Cavernous Malformations of the Central Nervous System: An International Consensus Statement

Introduction: Cavernous malformations (CM) of the central nervous system constitute rare vascular lesions. They are usually asymptomatic, which has allowed their management to become quite debatable. Even when they become symptomatic their optimal mode and timing of treatment remains controversial. Research question: A consensus may navigate neurosurgeons through the decision-making process of selecting the optimal treatment for asymptomatic and symptomatic CMs. Material and methods: A 17-item questionnaire was developed to address controversial issues in relation to aspects of the treatment, surgical planning, optimal surgical strategy for specific age groups, the role of stereotactic radiosurgery, as well as a follow-up pattern. Consequently, a three-stage Delphi process was ran through 19 invited experts with the goal of reaching a consensus. The agreement rate for reaching a consensus was set at 70%. Results: A consensus for surgical intervention was reached on the importance of the patient’s age, symptomatology, and hemorrhagic recurrence; and the CM’s location and size. The employment of advanced MRI techniques is considered of value for surgical planning. Observation for asymptomatic eloquent or deep-seated CMs represents the commonest practice among our panel. Surgical resection is considered when a deep-seated CM becomes symptomatic or after a second bleeding episode. Asymptomatic, image-proven hemorrhages constituted no indication for surgical resection for our panelists. Consensus was also reached on not resecting any developmental venous anomalies, and on resecting the associated hemosiderin rim only in epilepsy cases. Discussion and conclusion: Our Delphi consensus provides an expert common practice for specific controversial issues of CM patient management

The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus

IntroductionAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).MethodsWe performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.ResultsWe report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.DiscussionWe conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy

Disease modification achievement in patients with lupus nephritis in a real-life setting: mission impossible?

Objective A preliminary definition of disease modification (DM) in lupus nephritis (LN) was recently developed focusing on long-term remission and damage prevention, with minimal treatment-associated toxicity. We aimed to further specify aspects of DM criteria in LN, assess DM achievement in a real-world setting and examine potential DM predictors and long-term outcomes.Methods We collected clinical/laboratory and histological inception cohort data from biopsy-proven LN patients (82% females) with ≥72 months follow-up at two joint academic centres. Specific criteria for 24-hour proteinuria, estimated glomerular filtration rate (eGFR), renal flares and glucocorticoids dose were set at three time frames (months 0–12, 13–60 and 72) to assess DM. In the first model, DM was achieved if patients fulfilled all four criteria at all three time frames (achievers). In the second model, the continued glucocorticoids reduction criterion was excluded. Logistic regression analyses were performed. Possible different trends in DM achievement between past and recent decades were also investigated.Results DM was achieved by 60% of patients, increased to 70% when glucocorticoids excluded from DM criteria. 24-hour proteinuria at 9 months predicted DM achievement (OR 0.72, 95% CI 0.53 to 0.97, p=0.03), but none of baseline characteristics. Among patients with >72 month follow-up, non-achievers had worse renal outcomes (flares, >30% proteinuria increase, eGFR decline) than achievers at the end of follow-up (median 138 months). Patients diagnosed between 1992 and 2005 were found to have significantly lower percentages of DM achievement and met less often the glucocorticoids dose reduction criterion in all three time frames, compared with those diagnosed between 2006 and 2016 (p=0.006 and p<0.01, respectively).Conclusions DM was achieved by only 60% of LN patients in a real-life setting, partly due to lack of glucocorticoids dose target attainment, while DM failure was associated with worse long-term renal outcomes. This may imply limitations in the effectiveness or implementation of current LN treatments, supporting the need for novel therapeutic strategies

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases

Objective tau o report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs). Methods Patients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients. Results Between 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients. Conclusions Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics

Listening to patients, for the patients: The COVAD Study-Vision, organizational structure, and challenges

Background: The pandemic presented unique challenges for individuals with autoimmune and rheumatic diseases (AIRDs) due to their underlying condition, the effects of immunosuppressive treatments, and increased vaccine hesitancy. Objectives: The COVID-19 vaccination in autoimmune diseases (COVAD) study, a series of ongoing, patient self-reported surveys were conceived with the vision of being a unique tool to gather patient perspectives on AIRDs. It involved a multinational, multicenter collaborative effort amidst a global lockdown. Methods: Leveraging social media as a research tool, COVAD collected data using validated patient-reported outcomes (PROs). The study, comprising a core team, steering committee, and global collaborators, facilitated data collection and analysis. A pilot-tested, validated survey, featuring questions regarding COVID-19 infection, vaccination and outcomes, patient demographics, and PROs was circulated to patients with AIRDs and healthy controls (HCs). Discussion: We present the challenges encountered during this international collaborative project, including coordination, data management, funding constraints, language barriers, and authorship concerns, while highlighting the measures taken to address them. Conclusion: Collaborative virtual models offer a dynamic new frontier in medical research and are vital to studying rare diseases. The COVAD study demonstrates the potential of online platforms for conducting large-scale, patient-focused research and underscores the importance of integrating patient perspective into clinical care. Care of patients is our central motivation, and it is essential to recognize their voices as equal stakeholders and valued partners in the study of the conditions that affect them