A systematic review of patient reported outcome measures in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

OBJECTIVES: ANCA associated vasculitis (AAV) is associated with significant morbidity, fatigue, pain and poor health-related quality of life (HRQoL). This review aims to assess the comprehensiveness of existing patient reported outcome measures (PROMs) used in AAV and identify associations with poorer HRQoL outcomes. METHODS: A literature review of studies using PROMs, including those labelled HRQoL in people with AAV as a primary or secondary study outcome were screened and reviewed up to July 2023. Quality was assessed using the Critical Appraisal Skills Programme. RESULTS: A total of 30 articles were included which utilised 22 different PROM tools. 76.7% (n = 23) used the SF-36 or a variation as a generic measure of health status and or HRQoL. Two studies developed a disease specific PROM. The AAV-PRO showed good psychometric properties but potential limitations in capturing all relevant aspects of the disease experience for AAV patients. Factors associated with poorer HRQoL included: neurological and sinonasal involvement, women and younger patients. 86.6% of studies showed no meaningful relationships between the SF-36 and BVAS, VDI or disease duration. Depression and anxiety were common and socioeconomic factors such as unemployment were significantly associated with poorer mental health outcomes. Glucocorticoids were found to be independently associated with worse SF-36 scores. CONCLUSION: Generic PROMs are useful in measuring significant changes but lack sensitivity to specific symptoms and unique AAV-related issues, while existing disease specific PROMs have limitations and may not fully capture AAV patient's perspective on disease and treatment burden.

Rituximab in the treatment of primary FSGS: time for its use in routine clinical practice?

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and whilst advances have been made in the pathophysiology, diagnostics and management of other podocytopathies, primary FSGS remains the most elusive. It has been assumed for a long time that a circulatory permeability factor exists that mediates podocyte injury, and the potential for autoantibody-mediated disease therefore raises the question as to whether patients may benefit from targeted B-cell therapy with rituximab. The prospective case series of seven patients by Roccatello et al. adds to the limited but growing evidence suggesting that B-cell depletion therapy can be safe and effective in the treatment of primary FSGS. In this editorial we explore the available evidence that suggests how and in whom rituximab may play a role in the management of primary FSGS, as well as the limitations and other potential future treatments. Further research and randomized controlled trials are needed to include larger numbers of patients, feature genetic screening and incorporate data on B-cell kinetics as a potential guide for dosing and frequency of rituximab.

A Meta-Analysis and Cohort Study of Histopathologic and Clinical Outcomes in ANCA-Negative versus -Positive Vasculitis.

BACKGROUND: ANCA-negative pauci-immune glomerulonephritis (PIGN) represents a rare and often under-studied subgroup of the vasculitides. This study aims to investigate differences in the clinical phenotype, renal histological features, and clinical outcomes of patients with PIGN, with and without serum ANCA positivity. METHODS: A cohort of biopsy-proven PIGN with and without detectable circulating ANCA was constructed from a single center between 2006 and 2016. Primary outcomes compared clinical presentation and histopathological features according to ANCA status, with multivariate Cox regression to compare mortality and ESKD. A systematic review and meta-analysis of the published literature was undertaken. RESULTS: In our cohort of 146 patients, 22% (n=32) had ANCA-negative disease, with a comparatively younger mean age at diagnosis; 51.4 versus 65.6 years (P<0.001). In total, 14 studies, inclusive of our cohort, were eligible for meta-analysis, totaling 301 patients who were ANCA negative. Those with ANCA-negative disease tended to have fewer extrarenal symptoms and a higher frequency of renal-limited disease, but both failed to reach statistical significance (P=0.92 and P=0.07). The risk of ESKD was significantly higher in seronegative disease (RR, 2.28; 95% confidence interval, 1.42 to 3.65; P<0.001), reflecting our experience, with a fivefold increased risk of ESKD in ANCA-negative disease (P<0.001). No significant difference in the chronicity of histopathological findings was seen and the meta-analysis showed no difference in morality (RR, 1.22; 95% confidence interval, 0.63 to 2.38; P=0.55). CONCLUSION: Our findings demonstrate that ANCA-negative PIGN presents in younger patients, with fewer extrarenal manifestations and higher ESKD risk, despite a lack of difference in histopathology. This study provides the impetus for further research into the pathogenesis, treatment response, and duration of immunotherapy in ANCA-negative disease. We suggest that the absence of positive ANCA serology should not discourage treatment and for clinical trials to include patients who are ANCA negative.

Temporal trends of mercury in Arctic biota: 10 more years of progress in Arctic monitoring.

Temporal trend analysis of (total) mercury (THg) concentrations in Arctic biota were assessed as part of the 2021 Arctic Monitoring and Assessment Programme (AMAP) Mercury Assessment. A mixed model including an evaluation of non-linear trends was applied to 110 time series of THg concentrations from Arctic and Subarctic biota. Temporal trends were calculated for full time series (6-46 years) and evaluated with a particular focus on recent trends over the last 20 years. Three policy-relevant questions were addressed: (1) What time series for THg concentrations in Arctic biota are currently available? (2) Are THg concentrations changing over time in biota from the Arctic? (3) Are there spatial patterns in THg trends in biota from the Arctic? Few geographical patterns of recent trends in THg concentrations were observed; however, those in marine mammals tended to be increasing at more easterly longitudes, and those of seabirds tended to be increasing in the Northeast Atlantic; these should be interpreted with caution as geographic coverage remains variable. Trends of THg in freshwater fish were equally increasing and decreasing or non-significant while those in marine fish and mussels were non-significant or increasing. The statistical power to detect trends was greatly improved compared to the 2011 AMAP Mercury Assessment; 70% of the time series could detect a 5% annual change at the 5% significance level with power ≥ 80%, while in 2011 only 19% met these criteria. Extending existing time series, and availability of new, powerful time series contributed to these improvements, highlighting the need for annual monitoring, particularly given the spatial and temporal information needed to support initiatives such as the Minamata Convention on Mercury. Collecting the same species/tissues across different locations is recommended. Extended time series from Alaska and new data from Russia are also needed to better establish circumarctic patterns of temporal trends.

Cardiovascular disease and ANCA-associated vasculitis: are we missing a beat?

The association between cardiovascular (CV) disease and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is well documented. The recent work by Massicotte-Azarniouch et al. confirms the risk and adds to the existing evidence by describing the highest risk in the first 3 months after diagnosis. In this review, we aim to put their findings into perspective and formulate implications for the care of AAV patients. We discuss mechanisms for increased CV disease in AAV, including the impact of traditional risk factors and disease-related risks such as renal impairment and anti-myeloperoxidase (MPO) ANCA serotype. We also provide a brief primer on the impact of inflammatory-driven endothelial dysfunction and platelet activation on accelerated atherosclerosis in AAV patients. These features alongside the impact of disease activity and systemic inflammation provide potential explanations to why the incidence of CV events is highest in the first 3 months from diagnosis. We suggest future avenues of research, provide some suggestions to address and treat CV risk based on current evidence, and highlight the importance of addressing this topic early on. Addressing modifiable risk factors, dialogue with patients, patient information and a structured approach overall will be key to improve CV outcomes in AAV.

Climate change and mercury in the Arctic: Biotic interactions.

