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Many new drugs, sometimes promising, are now available to treat systemic auto-immune diseases. Treatment strategies and objectives are different according to each auto-immune disease. Major advances have been obtained in vasculitides treatments. In systemic lupus erythematosus, many drugs have been evaluated, targeting one of the multiple pathogenic mechanisms of the disease. Unfortunately, new drugs remain rare on the market and no major advances have been obtained. In systemic sclerosis, symptomatic treatments improved outcomes but effective drugs targeting all disease manifestations are missing. Autologous hematopoietic stem cell transplantation could be one of the future innovative treatment of systemic sclerosis despite the occurrence of adverse events.
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BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12â months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6â months, 83% improved with remission in 34% and partial response in 49%, and by 12â months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12â months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12â months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.
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Síndrome de Churg-Strauss/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Adulto , Anticorpos Anticitoplasma de Neutrófilos/sangue , Síndrome de Churg-Strauss/sangue , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de TempoRESUMO
Autoantibodies targeting the melanoma-differentiation-associated gene-5 (MDA5)-encoded ribonucleic acid helicase are associated with clinically amyopathic dermatomyopathy (CADM). Marked systemic inflammation, skin ulcers and severe interstitial lung disease seem frequent. DM treatment consists of immunosuppressants and/or intravenous immunoglobulins, but evidence-based knowledge is lacking. Anakinra (an interleukin-1 receptor antagonist (IL-1RA)) use in this setting has never been reported. Herein, we report on a case of anakinra dramatic and rapid efficacy against general and extramuscular (e.g. calcinosis, arthritis, skin ulcers) in a patient with severe and refractory CADM. Unfortunately, short-term follow-up prevented efficacy evaluation against interstitial lung disease. IL-1RA could be a promising treatment for refractory CADM.
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RNA Helicases DEAD-box/imunologia , Dermatomiosite , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Receptores de Interleucina-1/antagonistas & inibidores , Antirreumáticos/administração & dosagem , Biomarcadores/sangue , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Dermatomiosite/fisiopatologia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon , Pessoa de Meia-Idade , Monitorização Imunológica , Resultado do TratamentoRESUMO
OBJECTIVES: To describe the clinical-biological phenotype of ANCA-associated vasculitides (AAV) according to tobacco consumption. METHODS: We conducted a descriptive study to describe that phenotype at diagnosis according to tobacco use. AAV patients entered in the French Vasculitis Study Group database with data on smoking habits were analysed. The clinical-biological phenotypes at diagnosis were compared according to current tobacco use (current smokers) or not (including previous and never smokers). RESULTS: AAV diagnoses were: granulomatosis with polyangiitis (GPA) for 583 (50%), eosinophilic granulomatosis with polyangiitis (EGPA) for 326 (28%) and microscopic polyangiitis (MPA) for 256 (22%). Among them, 973 patients (84%) never smoked, 116 (10%) were previous smokers and only 76 (6%) were current smokers. Current smokers were younger age (p=0.01), male gender (p=0.004), less frequently EGPA (p=0.017) and MPA (p=0.036), and had less frequent kidney involvement (p=0.10). Among GPA patients, current smokers, compared to non-current smokers, were younger age (p=0.02), male gender (p=0.08), more frequent skin involvement (p=0.03) and less frequent ENT involvement (p=0.06). Among EGPA patients, current smokers, compared to non-current smokers, were also younger (p=0.028) and had less frequent constitutional symptoms (p=0.02), arthralgias (p=0.04), renal involvement (p=0.025) and MPO-ANCA (p=0.02). Finally, analysis of MPA patients was impossible because only 6 (2%) were current smokers. CONCLUSIONS: These results suggest that tobacco use could differentially affect GPA and EGPA clinical-biological phenotypes, and support the role of environmental exposures in AAV development and its phenotype.
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Síndrome de Churg-Strauss/epidemiologia , Granulomatose com Poliangiite/epidemiologia , Poliangiite Microscópica/epidemiologia , Fumar/epidemiologia , Adulto , Distribuição por Idade , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Artralgia/etiologia , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/imunologia , Feminino , Febre/etiologia , França/epidemiologia , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Doenças do Sistema Nervoso Periférico/etiologia , Peroxidase/imunologia , Fenótipo , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Dermatopatias Vasculares/etiologia , Redução de PesoRESUMO
OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.
