Sudden Visual Loss due to Arteritic Anterior Ischaemic Optic Neuropathy: A Rare Manifestation of Eosinophilic Granulomatosis with Polyangiitis.

Background: eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem inflammatory disease characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of various organs. While the eye is uncommonly affected in patients with EGPA, multiple ophthalmic manifestations have been reported, which can result in serious visual impairment without timely treatment. Case report: we report the case of a 79-year-old woman with a history of asthma and nasal polyps who presented with low-grade fever, mild alteration of mental status, and fatigue. Chest X-ray revealed bilateral interstitial infiltrates. Lab tests showed elevated C-reactive protein level and eosinophilia (eosinophil count, 4.6 x109 cells/l); blood cultures and parasitological examination of stools tested negative. Four days after presentation, the patient reported sudden and severe blurring of vision in her left eye. Ophthalmological examination revealed bilateral swollen optic disc and visual field loss, more severe in the left eye. A diagnosis of EGPA complicated by arteritic anterior ischaemic optic neuropathy (A-AION) was proposed, while an alternative or concurrent diagnosis of giant cell arteritis was ruled out based on clinical picture. Immunosuppressive treatment with high-dose intravenous glucocorticoids was promptly started. The patient's visual defect did not improve; however, two months later, no worsening was registered on ophthalmic reassessment. Conclusions: A-AION is an infrequent but severe manifestation of EGPA, requiring prompt diagnosis and emergency-level glucocorticoid therapy to prevent any further vision loss. Disease awareness and a multidisciplinary approach are crucial to expedite diagnostic work-up and effective management of EGPA-related ocular complications. LEARNING POINTS: Arteritic ischaemic optical neuropathy is a potential cause of sudden and severe visual loss in eosinophilic granulomatosis with polyangiitis (EGPA) patients.Visual loss due to arteritic ischaemic optical neuropathy is rarely reversible; however, a timely glucocorticoid treatment may prevent further progression of visual impairment.Multidisciplinary approach is crucial to expedite diagnostic work-up and effective management of EGPA patients with ocular complications.

A critical view on autoantibodies in lupus nephritis: Concrete knowledge based on evidence.

Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.

Rare Onset of Erdheim-Chester Disease in Children and Young Adults: A Case Series and Review of the Literature.

INTRODUCTION: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm that affects patients, predominantly males aged 40-70 years, with very heterogeneous clinical presentation and prognosis. In 2020, Goyal et al. proposed consensus recommendations for the management of patients with ECD, remarking on the exceptional presentation of the disease in the pediatric population. CASE PRESENTATION: The first patient, a 20-year-old male, underwent cervical laminectomy and partial removal of a cervical spine lesion, initially apparently consistent with cervical schwannomas. The second patient, a 9-year-old female, received surgery for an extra-axial lesion of the greater sphenoid wing, radiologically consistent with a meningioma. CONCLUSION: At present, 15 pediatric cases have been reported in the literature with involvement of the central nervous system, with no consensus on the diagnostic and therapeutic management, as Pegoraro et al. evidenced in their pediatric multicenter case series. The present article adds two new cases of ECD with onset in childhood and young adulthood, who received the diagnosis after neurosurgical procedures.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

BACKGROUND: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

OBJECTIVES: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. METHODS: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. RESULTS: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. CONCLUSIONS: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in pediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of pediatric patients with GPA in 20 centers from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls (immunoglobulin A vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1), and Cogan's syndrome (n = 1)) with a median age of 17.8 and 15.2 years, respectively. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (p= 0.229 and p= 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

Glomerular Diseases Across Lifespan: Key Differences in Diagnostic and Therapeutic Approaches.

Glomerular diseases are common causes of chronic kidney disease in childhood, adolescence, and adulthood. The epidemiology of glomerular diseases differs between different age groups, with minimal change disease being the leading cause of nephrotic syndrome in childhood, while membranous nephropathy and focal segmental glomerulosclerosis are more common in adulthood. IgA vasculitis is also more common in childhood. Moreover, there is a difference in disease severity with more children presenting with a relapsing form of nephrotic syndrome and a more acute presentation of antineutrophil cytoplasmic antibody-associated vasculitis and concomitant glomerulonephritis, as highlighted by the higher percentage of cellular crescents on kidney biopsy specimens in comparison with older patients. There is also a female preponderance in antineutrophil cytoplasmic antibody-associated vasculitis and more children present with tracheobroncholaryngeal disease. This article aims to summarize differences in the presentation of different glomerular diseases that are encountered commonly by pediatric and adult nephrologists and potential differences in the management.