Global climate change has led to profound alterations of the Arctic environment and ecosystems, with potential secondary effects on mercury (Hg) within Arctic biota. This review presents the current scientific evidence for impacts of direct physical climate change and indirect ecosystem change on Hg exposure and accumulation in Arctic terrestrial, freshwater, and marine organisms. As the marine environment is elevated in Hg compared to the terrestrial environment, terrestrial herbivores that now exploit coastal/marine foods when terrestrial plants are iced over may be exposed to higher Hg concentrations. Conversely, certain populations of predators, including Arctic foxes and polar bears, have shown lower Hg concentrations related to reduced sea ice-based foraging and increased land-based foraging. How climate change influences Hg in Arctic freshwater fishes is not clear, but for lacustrine populations it may depend on lake-specific conditions, including interrelated alterations in lake ice duration, turbidity, food web length and energy sources (benthic to pelagic), and growth dilution. In several marine mammal and seabird species, tissue Hg concentrations have shown correlations with climate and weather variables, including climate oscillation indices and sea ice trends; these findings suggest that wind, precipitation, and cryosphere changes that alter Hg transport and deposition are impacting Hg concentrations in Arctic marine organisms. Ecological changes, including northward range shifts of sub-Arctic species and altered body condition, have also been shown to affect Hg levels in some populations of Arctic marine species. Given the limited number of populations and species studied to date, especially within Arctic terrestrial and freshwater systems, further research is needed on climate-driven processes influencing Hg concentrations in Arctic ecosystems and their net effects. Long-term pan-Arctic monitoring programs should consider ancillary datasets on climate, weather, organism ecology and physiology to improve interpretation of spatial variation and time trends of Hg in Arctic biota.

Automated Computational Detection of Disease Activity in ANCA-Associated Glomerulonephritis Using Raman Spectroscopy: A Pilot Study.

Biospectroscopy offers the ability to simultaneously identify key biochemical changes in tissue associated with a given pathological state to facilitate biomarker extraction and automated detection of key lesions. Herein, we evaluated the application of machine learning in conjunction with Raman spectroscopy as an innovative low-cost technique for the automated computational detection of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Consecutive patients with active AAGN and those in disease remission were recruited from a single UK centre. In those with active disease, renal biopsy samples were collected together with a paired urine sample. Urine samples were collected immediately prior to biopsy. Amongst those in remission at the time of recruitment, archived renal tissue samples representative of biopsies taken during an active disease period were obtained. In total, twenty-eight tissue samples were included in the analysis. Following supervised classification according to recorded histological data, spectral data from unstained tissue samples were able to discriminate disease activity with a high degree of accuracy on blind predictive modelling: F-score 95% for >25% interstitial fibrosis and tubular atrophy (sensitivity 100%, specificity 90%, area under ROC 0.98), 100% for necrotising glomerular lesions (sensitivity 100%, specificity 100%, area under ROC 1) and 100% for interstitial infiltrate (sensitivity 100%, specificity 100%, area under ROC 0.97). Corresponding spectrochemical changes in paired urine samples were limited. Future larger study is required, inclusive of assigned variables according to novel non-invasive biomarkers as well as the application of forward feature extraction algorithms to predict clinical outcomes based on spectral features.

Temporal change and the influence of climate and weather factors on mercury concentrations in Hudson Bay polar bears, caribou, and seabird eggs.

Temporal trends of mercury in Arctic wildlife are inconsistent within and between species and are often insignificant, which limits data interpretation. Recent multivariate analyses have shown that weather and climate factors (e.g. temperatures, sea ice conditions) are related to total Hg (THg) concentrations in wildlife tissues, though relatively few studies have explored these relationships. The present study compared time series of THg concentrations in liver of polar bear (Ursus maritimus, 2007/08-2015/16), eggs of thick-billed murres (Uria lomvia, 1993-2015) and kidney of caribou (Rangifer tarandus groenlandicus, 2006-2015) from the Hudson Bay region of Canada and statistically modelled THg over time with available climate and weather data. Significant temporal trends of THg concentrations were not detected in any species. However, in multivariate models that included time-lagged sea ice freeze up dates, THg concentrations increased 4.4% yr-1 in Qamanirjuaq caribou. Sea ice conditions were also related to THg levels in polar bear liver but not those in eggs of murres, though year was not a signifcant factor. Greater precipitation levels one to two years prior to sampling were associated with greater THg concentrations in polar bears and caribou, likely due to greater deposition, flooding and discharge from nearby wetlands and rivers. Time-lagged Arctic and/or North Atlantic Oscillation (AO/NAO) indices also generated significant, inverse models for all three species, agreeing with relationships in other time series of similar length. The magnitude and direction of many relationships were affected by season, duration of time-lags, and the length of the time series. Our findings support recent observations suggesting that temporal studies monitoring Hg in Arctic wildlife should consider including key climatic or weather factors to help identify consistent variables of influence and to improve temporal analyses of THg time series.

