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1.
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).

2.
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.

3.
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.

4.
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.

5.
Mediterr J Rheumatol ; 31(2): 216-219, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32676560

RESUMO

Systemic lupus erythematosus (SLE) is a heterogeneous disease with a broad spectrum of clinical manifestations. Periaortitis is a rare disorder which may manifest isolated or in association with other autoimmune diseases, including SLE. Another rare, yet severe cardiovascular manifestation of lupus is diffuse subendocardial vasculitis (DSV), which should be suspected in patients presenting with myocardial hypokinesis, impaired ejection fraction and normal coronary angiography. Cardiovascular Magnetic Resonance (CMR) imaging is crucial to distinguish between DSV and lupus myocarditis, which should also be included in the differential diagnosis. Herein, we describe a case of a female patient with pre-existing SLE, who presented with both periaortitis and DSV, and discuss the diagnostic challenges associated with these rare manifestations.

7.
Semin Arthritis Rheum ; 50(6): 1387-1393, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32229040

RESUMO

OBJECTIVE: Detailed analysis of hematological manifestations (HM) in systemic lupus erythematosus (SLE) are limited and their clinical impact on disease remain obscure. Here, we aimed to decipher factors associated with different hematological abnormalities in SLE patients and to assess their impact on disease related outcomes. METHODS: A dataset (GIPT) originating from SLE patients of six European tertiary centers was assessed. Six-monthly visits of each patient for at least 2 years were registered. The association between hematologic manifestations (HM; per ACR-1997criteria) and clinical/serologic variables, as well as the impact of HM on disease related outcomes (damage, infection and hemorrhage) were explored. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI2K), the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and events for any infection and hemorrhage were recorded. Results were compared with a cross-sectional, well-characterized SLE dataset from Sweden. Descriptive statistics, the generalized estimating equations (GEE), general linear models (GLM), Cox regression models were applied. RESULTS: We monitored 1425 longitudinal visits in 286 SLE patients with HM (GIPT dataset: 88% female, 95% Caucasian, 68% dsDNA positive). Thrombocytopenia (regression coefficient [95% confidence interval] 1.86[1.1-3.13]) and neurologic involvement (ACR-8) (2.1[1.10-3.89]) were associated with lymphopenia (<1000/mm3); the latter was an independent predictor of organ damage accrual (1.68[1.2-2.62]). These associations were confirmed in an independent dataset of 1348 SLE patients (86% female, 93% Caucasian, 61% dsDNA positive) in Sweden.Severe lymphopenia (<500/mm3) and severe thrombocytopenia (<20 K/mm3) were associated with increased risk for infection (hazard ratio [95% confidence interval] 2.56[1.23-5.31]) and hemorrhage (4.38[2.10-11.1]), respectively, independent of the effect of other predictors. CONCLUSION: Lymphopenia in SLE is independently associated with neurologic involvement and organ damage accrual, and thus, may be considered as a marker of severe/progressive disease.

9.
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
10.
BioDrugs ; 34(2): 133-147, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32002918

RESUMO

Following the approval of belimumab, the first drug to be approved for systemic lupus erythematosus (SLE) in over 50 years, advances in our understanding of the pathogenesis of the disease have led to a remarkable number of clinical trials for investigational drugs, each with a unique mechanism of action. These include, but are not limited to, antibodies targeting B or T cells or their interaction, dendritic cells, interferon, and other cytokines. Frustratingly, this boost of studies has not been accompanied by a corresponding success and subsequent approval of novel agents, for reasons only partly attributed to the efficacy of the drugs per se. Successful phase II trials are often followed by failed phase III studies, which typically require many more patients. Nevertheless, recent successes, such as the ustekinumab and baricitinib trials and the positive results from the phase III TULIP-2 study of anifrolumab, provide room for cautious optimism. In this review, we attempt to draw the current landscape of the drug pipeline in SLE, focusing on the rationale behind each drug development, its mechanism of action, and the available preclinical and clinical data. We also highlight lessons learned from failed attempts that have helped to optimize clinical trial design for this challenging disease. We conclude with a look into the future, commenting on the surge of studies in the field of biomarkers and the use of omics technologies in lupus, which aim to pinpoint different disease phenotypes and, ideally, identify subsets of patients with disease that will respond to different biologic drugs.

11.
Turk J Med Sci ; 50(1): 281-290, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31905489

RESUMO

Background/aim: Neonatal lupus erythematosus (NLE) is an autoimmune syndrome caused by transplacental transmission of maternal autoantibodies, often with devastating consequences. The objective of this systematic literature review was to analyze the demographic data, geoepidemiology, clinical, and serological characteristics associated with NLE. Materials and methods: We performed a systematic literature search of the Pubmed database covering the period from 1976 to August 2015, using the MeSH terms "neonatal lupus" or "congenital heart block". To be included in the study, articles of any type (original articles, case series, and case reports) had to report on infants with NLE on an individualized (i.e. patient-by-patient) basis. Results: A total of198 studies were included in the review, reporting on a total of 755 NLE patients. The most frequently reported clinical manifestations of NLE were congenital heart block (CHB, 65.2%), cutaneous lupus (33.1%), and cytopenias (15.5%). We found differences in NLE characteristics based on study geographical origin, with CHB being much more frequent in patients of European or American descent (49.4% and 35%, respectively), while reports originating from Asia reported a higher prevalence of skin involvement (45.2%). Most CHB cases (72.9%) were diagnosed between the 18th and 26th week of gestation. Conclusions: Phenotypic differences of NLE depending on race and country may reflect true pathophysiologic differences or methodologic discrepancies. While maternal autoimmune disease is not a prerequisite for the development of NLE, the existence of a truly "immunonegative" CHB is questionable.

