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Objectives: To evaluate differences in presentation and outcome of giant cell arteritis (GCA) patients with and without large vessel vasculitis (LVV) and according to the extent and severity of LVV., Methods: Consecutive patients diagnosed with GCA between 2003 and 2020 who have had FDG PET imaging at diagnosis ≤3 days after initiation of glucocorticoids and followed for ≥12 months at the University Hospitals Leuven (Belgium), were included retrospectively. PET scans were visually scored (0-3) in 7 vascular areas and a total vascular score (TVS) was calculated. LVV was defined as FDG uptake ≥2 in any large vessel., Results: We included 238 GCA patients, of which 169 (71%) had LVV. LVV patients were younger (69 vs 74 years, p< 0.001) and more frequently female (72% vs 49%, p= 0.001). In patients without PMR symptoms, the presence of LVV was associated with relapse (aOR 3.05 [95%CI 1.32-7.43], p= 0.011) and with a lower probability of stopping glucocorticoids (aHR 0.59 [95%CI 0.37-0.94], p= 0.025). However, in those with PMR symptoms, there was no difference in relapse risk (aOR 1.20 [95%CI 0.53-2.66], p= 0.657) and in the probability of stopping glucocorticoids (aHR 1.25 [95%CI 0.75-2.09], p= 0.394) between patients with and without LVV. A higher TVS was associated with an increased risk of relapse (aOR 1.09 [95%CI 1.04-1.15], p= 0.001] in patients without PMR symptoms, but not in those with PMR symptoms (aOR 1.01 [95%CI 0.96-1.07], p= 0.693)., Conclusion: LVV is a risk factor for relapse in GCA patients without PMR symptoms with a higher relapse risk in those with higher TVS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Two recent meta-analyses reported subclinical vasculitis in 22-23% of patients with polymyalgia rheumatica (PMR). We aimed to evaluate the prevalence, characteristics, and outcome of subclinical vasculitis among our PMR patients., Methods: Consecutive patients with GCA/PMR spectrum disease with isolated PMR symptoms who underwent FDG PET imaging between 2003-2020 and who were followed for ≥6 months, were included retrospectively. Vasculitis was defined as FDG uptake ≥ grade 2 in any vessel., Results: We included 337 patients, of whom 31 (9%) with subclinical vasculitis. Among those with subclinical vasculitis, 21 (58%) had isolated large vessel vasculitis, 3 (10%) had isolated cranial vasculitis and 7 (23%) had both cranial and large vessel vasculitis. The glucocorticoid (GC) starting dose and GC doses during follow-up were higher in those with subclinical vasculitis until 12 months after diagnosis (p< 0.001). There was no difference in the duration of GC treatment (25 vs 20 months, p= 0.187). Cox proportional hazard regression analyses showed no difference in the proportion of patients able to stop GC (HR 0.78 [95% CI 0.49-1.25], p= 0.303) and in the proportion of patients with relapse (HR 0.82 [95%CI 0.50-1.36], p= 0.441)., Conclusion: Only 9% of our PMR patients had subclinical vasculitis with a predilection for large vessel vasculitis. There were no differences in relapse rate and duration of GC treatment, however those with subclinical vasculitis received higher GC doses until 12 months after diagnosis. Prospective interventional trials are needed to evaluate the outcome of PMR patients with and without subclinical vasculitis treated with similar GC protocol., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Tocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with GCA. However, its long-term benefits in new-onset vs relapsing disease are uncertain, and the value of weekly vs every-other-week dosing has not been evaluated., Methods: In Giant-Cell Arteritis Actemra (GiACTA) part 1, patients with new-onset or relapsing GCA received blinded tocilizumab weekly (TCZ QW), tocilizumab every-other-week (TCZ Q2W) or placebo for 52 weeks, with a prednisone taper. In part 2 (open-label), patients were treated at investigator discretion for 104 weeks. In this analysis, patients were evaluated according to their original treatment assignments, and outcomes beyond 52 weeks were assessed. Outcomes of interest included time to first flare and cumulative glucocorticoid exposure over 3 years according to baseline disease status., Results: Part 1 enrolled 250 patients; 215 entered part 2. At baseline, 48% had new-onset disease and 52% had relapsing disease. In patients with new-onset and relapsing disease, the median time to first flare in the TCZ QW group was 577 and 575 days, respectively, vs 479 and 