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy.

The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment.

Biomarkers in ANCA-Associated Vasculitis: Potential Pitfalls and Future Prospects.

Over the past 3 decades, significant advancements in the understanding of the pathophysiology of ANCA-associated vasculitis has led to the development of a multitude of potential candidate biomarkers. Accompanied by the advent of increasingly effective therapeutic strategies, the need for a dependable biomarker to help determine the extent of disease activity and risk of relapse is ever present. Implementation of such a biomarker would enable tailored therapy, optimizing disease control while helping to mitigate unnecessary exposure to therapy and potential treatment-related damage. Although far from perfect, ANCA serology and B-cell population are the two main staple biomarker tools widely used in practice to help supplement clinical assessment. Over recent years, the application and progress of more novel biomarker tools have arisen in both organ-limited and multisystem disease, including genomics, urinary proteins, degradation products of the alternative complement system, cytokines, metabolomics, and biospectroscopy. Validation studies and clinical translation of these tools are required, with serial assessment of disease activity and determination of therapy according to biomarker status correlated with patient outcomes.

Treatment Outcomes of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Patients Over Age 75 Years: A Meta-Analysis.

BACKGROUND: The benefits of treating anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) in advancing age remains unclear with most published studies defining elderly as ≥65 years. This study aims to determine outcomes of induction immunosuppression in patients aged ≥75 years. METHODS: A cohort of patients aged ≥75 years with a diagnosis of AAV between 2006 and 2018 was constructed from 2 centres. Follow-up was to 2 years or death. Analysis included multivariable Cox regression to compare mortality and end-stage renal disease (ESRD) based on receipt of induction immunosuppression therapy with either cyclophosphamide or rituximab. A systematic review of outcome studies was subsequently undertaken amongst this patient group through Pubmed, Cochrane and Embase databases from inception until October 16, 2019. RESULTS: Sixty-seven patients were identified. Mean age was 79 ± 2.9 years and 82% (n = 55) received induction immunosuppression. Following systematic review, 4 studies were eligible for inclusion, yielding a combined total of 290 patients inclusive of our cohort. The aggregated 1-year mortality irrespective of treatment was 31% (95% CI 25-36%). Within our cohort, induction immunosuppression therapy was associated with a significantly lower 2-year mortality risk (hazard ratio [HR] 0.29 [95% CI 0.09-0.93]). The pooled HR by meta-analysis confirmed this with a significant risk reduction for death (HR 0.31 [95% CI 0.16-0.57], I2 = 0%). Treated patients had a lower pooled rate of ESRD, but was not statistically significant (HR 0.71 [95% CI 0.15-3.35]). CONCLUSION: This meta-analysis suggests that patients ≥75 years with AAV do benefit from induction immunosuppression with a significant survival benefit. Age alone should not be a limiting factor when considering treatment.

Propensity score matched mortality comparisons of peritoneal and in-centre haemodialysis: systematic review and meta-analysis.