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Granulomatose com Poliangiite/epidemiologia , Poliangiite Microscópica/epidemiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Distribuição por Idade , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Estudos de Coortes , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/imunologia , Humanos , Nefropatias/etiologia , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/etiologia , Seleção de Pacientes , Peroxidase/imunologia , Índice de Gravidade de DoençaRESUMO
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) treatment strategy is based on immunosuppressive agents. Little information is available concerning mycophenolic acid (MPA) and the area under the curve (AUC) in patients treated for AAV. We evaluated the variations in pharmacokinetics for MPA in patients with AAV and the relationship between MPA-AUC and markers of the disease. MPA blood concentrations were measured through the enzyme-multiplied immunotechnique (C(0), C(30), C(1), C(2), C(3), C(4), C(6) and C(9)) to determine the AUC. Eighteen patients were included in the study. The median (range) MPA AUC(0-12) was 50·55 (30·9-105·4) mg/h/l. The highest coefficient of determination between MPA AUC and single concentrations was observed with C(3) (P < 0·0001) and C(2) (P < 0·0001) and with C(4) (P < 0·0005) or C(0) (P < 0·001). Using linear regression, the best estimation of MPA AUC was provided by a model including C(30), C(2) and C(4): AUC = 8·5 + 0·77 C(30) + 4·0 C(2) + 1·7 C(4) (P < 0·0001). Moreover, there was a significant relationship between MPA AUC(0-12) and lymphocyte count (P < 0·01), especially CD19 (P < 0·005), CD8 (P < 0·05) and CD56 (P < 0·05). Our results confirm the interindividual variability of MPA AUC in patients treated with MMF in AAV and support a personalized therapy according to blood levels of MPA.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Modelos Lineares , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Estudos ProspectivosRESUMO
Progressive multifocal encephalopathy (PML) is a rare demyelinating disorder targeting the central nervous system and resulting from JC virus reactivation. PML occurs in patients immunocompromised because of haematological malignancies, HIV infection or treatment with cytotoxic drugs. Herein, we describe PML occurring in 2 granulomatosis with polyangiitis (Wegener) patients treated with steroids and cyclophosphamide. The outcome was progressively favourable after immunosuppressant discontinuation for 1 patient and fatal for the other. Four previously reported GPA patients developed PML in the course of their disease. One of them improved gradually after immunosuppressant withdrawal. PML should be strongly suspected whenever unusual central neurological manifestations appear in this context. No effective treatment is available, but immunosuppressants should be discontinued if possible.
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Encéfalo/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Encéfalo/patologia , Evolução Fatal , Granulomatose com Poliangiite/diagnóstico , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/terapia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
The management of orphan rare diseases has been the goal of two successive government plans since 2004. They allowed the management of these diseases to be handled initially through reference centers, then by specialized centers that were specifically created. The resulting benefits to patients, standardization of management protocols, dissemination of information through ORPHANET, and the development of both fundamental and clinical research have clearly justified the setting up of these plans. Other associated plans are expected to follow in the years to come.
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Programas Governamentais/tendências , Doenças Raras/terapia , Bases de Dados Factuais , França , Programas Governamentais/história , História do Século XXI , Humanos , Disseminação de Informação/legislação & jurisprudência , Serviços de Informação/história , Serviços de Informação/legislação & jurisprudência , Internet , Produção de Droga sem Interesse ComercialRESUMO
INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of necrotizing vasculitis affecting small vessels and typically characterized by severe glucocorticoid (GC)-dependent eosinophilic asthma. While mepolizumab, which is indicated at a dose of 100mg/4weeks in severe eosinophilic asthma, has been shown to be an effective treatment for EGPA-related asthma at a dose of 300mg/4weeks, it was only recently approved at this dose. METHODS: This retrospective, single-center, observational study was conducted to investigate over a 5-year period (2014-2019) the effect of mepolizumab 100mg/4weeks at 12months in patients with EGPA and glucocorticoid-dependant severe asthma. Response to treatment was defined as reduction in daily dose of oral corticosteroids to at most 5mg/day or reduction in annual exacerbation by at least 50%. RESULTS: Thirty patients were included, of whom twenty-three were treated (two were not fully evaluable). Among the 21 evaluable treated patients, 13 (62%) had responded at 12months. At baseline, non-responders had lower FEV1 levels and lower blood eosinophil levels than responders. CONCLUSIONS: Mepolizumab at a "severe asthma" dose (100mg/4weeks) is effective in treatment of GC-dependent severe asthma in most patients with EGPA.
