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Vasculitis
Subclinical giant cell arteritis increases the risk of relapse in polymyalgia rheumatica
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  1. Eugenio De Miguel1,
  2. Rositsa Karalilova2,
  3. Pierluigi Macchioni3,
  4. Cristina Ponte4,5,
  5. Edoardo Conticini6,
  6. Sharon Cowley7,
  7. Alessandro Tomelleri8,
  8. Sara Monti9,
  9. Irene Monjo1,
  10. Zguro Batalov10,11,
  11. Giulia Klinowski3,
  12. Paolo Falsetti12,
  13. David J Kane13,
  14. Corrado Campochiaro14,
  15. Alojzija Hočevar15,16
  1. 1 Rheumatology, La Paz University Hospital, Madrid, Spain
  2. 2 Clinic of Rheumatology, Medical University Plovdiv, Plovdiv, Bulgaria
  3. 3 Rheumatology Department, Ospedale S Maria Nuova, Reggio Emilia, Italy
  4. 4 Rheumatology, Centro Hospitalar Universitario Lisboa Norte EPE, Lisboa, Portugal
  5. 5 Rheumatology Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal
  6. 6 Rheumatology Unit, University of Siena, Siena, Italy
  7. 7 Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
  8. 8 Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
  9. 9 Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  10. 10 Internal Diseases, Medical University of Plovdiv, Plovdiv, Bulgaria
  11. 11 Rheumatology, University Hospital Kaspela, Plovdiv, Bulgaria
  12. 12 Department of Medical Sciences, Surgery and Neurosciences, Rheumatology Unit, University of Siena, Siena, Italy
  13. 13 Rheumatology, Adelaide and Meath Hospital, Dublin, Ireland
  14. 14 Università Vita-Salute San Raffaele, School of Medicine; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, San Raffaele Scientific Institute, Milan, Italy
  15. 15 Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
  16. 16 Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
  1. Correspondence to Dr Eugenio De Miguel, Rheumatology, La Paz University Hospital, Madrid, Madrid, Spain; eugenio.demiguel{at}gmail.com

Abstract

Objective The aim of the present study was to determine the clinical significance of subclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) and ascertain its optimal treatment approach.

Methods Patients with PMR who fulfilled the 2012 European Alliance of Associations for Rheumatology/American College of Rheumatology Provisional Classification Criteria for PMR, did not have GCA symptoms and were routinely followed up for 2 years and were stratified into two groups, according to their ultrasound results: isolated PMR and PMR with subclinical GCA. The outcomes (relapses, glucocorticoid use and disease-modifying antirheumatic drug treatments) between groups were compared.

Results We included 150 patients with PMR (50 with subclinical GCA) with a median (IQR) follow-up of 22 (20–24) months. Overall, 47 patients (31.3 %) had a relapse, 31 (62%) in the subclinical GCA group and 16 (16%) in the isolated PMR group (p<0.001). Among patients with subclinical GCA, no differences were found in the mean (SD) prednisone starting dosage between relapsed and non-relapsed patients (32.4±15.6 vs 35.5±12.1 mg, respectively, p=0.722). Patients with subclinical GCA who relapsed had a faster prednisone dose tapering in the first 3 months compared with the non-relapsed patients, with a mean dose at the third month of 10.0±5.2 versus 15.2±7.9 mg daily (p<0.001). No differences were found between relapsing and non-relapsed patients with subclinical GCA regarding age, sex, C reactive protein and erythrocyte sedimentation rate.

Conclusions Patients with PMR and subclinical GCA had a significantly higher number of relapses during a 2-year follow-up than patients with isolated PMR. Lower starting doses and rapid glucocorticoid tapering in the first 3 months emerged as risk factors for relapse.

  • Polymyalgia Rheumatica
  • Giant Cell Arteritis
  • Outcome Assessment, Health Care
  • Therapeutics
  • Ultrasonography

Data availability statement

Data are available upon reasonable request to the authors.

https://doi.org/10.1136/ard-2023-224768

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Subclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) by imaging or biopsy has a pooled prevalence of 23%. However, currently, there is no knowledge of the relevance of this subclinical finding or about the standard of care needed.