BACKGROUND: Accurate comparisons of haemodialysis (HD) and peritoneal dialysis (PD) survival based on observational studies are difficult due to substantial residual confounding that arises from imbalances between treatments. Propensity score matching (PSM) comparisons confer additional advantages over conventional methods of adjustment by further reducing selection bias between treatments. We conducted a systematic review of studies that compared mortality between in-centre HD with PD using a PSM-based approach. METHODS: A sensitive search strategy identified all citations in the PubMed, Cochrane and EMBASE databases from inception through November 2018. Pooled PD versus HD mortality hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated through random-effects meta-analysis. A subsequent meta-regression explored factors to account for between-study variation. RESULTS: The systematic review yielded 214 citations with 17 cohort studies and 113 578 PSM incident dialysis patients. Cohort periods spanned the period 1993-2014. The pooled HR for PD versus HD was 1.06 (95% CI 0.99-1.14). There was considerable variation by country, however, mortality risks for PD versus HD remained virtually unchanged when stratified by geographical region with HRs of 1.04 (95% CI 0.94-1.15), 1.14 (95% CI 0.99-1.32) and 0.98 (0.87-1.10) for European, Asian and American cohorts, respectively. Subgroup meta-analyses revealed similar risks for patients with diabetes [HR 1.09 (95% CI 0.98-1.21)] and without diabetes [HR 0.99 (95% CI 0.90-1.09)]. Heterogeneity was substantial (I2 = 87%) and was largely accounted for by differences in cohort period, study type and country of origin. Together these factors explained a substantial degree of between-studies variance (R2 = 90.6%). CONCLUSIONS: This meta-analysis suggests that PD and in-centre HD carry equivalent survival benefits. Reported differences in survival between treatments largely reflect a combination of factors that are unrelated to clinical efficacy.

State of knowledge on current exposure, fate and potential health effects of contaminants in polar bears from the circumpolar Arctic.

The polar bear (Ursus maritimus) is among the Arctic species exposed to the highest concentrations of long-range transported bioaccumulative contaminants, such as halogenated organic compounds and mercury. Contaminant exposure is considered to be one of the largest threats to polar bears after the loss of their Arctic sea ice habitat due to climate change. The aim of this review is to provide a comprehensive summary of current exposure, fate, and potential health effects of contaminants in polar bears from the circumpolar Arctic required by the Circumpolar Action Plan for polar bear conservation. Overall results suggest that legacy persistent organic pollutants (POPs) including polychlorinated biphenyls, chlordanes and perfluorooctane sulfonic acid (PFOS), followed by other perfluoroalkyl compounds (e.g. carboxylic acids, PFCAs) and brominated flame retardants, are still the main compounds in polar bears. Concentrations of several legacy POPs that have been banned for decades in most parts of the world have generally declined in polar bears. Current spatial trends of contaminants vary widely between compounds and recent studies suggest increased concentrations of both POPs and PFCAs in certain subpopulations. Correlative field studies, supported by in vitro studies, suggest that contaminant exposure disrupts circulating levels of thyroid hormones and lipid metabolism, and alters neurochemistry in polar bears. Additionally, field and in vitro studies and risk assessments indicate the potential for adverse impacts to polar bear immune functions from exposure to certain contaminants.

Bioaccumulation of Polybrominated Diphenyl Ethers and Alternative Halogenated Flame Retardants in a Vegetation-Caribou-Wolf Food Chain of the Canadian Arctic.

The trophodynamics of halogenated flame retardants (HFRs) including polybrominated diphenyl ethers (PBDEs) and alternative HFRs were investigated in the terrestrial, vegetation-caribou-wolf food chain in the Bathurst Region of northern Canada. The greatest concentrations in vegetation (geometric mean of lichens, moss, grasses, willow, and mushrooms) were of the order 2,4,6-tribromophenyl allyl ether (TBP-AE) (10 ng g-1 lw) > BDE47 (5.5 ng g-1 lw) > BDE99 (3.9 ng g-1 lw) > BDE100 (0.82 ng g-1 lw) > 1,2,3,4,5-pentabromobenzene (PBBz) (0.72 ng g-1 lw). Bioconcentration among types of vegetation was consistent, though it was typically greatest in rootless vegetation (lichens, moss). Biomagnification was limited in mammals; only BDE197, BDE206-208 and ∑PBDE biomagnified to caribou from vegetation [biomagnification factors (BMFs) = 2.0-5.1]. Wolves biomagnified BDE28/33, BDE153, BDE154, BDE206, BDE207, and ∑PBDE significantly from caribou (BMFs = 2.9-17) but neither mammal biomagnified any alternative HFRs. Only concentrations of BDE28/33, BDE198, nonaBDEs, and ∑PBDE increased with trophic level, though the magnitude of biomagnification was low relative to legacy, recalcitrant organochlorine contaminants [trophic magnification factors (TMFs) = 1.3-1.8]. Despite bioaccumulation in vegetation and mammals, the contaminants investigated here exhibited limited biomagnification potential and remained at low parts per billion concentrations in wolves.

