Large vessel vasculitis is a risk factor for relapse only in giant cell arteritis patients without polymyalgia rheumatica.

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.

Prevalence, characteristics, and outcome of subclinical vasculitis in polymyalgia rheumatica: a retrospective cohort study.

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.

Association Between Vascular 18F-Fluorodeoxyglucose Uptake at Diagnosis and Change in Aortic Dimensions in Giant Cell Arteritis : A Cohort Study.

BACKGROUND: Previous studies have shown that patients with giant cell arteritis (GCA) who have vascular 18F-fluorodeoxyglucose (FDG) uptake at diagnosis are at increased risk for thoracic aortic complications. OBJECTIVE: To measure the association between vascular FDG uptake at diagnosis and the change in aortic dimensions. DESIGN: Prospective cohort study. SETTING: University Hospitals Leuven. PATIENTS: 106 patients with GCA and FDG positron emission tomography (PET) imaging 3 days or less after initiation of glucocorticoids. MEASUREMENTS: Patients had PET and computed tomography (CT) imaging at diagnosis and CT imaging yearly for a maximum of 10 years. The PET scans were scored 0 to 3 in 7 vascular areas and summed to a total vascular score (TVS). The PET scan results were positive when FDG uptake was grade 2 or greater in any large vessel. The association between vascular FDG uptake and aortic dimensions was estimated by linear mixed-effects models with random intercept and slope. RESULTS: When compared with patients with a negative PET scan result, those with a positive scan result had a greater increase in the diameter of the ascending aorta (difference in 5-year progression, 1.58 mm [95% CI, 0.41 to 2.74 mm]), the diameter of the descending aorta (1.32 mm [CI, 0.38 to 2.26 mm]), and the volume of the thoracic aorta (20.5 cm³ [CI, 4.5 to 36.5 cm³]). These thoracic aortic dimensions were also positively associated with TVS. Patients with a positive PET scan result had a higher risk for thoracic aortic aneurysms (adjusted hazard ratio, 10.21 [CI, 1.25 to 83.3]). LIMITATION: The lengthy inclusion and follow-up period resulted in missing data and the use of different PET machines. CONCLUSION: Higher TVS was associated with greater yearly increase in thoracic aortic dimensions. Performing PET imaging at diagnosis may help to estimate the risk for aortic aneurysm formation. PRIMARY FUNDING SOURCE: None.

Biallelic mutations in the CFHR genes underlying atypical hemolytic uremic syndrome in a patient with catastrophic adult-onset Still's disease and recurrent macrophage activation syndrome: A case report.

We report the fatal case of a 20-year-old woman with refractory adult-onset Still's disease (AOSD) accompanied by fulminant macrophage activation syndrome (MAS) and atypical hemolytic uremic syndrome (aHUS). Anakinra and tocilizumab temporarily controlled AOSD. In 2021, she presented to ICU with generalized tonic-clonic seizure, lymphocytic aseptic meningitis, and acute kidney injury. Despite hemodialysis and methylprednisolone, she developed another seizure, MAS, and disseminated intravascular coagulation (DIC). Following brief control, MAS flares -reflected by increased plasma CXCL9 and CXCL10- re-emerged and were controlled through dexamethasone, etoposide, cyclosporin and tofacitinib. No mutations were detected in haemophagocytic lymphohistiocytosis (HLH)-associated genes, nor in genes associated with periodic fever syndromes. Post-mortem genetic testing revealed loss-of-function biallelic deletions in complement factor H-related proteins (CFHR) genes, predisposing aHUS. This case underscores the importance of prompt genetic assessment of complement-encoding alleles, in addition to HLH-related genes, in patients with severe AOSD with recurrent MAS and features of thrombotic microangiopathy (TMA).

Duration of Treatment With Glucocorticoids in Giant Cell Arteritis: A Systematic Review and Meta-analysis.