    WHAT THIS STUDY ADDS

    • Our study shows that patients with PMR and subclinical GCA have a four times higher rate of relapses than patients with isolated PMR and that a lower starting dose and a faster glucocorticoid dose tapering increase the relapsing risk in patients with subclinical GCA.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Our results suggest that in PMR with subclinical GCA, the treatment and tapering scheme could be similar to those recommended for classical GCA.

    • If future studies confirm our data, it could significantly impact patient stratification in clinical practice using ultrasound, particularly in the differentiation of patients with PMR from those with PMR and subclinical GCA.

    Introduction

    Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two frequently overlapping diseases.1 2 Patients with PMR usually have pain and stiffness involving the shoulders, pelvic girdle and neck.2 3 The main symptoms of GCA include headache, scalp tenderness, jaw claudication and visual disturbances (ie, ‘cranial’ symptoms), which are usually associated with the involvement of temporal arteries and their main branches.1–5 GCA can also affect the aorta and other large-sized arteries (eg, carotid and subclavian arteries) and in these cases non-specific symptoms, such as low-grade fever and weight loss, usually prevail.5 Both diseases are associated with the elevation of acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C reactive protein (CRP).1–5

    GCA and PMR can appear isolated or associated with each other. Patients with GCA have manifestations of PMR in 40%–60% of cases, whereas 10%–16% of patients with PMR have or will develop manifestations of GCA.4 6 7 GCA should be suspected in patients with PMR when ischaemic cranial symptoms are present.8 However, when cranial symptoms are not apparent, the diagnosis is more challenging. In addition, some patients with PMR can have arterial involvement without any associated symptoms (subclinical GCA) in whom the diagnosis of GCA can only be made by imaging or pathological studies. Current imaging evidence shows that approximately 23% of patients with PMR have a subclinical GCA.9 10

    There is some uncertainty regarding how patients with subclinical GCA should be treated. While recent treat-to-target recommendations for GCA and PMR,11 along with updated guidelines on the use of imaging in large vessel vasculitis,12 have been published, there remains a notable gap concerning the significance of subclinical GCA. This diagnosis has become increasingly prevalent following the widespread use of advanced vascular imaging modalities, yet questions persist about its most appropriate management. Indeed, although glucocorticoids are the treatment of choice for both PMR and GCA,13 14 patients with GCA usually require higher starting dosages with slower tapering. In addition, to date, biological drugs such as tocilizumab are approved in most countries for the treatment of GCA. It is still unknown whether patients with subclinical GCA carry the same risk of short-term (eg, ischaemic visual loss) and long-term (eg, aortic aneurysms) complications as patients with overt GCA or whether these patients warrant the same therapeutic approaches as those with GCA. Moreover, there are no recommended guidelines concerning the appropriate timing or modalities to screen for subclinical GCA in patients with apparently isolated PMR.

    The aim of the present study was to investigate the main clinical outcomes of patients with PMR and subclinical GCA, as disclosed through vascular ultrasound, within a comprehensive multicentric cohort, and to determine the clinical significance of subclinical GCA in PMR and ascertain its optimal treatment approach.