428 days with TCZ Q2W and 179 and 224 days with placebo; the median cumulative glucocorticoid dose was 3068 mg and 2191 mg with TCZ QW, 4080 mg and 2353 mg with TCZ Q2W, and 4639 mg and 6178 mg with placebo., Conclusion: TCZ QW delayed the time to flare and reduced the cumulative glucocorticoid dose in patients with relapsing GCA and new-onset GCA. These data support initiating TCZ QW as part of first-line therapy in all patients with active GCA., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01791153., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort., Methods: We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy., Results: Sixty-three patients [27 women, median age 60 years (18-83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1-296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation., Conclusion: Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Previous studies have shown that the majority of patients with PMR have increased 18F-fluorodeoxyglucose (FDG) uptake around the shoulders, hips and processes of the cervical and lumbar spine on PET. The specificity of these findings for PMR is, however, not known., Methods: We prospectively included 99 consecutive patients with a possible clinical diagnosis of PMR. All patients underwent 18F-FDG-PET scanning before treatment with glucocorticoids was started. The clinical suspicion of PMR was quantified by the treating physician on a scale from 1 to 5. FDG uptake was scored visually in 12 articular regions (scores 0-2) and a total skeletal score was calculated reflecting the FDG uptake in these 12 articular regions. Receiver operating characteristics analysis was performed to determine the optimal clinical and total skeletal score for diagnosing PMR. The gold standard for a diagnosis of PMR was the judgement of an experienced clinician after at least 6 months of follow-up., Results: Sixty-seven patients were diagnosed with PMR while 32 patients got another diagnosis. A clinical score of 4 or more had a sensitivity of 67.2%, specificity of 87.5%, positive predictive value (PPV) of 91.8% and a negative predictive value (NPV) of 56.0% for the diagnosis of PMR. A total skeletal score of 16 or more had a sensitivity, specificity, PPV and NPV of, respectively, 85.1, 87.5, 93.4 and 73.7%., Conclusion: 18F-FDG-PET before starting glucocorticoid therapy improves the diagnostic accuracy compared with a clinical scoring system in patients with clinical suspicion of PMR.

Objective: The objective of this multicentre study was to improve the clinical interpretation of PR3- and MPO-ANCAs as an adjunct for the diagnosis of ANCA-associated vasculitis (AAV) by defining thresholds and test result intervals based on predefined specificities and by calculating test result interval-specific likelihood ratios (LRs)., Methods: Eight different PR3- and MPO-ANCA immunoassays from seven companies were evaluated using 251 diagnostic samples from AAV patients and 924 diseased controls., Results: Thresholds for antibody levels were determined based on predefined specificities (95, 97.5, 99 and 100%) and used to delimit test result intervals. Test result interval-specific LRs were determined. For all assays, the LR for AAV increased with increasing antibody level. For all but one immunoassay, high antibodies levels (associated with LR >55) were found in a substantial fraction (>65%) of patients. The area under the curve (AUC) of receiver operating characteristics analysis of a diagnostic approach in which positive results were confirmed by IIF or another immunoassay was not substantially higher than the AUC of performing immunoassay only. The highest AUC was found when immunoassay was combined with another immunoassay or with IIF., Conclusion: To diagnose AAV based on PR3- and MPO-ANCA, it is useful to define thresholds for antibody levels and to assign test result interval-specific LRs. Higher antibody levels are associated with a higher likelihood for disease. Such information improves clinical interpretation., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: The diagnosis of (isolated) IgG4-related periaortitis is often based on elevated serum IgG4 levels since in tissues such as the aorta, biopsies cannot be easily performed. However, the role for serum IgG4 as a biomarker for IgG4-related periaortitis is indistinct. The main purpose of our study was to identify clinical differences between periaortitis with elevated vs normal serum IgG4 levels., Methods: A retrospective study was performed on 68 non-infectious periaortitis