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Asma , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Humanos , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Glucocorticoides/uso terapêutico , Estudos Retrospectivos , Asma/complicações , Asma/diagnóstico , Asma/tratamento farmacológicoRESUMO
Deaths occurring in the context of acquired haemophilia (AH) may be related to inter-connected causes and mechanisms including bleeding, specific or older patient co-morbidities or iatrogenic complications. However, their magnitude remains unknown. This study aimed to determine the respective weight and frequency of the various causes of death in AH. Multiple-cause analysis based on death certificates data is used in this purpose. Over a 10-year period (2000-2009), 121 deaths with AH as a cause were registered in France. All the deaths were of adults (extremes: 47 and 99 years; mean age: 80.7 years). The average number of causes per death certificate was 4.7. AH was the underlying cause of death (UCD) in 69.4% of the cases, and was more frequent in the older subjects. In contrast, before age of 75 years, AH was more often a contributing cause of death. No postpartum or obvious thromboembolism-related deaths were registered. Haemorrhagic shock was the most frequent direct cause of death (DCD), followed by infectious events, cardiac dysfunction, metabolic and nutritional disorders with muscle wasting and decubitus complications, and cancers (52.9%, 26.4%, 7.5%, 5.8% and 4.1%, respectively). However, when AH was not reported as an UCD, infections become the first DCD (32.4%) followed by bleeding events (16.2%). Best prophylactic and curative strategies for infections are particularly required to improve the prognosis in AH. Moreover, as several of its DCD correspond also to steroids side effects, best tolerated immunosuppressant regimen with steroid-sparing agents adjoining are particularly awaited in AH population.
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Hemofilia A/mortalidade , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Criança , Pré-Escolar , Atestado de Óbito , Feminino , França/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Adulto JovemRESUMO
OBJECTIVE: To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). METHODS: We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. RESULTS: Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3-6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3-8) and 2 (1-6), and 20 (13-30) mg/day and 20 (15-25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6-13) and 11 months (IQR 6-18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. CONCLUSION: This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.
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Produtos Biológicos , Granulomatose com Poliangiite , Produtos Biológicos/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Uso Off-Label , Estudos Retrospectivos , Resultado do Tratamento , Inibidores do Fator de Necrose TumoralRESUMO
Lung fibrosis is considered a severe manifestation of microscopic polyangiitis (MPA). Antimyeloperoxidase (anti-MPO) antibodies in MPA patients' sera can activate MPO and lead to the production of reactive oxygen species (ROS). While high levels of ROS are cytotoxic, low levels can induce fibroblast proliferation. Therefore, we hypothesised that the oxidative stress induced by anti-MPO antibodies could contribute to lung fibrosis. 24 MPA patients (45 sera) were enrolled in the study, including nine patients (22 sera) with lung fibrosis. Serum advanced oxidation protein products (AOPP), MPO-induced hypochlorous acid (HOCl) and serum-induced fibroblast proliferation were assayed. AOPP levels, MPO-induced HOCl production and serum-induced fibroblast proliferation were higher in patients than in healthy controls (p<0.0001, p=0.0001 and p=0.0005, respectively). Increased HOCl production was associated with active disease (p=0.002). Serum AOPP levels and serum-induced fibroblast proliferation were higher in patients with active MPA and lung fibrosis (p<0.0001). A significant linear relationship between fibroblast proliferation, AOPP levels and HOCl production was observed only in patients with lung fibrosis. Oxidative stress, in particular the production of HOCl through the interaction of MPO with anti-MPO antibodies, could trigger the fibrotic process observed in MPA.
