Ecosystem-level effects of re-oligotrophication and N:P imbalances in rivers and estuaries on a global scale

ABSTRACT: Trends and ecological consequences of phosphorus (P) decline and increasing nitrogen (N) to phosphorus (N:P) ratios in rivers and estuaries are reviewed and discussed. Results suggest that re-oligotrophication is a dominant trend in rivers and estuaries of high-income countries in the last two-three decades, while in low-income countries widespread eutrophication occurs. The decline in P is well documented in hundreds of rivers of United States and the European Union, but the biotic response of rivers and estuaries besides hytoplankton decline such as trends in phytoplankton composition, changes in primary production, ecosystem shifts, cascading effects, changes in ecosystem metabolism, etc., have not been sufficiently monitored and investigated, neither the effects of N:P imbalance. N:P imbalance has significant ecological effects that need to be further investigated. There is a growing number of cases in which phytoplankton biomass have been shown to decrease due to re-oligotrophication, but the potential regime shift from phytoplankton to macrophyte dominance described in shallow lakes has been documented only in a few rivers and estuaries yet. The main reasons why regime shifts are rarely described in rivers and estuaries are, from one hand the scarcity of data on macrophyte cover trends, and from the otherhand physical factors such as peak flows or high turbidity that could prevent a general spread of submerged macrophytes as observed in shallow lakes. Moreover, re-oligotrophication effects on rivers may be different compared to lakes (e.g., lower dominance of macrophytes) or estuaries (e.g., limitation of primary production by N instead of P) or may be dependent on river/estuary type. We conclude that river and estuary re-oligotrophication effects are complex, diverse and still little known, and in some cases are equivalent to those described in shallow lakes, but the regime shift is more likely to occur in mid to high-order rivers and shallow estuaries.This work was supported by a grant from the U.S. National Science Foundation (#DBI-1639145) to the National Socio-Environmental Synthesis Center (Rivershift Project). The work was also financially supported by the Catalan Government through the funding grant ACCIÓ-Eurecat (Project AquaSCI-2022)

Biologic Sequencing in Systemic Lupus Erythematosus: After Secondary Non-response to Rituximab, Switching to Humanised Anti-CD20 Agent Is More Effective Than Belimumab

Background: Rituximab is commonly used for systemic lupus erythematosus (SLE) but secondary non-depletion and non-response (2NDNR) associated with anti-drug antibodies is a notable problem with repeat rituximab cycles. Other B cell-targeted therapies include other anti-CD20 monoclonal antibodies or belimumab. Objective: To compare efficacy of switching to alternative anti-CD20 agents vs. belimumab in SLE patients with 2NDNR to rituximab. Methods: One hundred and twenty five patients received rituximab and had evaluable data. 77/125 received repeat rituximab cycles. Of these, 14/77 (18%) had 2NDNR. 8/14 patients were switched to belimumab (CD20-to-belimumab group) and 6/14 patients were switched to an alternative humanised anti-CD20 agent (CD20-to-CD20 group, ocrelizumab n = 3, ofatumumab n = 2, obinutuzumab n = 1). Efficacy was assessed using the BILAG-2004, SLEDAI-2K, SRI-4, and daily prednisolone requirement at baseline and 6 months. Results: In the CD20-to-belimumab group, only one patient achieved an SRI-4 and 2/8 patients had new/worsening BILAG-2004 grade A for lupus nephritis. There was no improvement in SLEDAI-2K; median (IQR) was 11.0 (9.5–14.8) at baseline and 10 (9.5–15.5) at 6 months. Median (IQR) prednisolone dose increased from 7.5 mg (4.4–12.5) to 10 mg (6.3–10). In the CD20-to-CD20 group, all 6 patients achieved an SRI-4. Median (IQR) SLEDAI-2K improved from 16.0 (10.3–24.0) at baseline to 5.0 (2.5–6.0) at 6 months. Median (IQR) prednisolone dose decreased from 15 mg (15–15) to 10.5 mg (5.3–15.0). Conclusion: This is the first assessment of belimumab’s efficacy in a post-rituximab population. Our data suggests that patients with 2NDNR to rituximab, which constituted 11% of all patients initiated on this drug, should be switched within the same biologic class to another anti-CD20 agent

Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort

OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up.The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used.31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors.In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis

Psychosis in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study

Objectives: To determine, in a multi-ethnic/racial, prospective SLE inception cohort, the frequency, attribution, clinical and autoantibody associations with lupus psychosis and the short and long-term outcome as assessed by physicians and patients. Methods: Patients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. SLE disease activity 2000, SLICC/ACR damage index and SF-36 scores were collected. Time to event and linear regressions were used as appropriate. Results: Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian. The meanSD age was 35.1±13.3 years, disease duration 5.64.2 months and follow-up 7.44.5 years. There were 31 psychotic events in 28/1,826 (1.53%) patients and most [(26/28; 93%)] had a single event. In the majority of patients [20/25; (80%)] and events [28/31; (90%)] psychosis was attributed to SLE, usually within 3 years of SLE diagnosis. Positive associations [hazard ratio and 95% confidence interval [HR (95%CI)] with lupus psychosis were prior SLE NP events [3.59, (1.16, 11.14), male sex [3.0, (1.20, 7.50)], younger age at SLE diagnosis [(per 10 years younger), 1.45 (1.01, 2.07)] and African ancestry [4.59 (1.79, 11.76)]. By physician assessment most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient reported SF-36 summary and subscale scores. Conclusion: Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short and long term outlook is good for most patients, though careful follow-up is required

