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1.
J Infect Dis ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33625513

RESUMO

BACKGROUND: Activins are members of the TGFß-superfamily implicated in the pathogenesis of several immuno-inflammatory disorders. Based on our previous studies demonstrating that over-expression of Activin-A in murine lung causes pathology sharing key features of COVID-19, we hypothesized that Activins and their natural inhibitor Follistatin might be particularly relevant to COVID-19 pathophysiology. METHODS: Activin-A, Activin-B and Follistatin levels were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in three independent centers, and compared with common demographic, clinical and laboratory parameters. Optimal-scaling with ridge-regression was used to screen variables and establish a prediction model. RESULT: The Activin/Follistatin-axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin>6235pg/ml, Activin-A>591pg/ml, Activin-B>249pg/ml, CRP>10.3mg/dL, LDH>427U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio>5.6, Age>61, Comorbidities>1 and D-dimers>1097ng/ml, efficiently predicted fatal outcome in an initial cohort (AUC: 0.951; 95%CI: 0.919-0.983, p<10 -6). Two independent cohorts that were used for validation indicated similar AUC values. CONCLUSIONS: This study unravels strong link between Activin/Follistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.

2.
Ann Rheum Dis ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568386

RESUMO

BACKGROUND/OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

3.
Ann Rheum Dis ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568388

RESUMO

OBJECTIVES: Diagnostic reasoning in systemic lupus erythematosus (SLE) is a complex process reflecting the probability of disease at a given timepoint against competing diagnoses. We applied machine learning in well-characterised patient data sets to develop an algorithm that can aid SLE diagnosis. METHODS: From a discovery cohort of randomly selected 802 adults with SLE or control rheumatologic diseases, clinically selected panels of deconvoluted classification criteria and non-criteria features were analysed. Feature selection and model construction were done with Random Forests and Least Absolute Shrinkage and Selection Operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in a validation cohort (512 SLE, 143 disease controls). RESULTS: A novel LASSO-LR model had the best performance and included 14 variably weighed features with thrombocytopenia/haemolytic anaemia, malar/maculopapular rash, proteinuria, low C3 and C4, antinuclear antibodies (ANA) and immunologic disorder being the strongest SLE predictors. Our model produced SLE risk probabilities (depending on the combination of features) correlating positively with disease severity and organ damage, and allowing the unbiased classification of a validation cohort into diagnostic certainty levels (unlikely, possible, likely, definitive SLE) based on the likelihood of SLE against other diagnoses. Operating the model as binary (lupus/not-lupus), we noted excellent accuracy (94.8%) for identifying SLE, and high sensitivity for early disease (93.8%), nephritis (97.9%), neuropsychiatric (91.8%) and severe lupus requiring immunosuppressives/biologics (96.4%). This was converted into a scoring system, whereby a score >7 has 94.2% accuracy. CONCLUSIONS: We have developed and validated an accurate, clinician-friendly algorithm based on classical disease features for early SLE diagnosis and treatment to improve patient outcomes.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33404657

RESUMO

OBJECTIVE: Central nervous system (CNS) demyelinating syndromes occurring in the context of systemic lupus erythematosus (SLE) may represent a manifestation of neuropsychiatric lupus, or an overlap of SLE and multiple sclerosis (MS). We evaluated prospectively patients presenting with demyelinating syndrome for clinical and serologic evidence of SLE and characterized the evolution of their clinical syndrome to a defined disease. METHODS: Patients with CNS demyelinating syndromes not fulfilling the criteria for MS were evaluated in a rheumatology unit for features of SLE and followed longitudinally (enrolment period 2016-2020). Clinical, laboratory and neuroimaging data were recorded at every visit, following multidisciplinary evaluation. At end of follow-up, patients were assessed for their final neurologic and rheumatologic diagnosis and classified accordingly. RESULTS: 79 patients were included in the study [91.1% female, mean (SD) age at first demyelinating episode 38.4 (10.3), median (IQR) observation period 39 (57) months]. At last follow-up, 38 patients (48.1%) had evolved into MS. Of the remaining, 7 patients (17.1%) had SLE, while 34 (82.9%) had features of systemic autoimmunity without fulfilling classification criteria for SLE. Most common rheumatologic features of these patients were inflammatory arthritis (73.5%), acute cutaneous lupus (47.1%) and positive anti-nuclear antibodies (72.1%). Importantly, these patients were less likely to have elevated IgG index (OR = 0.11, 95%CI 0.04-0.32) and positive oligoclonal bands (OR = 0.21, 95%CI 0.08-0.55). CONCLUSION: A significant number of patients with demyelination do not fulfill criteria for either MS or SLE at follow-up. These patients exhibit lupus-like autoimmune features and may represent a distinct entity, demyelination with autoimmune features (DAF).

5.
Mediterr J Rheumatol ; 31(3): 366-368, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33163873

RESUMO

ANCA-associated vasculitides (AAVs) are characterised by heterogeneous molecular and pathophysiological traits, causing ambiguous differential diagnosis and taxonomy. Response to therapy has proven far from successful, contributing to high mortality. Transcriptome analysis of different vasculitis subtypes adds new leads in elucidating mechanisms of disease and the role of specific cell subsets to them. Recent findings have shown that mitophagy is a procedure whose imbalance could lead to immune dysregulation with certain involvement to autoimmunity. Inflammatory response related mitophagy is yet to be described in AAVs. We here describe a research protocol to investigate mitophagy in monocytes, neutrophils, and T cells in AAV patients, and the relationship of disturbed mitophagy with ANCA seropositivity.

