptoms of GCA, date of diagnosis of GCA, a low clinical probability and a negative imaging result, clinical manifestations (headache, scalp hypersensitivity, the diagnosis of GCA can be considered unlikely. In all facial pain, dysphagia, jaw claudication, amaurosis fugax, other situations, additional efforts towards a diagnosis permanent blindness, diplopia, confirmed optic neuritis, are necessary.7 vertigo, hearing loss, transient ischaemic attack, stroke, To standardise research studies, various classification upper and/or lower limb claudication, polymyalgia rheu- systems have been used. Currently, the 1990 American matica, peripheral synovitis, asthenia, anorexia, weight College of Rheumatology (ACR) criteria for the classifi- loss, fever); (3) comorbidities at diagnosis; (4) laboratory cation of GCA8 are probably the most widely used, but test results: erythrocyte sedimentation rate and standard the positive predictive value of these criteria is based on C reactive protein level; (5) date and result of the TAB the high specificity of TAB, though it has been reported and/or other imaging techniques (ultrasound, PET, to have insufficient sensitivity. Therefore, in the latest MRI, CT) and (6) use of glucocorticoids and immuno- EULAR recommendations on the use of imaging in suppressants (methotrexate, leflunomide, azathioprine by copyright. GCA,7 9 imaging techniques were accepted as new useful and biological therapy such as anti-­interleukin 6) at base- tools in GCA with high sensitivity and specificity in the line and during the follow-­up of the patients. diagnosis and assessment of large vessel vasculitis. This Statistical analysis means that the GCA classification criteria are currently Continuous data were described as mean and SD under discussion and evolution. Meanwhile, the diag- (mean±SD) and categorical variables such as diagnostic nosis is based on the experience and judgement of the test results as numbers and percentages. All analyses were clinician. Our main objective was to determine how TAB performed using IBM SPSS V.28.0 software. and the new imaging techniques are being used in the . diagnosis of GCA in recent years and whether the publi- cation of the EULAR recommendations has changed diagnostic practice in our hospitals. RESULTS During the study period, we included 1675 patients with GCA (mean age±SD of 76.9±8.1 years, 1178 women METHODS (70.3%)) from 26 hospitals. Analysing data related to the Study Design main objective of the study, 776 patients were found to ARTESER is a multicentre observational retrospective have a positive TAB (46.3%), 503 (30.0%) a positive ultra- longitudinal study conducted in 26 hospitals with the sound, 245a positive PET (14.6%) and 64 a positive MRI/ support of the Spanish Society of Rheumatology. All CT angiography (3.8%). These percentages changed patients diagnosed with GCA between 1 June 2013 and substantially over the study observation time, with the use 29 March 2019 (date of approval by first ethics review of TAB decreasing and that of imaging techniques, espe- board) were included. The data were obtained by review cially ultrasound, increasing (figure 1). of medical records. Many patients underwent several complementary diag- nostic procedures. Analysing patients with positive results Study population in several objective diagnostic tests confirming their GCA All consecutive patients were included if they were aged diagnosis, it was found that TAB was the only specific 50 years or older and had a confirmed diagnosis of GCA, test performed in 531 patients (31.7%), ultrasound in that is, they met at least one of the following criteria: posi- 257 (15.3%), PET in 135 patients (8.1%) and MRI/CT tive result in an objective diagnostic test, at least three angiography in 14 patients (0.8%). Furthermore, the 1990 ACR criteria for GCA satisfied, and/or a diagnosis data showed that the diagnosis had been made based on made based on the clinical judgement of the investigator. clinical criteria or physician’s judgement without TAB 2 De Miguel E, et al. RMD Open 2022;8:e002507. doi:10.1136/rmdopen-2022-002507 RMD Open: first published as 10.1136/rmdopen-2022-002507 on 5 December 2022. Downloaded from http://rmdopen.bmj.com/ on July 18, 2023 at Sant Paul Hospital Consortia. Protected Vasculitis Figure 1 Rates of use of diagnostic tests for GCA over the study period. GCA, giant cell arteritis; PET, positron emission tomography; TAB, temporal artery biopsy. or imaging tests in 417 patients (24.9%). Between 2013 differences between patients with or without cranial and 2019, the percentage of patients in which ultrasound symptoms. In the analysis of the results, the use of biopsy by copyright. was used for diagnosis increased from 25.8% to 52.9%, or image was clearly related with the hospital preferences and PET use grew from 12.3% to 19.6%, while TAB use or availability in every centre (online supplemental table decreased from 50.3% to 33.3%. S1). Analysing the subtypes of GCA by vessel size, the results showed 1091 patients had cranial involvement, 331 extra- cranial involvement and 170 patients had mixed patterns DISCUSSION (cranial and extracranial), while in 253 patients, the The procedures to confirm the diagnosis of GCA have subtype of vascular compromise was not recorded. The changed over the last decade. In a recent study based rate of extracranial involvement has increased in recent on data from a Danish register for 1 January 1996 to years coinciding with the growth in the use of imaging 31 December 2018, Therkildsen et al reported that the in the diagnosis, as is seen by comparing figures 1 and percentage of GCA patients diagnosed by TAB remained 2. The use of image or biopsy did not show significant constant until 2016, after which it sharply declined from 70%–80% to 29%–39%; in contrast, the percentage of patients undergoing diagnostic imaging increased from 2% to 66% between 2000 and 2018.10 Similar patterns are observed in our nationwide register (ARTESER), TAB being the leading test for diagnosis in 2013, but its popu- larity declining such that, by 2019, it was only used in a third of cases. Diagnostic imaging, on the other hand, has become more popular, with ultrasound at the top of the list, it is used in 53% of patients in 2019, followed by PET-­TC used in 20%. The diagnostic approach has changed progressively over time, probably associated with stronger evidence emerging and an increasing interest in extracranial vessel disease. After the emergence of the EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice7 and the publication of Figure 2 Rates of cranial and extracranial (large vessel) the definitions and reliability of elementary ultrasound involvement in giant cell arteritis detected over the study lesions in GCA,11 the use of ultrasound rose sharply, by as period. much as 20.3% in a year. De Miguel E, et al. RMD Open 2022;8:e002507. doi:10.1136/rmdopen-2022-002507 3 RMD Open: first published as 10.1136/rmdopen-2022-002507 on 5 December 2022. Downloaded from http://rmdopen.bmj.com/ on July 18, 2023 at Sant Paul Hospital Consortia. Protected RMD Open 8 Another important finding associated with the intro- Rheumatology Department, Hospital Universitari Parc Tauli Sabadell, Sabadell, duction of imaging techniques for the assessment in GCA Spain 9 Rheumatology Department, Hospital Germans Trias i Pujol, Badalona, Spain is the increase in the diagnosis of the large vessel vascu- 10 Rheumatology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain litis subtype, this increasing by 65%, with no decrease in 11 Rheumatology Department, Hospital del Mar, Barcelona, Spain the rate of diagnosis of cranial forms, which suggests that 12 Rheumatology Department, Hospital Universitario Araba, Vitoria-­Gasteiz, Spain 13 the inclusion of imaging leads to an expansion in the Rheumatology, Hospital Universitario Lucus Augusti, Lugo, Galicia, Spain 14 diagnosis of all GCA subtypes. This higher rate of diag- Hospital Universitario de Canarias, La Laguna, Canarias, Spain 15 Rheumatology, Consorci Hospital General Universitari de València, Valencia, nosis of large vessel involvement is consistent with recent Comunitat Valenciana, Spain publications that show a higher frequency of the large 16 Rheumatology Department, Hospital Universitario Severo Ochoa Leganes, vessel subtype in this disease, and the value of imaging for Leganes, Madrid, Spain improving the accuracy of GCA diagnosis12 13 17 Rheumatology Department, Hospital Universitari Son Llàtzer, Palma de Mallorca, Limitations of the study include its retrospective nature, Spain 18 Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, which implies a risk of information bias caused by inaccurate Cantabria, Spain recording of the data. To address this, all researchers had a previous meeting with the principal investigator to clarify Correction notice This article has been corrected since it was first published the procedure for accurate retrieval of the data of interest. online. Clara Molina-­Almela was incorrectly listed as Clara Molina-­Almeda. Another limitation of the study was the potential variability in Acknowledgements To the Spanish Society of Rheumatology that has promoted the use of imaging tests and biopsies between the hospitals. and provided coverage for this study. To Roche for its financial contribution that made this epidemiological study possible. The different hospitals have used the best standard methods Contributors DM and RB-­A participated in the design of the work, the acquisition and evidence in the use of PET, but the cited standards were and interpretation of data, and were major contributors in writing the manuscript. changed along the time, PET studies. The US machine/ J.T.S-­C participated in the design of the work, the analysis and interpretation of probes and expertise of the ultrasonographers differ in the data, and was a major contributor in writing the manuscript. PE, AM, CVM, PMA, M.J.G-­V, V.A.NA, C.G.LDV, ARF, J.A.RI, SLA, MVR, C.L.I-­U, MG-­G, CM-­A, MAV and different hospitals. Nonetheless, with the participation of AJM made substantial contributions to the acquisition of data. M.A.G-­G participated 26 hospitals across different regions and data collected on in the design of the work. All authors revised the manuscript critically, and read and 1675 cases, we believe that the results are a good reflection approved the final version. of real clinical practice in Spain. An additional limitation is Funding Roche contributes to the financial support of this study. that we did not exclusively use the ACR classification criteria, Competing interests EDM: Speakers bureau: Abbvie, Novartis, Pfizer, MSD, BMS, by