17.
Ann Rheum Dis ; 79(2): 232-241, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31704720

RESUMO

OBJECTIVES: Classification criteria are biased towards classifying long-standing disease. We compared the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)-2019, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and ACR-1997 criteria in an early (median 48 months) systemic lupus erythematosus (SLE) cohort. METHODS: Patients diagnosed with SLE (n=690) or control diseases (n=401). Sensitivity, specificity of the criteria and time-to-classification were calculated. Modified classification algorithms were derived from a random 80% and validated in the remaining 20% of the dataset running multiple iterations. RESULTS: At last assessment, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 85.7%, 91.3% and 88.6%, with specificities 93.0%, 93.8% and 97.3%, respectively. Both SLICC and EULAR/ACR enabled earlier classification. Only 76.7% of patients with SLE met all three criteria suggesting non-overlapping groups. Notably, unclassified patients had high prevalence of British Isles Lupus Assessment Group moderate/severe manifestations (43.3%-60%) and SLICC/ACR organ damage (30%-50%). At diagnosis, criteria missed 25.6%-30.5% of patients. Modification of EULAR/ACR and SLICC algorithms to include hypocomplementaemia and/or positive anti-phospholipid antibodies as alternative entry criterion, and/or allow classification with fewer clinical criteria from multiple organs, increased their sensitivity at diagnosis (median 82.0% and 86.2%) and overall (93.7% and 97.1%) with modest decreases in specificity. Importantly, patients who were still missed by the modified criteria had lower incidence of major organ involvement, use of immunosuppressive/biological therapies and organ damage. CONCLUSIONS: The SLICC and EULAR/ACR are more sensitive than the ACR and the EULAR/ACR criteria have superior specificity in early SLE, although patients with significant disease can be missed. Combination and/or modification of the classification algorithms may enhance their sensitivity, allowing earlier classification and treatment of more patients with high disease burden.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/diagnóstico , Reumatologia/métodos , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos , Adulto , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reumatologia/normas , Sensibilidade e Especificidade , Avaliação de Sintomas/normas
18.
Cells ; 8(8)2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443172

RESUMO

Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.


Assuntos
Azetidinas/administração & dosagem , Janus Quinases/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Transcrição STAT/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Animais , Azetidinas/farmacologia , Células Cultivadas , Ensaios Clínicos Fase II como Assunto , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia
19.
Curr Opin Rheumatol ; 31(6): 669-677, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31415031

RESUMO

PROPOSE OF REVIEW: Neuropsychiatric systemic lupus erythematosus (NPSLE) is an emerging frontier in lupus care encompassing a wide spectrum of clinical manifestations. Its pathogenesis remains poorly understood because of the complexity of pathophysiologic mechanisms involved and limited access to tissue. We highlight recent advances in the pathophysiology of neuropsychiatric lupus. RECENT FINDINGS: Disruption of blood-brain barrier (BBB) facilitating entrance of neurotoxic antibodies into the central nervous system (CNS), neuroinflammation and cerebral ischemia are the key mechanisms. Disruption of the BBB may occur not only at the traditional BBB, but also at the blood-cerebrospinal fluid barrier. Certain autoantibodies, such as anti-N-methyl-D-aspartate receptors, antiribosomal P and antiphospholipid antibodies may cause injury in subsets of patients with diffuse neuropsychiatric disease. Activation of microglia via autoantibodies, interferon-a or other immune reactants, may amplify the inflammatory response and promote neuronal damage. New inflammatory pathways, such as TWEAK/Fn14, Bruton's tyrosine kinase, Nogo-a and ACE may represent additional potential targets of therapy. Novel neuroimaging techniques suggest alterations in brain perfusion and metabolism, increased concentration of neurometabolites, indicative of glial activation, vasculopathy and neuronal impairment. SUMMARY: NPSLE encompasses a diverse phenotype with distinct pathogenic mechanisms, which could be targeted by novel therapies or repositioning of existing drugs.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Barreira Hematoencefálica/fisiologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Imagem por Ressonância Magnética/métodos , Microglia/fisiologia , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Transdução de Sinais
20.
Urologia ; 86(3): 156-160, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431168

RESUMO

Digital ischemia has been rarely associated, as a paraneoplastic syndrome, with renal cancer. Since it can severely compromise the patients' quality of life, early recognition is important, in order to optimally address it with currently available treatment options, such as tyrosine inhibitors. Digital ischemia may occur in the general population and it can be the result of other non-cancerous diseases; accordingly, a thorough and aggressive work-up is mandatory, together with appropriate therapeutic steps such as tyrosine kinase inhibitors, vasodilators, and antiaggregants. Herein, we report a 78-year-old male patient with a history of clear-cell renal-cell cancer, who presented in the emergency department with critical ischemia in the upper limbs.


Assuntos
Carcinoma de Células Renais/complicações , Dedos/irrigação sanguínea , Isquemia/etiologia , Neoplasias Renais/complicações , Síndromes Paraneoplásicas/etiologia , Idoso , Humanos , Masculino
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