ABSTRACT: The aim of this meta-analysis was to estimate the mean duration of glucocorticoid (GC) treatment in patients with giant cell arteritis. PubMed, EMBASE, and Cochrane databases were searched from inception until November 30, 2021. The outcome measures were the proportion of patients on GCs at years 1, 2, and 5 after diagnosis and the mean GC dose (in the entire cohort and expressed in prednisone equivalents) at these time points. Twenty-two studies involving a total of 1786 patients were included. The pooled proportions of patients taking GCs at years 1, 2, and 5 were 89.7% (95% confidence interval [CI], 83.2%-93.9%), 75.2% (95% CI, 58.7%-86.6%), and 44.3% (95% CI, 15.2%-77.6%), respectively. The pooled GC dose at years 1 and 2 was 9.1 mg/d (95% CI, 2.8-15.5 mg/d) and 7.8 mg/d (95% CI, 1.4-14.1 mg/d), respectively. The proportion of patients taking GCs at year 1 was lower in multicenter studies ( p = 0.003), in randomized controlled trials ( p = 0.01), and in studies using a GC-tapering schedule ( p = 0.01). There were no significant differences in the proportion of patients taking GCs at years 1 and 2 according to study design (retrospective vs. prospective), initial GC dose, use of pulse GCs, publication year, enrolment period, duration of follow-up, age, and sex. This meta-analysis showed that giant cell arteritis is a chronic disease that requires substantial and prolonged GC treatment in a considerable proportion of patients. A predefined GC-tapering schedule may help to avoid inadequately long GC treatment.

Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma.

BACKGROUND: Several randomised clinical trials have studied convalescent plasma for coronavirus disease 2019 (COVID-19) using different protocols, with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody titres, at different time-points and severities of illness. METHODS: In the prospective multicentre DAWn-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising antibody titres (50% neutralisation titre (NT50)) ≥1/320 was the product of choice for the study. RESULTS: Between 2 May 2020 and 26 January 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median (interquartile range) volume of 884 (806-906) mL) convalescent plasma was administered and 80.68% of the units came from donors with neutralising antibody titres (NT50) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on day 15 was not different between both groups (convalescent plasma 83.74% (n=267) versus control 84.05% (n=137)) (OR 0.99, 95% CI 0.59-1.66; p=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms and transfusion-related side-effects were reported in 19 out of 320 patients in the intervention group (5.94%). CONCLUSIONS: Transfusion of 4 units of convalescent plasma with high neutralising antibody titres early in hospitalised COVID-19 patients did not result in a significant improvement of clinical status or reduced mortality.

Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases.

PURPOSE: Familial Mediterranean Fever (FMF) and Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) are clinically distinct autoinflammatory disorders caused by mutations in the pyrin-encoding gene MEFV. We investigated the transcriptional, phenotypical, and functional characteristics of patient neutrophils to explore their potential role in FMF and PAAND pathophysiology. METHODS: RNA sequencing was performed to discover transcriptional aberrancies. The phenotypical features, degranulation properties, and phagocytic capacity of neutrophils were assessed by flow cytometry. Production of reactive oxygen species (ROS), myeloperoxidase (MPO) release, and chemotactic responses were investigated via chemiluminescence, ELISA, and Boyden chamber assays, respectively. RESULTS: Neutrophils from PAAND and FMF patients showed a partially overlapping, activated gene expression profile with increased expression of S100A8, S100A9, S100A12, IL-4R, CD48, F5, MMP9, and NFKB. Increased MMP9 and S100A8/A9 expression levels were accompanied by high plasma concentrations of the encoded proteins. Phenotypical analysis revealed that neutrophils from FMF patients exhibited an immature character with downregulation of chemoattractant receptors CXCR2, C5aR, and BLTR1 and increased expression of Toll-like receptor 4 (TLR4) and TLR9. PAAND neutrophils displayed an increased random, but reduced CXCL8-induced migration. A tendency for enhanced random migration was observed for FMF neutrophils. PAAND neutrophils showed a moderately but significantly enhanced phagocytic activity as opposed to neutrophils from FMF patients. Neutrophils from both patient groups showed increased MPO release and ROS production. CONCLUSIONS: Neutrophils from patients with FMF and PAAND, carrying different mutations in the MEFV gene, share a pro-inflammatory phenotype yet demonstrate diverse features, underscoring the distinction between both diseases.

