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1.
Artigo em Inglês | MEDLINE | ID: mdl-31642908

RESUMO

OBJECTIVES: Patients with SLE are often exposed to prolonged immunosuppression since few data on flare recurrence in remitted patients who discontinued immunosuppressants are available. We aimed to assess the rate and predictors of flare after immunosuppressant withdrawal in SLE patients in remission. METHODS: SLE patients diagnosed between 1990 and 2018 (according to the ACR criteria), ever treated with immunosuppressants and currently in follow-up were considered. Immunosuppressant discontinuation was defined as complete withdrawal of any immunosuppressive drug. Reasons for discontinuation were remission, defined as clinical SLEDAI-2K = 0 on a stable immunosuppressive and/or antimalarial therapy and/or on prednisone ⩽5 mg/day, or poor adherence/intolerance. Flares were defined according to the SLEDAI Flare Index. Predictors of a subsequent flare were analysed by multivariate logistic regression. RESULTS: There were 319 eligible patients out of 456 (69.9%). Of the 319 patients, 139 (43.5%) discontinued immunosuppressants, 105 (75.5%) due to remission, 34 (24.5%) due to poor adherence/intolerance. The mean (s.d.) follow-up time after immunosuppressant withdrawal was 91 (71) months (range 6-372). Among the patients who discontinued immunosuppressants, 26/105 remitted (24.7%) and 23/34 unremitted patients (67.6%) experienced a flare (P < 0.001) after a median (range) follow-up of 57 (6-264) and 8 months (1-72), respectively (P = 0.009). In patients who discontinued immunosuppressants due to remission, maintenance therapy with antimalarials (OR 0.243, 95% CI 0.070, 0.842) and the duration of remission at immunosuppressant discontinuation (OR 0.870, 0.824-0.996) were independent protective factors against disease flare. CONCLUSION: SLE flares are not uncommon after immunosuppressant discontinuation, even in remitted patients; however, antimalarial therapy and durable remission can significantly reduce the risk of flare.

2.
Curr Opin Rheumatol ; 31(6): 603-610, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31503025

RESUMO

PURPOSE OF REVIEW: Lung involvement is a distinctive feature of antisynthetase syndrome (ASS) and it is considered a basic disease-classifying criterion. In this review, we go over clinical features, radiological patterns, prognostic factors, pathogenesis and treatment of lung involvement in ASS patients, focusing on the clinical differences linked to the different antibody specificities known so far. RECENT FINDINGS: The lung is the most common extramuscular organ involved in ASS and has the greatest impact on patient prognosis. The pulmonary disease-defining manifestation in ASS is interstitial lung disease (ILD), yet a proportion of patients also develop pulmonary arterial hypertension and, less frequently, obstructive bronchiolitis or acute respiratory failure according to drivers not yet fully understood but likely associated with the underlying autoantibody pattern. Clinical presentation of pulmonary involvement can range from milder forms to a rapidly progressive disease which may lead to chronic lung damage if misdiagnosed and not properly treated. SUMMARY: The knowledge of risk factors associated with progressive or refractory lung damage is important to identify and properly treat patients with the poorest prognosis. For those with a disease not responsive to conventional therapy the efficacy of other therapeutic option is under evaluation.

3.
Front Immunol ; 9: 2081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254646

RESUMO

Objective: To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. Methods: 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 µg/0.1 mL or 15 µg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria (≥100 mg/dl). Two additional mice groups were provided by including 20 MRL/lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/lpr mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Results: Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/lpr mice treated with SERPINB3, compared to untreated control mice. Conclusions: SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype.

4.
Clin Rev Allergy Immunol ; 55(2): 237, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30140999

RESUMO

The following changes are made for this article: (1.) Maddalena Larosa's given name and surname were inadvertently interchanged. The authorgroup section is now corrected. (2.) The author(s)' decision to opt for Open Choice.

5.
Clin Rev Allergy Immunol ; 54(2): 331-343, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29512034

RESUMO

To date, belimumab is the only biological drug approved for the treatment of patients with active refractory SLE. We compared and critically analyzed the results of 11 observational clinical-practice-based studies, conducted in SLE referral centers. Despite the differences in endpoints and follow-up duration, all studies remarked that belimumab provides additional benefits when used as an add-on to existing treatment, allowing a higher rate of patients to reach remission and to taper or discontinue corticosteroids. In the OBSErve studies, 2-9.6% of patients discontinued corticosteroids and 72-88.4% achieved a ≥ 20% improvement by physician's judgment at 6 months. In Hui-Yuen's study, 51% of patients attained response by simplified SRI at month 6. In Sthoeger's study, 72.3% of patients discontinued corticosteroids and 69.4% achieved clinical remission by PGA after a median follow-up of 2.3 years. In the multicentric Italian study, 77 and 68.7% of patients reached SRI-4 response at months 6 and 12, respectively. In all the studies, disease activity indices decreased over time. Retention rates at 6, 9, and 12 months were 82-94.1, 61.2-83.3, and 56.7-79.2%, respectively. The main limitations of these studies include the lack of a control group, the short period of observation (6-24 months) and the lack of precise restrictions regarding concomitant medication management. This notwithstanding, these experiences provide a more realistic picture of real-life effectiveness of the drug compared with the randomized controlled clinical trials, where stringent inclusion/exclusion criteria and changes in background therapy could limit the inference of data to the routine clinical care.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ensaios Clínicos como Assunto , Resistência a Medicamentos , Quimioterapia Combinada , Medicina Baseada em Evidências , Humanos , Recidiva , Resultado do Tratamento
6.
Ann Rheum Dis ; 77(1): 104-110, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28970217

RESUMO

OBJECTIVE: To evaluate the prevalence, duration and effect on damage accrual of the 'Lupus Low Disease Activity State' (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE). METHODS: We studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0-3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials. RESULTS: LLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, p<0.001). On average, 84% of patients in LLDAS also fulfilled the criteria for remission. CONCLUSIONS: LLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.