Current-use pesticides in seawater and their bioaccumulation in polar bear-ringed seal food chains of the Canadian Arctic.

The distribution of current-use pesticides (CUPs) in seawater and their trophodynamics were investigated in 3 Canadian Arctic marine food chains. The greatest ranges of dissolved-phase concentrations in seawater for each CUP were endosulfan sulfate (less than method detection limit (MDL) to 19 pg L(-1) ) > dacthal (0.76-15 pg L(-1) ) > chlorpyrifos (less than MDL to 8.1 pg L(-1) ) > pentachloronitrobenzene (less than MDL to 2.6 pg L(-1) ) > α-endosulfan (0.20-2.3 pg L(-1) ). Bioaccumulation factors (BAFs, water-respiring organisms) were greatest in plankton, including chlorothalonil (log BAF = 7.4 ± 7.1 L kg(-1) , mean ± standard error), chlorpyrifos (log BAF = 6.9 ± 6.7 L kg(-1) ), and α-endosulfan (log BAF = 6.5 ± 6.0 L kg(-1) ). The largest biomagnification factors (BMFs) were found for dacthal in the capelin:plankton trophic relationship (BMF = 13 ± 5.0) at Cumberland Sound (Nunvavut), and for ß-endosulfan (BMF = 16 ± 4.9) and α-endosulfan (BMF = 9.3 ± 2.8) in the polar bear-ringed seal relationship at Barrow and Rae Strait (NU), respectively. Concentrations of endosulfan sulfate exhibited trophic magnification (increasing concentrations with increasing trophic level) in the poikilothermic portion of the food web (trophic magnification factor = 1.4), but all of the CUPs underwent trophic dilution in the marine mammal food web, despite some trophic level-specific biomagnification. Together, these observations are most likely indicative of metabolism of these CUPs in mammals. Environ Toxicol Chem 2016;35:1695-1707. © 2016 SETAC.

Trophodynamics of current use pesticides and ecological relationships in the Bathurst region vegetation-caribou-wolf food chain of the Canadian Arctic.

The bioaccumulation of current use pesticides (CUPs) and stable isotopes of carbon and nitrogen were investigated in vegetation-caribou-wolf food chain in the Bathurst region (Nunavut, Canada). Volumetric bioconcentration factors (BCF(v)) in vegetation were generally greatest for dacthal (10-12) ≥ endosulfan sulfate (10-11) > ß-endosulfan (>9.0-9.7) ≥ pentachloronitrobenzene (PCNB; 8.4-9.6) > α-endosulfan (8.3-9.3) > chlorpyrifos (8.0-8.7) >chlorothalonil (7.6-8.3). The BCF(v) values in vegetation were significantly correlated with the logarithm of the octanol-air partition coefficients (log K(OA)) of CUPs (r(2) = 0.90, p = 0.0040), although dacthal was an outlier and not included in this relationship. Most biomagnification factors (BMFs) for CUPs in caribou:diet comparisons were significantly less than 1. Similarly, the majority of wolf:caribou BMFs were either significantly less than 1 or were not statistically greater than 1. Significant trophic magnification factors (TMFs) were all less than 1, indicating that these CUPs exhibit trophic dilution through this terrestrial food chain. The log K(OA) reasonably predicted bioconcentration in vegetation for most CUPs but was not correlated with BMFs or TMFs in mammals. Our results, along with those of metabolic studies, suggest that mammals actively metabolize these CUPs, limiting their biomagnification potential despite entry into the food chain through effective bioconcentration in vegetation.