Update on imaging in fever and inflammation of unknown origin: focus on infectious disorders.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostic challenges that often require an extensive work-up. When first-line tests do not provide any or only misleading clues, second-line investigations such as specialized imaging techniques are often warranted. OBJECTIVES: To provide an overview of the diagnostic value of imaging techniques that are commonly used in patients with FUO/IUO. SOURCES: MEDLINE database was searched to identify the most relevant studies, trials, reviews, or meta-analyses until 31 March 2023. CONTENT: The most important types of second-line imaging tests for FUO and IUO are outlined, including [67Ga]-citrate single-photon emission computed tomography/computed tomography (CT), labelled leukocyte imaging, [18F]-fluorodeoxyglucose positron emission tomography CT ([18F]-FDG-PET), and whole-body magnetic resonance imaging. This review summarizes the diagnostic yield, extends on potential future imaging techniques (pathogen-specific bacterial imaging and [18F]-FDG-PET/magnetic resonance imaging), discusses cost-effectiveness, highlights practical implications and pitfalls, and addresses future perspectives. Where applicable, we provide additional data specifically for the infection subgroup. IMPLICATIONS: Although many imaging examinations are proven to be useful in FUO and IUO, [18F]-FDG-PET/CT is the preferred second-line test when available as it provides a high diagnostic yield in a presumably cost-effective way.

Association between vascular FDG uptake during follow-up and the development of thoracic aortic aneurysms in giant cell arteritis.

Background: A positive PET scan at diagnosis was associated with a greater yearly increase in ascending and descending aortic diameter and thoracic aortic volume in patients with giant cell arteritis (GCA). Radiologic and histopathologic vascular abnormalities persist in a subset of treated patients despite clinical remission. The aim of this study was to evaluate the association between vascular FDG uptake during follow-up and the development of thoracic aortic aneurysms. Methods: We recently performed a prospective cohort study of 106 GCA patients, who underwent FDG PET and CT imaging at diagnosis and CT imaging yearly for a maximum of 10 years. In this post hoc analysis, GCA patients who also have had FDG PET imaging during follow-up were included. PET scans were visually scored (0-3) at 7 vascular areas. PET scans were considered positive in case of FDG uptake ≥grade 2 in any large vessel. Results: Eighty-eight repeat PET scans were performed in 52 out of 106 GCA patients, who were included in the original prospective cohort. Fifty-five (63%) PET scans were done at the time of a relapse and 33 (38%) were done while in remission. Nine out of ten patients with an incident thoracic aortic aneurysm had both a positive PET scan at diagnosis and during follow-up. Conclusion: In addition to the intensity and extent of the initial vascular inflammation, ongoing aortic inflammation may contribute to the development of thoracic aortic aneurysms in GCA. However, this hypothesis should be confirmed in a large prospective trial with repeat PET scans at predefined time points during follow-up.

Polymyalgia rheumatica is a risk factor for more recalcitrant disease in giant cell arteritis: A retrospective cohort study.

OBJECTIVES: To evaluate differences in presentation and outcome of giant cell arteritis (GCA) patients with and without polymyalgia rheumatica (PMR) symptoms. METHODS: Consecutive patients diagnosed with GCA between 2000 and 2020 and followed for ≥12 months at the University Hospitals Leuven (Belgium), were included retrospectively. RESULTS: We included 398 GCA patients, of which 181 (45%) with PMR symptoms. Patients with PMR symptoms had a longer symptom duration (11 vs 6 weeks, p < 0.001). They less frequently reported fever (19% vs 28%, p = 0.030) and fatigue (52% vs 64%, p = 0.015) and tended to have less permanent vision loss (12% vs 19%, p = 0.052). There was no difference in the cumulative oral GC dose at 2 years (4.4 vs 4.3 g methylprednisolone, p = 0.571). However, those with PMR symptoms were treated with higher GC doses during subsequent follow-up (p < 0.05 from 38 months after diagnosis) and had a lower probability of stopping GC (62% vs 71%, HR 0.74 [95%CI 0.58-0.94], p = 0.018) with a longer median duration of GC treatment (29 vs 23 months, p = 0.021). In addition, presence of PMR symptoms was associated with an increased risk of relapse (64% vs 51%, HR 1.38 [95%CI 1.06-1.79], p = 0.017) with a higher number of relapses (1.47 [95%CI 1.30-1.65] vs 1.16 relapses [95%CI 1.02-1.31], p = 0.007). Patients with PMR symptoms less frequently developed thoracic aortic aneurysms during follow-up (3% vs 11%, p = 0.005). CONCLUSION: GCA patients with PMR symptoms had more recalcitrant disease with a higher risk of relapse and longer duration of GC treatment with need for higher GC doses.

Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods: A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results: Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions: These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.