    Methods

    Patient selection

    Patients with newly diagnosed PMR were prospectively recruited between 1 July 2020 and 31 July 2022 from eight participating centres belonging to six European countries (Bulgaria, Italy, Portugal, Slovenia and Spain). These were all consecutive, non-selected patients with PMR without clinical features suggestive of concomitant GCA. In addition, all patients had to fulfil the 2012 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria15 and only a limited period of glucocorticoid treatment before inclusion in the study was allowed (<14 days and <20 mg/day). Patients were then stratified into two groups: (a) PMR with subclinical GCA and (b) pure PMR based on the presence or absence of an arterial halo sign using ultrasound. A detailed description of this cohort and recruitment has already been reported elsewhere.10 For this present study, only patients who received regular follow-up visits for at least the initial 12 months of treatment were included. In the cohort from the original ‘mother study’, we identified 79 subclinical GCA, but 39 patients had to be subsequently excluded during follow-up due to incomplete data, or not meeting the 1-year follow-up criterion. Therefore, in order to increase the statistical power and robustness of this current study, we included additional patients with subclinical GCA from two centres, one already participating centre and a new centre from Ireland that used the same methodology. Our target for the inclusion of subclinical GCA cases was set at 50 patients, while additionally permitting the inclusion of two pure PMR control cases for each subclinical GCA case. These control cases consisted of consecutive, non-selected patients from the original cohort with similar follow-up times.10

    For all patients, demographic, clinical and laboratory baseline data were collected prospectively. The clinicians were not blinded to the ultrasound results or clinical data. Treatment selection was at the physician’s discretion, in agreement with their local recommendations. Follow-up data regarding treatment and occurrence of relapses at months 3, 6, 12, 18 and 24 were retrieved retrospectively. A relapse in patients with ‘pure’ PMR was characterised by the recurrence of PMR symptoms and an elevation in inflammatory markers (eg, ESR, CRP), following the exclusion of other potential causes for the increase in these inflammatory parameters, such as infection or malignancy. For GCA, the EULAR-proposed definition of relapse was used, which encompasses subcategories distinguishing between ‘minor’ and ‘major’ relapse.13 In cases of relapse, data on time to first relapse, type of relapse, clinical and laboratory features, and relapse management were collected.

    Ultrasound examination

    Ultrasound was performed on the temporal superficial arteries (including the common temporal, frontal and parietal branches) and the extracranial arteries (axillary and subclavian arteries) at baseline. The presence or absence of a halo sign was used to identify subclinical GCA. Figure 1 shows a halo sign in both cranial and axillary branches in a patient with subclinical GCA. High-quality ultrasound machines with linear high-frequency probes were used with the following settings: a grayscale frequency of ≥18 MHz for temporal arteries and 4–18 MHz for extracranial arteries, a colour Doppler pulse repetition frequency of 2–3.5 kHz for temporal arteries and 3–4 kHz for extracranial arteries, colour box with angle correction of ≤60° and the gain adjusted to fill only the lumen. All examinations were performed by expert sonographers, who had conducted more than 300 vascular ultrasounds prior to this study. These sonographers are actively engaged in the Outcome Measures in Rheumatology (OMERACT) group focused on ultrasound for large vessel vasculitis, and the majority of them have participated in the reliability exercises for ultrasound assessment in GCA.16 17 Information on specific ultrasound machines and other ultrasound additional information has been reported elsewhere.10

    Figure 1
    Figure 1

    Halo sign in cranial and axillary branches in a patient with subclinical giant cell arteritis.

    Statistical analysis

    Descriptive analysis of the data was performed. Data were expressed as the mean±SD for normally distributed continuous variables, as median (IQR) for non-normally distributed variables, and as percentages and frequencies for categorical variables. A comparison between patients with PMR and subclinical GCA and patients with pure PMR was performed using the χ2 test, Fischer’s exact test, Student’s t test and Mann-Whitney U test for the univariate analyses, as appropriate. All analyses were performed on complete data without imputation. Using relapse as the dependent variable, logistic regression models were employed to investigate the association between relapses and clinical features and glucocorticoids doses. Prior to adjusting the multivariate analysis, we performed a multicollinearity test analysing variance inflation factor (>5) to check for any possible correlations between the independent variables. Variables with a p<0.1 in the univariable model and variables of clinical interest were included in the multivariable model with enter method and retained if significantly contributing to explain the outcome (p<0.05). To search for outliers, we used the Mahalanobis distance. In addition, we checked for standardised residuals (less than 5% had an absolute value greater than 2). Relapse-free survival was studied using Kaplan-Meier curves and the log-rank Mantel-Cox test was used to assess differences between groups. A cut-off of p<0.05 was adopted to define the statistical difference. The data were analysed using IBM SPSS Statistics V.25.0.

    Ethical aspects

    The protocol of this study was first approved by the Ethics Committee of the University Hospital ‘La Paz’ on 9 March 2020 (code HULP: PI-3992). Thereafter, it was approved by the Ethics Committees of the other participant centres. All patients provided written informed consent prior to inclusion in the study.

    Results

    Baseline features

    A total of 150 patients with PMR were included (50 patients with subclinical GCA and 100 patients with isolated PMR) (table 1). The mean patient age at inclusion was 72.5±8.2 years and 58% were females. The female sex was slightly more frequent in the isolated PMR group than in the PMR with subclinical GCA group, and patients were also slightly younger but without statistical significance (table 1). Glucocorticoid doses at baseline and at different time points during the first year of follow-up were significantly higher in patients with PMR with subclinical GCA than in those with pure PMR (table 1). The ultrasound of the subclinical GCA group included 22 exclusive extracranial, 13 exclusive cranial and 15 mixed cases. Table 1 shows the results of univariate analysis on the comparison between pure PMR and PMR with subclinical GCA.

    View this table:
    Table 1

    Demographic, relapses and treatments in pure PMR and PMR with subclinical GCA

    Follow-up: relapses

    Patients were followed for a median (IQR) of 22 (20–24) months, without significant differences between pure PMR and PMR with subclinical GCA. In the subclinical GCA group, 6 patients had a follow-up of 12 months, 14 patients of 18 months, 36 patients of 24 months and 16 patients between 25 and 36 months.

    During follow-up, 47 patients (31.3%) had at least one relapse, 31 (62%) in the PMR with subclinical GCA group and 16 (16 %) in the pure PMR group (p<0.001). All relapses were minor, with the only exception of one patient in the subclinical GCA group who was classified as a major relapse (marked increase in the wall thickness of the axillary arteries on ultrasound with differences in blood pressure measurement between the two arms) at month 7.

    The first episodes of relapses occurred mostly in the first 12 months of follow-up. In the subclinical GCA group, 14/31 (45.2%) patients had a relapse in the first 6 months, and 26/31 (83.9%) had a relapse in the first 12 months. Between months 13 and 21, we recorded five additional first relapses. No relapse was observed after 21 months of follow-up. In the pure PMR group, 6/16 patients (37.5%) relapsed in the first 6 months, 9/16 (56.2%) relapsed in the first 12 months and 1 patient relapsed by month 18. Figure 2 shows the Kaplan-Meier curve of relapses in isolated PMR and subclinical GCA; patients with subclinical GCA had significantly more relapses (log rank; Mantel-Cox p<0.001).

    Figure 2
    Figure 2

    Kaplan-Meier survival curves of relapse in patients with isolated PMR and subclinical GCA, and number at risk in the follow-up (months). GCA, giant cell arteritis; PMR, polymyalgia rheumatica.

    There were additional relapses in some patients. Seven patients experienced more than one relapse, with a second relapse occurring in four patients in the subclinical GCA group and three in the isolated PMR group. There were three-third relapses in the cohort, two in the subclinical GCA group and one in the isolated PMR group.

    There were no significant differences regarding age, sex, baseline CRP and ESR levels between patients who relapsed and patients who did not relapse in the subclinical GCA group. In patients with isolated PMR, only the female sex was significantly associated with relapses (p=0.041) (table 2). There was a trend towards more frequent relapses in younger patients in the pure PMR group (mean (SD) age of 67.7±8.6 and 72.4±8.2 years in relapsing and non-relapsing patients with pure PMR, respectively, p=0.063) and higher values of basal CRP 79.2 versus 50.9 mg/L (p=0.063; table 2).