Assuntos
Anti-Inflamatórios/uso terapêutico , Progressão da Doença , Lúpus Eritematoso Sistêmico/patologia , Prednisona/uso terapêutico , Índice de Gravidade de Doença , Adulto , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
7.
J Autoimmun ; 86: 1-8, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28935492

RESUMO

OBJECTIVE: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. PATIENTS AND METHODS: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. RESULTS: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. CONCLUSION: Belimumab is effective and safe when used in clinical practice setting.

8.
Autoimmun Rev ; 16(1): 34-47, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27666815

RESUMO

Galectins are evolutionary conserved ß-galactoside binding proteins with a carbohydrate-recognition domain (CRD) of approximately 130 amino acids. In mammals, 15 members of the galectin family have been identified and classified into three subtypes according to CRD organization: prototype, tandem repeat-type and chimera-type galectins. Galectin-3 (gal-3) is the only chimera type galectin in vertebrates containing one CRD linked to an unusual long N-terminal domain which displays non-lectin dependent activities. Although recent studies revealed unique, pleiotropic and context-dependent functions of gal-3 in both extracellular and intracellular space, gal-3 specific pathways and its ligands have not been clearly defined yet. In the kidney gal-3 is involved in later stages of nephrogenesis as well as in renal cell cancer. However, gal-3 has recently been associated with lupus glomerulonephritis, with Familial Mediterranean Fever-induced proteinuria and renal amyloidosis. Gal-3 has been studied in experimental acute kidney damage and in the subsequent regeneration phase as well as in several models of chronic kidney disease, including nephropathies induced by aging, ischemia, hypertension, diabetes, hyperlipidemia, unilateral ureteral obstruction and chronic allograft injury. Because of the pivotal role of gal-3 in the modulation of immune system, wound repair, fibrosis and tumorigenesis, it is not surprising that gal-3 can be an intriguing prognostic biomarker as well as a promising therapeutic target in a great variety of diseases, including chronic kidney disease, chronic heart failure and cardio-renal syndrome. This review summarizes the functions of gal-3 in kidney pathophysiology focusing on the reported role of gal-3 in autoimmune diseases.


Assuntos
Galectina 3/fisiologia , Animais , Síndrome Cardiorrenal , Fibrose , Humanos , Rim/imunologia , Rim/metabolismo , Rim/patologia , Nefrite Lúpica , Transdução de Sinais
9.
Ann Rheum Dis ; 76(3): 562-565, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27884821

RESUMO

AIM: To identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE). METHODS: We studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1-5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis. RESULTS: Among patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (p<0.001).In multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)). CONCLUSIONS: Two consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.


Assuntos
Síndrome Antifosfolipídica/complicações , Grupo com Ancestrais do Continente Europeu , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Prednisona/administração & dosagem , Vasculite/complicações , Adulto , Anti-Inflamatórios/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Prospectivos , Indução de Remissão , Índice de Gravidade de Doença , Exacerbação dos Sintomas , Fatores de Tempo , Adulto Jovem
10.
J Autoimmun ; 74: 94-105, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27373904

RESUMO

Patients affected with systemic lupus erythematosus (SLE) still display increased mortality and decreased quality of life in respect to general population. The major determinant of poor long term prognosis is organ damage, which is predictive of more damage and death. Damage is in turn triggered by uncontrolled disease activity and especially by the long-standing corticosteroid use which often accompanies SLE patients over their disease course, owing both to the need of reaching disease remission and to the habit of keeping patients on a small steroid dose for an indefinite period of time. Hence, the need for new drugs and therapeutic strategies aiming at minimizing damage accrual through a better control of disease activity and a steroid-sparing potential is paramount. So far, however, the therapeutic strategy in SLE requires a multitarget approach which is not devoid of widespread immunesuppression. In fact, several studies have been carried out in recent years targeting both the adaptive and the innate immune system, the majority of which did not achieve their primary endpoint, being often divergent from successful clinical experience and thereby committing physician to off-label use of targeted therapies in face of refractory SLE manifestations. The study designs and the chosen endpoints were often blamed for inadequacy, being at least in part responsible for study failures. In this review, we go over major clinical trials conducted in SLE by analyzing any critical aspects related to study design, predefined endpoints and biological activity of novel compounds that may have hampered study outcome, despite the great effort of providing less toxic drugs within a targeted, pathogenic-based approach.


Assuntos
Terapia Biológica , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Terapia Biológica/efeitos adversos , Terapia Biológica/métodos , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/metabolismo , Terapia de Alvo Molecular , Falha de Tratamento , Resultado do Tratamento
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