Antinuclear Antibody–Negative Systemic Lupus Erythematosus in an International Inception Cohort

Objectives: The spectrum of antinuclear antibodies (ANA) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change in terminology to anti‐cellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anti‐cellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort. / Methods: Anti‐cellular antibodies were detected by IIF on HEp‐2000 substrate utilizing the baseline serum. Three serological subsets were examined: 1) ANA‐positive (presence of either nuclear or mixed nuclear/CMP staining), 2) anti‐cellular antibody‐negative (absence of any intracellular staining), and 3) isolated CMP staining. The odds of being anti‐cellular antibody‐negative versus ANA or isolated CMP‐positive was assessed by multivariable analysis. / Results: 1137 patients were included; 1049/1137 (92.3%) were ANA‐positive, 71/1137 (6.2%) were anti‐cellular antibody‐negative, and 17/1137 (1.5%) had isolated CMP. The isolated CMP group did not differ from the ANA‐positive or anti‐cellular antibody‐negative group in clinical, demographic or serologic features. Patients who were older (OR 1.02 [95% CI: 1.00, 1.04]), of Caucasian race/ethnicity (OR 3.53 [95% CI: 1.77, 7.03]), or on high dose glucocorticoids at or prior to enrolment (OR 2.39 [95% CI: 1.39, 4.12]) were more likely to be anti‐cellular antibody‐negative. Patients on immunosuppressants (OR 0.35 [95% CI: 0.19, 0.64]) or with anti‐SSA/Ro60 (OR 0.41 [95% CI: 0.23, 0.74]) or anti‐UI‐RNP (OR 0.43 [95% CI: 0.20, 0.93]) were less likely to be anti‐cellular antibody‐negative. / Conclusions: In newly diagnosed SLE, 6.2% of patients were anti‐cellular antibody‐negative and 1.5% had isolated CMP. The prevalence of anti‐cellular antibody‐negative SLE will likely decrease as emerging nomenclature guidelines recommend that non‐nuclear patterns should also be reported as a positive ANA

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. / Methods: A large 33‐center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient‐years, and univariable and multivariable relative risk regression models. / Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow‐up visit after enrollment, for a total of 13,666 patient‐years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient‐years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32–0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55–10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04–7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17–9.27], P < 0.001). / Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors

Prediction of damage accrual in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index (SLICC-FI)

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC-FI values with damage accrual in the SLICC inception cohort. METHODS: The baseline visit was defined as the first at which both organ damage (SLICC/ACR Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36]) were assessed. Baseline SLICC-FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression estimated the association between baseline SLICC-FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. RESULTS: The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (standard deviation, SD) age 35.7 (13.3) years and median (interquartile range) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08) with a range of 0-0.51. Over a mean (SD) follow-up of 7.2 (3.7) years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC-FI values (per 0.05 increment) were associated with higher rates of increase in the SDI during follow-up (Incidence Rate Ratio [IRR] 1.19; 95% CI 1.13-1.25), after adjusting for age, sex, ethnicity/region, education, baseline SLEDAI-2K, baseline SDI, and baseline use of corticosteroids, antimalarials, and immunosuppressives. CONCLUSION: The SLICC-FI predicts damage accrual in incident SLE, which further supports the SLICC-FI as a valid health measure in SLE

Economic evaluation of damage accrual in an international SLE inception cohort using a multi-state model approach

OBJECTIVES: There is a paucity of data regarding healthcare costs associated with damage accrual in systemic lupus erythematosus (SLE). We describe costs associated with damage states across the disease course using multi-state modeling. METHODS: Patients from 33 centres in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology (ACR) Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multi-state model. RESULTS: 1687 patients participated, 88.7% female, 49.0% of Caucasian race/ethnicity, mean age at diagnosis 34.6 years (SD 13.3), and mean follow up 8.9 years (range 0.6-18.5). Annual costs were higher in those with higher SDIs (SDI ≥ 5: $22 006 2019 CDN, 95$16 662, $27 350 versus SDI=0:$1833, 95% CI $1134,$2532). Similarly, 10-year cumulative costs were higher in those with higher SDIs at the beginning of the 10-year interval (SDI ≥ 5: $189 073, 95$142 318, $235 827 versus SDI=0:$21 713, 95% CI $13 639,$29 788). CONCLUSION: Patients with the highest SDIs incur 10-year cumulative costs that are almost 9-fold higher than those with the lowest SDIs. By estimating the damage trajectory and incorporating annual costs, damage can be used to estimate future costs, critical knowledge for evaluating the cost-effectiveness of novel therapies

Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies

Objective. To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. Methods. The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immu-nological phenotypes: Double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/ SSB, and immunonegative. Results. The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥ 1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/ SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in com-parison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/ SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. Conclusion. Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients