Response of the East Antarctic Ice Sheet to past and future climate change.

The East Antarctic Ice Sheet contains the vast majority of Earth's glacier ice (about 52 metres sea-level equivalent), but is often viewed as less vulnerable to global warming than the West Antarctic or Greenland ice sheets. However, some regions of the East Antarctic Ice Sheet have lost mass over recent decades, prompting the need to re-evaluate its sensitivity to climate change. Here we review the response of the East Antarctic Ice Sheet to past warm periods, synthesize current observations of change and evaluate future projections. Some marine-based catchments that underwent notable mass loss during past warm periods are losing mass at present but most projections indicate increased accumulation across the East Antarctic Ice Sheet over the twenty-first century, keeping the ice sheet broadly in balance. Beyond 2100, high-emissions scenarios generate increased ice discharge and potentially several metres of sea-level rise within just a few centuries, but substantial mass loss could be averted if the Paris Agreement to limit warming below 2 degrees Celsius is satisfied.

Autoantibodies against the NineTeen complex and U5 RNP in systemic sclerosis.

ObjectiveMultiple spliceosome components are known autoantigens in systemic sclerosis (SSc). Here we aim to identify new and characterize rare anti-spliceosomal autoantibodies in patients with SSc without known autoantibody specificity. MethodsSera that precipitated spliceosome subcomplexes, as detected by immunoprecipitation-mass spectrometry (IP-MS), were identified from a database of 106 patients with SSc without known autoantibody specificity. New autoantibody specificities were confirmed with immunoprecipitation-western blot. The IP-MS pattern of new anti-spliceosomal autoantibodies was compared with anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases and anti-SmD-positive sera of patients with systemic lupus erythematosus (n = 24). ResultsThe NineTeen Complex (NTC) was identified and confirmed as new spliceosomal autoantigen in one patient with SSc. U5 RNP, as well as additional splicing factors, were precipitated by the serum of another patient with SSc. The IP-MS patterns of anti-NTC and anti-U5 RNP autoantibodies were distinct from those of anti-U1 RNP- and anti-SmD-positive sera. Furthermore, there was no difference in IP-MS patterns between a limited number of anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases. ConclusionAnti-NTC autoantibodies are a new anti-spliceosomal autoantibody specificity, here first identified in a patient with SSc. Anti-U5 RNP autoantibodies are a distinct but rare anti-spliceosomal autoantibody specificity. All major spliceosomal subcomplexes have now been described as target of autoantibodies in systemic autoimmune diseases.

Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis.

PURPOSE: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity. METHODS: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n = 467), other systemic autoimmune rheumatic diseases (n = 923), non-rheumatic disease controls (n = 187) and healthy controls (n = 199). RESULTS: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n = 3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n = 1), homeobox-containing protein 1 (HMBOX1, n = 2), regulator of chromosome condensation 1 (RCC1, n = 1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n = 1), dyskerin (DKC1, n = 1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n = 1) and nuclear valosin-containing protein-like (NVL, n = 2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB. CONCLUSION: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.

Peripheral manifestations are major determinants of disease phenotype and outcome in new onset spondyloarthritis.

OBJECTIVES: To delineate the impact of peripheral musculoskeletal manifestations on stratification of disease phenotype and outcome in new-onset spondyloarthritis (SpA), using a prospective observational nationwide inception cohort, the BelGian Inflammatory Arthritis and spoNdylitis cohorT (Be-Giant). METHODS: Newly diagnosed adult SpA patients, fulfilling the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral SpA, were included in Be-Giant and prospectively followed every six months. Peripheral involvement (defined as arthritis, enthesitis and/or dactylitis) was determined in relation to clinically similar patient subsets at baseline and disease activity patterns during two-year follow-up, identified through K-means cluster analysis and latent class growth analysis. RESULTS: From November 2010 to March 2020, 367 patients were enrolled in Be-Giant, of whom 162 (44%) had peripheral manifestations. Two patient clusters [A, axial predominant (n = 248) and B, peripheral predominant (n = 119)] were identified at diagnosis. Longitudinal analysis (n = 115) revealed two trajectories of disease activity in each cluster: one with persistently high disease activity over time ('High'), the other rapidly evolving to low disease activity ('Low'). In cluster A patients, peripheral manifestations predisposed to the 'High' trajectory [odds ratio (OR) = 2.0, 95% CI: 1.3, 3.1, P = 0.001], despite more rapid initiation of biologics compared with patients without peripheral manifestations (hazard ratio (HR) = 2.1, 95% CI: 1.0, 4.4, P = 0.04 - Cox proportional-hazards model). CONCLUSION: Peripheral musculoskeletal manifestations are major determinants of phenotypical diversity in new-onset SpA. Intriguingly, stratification of axial SpA according to concomitant peripheral involvement identified an endotype with an unfavorable outcome despite more prompt therapeutic intensification with biologics. These observations justify an endotype-tailored approach beyond current ASAS/EULAR management recommendations.

Contribution of Atmospheric Rivers to Antarctic Precipitation.

Atmospheric rivers (ARs) are efficient mechanisms for transporting atmospheric moisture from low latitudes to the Antarctic Ice Sheet (AIS). While AR events occur infrequently, they can lead to extreme precipitation and surface melt events on the AIS. Here we estimate the contribution of ARs to total Antarctic precipitation, by combining precipitation from atmospheric reanalyses and a polar-specific AR detection algorithm. We show that ARs contribute substantially to Antarctic precipitation, especially in East Antarctica at elevations below 3,000 m. ARs contribute substantially to year-to-year variability in Antarctic precipitation. Our results highlight that ARs are an important component for understanding present and future Antarctic mass balance trends and variability.

Efficacy of a tight-control and treat-to-target strategy in axial spondyloarthritis: results of the open-label, pragmatic, cluster-randomised TICOSPA trial.

OBJECTIVES: To compare the benefits of a tight-control/treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA) with those of usual care (UC). METHODS: Pragmatic, prospective, cluster-randomised, controlled, open, 1-year trial (NCT03043846). 18 centres were randomised (1:1). Patients met Axial Spondylo Arthritis International Society (ASAS) criteria for axSpA, had an Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥2.1, received non-optimal treatment by non-steroidal anti-inflammatory drugs and were biologic-naive. INTERVENTIONS: (1) TC/T2T: visits every 4 weeks and prespecified strategy based on treatment intensification until achieving target (ie, ASDAS <2.1); (2) UC: visits every 12 weeks and treatment at the rheumatologist's discretion. MAIN OUTCOME: Percentage of patients with a ≥30% improvement on the ASAS-Health Index (ASAS-HI). Other efficacy outcomes and adverse events were recorded. A health economic evaluation was performed. STATISTICAL ANALYSIS: Two-level mixed models were used to estimate efficacy outcomes. Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained for TC/T2T versus UC. RESULTS: 160 patients were included (80/group). Mean (SD) age was 37.9 (11.0) years and disease duration was 3.7 (6.2) years; 51.2% were men. ASDAS at inclusion was 3.0 (0.7), and ASAS-HI was 8.6 (3.7). ASAS-HI improved by ≥30% in 47.3% of the TC/T2T arm and in 36.1% of those receiving UC (non-significant). All secondary efficacy outcomes were more frequent in the TC/T2T arm, although not all statistically significant. Safety was similar in both arms. From a societal perspective, TC/T2T resulted in an additional 0.04 QALY, and saved €472 compared with UC. CONCLUSION: TC/T2T was not significantly superior to UC for the primary outcome, while many secondary efficacy outcomes favoured it, had a similar safety profile and was favourable from a societal health economic perspective. TRIAL REGISTRATION NUMBER: NCT03043846.

Can We Expect Any Effect of Rituximab on Fatigue in Primary Sjögren Syndrome?: A Systematic Review and Critical Appraisal.

INTRODUCTION: Fatigue is a major determinant of impaired quality of life in primary Sjögren syndrome (pSS) patients. Effective therapeutic strategies are lacking. OBJECTIVES: To review the potential benefit of rituximab, a chimeric anti-CD20 antibody, in the treatment of fatigue in pSS. METHODS: A systematic review on the effect of rituximab on fatigue-related outcome measures was conducted, retrieving evidence from CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE (via PubMed), EMBASE, and Scopus. RESULTS: No benefit of rituximab over placebo on any fatigue-related outcome measure could be demonstrated in the included trials. Significant effects were only observed when compared with baseline, but not when compared with placebo. CONCLUSIONS: The use of rituximab for the treatment of pSS-related fatigue cannot be supported by the currently available evidence.

Understanding of Contemporary Regional Sea-Level Change and the Implications for the Future.

Global sea level provides an important indicator of the state of the warming climate, but changes in regional sea level are most relevant for coastal communities around the world. With improvements to the sea-level observing system, the knowledge of regional sea-level change has advanced dramatically in recent years. Satellite measurements coupled with in situ observations have allowed for comprehensive study and improved understanding of the diverse set of drivers that lead to variations in sea level in space and time. Despite the advances, gaps in the understanding of contemporary sea-level change remain and inhibit the ability to predict how the relevant processes may lead to future change. These gaps arise in part due to the complexity of the linkages between the drivers of sea-level change. Here we review the individual processes which lead to sea-level change and then describe how they combine and vary regionally. The intent of the paper is to provide an overview of the current state of understanding of the processes that cause regional sea-level change and to identify and discuss limitations and uncertainty in our understanding of these processes. Areas where the lack of understanding or gaps in knowledge inhibit the ability to provide the needed information for comprehensive planning efforts are of particular focus. Finally, a goal of this paper is to highlight the role of the expanded sea-level observation network-particularly as related to satellite observations-in the improved scientific understanding of the contributors to regional sea-level change.

Observing and Modeling Ice Sheet Surface Mass Balance.

Surface mass balance (SMB) provides mass input to the surface of the Antarctic and Greenland Ice Sheets and therefore comprises an important control on ice sheet mass balance and resulting contribution to global sea level change. As ice sheet SMB varies highly across multiple scales of space (meters to hundreds of kilometers) and time (hourly to decadal), it is notoriously challenging to observe and represent in models. In addition, SMB consists of multiple components, all of which depend on complex interactions between the atmosphere and the snow/ice surface, large-scale atmospheric circulation and ocean conditions, and ice sheet topography. In this review, we present the state-of-the-art knowledge and recent advances in ice sheet SMB observations and models, highlight current shortcomings, and propose future directions. Novel observational methods allow mapping SMB across larger areas, longer time periods, and/or at very high (subdaily) temporal frequency. As a recent observational breakthrough, cosmic ray counters provide direct estimates of SMB, circumventing the need for accurate snow density observations upon which many other techniques rely. Regional atmospheric climate models have drastically improved their simulation of ice sheet SMB in the last decade, thanks to the inclusion or improved representation of essential processes (e.g., clouds, blowing snow, and snow albedo), and by enhancing horizontal resolution (5-30 km). Future modeling efforts are required in improving Earth system models to match regional atmospheric climate model performance in simulating ice sheet SMB, and in reinforcing the efforts in developing statistical and dynamic downscaling to represent smaller-scale SMB processes.

Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial.

OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.

Diverging illness perceptions between physicians about patients with systemic lupus erythematosus and systemic sclerosis: a vignette-based study.

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are complex chronic auto-immune diseases characterized by multiple organ involvement, comorbidities, and complications. This complexity results in a need for a multidisciplinary management and treatment of SLE and SSc by physicians from a number of medical disciplines, all of who may have different perceptions concerning the condition of a particular patient. The aim of this study was to explore differences in physicians' perceptions on the illness of SLE and SSc patients. Physicians from nine disciplines working at three hospitals in Belgium completed illness perception questionnaires for healthcare professionals based on four patient vignettes, i.e., two vignettes per disease (SLE-SSc). Statistical analysis was carried out by a k-means clustering technique for clustering physicians according to their illness perceptions. Fifty physicians, 62% men with a mean age of 42.8 years (SD 11.3) and mean working experience of 12.7 years (SD 11.6), participated. For each disease, three clusters of physicians with different scores in illness perceptions were identified. For SLE, these clusters were specified as the 'optimistic' group, the 'realistic' group, and the 'overwhelming impact by disease' group. For SSc, the clusters were characterized as the 'optimistic' group, the 'realistic' group, and the 'skeptical' group. We found divergent illness perceptions across physicians of the same and other disciplines. Our study yielded three clusters of physicians per disease with a large variability in illness perceptions. Further studies should focus on the factors that determine these differences and their consequences for patient care.

Partial remission in ankylosing spondylitis and non-radiographic axial spondyloarthritis in treatment with infliximab plus naproxen or naproxen alone: associations between partial remission and baseline disease characteristics.

OBJECTIVES: To evaluate partial remission during treatment with infliximab (IFX) + naproxen (NPX) vs NPX alone in patients from the two subgroups of SpA and explore baseline predictors of partial remission. METHODS: Infliximab as First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial was a double-blind, randomised controlled trial of IFX in biologic-naïve patients with early, active axial SpA. Patients were randomised (2:1) to receive 28 weeks of treatment with i.v. IFX 5 mg/kg (weeks 0, 2, 6, 12, 18 and 24) + NPX 1000 mg/day or i.v. placebo (PBO) + NPX 1000 mg/day. The current post hoc analysis evaluated outcomes in patients who did or did not meet modified New York radiographic criteria for AS. RESULTS: The analysis included 94 patients who met AS criteria and 56 with non-radiographic axial SpA (nr-axSpA). At week 28, Assessment of SpondyloArthritis international Society (ASAS) partial remission was greater with IFX + NPX than PBO + NPX for both the AS group (70.5 vs 33.3%, respectively) and the nr-axSpA group (50.0 vs 37.5%, respectively). A similar pattern occurred with several efficacy measures. Larger treatment effects occurred in the AS group than the nr-axSpA group, possibly due to baseline differences in disease characteristics. Multivariable analyses identified the type of treatment, age and HLA-B27 status as predictors of ASAS partial remission in the total study population. MRI sacroiliac joint scores were associated with partial remission during IFX + NPX treatment. CONCLUSION: Patients with AS had greater partial remission with IFX + NSAID than NSAID therapy alone; patients with nr-axSpA had a smaller treatment effect. Baseline disease characteristics and age were associated with partial remission with IFX therapy.

Autoantibodies to two novel peptides in seronegative and early rheumatoid arthritis.

OBJECTIVES: Despite recent progress in biomarker discovery for RA diagnostics, still over one-third of RA patients-and even more in early disease-present without RF or ACPA. The aim of this study was to confirm the presence of previously identified autoantibodies to novel Hasselt University (UH) peptides in early and seronegative RA. METHODS: Screening for antibodies against novel UH peptides UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21, was performed in two large independent cohorts. Peptide ELISAs were developed to screen for the presence of antibodies to UH-RA peptides. First, 292 RA patients (including 39 early patients), 90 rheumatic and 97 healthy controls from UH were studied. Antibody reactivity to two peptides (UH-RA.1 and UH-RA.21) was also evaluated in 600 RA patients, 309 patients with undifferentiated arthritis and 157 rheumatic controls from the Leiden Early Arthritis Clinic cohort. RESULTS: In both cohorts, 38% of RA patients were seronegative for RF and ACPA. Testing for autoantibodies to UH-RA.1 and UH-RA.21 reduced the serological gap from 38% to 29% in the UH cohort (P = 0.03) and from 38% to 32% in the Leiden Early Arthritis Clinic cohort (P = 0.01). Furthermore, 19-33% of early RA patients carried antibodies to these peptides. Specificities in rheumatic controls ranged from 82 to 96%. Whereas antibodies against UH-RA.1 were related to remission, anti-UH-RA.21 antibodies were associated with inflammation, joint erosion and higher tender and swollen joint counts. CONCLUSION: This study validates the presence of antibody reactivity to novel UH-RA peptides in seronegative and early RA. This might reinforce current diagnostics and improve early diagnosis and intervention in RA.