copyright. UCB, Roche, Grunental, Janssen, Sanofi; Paid instructor for: Janssen, Novartis, since imaging tests are not yet included in these criteria. Roche; Consultant of: Abbvie, Novartis, Pfizer, Galapagos; Grant/research support Our gold standard for diagnosis was the clinical judgement from: Abbvie, Novartis, Pfizer. MAG-­G: received grants/research supports from of the physician, and the results show that the adoption of Abbvie, Jansen and Roche, and had consultation fees/participation in company sponsored speaker's bureau from Abbvie, Roche, Sanofi, Lilly, Novartis, GSK and image techniques in daily clinical practice could account for Celgene. RB-­A: received grants/research supports from Abbvie, MSD, and Roche, updating criteria for classifying the disease. and had consultation fees/participation in company sponsored speaker's bureau In summary, TAB was the most widely used diagnostic from Abbvie, Pfizer, Roche, Bristol-­Myers, Janssen, Lilly and MSD. CLI-­U: received supports and speaker's fees from Pfizer, AbbVie, Fresenius - Kiabi, Novartis, GSK, method for confirming GCA, but today, following the Sanofi y Janssen por asistencia cursos y congresos. Other authors: None declared. publication of the EULAR recommendations in 2018, Patient consent for publication Not applicable. ultrasound has displaced biopsy as the leading diagnostic Ethics approval This study involves human participants and was approved by test. The use of PET-­TC for diagnosis is also growing, 05/2019 Ethics Committee for Research with Medicines of Cantabria, Santander, this type of imaging having been performed in around Spain. The study was conducted following the principles outlined in the Declaration 20% of patients in the last 3 years of the study. There of Helsinki. Retrospective study in clinical records. It would not be possible to contact patients in most cases and was approved by the ethical board. is a wide margin for improvement in the diagnosis of Provenance and peer review Not commissioned; externally peer reviewed. GCA; however, a quarter of diagnoses still being made Data availability statement Data are available upon reasonable request to the clinically, without TAB or additional imaging tests. Spanish Society of Rheumatology. Concerning the subtypes of GCA, cranial involvement Supplemental material This content has been supplied by the author(s). It has is the most common, but the diagnosis of the extracra- not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been nial large vessel subtype has increased in recent years in peer-­reviewed. Any opinions or recommendations discussed are solely those line with the use of imaging, and the rate of this subtype of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content detected is likely to increase further in the coming years. includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, Author affiliations terminology, drug names and drug dosages), and is not responsible for any error 1 Hospital Universitario La Paz, Madrid, Madrid, Spain and/or omissions arising from translation and adaptation or otherwise. 2 Rheumatology, Research Unit, Madrid, Madrid, SPAIN, Spain Open access This is an open access article distributed in accordance with the 3 Rheumatology Department, Hospital de Sant Joan Despí Moisès Broggi, Sant Joan Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Despi, Spain permits others to distribute, remix, adapt, build upon this work non-­commercially, 4 Rheumatology Department, Hospital Universitario Virgen del Rocío Sevilla, Sevilla, and license their derivative works on different terms, provided the original work is Spain properly cited, appropriate credit is given, any changes made indicated, and the 5 use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. Rheumatology Department, Hospital Universitario de la Princesa, Madrid, Spain 6 Rheumatology Department, Hospital de la Santa Creu i Sant Pau Barcelona, ORCID iDs Barcelona, Spain Eugenio De Miguel http://orcid.org/0000-0001-5146-1964 7 Hospital Universitario Ramon y Cajal, Madrid, Madrid, Spain Miguel A Gonzalez-­Gay http://orcid.org/0000-0002-7924-7406 4 De Miguel E, et al. RMD Open 2022;8:e002507. doi:10.1136/rmdopen-2022-002507 RMD Open: first published as 10.1136/rmdopen-2022-002507 on 5 December 2022. Downloaded from http://rmdopen.bmj.com/ on July 18, 2023 at Sant Paul Hospital Consortia. Protected Vasculitis Ricardo Blanco http://orcid.org/0000-0003-2344-2285 7 Dejaco C, Ramiro S, Duftner C, et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis 2018;77:636–43. 8 Hunder GG, Bloch DA, Michel BA, et al. 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RMD Open 2022;8:e002507. doi: 10.1136/rmdopen-­ 2022-­002507 This article has been corrected since it was first published online. Clara Molina-­Almela was incorrectly listed as Clara Molina-­Almeda. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-­commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-­commercial. See http://creativecommons.org/licenses/by-nc/4.0/. © Author(s) (or their employer(s)) 2023. Re-­use permitted under CC BY-­NC. No commercial re-­use. See rights and permissions. Published by BMJ. J Immunother Cancer 2023;9:e002507corr1. doi:10.1136/rmdopen-2022-002507corr1 J Immunother Cancer 2023;9:e002507corr1. doi:10.1136/rmdopen-2022-002507corr1 1