6.
Ann Rheum Dis ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051219

RESUMO

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

7.
Sci Rep ; 10(1): 16648, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024230

RESUMO

Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. In this work we propose a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). Application of this method on a large transcriptome profiling dataset of 148 SLE patients and 52 healthy individuals enabled the identification of significant disease-associated alterations in gene co-regulation patterns, which also correlate with SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to overall fewer DCEs of smaller size. High disease activity genomes display extensive redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. The dynamics of domain fragmentation and redistribution are associated with SLE clinical endophenotypes, with genes of the interferon pathway being highly enriched in DCEs that become disrupted and with functions associated to more generalized symptoms, being located in domains that emerge anew in high disease activity genomes. Our results suggest strong links between the SLE phenotype and the underlying genome structure and underline an important role for genome organization in shaping gene expression in SLE.

8.
Cell Metab ; 32(4): 591-604.e7, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-32738205

RESUMO

Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. Scavenging of mtROS in Tregs of EAE mice reversed the DDR and prevented Treg death, while attenuating the Th1 and Th17 autoimmune responses. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance.

9.
Ann Rheum Dis ; 79(10): 1333-1339, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32816709

RESUMO

OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%). CONCLUSIONS: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Índice de Gravidade de Doença , Feminino , Humanos , Masculino , Seleção de Pacientes , Sensibilidade e Especificidade
10.
Lupus Sci Med ; 7(1)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32601172

RESUMO

OBJECTIVE: Changes in the care of patients with SLE dictate a re-evaluation of its natural history and risk factors for disease deterioration and damage accrual. We sought to decipher factors predictive of a deterioration in phenotype ('transition') in patients initially presenting with non-severe disease. METHODS: Patients from the 'Attikon' cohort with disease duration ≥1 year were included. Disease at diagnosis was categorised as mild, moderate or severe, based on the British Isles Lupus Assessment Group manifestations and physician judgement. 'Transition' in severity was defined as an increase in category of severity at any time from diagnosis to last follow-up. Multivariable logistic regression was performed to identify baseline factors associated with this transition. RESULTS: 462 patients were followed for a median (IQR) of 36 (120) months. At diagnosis, more than half (56.5%) had a mild phenotype. During disease course, transition to more severe forms was seen in 44.2%, resulting in comparable distribution among severity patterns at last follow-up (mild 28.4%, moderate 33.1%, severe 38.5%). Neuropsychiatric involvement at onset (OR 6.33, 95% CI 1.22 to 32.67), male sex (OR 4.53, 95% CI 1.23 to 16.60) and longer disease duration (OR 1.09 per 1 year, 95% CI 1.04 to 1.14) were independently associated with transition from mild or moderate to severe disease. Patients with disease duration ≥3 years who progressed to more severe disease had more than 20-fold increased risk to accrue irreversible damage. CONCLUSION: Almost half of patients with initially non-severe disease progress to more severe forms of SLE, especially men and patients with positive anti-double-stranded DNA or neuropsychiatric involvement at onset. These data may have implications for the management of milder forms of lupus.

11.
RMD Open ; 6(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32699043

RESUMO

OBJECTIVES: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. METHODS: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. RESULTS: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). CONCLUSIONS: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

14.
Ann Rheum Dis ; 79(6): 713-723, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32220834

RESUMO

OBJECTIVE: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN). METHODS: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. RESULTS: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. CONCLUSIONS: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.


Assuntos
Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Sociedades Médicas , Antirreumáticos/uso terapêutico , Azatioprina/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Quimioterapia Combinada , Europa (Continente) , Taxa de Filtração Glomerular , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Nefrite Lúpica/complicações , Nefrite Lúpica/patologia , Nefrite Lúpica/fisiopatologia , Ácido Micofenólico/uso terapêutico , Proteinúria/etiologia , Proteinúria/terapia
15.
Dermatol Ther ; 33(3): e13283, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092214

RESUMO

Psoriasis (Pso) and psoriatic arthritis (PsA) are chronic and debilitating diseases which often develop in the same patient and are linked to a wide range of comorbid conditions. Dermatologists and rheumatologists need to cooperate in combined clinics, especially when they deal with severe, recalcitrant disease, and multiple comorbidities. The clinical and research benefits of this collaboration have been previously described to contribute to a better and more sustainable health care system. To apply a more holistic approach of patients with Pso and PsA, we established the first dual care clinic in Greece, for Pso and PsA patients, based at Attikon General University Hospital. Hereby, we describe the infrastructure and operation of a combined Pso and PsA clinic (PPAC), in the national health care system of Greece, and its impact on the management of Pso and PsA. The PPAC is a single-day joint clinic, held once a week, which consists of three dermatologists and three rheumatologists. We present the results of 185 newly diagnosed patients between December 2018 and January 2019. Mean age of onset of Pso was 34 ± 16 years old and 47 ± 12 years old for PsA. Most patients suffered from severe plaque Pso (144/185, 78%) and asymmetric oligoarticular arthritis (59/185, 32%), for which they were receiving treatment with biologic agents (105/185, 57%). Many required monitoring for hypertension (74/185, 40%), dyslipidemia (69/185, 37%), diabetes (17/185, 9%), and depression (20/185, 11%). Patients reported high levels of care satisfaction (visual analogue scale: 86 ± 11.5), using the PPAC facility, compared to different referrals between specialties. This is the first joint dermatology-rheumatology clinic in Greece, providing comprehensive care in patients with Pso and PsA. Our results support the concept of combined clinics delivering better integrated care for such patients.

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