patients. We compared demographic, clinical, biochemical and radiological data in patients with elevated serum IgG4 levels with data from patients with normal serum IgG4 levels. The calcium content of the aortic wall was calculated to determine the amount of atherosclerosis., Results: After applying exclusion criteria, our study population consisted of nine IgG4-related periaortitis patients and eight idiopathic periaortitis patients. Striking significant differences were male predominance (P = 0.001) and multifocal organ involvement (P = 0.004) in IgG4-related periaortitis patients compared with the idiopathic periaortitis group. The calcium content of the total aortic wall was significantly higher in IgG4-related periaortitis patients (P = 0.005). No other significant differences were found., Conclusion: Elevated serum IgG4 levels, male gender, a higher calcium content of the aortic wall and multifocal organ involvement are features that might provide a higher probability for IgG4-related periaortitis compared with idiopathic periaortitis. Our study results might be compatible with the hypothesis of Mitchinson and Parums that atherosclerotic plaque plays a role in the pathogenesis of chronic periaortitis., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Serum samples from patients with autoimmune connective tissue diseases that show a finely speckled antinuclear antibody (ANA) on indirect immune-fluorescence often have antibodies against unknown nuclear target antigens. To search for such autoantigens we applied a proteomic approach using sera from patients with a high ANA titer (>or=640) and finely speckled fluorescence but in whom no antibodies to extractable nuclear antigens (ENA) could be identified., Methods: Using an immunoproteomics approach we identified heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) as a novel nuclear target of autoantibody response., Results: Recombinant rat hnRNP H1 reacted in Western blot analyses with 48% of 93 sera from patients with primary Sjögren syndrome and with 5.2% of 153 sera from patients with other connective tissue diseases (diseased controls). For comparison, the diagnostic sensitivity and specificity of anti-Sjögren syndrome A (SSA) antibodies for primary Sjögren syndrome in the same patient cohort were 88.2% and 76.3%, respectively. Interestingly, 5 of 11 primary Sjögren syndrome patients with no anti-SSA or anti-SSB antibodies had anti-hnRNP H1 antibodies. Anti-hnRNP H1 antibodies were preabsorbed by hnRNP H1, as demonstrated by indirect immunofluorescence. In an evaluation of the presence of anti-hnRNP H1 antibodies in 188 consecutive samples submitted to the clinical laboratory with positive ANA (titer >or=160), anti-hnRNP H1 antibodies were found in 3 of 7 (2 primary and 5 secondary) Sjögren syndrome patients and in 8.3% of the diseased controls., Conclusions: HnRNP H1 is a newly discovered autoantigen that could become an additional diagnostic marker.

Objective: GCA carries an increased risk of developing thoracic aortic aneurysms. Previous work with fluorodeoxyglucose (FDG)-PET has shown that the aorta is frequently involved in this type of vasculitis. We wanted to investigate whether there is a correlation between the extent of vascular FDG uptake during the acute phase of GCA and the aortic diameter at late follow-up., Methods: All patients with biopsy-proven GCA who ever underwent an FDG-PET scan in our centre were asked to undergo a CT scan of the aorta. The diameter of the aorta was measured at six different levels (ascending aorta, aortic arch, descending aorta, abdominal suprarenal, juxtarenal and infrarenal aorta) and the volumes of the thoracic and of the abdominal aorta were calculated., Results: Forty-six patients agreed to participate (32 females, 14 males). A mean of 46.7 +/- 29.9 months elapsed between diagnosis and CT scan. All aortic dimensions were significantly smaller in women than in men, except for the diameter of the ascending aorta. Patients who had an increased FDG uptake in the aorta at diagnosis of GCA, had a significantly larger diameter of the ascending aorta (P = 0.025) and descending aorta (P = 0.044) and a significantly larger volume of the thoracic aorta (P = 0.029). In multivariate analysis, FDG uptake at the thoracic aorta was associated with late volume of the thoracic aorta (P = 0.039)., Conclusion: GCA-patients with increased FDG uptake in the aorta may be more prone to develop thoracic aortic dilatation than GCA patients without this sign of aortic involvement.

Objective: To study fluorodeoxyglucose (FDG) deposition in different vascular beds and in the large joints of patients with isolated polymyalgia rheumatica (PMR), and to investigate whether there is a relation between FDG-positron emission tomography (PET) results and risk of relapse., Methods: All consecutive patients with isolated PMR underwent a FDG-PET scan before treatment with steroids was started and--if logistics allowed--at 3 and 6 months. PET scans were scored at seven different vascular areas and a total vascular score (TVS) was calculated, ranging from 0 to 21. FDG uptake in the shoulders, the hips and the processi spinosi of the vertebrae was scored as 0 (no uptake), 1 (moderate uptake) or 2 (intense uptake)., Results: Thirty-five patients entered the study. At diagnosis, vascular FDG uptake was noted in 11 patients (31%), predominantly at the subclavian arteries. Mean TVS was low. FDG uptake in the shoulders was noted in 94% of patients, in the hips in 89% and in the processi spinosi of the vertebrae in 51%. The intensity of FDG uptake in the large vessels or in the shoulders, hips or processi spinosi did not correlate with the risk of relapse., Conclusions: Only one in three patients has an (moderately) increased vascular FDG uptake, especially in the subclavian arteries. The vast majority has inflammation of shoulders and hips, and half of them have increased FDG-uptake at the processi spinosi. Results of FDG-PET scans in patients with PMR did not correlate with their risk of relapse.

We describe the diagnostic contribution of [(18)F]fluoro-deoxyglucose (FDG) positron emission tomography (PET) scan in 58 consecutive cases of fever of unknown origin (FUO) and compare this new approach with gallium scintigraphy. This investigation was performed from March 1996 through October 1998 at Gasthuisberg University Hospital in Leuven, Belgium. A final diagnosis was established for 38 patients (64%). Forty-six FDG-PET scans (79%) were abnormal; 24 of these abnormal scans (41% of the total number of scans) were considered helpful in diagnosis, and 22 (38% of the total number) were considered noncontributory to the diagnosis. In a subgroup of 40 patients (69%), both FDG-PET and gallium scintigraphy were performed. FDG-PET scan and gallium scintigraphy were normal in 23% and 33% of these cases, respectively; helpful in diagnosis in 35% and 25%, respectively; and noncontributory in 42% each. All foci of abnormal gallium accumulation were also detected by use of an FDG-PET scan. We conclude that FDG-PET is a valuable second-step technique in patients with FUO because it yielded diagnostic information in 41% of the patients in whom the probability of a definite diagnosis was only 64%. FDG-PET scan compares favorably with gallium scintigraphy for this indication. Because of the quick results (within hours instead of days), FDG-PET scan may replace gallium scintigraphy as a radiopharmaceutical for the evaluation of patients with FUO.

Objective: To study the possible contribution of fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the diagnosis of giant cell arteritis and polymyalgia rheumatica., Methods: A consecutive case series consisting of five patients with polymyalgia rheumatica, six patients with temporal arteritis and 23 age-matched patients with other inflammatory conditions were evaluated with FDG-PET. Studies were performed before therapy with steroids was started., Results: A total of 4/6 patients with giant cell arteritis and 4/5 patients with polymyalgia had increased FDG uptake in their thoracic vessels, compared to 1/23 controls (P < 0.001). Increased vascular FDG uptake in the upper legs was seen in 8/11 patients with giant cell arteritis or polymyalgia compared to 8/23 control patients (P < 0.05), and in the lower legs in 6/11 patients compared to 6/23 controls (P = not significant)., Conclusions: FDG-PET scan is the first non-invasive technique which may indicate large-vessel vasculitis and which can show its extension throughout the body. It strongly suggests that polymyalgia rheumatica is a form of vasculitis.