    View this table:
    Table 2

    Clinical characteristics and glucocorticoid treatment in patients with or without relapses

    Follow-up: glucocorticoid use

    The prednisone dose was significantly higher in patients with subclinical GCA than in patients with pure PMR both at baseline (33.6±14.3 vs 19.5±7.4 mg, p<0.001) and at 12 months of follow-up (7.5±13.5 vs 2.4±3.4 mg, p=0.016) (table 1). The mean glucocorticoid dose used at predefined follow-up time points is displayed in tables 1 and table 2. In subclinical GCA, there was no significant difference in the prednisone starting dose between patients with or without relapses (32.4±15.6 vs 35.5±12.1 mg daily prednisone equivalent, p=0.722) (table 2). However, in patients with a starting dose below ≤20 mg of prednisone (14 patients), there was a relapse rate of 100% (table 3 shows the occurrence of relapses in patients with subclinical GCA according to their initial glucocorticoid doses). Patients who relapsed also had a faster dose reduction by 3 months (13.4±7.1 vs 18.8±7.5 mg daily, p=0.016) (table 2). This was confirmed by a logistic regression model, showing that there was an association between relapses and subclinical GCA (OR 6.99, 95% CI: 2.30 to 21.74; p<0.001) as well as the dose of glucocorticoids at 3 months (OR 0.90, 95% CI: 0.81 to 0.99; p=0.045) (table 4).

    View this table:
    Table 3

    Relapse occurrence and basal dose of prednisone in the subgroup of subclinical GCA

    View this table:
    Table 4

    Results of the logistic regression model of relapse adjusted for possible confounders

    Follow-up: glucocorticoid-sparing treatment

    Biological disease-modifying antirheumatic drugs (DMARDs) were used in 14 patients (13 anti-IL-6; 1 anti-IL-17) during follow-up, and 2 additional patients used upadacitinib. Among the subclinical GCA group, four patients received biological therapy (anti-IL-6) at baseline. Of them, one patient had a minor relapse with PMR features at 12 months while receiving 5 mg daily prednisone. In the follow-up, an anti-IL-6 drug was used in other eight patients, another patient was treated with anti-IL-17 and one additional patient received upadacitinib. In patients with isolated PMR, an anti-IL-6 was used in one patient since the basal visit and the patient never has relapse, and one patient was treated with upadacitinib after a relapse at 6 months.

    Conventional synthetic DMARDs were used throughout the study in 13 (13%) patients with isolated PMR (12 patients treated with methotrexate and 1 patient treated with leflunomide) and in 25 (50%) patients with subclinical GCA (methotrexate 20 cases, azathioprine 3 cases and leflunomide 2 cases).

    Comparison between the original cohort and the current cohort

    To address potential biases in our data, additional analyses were performed. First, we compared the 10 newly added subclinical GCA cases with the initial 40 subclinical GCA cases from the original PMR cohort, as presented in online supplemental table S1. This analysis revealed no significant differences in terms of baseline clinical characteristics, frequency of relapses and glucocorticoid doses used during follow-up between these two groups. Furthermore, as shown in online supplemental table S2, we demonstrated that similar findings would have been obtained if we had employed the original 40 patients with subclinical GCA instead of the 50 used in the comparison with the 100 patients diagnosed with isolated PMR. Finally, we conducted an analysis to compare the baseline characteristics of patients with subclinical GCA from the original cohort, focusing on those included in our present study (n=40) and those excluded due to not meeting the inclusion criteria (n=39). Once again, this analysis revealed no statistically significant differences between the two groups (online supplemental table S3).

    Supplemental material

    Discussion

    The use of imaging in patients with PMR without clinical symptoms of vasculitis showed that nearly one in four patients had subclinical large vessel vasculitis.9 10 The underlying question in clinical practice is whether the existence of subclinical vasculitis is a relevant finding for the patient. As far as we know, this question has not yet been resolved and our decisions in daily practice are commonly based on previous experiences and speculations.