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Anticorpos/imunologia , Poliangiite Microscópica/imunologia , Estresse Oxidativo , Peroxidase/imunologia , Peroxidase/metabolismo , Fibrose Pulmonar/imunologia , Adulto , Idoso , Proteínas Sanguíneas/metabolismo , Proliferação de Células , Feminino , Fibroblastos/metabolismo , Humanos , Ácido Hipocloroso/sangue , Masculino , Poliangiite Microscópica/enzimologia , Pessoa de Meia-Idade , Oxirredução , Fibrose Pulmonar/enzimologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Deficiência de alfa 1-Antitripsina/complicações , alfa 1-Antitripsina/genética , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Biópsia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Heterozigoto , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/genéticaAssuntos
Hemofilia A/tratamento farmacológico , Rituximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Ciclofosfamida/uso terapêutico , Fator VIII/análise , Feminino , Hemorragia/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.
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Anti-Hipertensivos/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bosentana , Comorbidade , Método Duplo-Cego , Teste de Esforço , Feminino , Humanos , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Testes de Função Respiratória , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/fisiopatologia , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS: The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS: Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION: The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.
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Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Infecções Bacterianas/imunologia , Sistema de Registros , Agamaglobulinemia/imunologia , Anticorpos Monoclonais Murinos , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Infecções Bacterianas/complicações , Contraindicações , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Rituximab , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVES: To assess subclinical central nervous system (CNS) involvement in primary Sjögren syndrome (pSS), by comparing standard brain MRI, in-depth neuropsychological testing and (99m)Tc-ECD brain single-photon emission computed tomography (SPECT) of patients with pSS with matched controls. METHODS: 10 women (<55 years old), with pSS defined using European-American criteria, presence of anti-SSA and/or anti-SSB antibodies and no history of neurological involvement were prospectively investigated, and compared with 10 age- and sex-matched controls. All subjects underwent, within 1 month, brain MRI, neuropsychological testing, including overall evaluation and focal cognitive function assessment, and (99m)Tc-ECD brain SPECT. RESULTS: (99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (10/10) than controls (2/10; p<0.05). Cognitive dysfunctions, mainly expressed as executive and visuospatial disorders, were also significantly more common in patients with pSS (8/10) than controls (0/10; p<0.01). Notably, between-group comparisons enabled a significant correlation to be established between neuropsychological assessment and (99m)Tc-ECD brain SPECT abnormalities in patients with pSS (r(s) = 0.49, p<0.01). MRI abnormalities in patients and controls did not differ significantly. CONCLUSIONS: Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS. The strong correlation between cortical hypoperfusion in (99m)Tc-ECD brain SPECT and cognitive dysfunction suggests an organic aetiology of CNS dysfunction in pSS. These data should be confirmed in a larger study.
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Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Síndrome de Sjogren/psicologia , Adolescente , Adulto , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico por imagem , Cisteína/análogos & derivados , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Síndrome de Sjogren/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
OBJECTIVE: To assess the impact of digital ulcers (DUs) on disability and health-related quality of life (HRQoL) in systemic sclerosis (SSc). METHODS: Two hundred and thirteen patients with SSc were evaluated at four annual meetings of a patient society between 2004 and 2007 (n = 177) or during hospital stay (n = 36). HRQoL was assessed by the SF-36, global disability by the health assessment questionnaire (HAQ), hand disability by the Cochin Hand Function Scale (CHFS) and global hand and wrist mobility by the Kapandji index. RESULTS: Sixty-seven patients (31.4%) had at least one DU at the time of evaluation. Patients with DUs showed significantly more pitting scars (p<0.001) and calcinosis (p<0.0001) than others. Patients with DU had significantly greater HAQ (mean (SD) 1.218 (0.723) vs 0.930 (0.717), p = 0.008), CHFS (mean (SD) 27.38 (20.68) vs 16.73 (18.19), p<0.0001) and aesthetic prejudice (mean (SD) 6.1 (2.2) vs 3.9 (2.5), p<0.0001) scores than others. Hand and wrist mobility were significantly diminished in patients with DU (mean (SD) Kapandji score 75.3 (22.8) vs 81.7 (19.2), p<0.0001). The presence of a DU did not significantly alter the physical component but influenced the mental component (mean (SD) 43.38 (12.53) vs 39.58 (9.54), p = 0.026) of the SF36. CONCLUSION: Patients with SSc with DUs have reduced wrist and hand mobility, increased global and hand disabilities and decreased mental component of HRQoL.
