Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

Reproducibility and accuracy of vessel wall MRI in diagnosing giant cell arteritis: a study with readers of varying expertise.

OBJECTIVE: To evaluate the reproducibility of vessel wall magnetic resonance imaging (VW-MRI) in diagnosing giant cell arteritis (GCA) among groups of radiologists with varying levels of expertise. METHODS: This institutional review board-approved retrospective single-center study recruited patients with suspected GCA between December 2014 and September 2021. Patients underwent 3 -T VW-MRI before temporal artery biopsy. Ten radiologists with varying levels of expertise, blinded to all data, evaluated several intracranial and extracranial arteries to assess GCA diagnosis. Interobserver reproducibility and diagnostic performance were evaluated. RESULTS: Fifty patients (27 women and 23 men) with a mean age of 75.9 ± 9 years were included. Thirty-one of 50 (62%) had a final diagnosis of GCA.VW-MRI had an almost perfect reproducibility among expert readers (kappa = 0.93; 95% CI 0.77-1) and substantial reproducibility among all readers, junior and non-expert senior readers (kappa = 0.7; 95% CI 0.66-0.73; kappa = 0.67 95% CI 0.59-0.74; kappa = 0.65; 95% CI 0.43-0.88 respectively) when diagnosing GCA. Substantial interobserver agreement was observed for the frontal branch of superficial temporal artery. Moderate interobserver agreement was observed for the superficial temporal artery and its parietal branch, as well as ophthalmic arteries in all groups of readers. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy varied depending on the group of readers. CONCLUSION: VW-MRI is a reproducible and accurate imaging modality for detecting GCA, even among less-experienced readers. This study advocates for the use of VW-MRI when diagnosing GCA even in less-experienced centers. CLINICAL RELEVANCE STATEMENT: VW-MRI is a reproducible and accurate imaging modality for detecting GCA, even among less-experienced readers, and it could be used as a first-line diagnostic tool for GCA in centers with limited expertise in GCA diagnosis. KEY POINTS: • Vessel wall magnetic resonance imaging (VW-MRI) is a reproducible and accurate imaging modality for detecting giant cell arteritis (GCA) in both extracranial and intracranial arteries. • The reproducibility of vessel wall magnetic resonance imaging for giant cell arteritis diagnosis was high among expert readers and moderate among less-experienced readers. • The use of vessel wall magnetic resonance imaging for giant cell arteritis diagnosis can be recommended even in centers with less-experienced readers.

ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

OBJECTIVES: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. METHODS: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. RESULTS: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. CONCLUSION: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

Characteristics and Prognosis of Binocular Diplopia in Patients With Giant Cell Arteritis.

BACKGROUND: Giant cell arteritis (GCA) is a large vessel vasculitis associated with a risk of permanent ophthalmologic complications. Data about diplopia prognosis in GCA are scarce. This study was designed to better characterize diplopia in newly diagnosed GCA patients. METHODS: All consecutive patients diagnosed with GCA from January 2015 to April 2021 in a French tertiary ophthalmologic center were retrospectively reviewed. GCA diagnosis relied on a positive temporal artery biopsy or high-definition MRI. RESULTS: Among 111 patients diagnosed with GCA, 30 patients (27%) had diplopia. Characteristics of patients with diplopia were similar to other GCA patients. Diplopia resolved spontaneously in 6 patients (20%). Diplopia was attributed to cranial nerve palsy in 21/24 patients (88%), especially third (46%) and sixth cranial nerve (42%). Ocular ischemic lesions occurred in 11 of the 30 patients with diplopia (37%); 2 patients developed vision loss after initiation of corticosteroids. In the remaining 13 patients, diplopia resolved after treatment onset in 12 patients (92%) with a median delay of 10 days. Patients treated intravenously tended to have a quicker improvement than those treated orally, but with a similar resolution rate of diplopia at 1 month. Two patients had relapse of diplopia at 4 and 6 weeks after an initial treatment course of 24 and 18 months, respectively. CONCLUSIONS: Diplopia is a rare feature at GCA diagnosis, but should raise clinician suspicion for GCA when associated with cephalic symptoms and prompt the initiation of corticosteroids to prevent ocular ischemic complications.

