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.

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.

Comparison of diagnostic spectrum between inflammation of unknown origin and fever of unknown origin: A systematic review and meta-analysis.

BACKGROUND: Patients with inflammation of unknown origin (IUO) and fever of unknown origin (FUO) are commonly considered a single population. Differences in underlying causes between both groups may steer the diagnostic work-up. METHODS: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched from July 2009 through December 2023. Studies including both FUO and IUO patients with a sample size of ≥20 were considered. The primary outcome was the difference in the rate of patients affected by predefined diagnostic categories according to meeting FUO or IUO criteria. Data were pooled using random-effects models. RESULTS: A total of 8 studies met criteria for inclusion, with a total of 1452 patients (466 with IUO and 986 with FUO). The median rate of IUO patients among the included studies was 32 % (range 25-39 %). Patients with IUO had a lower likelihood of infection (OR 0.59 [95 % CI; 0.36-0.95]; I2 0 %). There were no significant differences in the rate of noninfectious inflammatory disorders, malignancies, miscellaneous disorders, or remaining undiagnosed. Comparison of diagnostic subgroups revealed that IUO patients were less likely to have systemic autoinflammatory disorders (OR 0.17 [95 % CI, 0.05-0.58]; I2 42 %) and more likely to have vasculitis (OR 2.04 [95 % CI, 1.23-3.38]; I2 21 %) and rheumatoid arthritis or spondylarthritis (OR 3.52 [95 % CI, 1.16-10.69]; I2 0 %). CONCLUSION: Based on our findings, there is little reason to assume that FUO and IUO patients would benefit from a different initial diagnostic approach.

Development of a Consensus-Based List of Potential Quality Indicators for Fever and Inflammation of Unknown Origin.

With a growing emphasis on value-based reimbursement, developing quality indicators for infectious diseases has gained attention. Quality indicators for fever of unknown origin and inflammation of unknown origin are lacking. An assembled group of international experts developed 12 quality measures for these conditions, which could be validated with additional study.

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 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).

Diagnostic yield of combined cranial and large vessel PET/CT, ultrasound and MRI in giant cell arteritis: A systematic review and meta-analysis.

OBJECTIVES: To estimate the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound and MRI for giant cell arteritis (GCA). METHODS: PubMed, Embase, Cochrane and Web of Science databases were searched from inception till August 31, 2022. Studies were included if they involved patients with suspected GCA and assessed the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound or MRI with the final clinical diagnosis as reference standard. RESULTS: Eleven (1578 patients), 3 (149 patients) and 0 studies were included for the diagnostic accuracy of ultrasound, PET/CT and MRI, respectively. Combined cranial and large vessel ultrasound had a sensitivity of 86% (76-92%) and specificity of 96% (92-98%). PET/CT of both cranial and large vessels yielded a sensitivity of 82% (61-93%) and specificity of 79% (60-90%). No studies assessed both PET/CT and ultrasound, which precluded head-to-head comparison. Addition of large vessel ultrasound to ultrasound of the temporal arteries (7 studies) significantly increased sensitivity (91% versus 80%, p < 0.001) without decrease in specificity (96% versus 95%, p = 0.57). Evaluating cranial arteries in addition to large vessels on PET/CT (3 studies) tended to increase the sensitivity (82% versus 68%, p = 0.07) without decrease in specificity (81% versus 79%, p = 0.70). CONCLUSION: Combined cranial and large vessel ultrasound and PET/CT provided excellent accuracy for the diagnosis of GCA. Either PET/CT or ultrasound may be preferred depending on setting, expertise and clinical presentation. The diagnostic accuracy of combined cranial and large vessel MRI needs to be determined in future studies.

Higher diagnostic yield of 18F-FDG PET in inflammation of unknown origin compared to fever of unknown origin.

OBJECTIVE: 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is an important imaging technique in the workup of fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Studies comparing the diagnostic yield of 18F-FDG PET between both entities are lacking. METHODS: Retrospective analysis of FUO/IUO patients who underwent 18F-FDG PET between 2000 and 2019 in the University Hospitals of Leuven (Belgium). 18F-FDG PET images were assessed for accuracy and contribution towards the final diagnosis. Logistic regression was performed to evaluate the association between meeting FUO or IUO criteria and diagnostic contribution of 18F-FDG PET with and without adjustment for confounders. RESULTS: Out of 604 patients, 439 (73%, mean age 56 years, 43% female) underwent 18F-FDG PET imaging, including 349 (79%) classified as FUO and 90 (21%) as IUO. Noninfectious inflammatory disorders were significantly more frequent in the IUO group (37% versus 25%; P = 0.03). 18F-FDG PET imaging had a sensitivity of 93% (89-96%), a specificity of 35% (29-42%), and made a positive contribution to the final diagnosis in 25% (21-29%) of cases. IUO was significantly associated with contributive 18F-FDG PET imaging compared to FUO (aOR 2.21 [95% CI 1.31-3.72]; P = 0.003). Among those with contributive 18F-FDG PET imaging, giant cell arteritis (IUO 25% versus FUO 12%) and polymyalgia rheumatica (IUO 17% versus FUO 1%) were numerically more frequent in the IUO group. CONCLUSION: The diagnostic contribution of 18F-FDG PET was higher among those with IUO, most likely due to differences in diagnostic spectrum.

Epidemiology and predictors of relapse in giant cell arteritis: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to estimate the timing of relapse, the prevalence of multiple relapses and the predictors of relapse in patients with giant cell arteritis (GCA). METHODS: PubMed, Embase and Cochrane databases were searched from inception till November, 30 2021. Outcome measures include cumulative relapse rate (CRR) of first relapse at year 1, 2, and 5 after treatment initiation, CRR of second and third relapse and predictors of relapse. RESULTS: Thirty studies (2595 patients) were included for timing of relapse, 16 studies (1947 patients) for prevalence of multiple relapses and 40 studies (4213 patients) for predictors of relapse. One-year, 2-year and 5-year CRRs were 32% [95% confidence interval (CI) 22-43%], 44% [95% CI 31-59%], and 47% [95% CI 27-67%], respectively. The duration of scheduled glucocorticoid therapy was negatively associated with the 1-year CRR (P=0.03). CRR of second and third relapse were 30% [95% CI 21-40] and 17% [95% CI 8-33%], respectively. Female sex (OR 1.43) and large vessel involvement (OR 2.04) were predictors of relapse. CONCLUSION: Relapse occurred in almost half of GCA patients mainly during the first two years after diagnosis. One in three patients had multiple relapses. The optimal glucocorticoid tapering schedule, which seeks a balance between the lowest relapse risk and the shortest glucocorticoid duration, needs to be determined in future studies. Longer scheduled glucocorticoid therapy or early introduction of glucocorticoid-sparing agents may be warranted in female patients and patients with large vessel involvement.

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.

Modulation of thromboinflammation in hospitalized COVID-19 patients with aprotinin, low molecular weight heparin, and anakinra: The DAWn-Antico study.

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients. Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge. Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N = 67 vs. SOC N = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p = 0.24) or mortality (intervention n = 3 [4.6%] vs. SOC n = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding. Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19.