    In this sense, our study aimed to evaluate the natural evolution of patients with subclinical GCA and to determine whether subclinical vasculitis is relevant for the patient. The patients included in the study represented a prospective cohort of newly consecutive PMRs from nine centres from seven different European countries.10

    To study the possible relevance of subclinical GCA in PMR we analysed relapses, the dose of prednisone (or equivalent) used and glucocorticoid-sparing medications added to the treatment during follow-up.

    The first outcome investigated was the rate of relapses that patients with subclinical GCA develop compared with pure PMR. Our results are compelling and show that patients with PMR with subclinical GCA relapsed approximately four times more frequently than patients with pure PMR (62% vs 16%, respectively) during a median follow-up of 22 months. There are no previous studies on relapses in subclinical GCA. Previous studies in PMR reported a relapse rate between 27.6% and 55%,18–21 comparable to our cohort, 31.3% in the overall cohort including patients with PMR with and without subclinical GCA. However, these studies included relapses in the first 5 years of treatment.18–21 In a recent publication that included 450 patients, approximately 33% of them had at least one relapse within the first year of treatment, and 48% after 2 years.22 These figures adjusted by time are close to our rates of 31.3%. Most likely, the rates reported in the literature encompass the two subtypes of PMR with very different relapse frequencies, the subgroup of isolated PMR with lower relapse incidences and the subgroup of PMR with subclinical GCA that would present a very high probability of relapse. The high relapse rate in PMR with subclinical GCA highlights the appropriateness of screening for potentially associated GCA in PMR at diagnosis or at least during PMR relapse to improve personalised treatment medicine. Nevertheless, further investigation is warranted to confirm this suggested approach.

    Regarding the treatment, our data revealed that clinicians tend to initiate therapy with higher baseline doses of prednisone (or equivalent) at baseline when managing patients with subclinical GCA compared with those used in isolated PMR (36.6 vs 19.8 mg daily of prednisone equivalent, p<0.001) which was aligned with the previously established guidelines.14 23 24 Notably, despite commencing treatment with higher glucocorticoid doses, patients in the ‘PMR with subclinical GCA’ group experienced relapses more often than those with pure PMR. However, within the ‘PMR with subclinical GCA’ group, those who did not relapse started treatment with similar mean prednisone doses to those who relapsed (35.5±12.1 vs 32.4±15.6 mg daily; p=0.722) but interestingly, the lower starting doses of prednisone ≤20 mg had a relapse rate of 100% 14/14 cases (table 4). Furthermore, rapid glucocorticoid tapering in the first 3 months after diagnosis was associated with a relapsing course (13.4±7.1 vs 18.8±7.5; p<0.016). Today, the ideal tapering scheme in GCA has not been standardised, which is even more evident in subclinical GCA. The data in the trial of tocilizumab in GCA (GiACTA)25 showed that the placebo group, with a more rapid tapering protocol (6 months), experienced a higher frequency of relapses (68%). Thus suggesting a higher risk of relapses in faster tapering regimens, which aligns with our results obtained for the patients with subclinical GCA.

    The third studied outcome was the second-line treatment and biological therapy needed by the patients. Our results show, as expected, an increased use of these therapies in the subclinical GCA subgroup. Among second-line drugs, methotrexate was the most prescribed treatment, probably in agreement with the EULAR recommendations.13