A recurrent pleuropneumonia revealing Erdheim-Chester Disease.

Erdheim-Chester disease (ECD) is a rare form of L group histiocytosis, accounting for up to 1500 cases to date worldwide, which mainly affects men between their 5th and 7th decade of life. The most frequent manifestations are bone involvement, perirenal infiltration with an evocating appearance of "hairy kidneys", and a "coated aorta" aspect. Lung involvement in ECD is less common and includes pleural infiltration and interstitial lung disease. Herein, we report the case of a 76-year-old woman with recurrent pleuropneumonia revealing ECD.

Clinical phenotypes and long-term outcome of kidney involvement in Erdheim-Chester histiocytosis.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that frequently infiltrates the peri-kidney space ("hairy kidney" appearance), kidney pelvis and proximal ureters, leading to obstructive uropathy. Here, we analyzed the clinical characteristics, imaging findings and long-term kidney outcome of a large multicenter cohort comprising 195 consecutive patients with ECD. Retroperitoneal peri-kidney or peri-ureteral involvement was detected at diagnosis in 147 patients. Of them, 70 had hydronephrosis (bilateral in 47), and 16 with kidney atrophy (unilateral in 14). Kidney vascular peduncle infiltration was found in 60 patients, and kidney artery stenosis in 31. The estimated glomerular filtration rate (eGFR) at diagnosis was significantly lower in patients with than in those without peri-kidney involvement (median 74 vs. 98 mL/min/1.73 m2). Ureteral stenting often failed to achieve kidney function recovery. A total of 181 patients received medical therapies: first-line treatments included interferon-α (61%), BRAF-inhibitors (17%), mTOR-inhibitors (7%), or other drugs (15%). These therapies were efficacious for ECD but rarely induced kidney function improvement (one-year eGFR increase over 25% in under 10% of patients). After a median of 43 months, 19% of patients died and 5% developed kidney failure. Among patients with peri-kidney involvement, 44% developed chronic kidney disease (CKD) 3-5 at five years vs. 5% of those without. Unadjusted predictors of advanced CKD and kidney failure/death were age over 50 years, hypertension, BRAFV600E mutation, and baseline eGFR. At multivariable analysis, cardiovascular comorbidities were associated with advanced CKD, and age over 50 years with kidney failure/death. Thus, kidney involvement is common in ECD and can lead to CKD or kidney failure despite effective medical therapies or urological procedures.

Immune checkpoint inhibitor-associated hypercalcaemia.

Immune checkpoint inhibitors (CPIs) have recently become a cornerstone for the treatment of different advanced cancers. These drugs have the ability to reactivate the immune system against tumour cells but can also trigger a myriad of side effects, termed immune-related adverse events (irAEs). Although there are numerous reports of CPI-related endocrinopathies, hypercalcaemia as a suspected irAE is not well documented. The mechanisms of CPI hypercalcaemia are not clearly established. However, in our review, four distinct causes emerged: endocrine disease-related, sarcoid-like granuloma, humoral hypercalcaemia due to parathyroid-related hormone and hyperprogressive disease following CPI initiation. Prompt recognition of hypercalcaemia and the institution of therapy can be lifesaving, affording the opportunity to address the underlying aetiology. In this review we discuss the incidence, diagnosis and management of immune-related hypercalcaemia in oncological patients receiving CPI agents.

Sarcoidosis diagnosed on granulomas in the explanted heart after transplantation: Results of a French nationwide study.

BACKGROUND: Cardiac sarcoidosis (CS) is a challenging diagnosis. Patients may progress to end-stage congestive heart failure and require cardiac transplantation without ever having been diagnosed. Characteristics and outcomes of patients with granulomas in the explanted hearts are unknown. METHODS: All French heart transplantation centers were contacted to participate in the study. Each center searched through local databases for the cases of non-caseating granuloma in the explanted hearts between 2000 and 2017. Data before and after transplantation were recorded from medical charts. Survival of CS and all- cause heart transplantation patients were compared. RESULTS: Fifteen patients (10 men, 5 women) received a diagnosis of CS based on pathologic data of the explanted heart and were recruited for the study. All patients were diagnosed as non-ischemic dilated or hypertrophic cardiomyopathy and presented congestive heart failure. Eight patients (53%) had ventricular rhythm disturbances, and 3 (20%) a complete heart block. Ten out of 13 patients (77%) had extracardiac radiological signs compatible with sarcoidosis on chest computed tomography (CT) scans. One patient died 3 months after transplantation from infectious complications. The 14 remaining patients were still alive at the end of the study (median follow-up of 28.8 months). One patient had a second heart transplantation 5 years later because of chronic allograft vasculopathy. One patient presented a relapse of CS confirmed by myocardial biopsies 9 years after transplantation, requiring an escalation of immunosuppressive therapy. CONCLUSION: CS may be undiagnosed before heart transplantation. In 77% of cases, sarcoidosis could have been detected before transplantation with non-invasive imaging techniques.

Giant-cell arteritis-related mortality in France: A multiple-cause-of-death analysis.

OBJECTIVES: Giant-cell arteritis (GCA) is a large vessel vasculitis. Data regarding mortality are controversial. We describe the mortality data of the French death certificates for the period of 2005 to 2014. METHODS: Using multiple-cause-of-death (MCOD) analysis, we calculated age-adjusted mortality rates for GCA, examined differences in mortality rates according to age and gender and analyzed the underlying causes of death (UCD). RESULTS: We analyzed 4628 death certificates listing a diagnosis of GCA as UCD or non-underlying cause of death (NUCD). The mean age of death was 86 (±6.8) years. The overall age-standardized mortality rate among GCA patients was 7.2 per million population. Throughout the study period, the mean age of death was significantly increased (r = 0.17, p < .0001) in both genders. There was no significant difference with age repartition of death in the general population (p = .26). When GCA was listed as the UCD, most frequent associated diseases were cardiovascular (79%) and infectious diseases (35%). When GCA was reported as the NUCD, the listed UCD was a cardiovascular event in 40% of cases, neoplasm in 13%, neurodegenerative disorder in 11% and infectious disease in 10%. When GCA was the UCD or NUCD, an age-adjusted observed/expected ratio > 1 in GCA-associated mortality compared with the general population mortality was observed for tuberculosis, pneumonia and cardiovascular diseases. CONCLUSION: In this analysis of French death certificates mentioning GCA, we observed a stable standardized mortality rate between 2005 and 2014. The most frequent associated diseases were cardiovascular diseases and infections.

Cerebrovascular events in Takayasu arteritis: a multicenter case-controlled study.

OBJECTIVES: Takayasu arteritis (TA) is a giant cell arteritis usually affecting young women and characterized by inflammatory and ischemic signs of large vessel involvement, including extracranial cerebral arteries. The impact of stroke on TA prognosis has not been well evaluated. METHODS: We performed a retrospective multicenter review of patients with definite TA who experienced at least one stroke and compared the findings to 17 matched patients with TA diagnosis without neurological involvement. RESULTS: Seventeen patients (15 women, median age at stroke diagnosis 44 years) receiving a diagnosis of TA and stroke between 2002 and 2016 in our institution were included, from a cohort of 126 patients suffering from TA (13.5%). At diagnosis, patients from both groups had comparable cardiovascular risk factors. The first cerebrovascular event was ischemic stroke (n = 15) or transient ischemic attack (n = 2). In eight patients, stroke occurred after the TA diagnosis was made. In four patients, stroke occurred after carotid surgery. At the end of follow-up, 59% of patients had a neurological impairment, 35% had a recurrence of stroke, and 24% suffered from epilepsy. CONCLUSIONS: Stroke is a major cause of disability in TA patients. Internal carotid surgery may be performed with caution because of the risk of stroke after the procedure.