Epidemiology and geographic clustering of Erdheim-Chester disease in Italy and France.

This geoepidemiological study, performed in Italy and France, shows that Erdheim-Chester disease is increasingly diagnosed and cases cluster in specific geographic areas, namely southern Italy and central France. Disease frequency inversely correlates with the Human Development Index.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Overcoming challenges in rare disease registry integration using the semantic web - a clinical research perspective.

The growing number of disease-specific patient registries for rare diseases has highlighted the need for registry interoperability and data linkage, leading to large-scale rare disease data integration projects using Semantic Web based solutions. These technologies may be difficult to grasp for rare disease experts, leading to limited involvement by domain expertise in the data integration process. Here, we propose a data integration framework starting from the perspective of the clinical researcher, allowing for purposeful rare disease registry integration driven by clinical research questions.

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

CKD therapy to improve outcomes of immune-mediated glomerular diseases.

The management of immunoglobulin A nephropathy, membranous nephropathy, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, C3 glomerulonephritis, autoimmune podocytopathies and other immune-mediated glomerular disorders is focused on two major treatment goals, preventing overall mortality and the loss of kidney function. Since minimizing irreversible kidney damage best serves both goals, the management of immune-mediated kidney disorders must focus on the two central pathomechanisms of kidney function decline, i.e., controlling the underlying immune disease process (e.g. with immunotherapies) and controlling the non-immune mechanisms of chronic kidney disease (CKD) progression. Here we review the pathophysiology of these non-immune mechanisms of CKD progression and discuss non-drug and drug interventions to attenuate CKD progression in immune-mediated kidney disorders. Non-pharmacological interventions include reducing salt intake, normalizing body weight, avoiding superimposed kidney injuries, smoking cessation and regular physical activity. Approved drug interventions include inhibitors of the renin-angiotensin-aldosterone system and sodium-glucose cotransporter-2. Numerous additional drugs to improve CKD care are currently being tested in clinical trials. Here we discuss how and when to use these drugs in the different clinical scenarios of immune-mediated kidney diseases.

Unmet needs in ANCA-associated vasculitis: Physicians' and patients' perspectives.

In recent years, clinical research has increased significantly and therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have improved. However, there are still unanswered questions and unmet needs about AAV patients. The purpose of this review is to examine the frontiers of research related to emerging biomarkers eventually predicting relapse, and new therapeutic approaches, not to mention new quality of life assessment tools. Identifying predictors of relapse may help optimize therapeutic strategies, minimize disease recurrence, and reduce treatment-related side effects. In addition, it is important to recognize that patients may suffer long-term consequences of the disease and its treatment, which, although life-saving, is often associated with significant side effects. Our goal, therefore, is to highlight what has been achieved, the pitfalls, and what still needs to be done, comparing the views of physicians and patients.

IgG4-related disease: advances in pathophysiology and treatment.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory disease affecting multiple organs. In recent years basic and translational research has unveiled the role of different cellular subtypes and cytokines in inducing and perpetuating the pathological process, eventually leading to fibrosis of affected tissues. Hopefully, the growing knowledge of the disease pathogenesis will lead to patient-tailored treatments in the near future. AREAS COVERED: This review focuses on the most recent discoveries concerning the pathogenic mechanisms underlying IgG4-RD and highlights their potential role as specific therapeutic targets. EXPERT OPINION: IgG4-RD is a systemic and multifaceted disease. Its sensitivity to glucocorticoids is well known, however new targeted therapies are emerging that can reduce glucocorticoid exposure and achieve sustained clinical responses. Clinicians managing patients with such a rare and heterogeneous disease must therefore be aware of its varied phenotype and traditional and novel therapeutic strategies.