    Our study has limitations. Baseline treatment selection and prednisone doses were not standardised between participating centres. Moreover, as the follow-up protocol was not unified, the follow-up data quality between the centres varied. To minimise the variability of data collection, we only included patients with a follow-up of at least 1 year, which resulted in a significant dropout of nearly 50% of the patients from the original cohort.10 This high rate of follow-up loss can, in part, also be attributed to the disruptive influence of the COVID-19 pandemic on scheduled visits. However, it is important to highlight that we did not identify significant baseline differences when comparing patients who underwent regular follow-up visits with those who did not, as reflected in online supplemental table S3. It is also worth noting that, even though we aimed to enhance the study’s statistical power by increasing the number of patients included, the analyses presented in online supplemental tables S1 and S2 demonstrate that similar results would have been obtained if we had used the original 40 patients. An additional limitation of our study is the potential interference of classical and biological glucocorticoid-sparing treatments, fundamentally used in the relapse group, with the prednisone doses administered during follow-up. Furthermore, our definition of subclinical GCA solely relied on ultrasound imaging assessment, which lacks the possibility to capture isolated cases of aortitis. However, we have recently published a study comparing ultrasound and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT), using a cohort of 72 patients with GCA who underwent both imaging modalities, and of the 24 patients with documented aortitis in FDG-PET/CT, only 2 (8.3%) had negative ultrasound findings for LV-GCA.26 The retrospective data collection on treatment and relapses represents a further limitation of our study. Nevertheless, it is worth noting that all the crucial information regarding the occurrence and characterisation of relapses, treatment modifications and different prednisone doses during follow-up were readily available in our recruiting centres. These are all centres with longstanding experience in managing PMR and GCA, thus providing us with a high degree of confidence in the quality and consistency of these data. Lastly, physicians may have been influenced by the ultrasound findings. However, even with full awareness of the ultrasound results and the frequent administration of higher GC doses in patients with subclinical GCA compared with the pure PMR group, the subclinical GCA group still exhibited a significantly higher relapse rate. This underscores the existing uncertainties regarding the optimal treatment approach for patients with subclinical GCA. Notably, the use of GC doses, although higher than those conventionally prescribed for PMR, often involved lower doses or more rapid tapering than those recommended for GCA. We believe that our study offers evidence suggesting that these patients may benefit from a treatment approach more closely aligned with overt GCA.

    If future studies confirm our data, this may importantly impact patient stratification in clinical practice, particularly in distinguishing between patients with PMR and PMR with subclinical GCA. Vascular ultrasound for this purpose is a cost-effective imaging technique. It is currently increasingly available for GCA, and therefore, it could be easily implemented in the routine care of patients with PMR.

    In summary, previous studies have established a significant prevalence of subclinical GCA within the PMR population (23%).9 10 However, the clinical implications of these forms of subclinical vasculitis and whether their presence should influence the treatment of PMR remained unclear. We found that patients with PMR and subclinical GCA exhibit a fourfold higher relapse rate compared with those with isolated PMR. Furthermore, our findings indicate that in the context of PMR with subclinical GCA, administering a lower starting prednisone dose and implementing a rapid glucocorticoid tapering strategy result in a higher incidence of relapses. Therefore, the treatment and tapering scheme in this subset of patients could potentially be the same as recommended for classical GCA, although further research is needed to confirm this hypothesis.

    Data availability statement

    Data are available upon reasonable request to the authors.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Ethics Committee of the Hospital Universitario La Paz, Madrid, Spain (code HULP: PI-3992). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We would like to thank to the GCA/PMR study group for its contributions to the development of collaborative studies.

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    • Handling editor Josef S Smolen

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    • Contributors All authors were involved in the recruitment and follow-up of cases. EDM wrote the first version of the manuscript. All authors reviewed it and made extensive comments and appropriate changes to it. All authors approved the final version of the manuscript. EDM is the author responsible for the overall content as the guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests EDM: Research funding/consulting and conferences fees from AbbVie, Novartis, Roche, Pfizer, Janssen, Lilly, MSD, BMS, UCB, Grunenthal and Sanofi. RK, PM, EC, SC, SM, ZB, GK, PF, DK, CC and AH: No conflict of interest. CP: Research grants and/or consultancy fees from AbbVie, Vifor, Roche, GlaxoSmithKline and AstraZeneca. AT: Advisory board Novartis. IM: Speakers bureau: Roche, Novartis, UCB, Gedeon Richter and Janssen. Consultant: Roche.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those 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 includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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