Assuntos
Dedos , Dermatoses da Mão/etiologia , Qualidade de Vida , Escleroderma Sistêmico/complicações , Úlcera Cutânea/etiologia , Adulto , Idoso , Avaliação da Deficiência , Feminino , Dermatoses da Mão/fisiopatologia , Dermatoses da Mão/reabilitação , Articulação da Mão/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Amplitude de Movimento Articular , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/reabilitação , Úlcera Cutânea/fisiopatologia , Úlcera Cutânea/reabilitação , Articulação do Punho/fisiopatologiaRESUMO
OBJECTIVE: To identify target antigens of antifibroblast antibodies (AFA) in systemic sclerosis (SSc) patients. PATIENTS AND METHODS: In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension (PAH) and 12 without) and 36 idiopathic PAH patients, tested in pooled sera for groups of three, were compared with a sera pool from 14 healthy controls (HC). Serum IgG reactivity was analysed by the use of a two-dimensional electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for two groups: 158 SSc, 67 idiopathic PAH and 100 HC; and 35 SSc and 50 HC was tested against alpha-enolase from Saccharomyces cerevisiae and recombinant human (rHu) alpha-enolase, respectively, on ELISA. RESULTS: In the first part, alpha-enolase was identified as a main target antigen of AFA from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) idiopathic PAH patients and 4/100 (4%) HC (p<0.001) had anti-S cerevisiae alpha-enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HC had anti-rHu alpha-enolase antibodies (p = 0.001). In SSc, the presence of anti-S cerevisiae alpha-enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2% vs 89.7%; p<0.001) and diffusion capacity for carbon monoxide (47.4% vs 62.3%; p<0.001), and antitopoisomerase 1 antibodies (46% vs 21%; p = 0.005) but not anticentromere antibodies (11% vs 34%; p = 0.006). Results were similar with rHu alpha-enolase testing. CONCLUSION: In SSc, AFA recognise alpha-enolase and are associated with ILD and antitopoisomerase antibodies.
Assuntos
Autoanticorpos/imunologia , Fibroblastos/imunologia , Hipertensão Pulmonar/imunologia , Fosfopiruvato Hidratase/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Reações Antígeno-Anticorpo/imunologia , Autoantígenos/sangue , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Escleroderma Sistêmico/complicações , Adulto JovemRESUMO
OBJECTIVE: To explore perspectives among patients and rheumatologists on glucocorticoid (GC) therapy and European League Against Rheumatism (EULAR) recommendations on the management of systemic GC therapy in order to enhance implementation of the recommendations. METHODS: Rheumatologists (from eight countries) and patients (from five countries) acquainted with GCs participated in separate meetings, during which positive and negative aspects of GC therapy were discussed and possible adverse events (AEs) were ranked for importance; in addition participants were asked to evaluate the published EULAR recommendations. The reports from these meetings and themes related to implementation of the recommendations were discussed during an international forum of the experts who had formulated the recommendations and patient participants. RESULTS: In all, 140 patients (78% women; mean age 53 years; 61% patients with rheumatoid arthritis) and 110 rheumatologists (mean work experience 15 years) participated in the meetings. Osteoporosis, diabetes and cardiovascular diseases were ranked among the five most worrisome AEs by patients and rheumatologists. In both groups, there was agreement with most of the recommendations; the recommendations on GC information cards and GC use during pregnancy scored lowest. Ideas to improve implementation of the recommendations and a research agenda were generated. CONCLUSION: The patient and rheumatologist views on GCs corresponded to a large extent, reflected by concerns in both groups about osteoporosis, diabetes and cardiovascular diseases. Specific problems with the EULAR recommendations were identified and addressed to improve their implementation. This exercise shows that patient and rheumatologist perspectives should be included early in the process of formulating recommendations.