RESUMO
It has been reported that T helper 17 cells are involved in the pathogenesis of systemic lupus erythematosus, but there is no report on interleukin-17-targeted therapy. We report a case of a 62-year-old female who presented with psoriasis vulgaris and refractory lupus nephritis. Because her conditions were resistant to conventional treatment, and flow cytometry confirmed the proliferation of activated T helper 17 cells in peripheral blood, and examination of a renal biopsy tissue sample confirmed infiltration of numerous interleukin-17-positive lymphocytes to the renal interstitium, administration of the anti-interleukin-17A antibody secukinumab was initiated. After starting secukinumab the clinical and biological features were improved.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Interleucina-17/antagonistas & inibidores , Nefrite Lúpica/complicações , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Interleucina-17/sangue , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, causes drug resistance by exclusion of intracellular drugs. Here, we elucidate the clinical relevance of P-gp expression on lymphocytes to drug resistance in patients with rheumatoid arthritis (RA). METHODS: P-gp expression on lymphocytes from 20 normal volunteers and 100 RA patients was analysed by flow cytometry. Drug exclusion analysis of lymphocytes was conducted by radioisotope-labelled dexamethasone. RESULTS: P-gp was overexpressed on RA lymphocytes compared with normal lymphocytes. P-gp expression levels were higher in partial responders with a Disease Activity Score (DAS) 28-3 of >5.1 despite taking at least two disease-modifying antirheumatic drugs (DMARDs) or one DMARD and corticosteroids for at least 2 years. P-gp expression levels correlated with DAS28-3. Intracellular dexamethasone levels (IDLs) in RA lymphocytes decreased according to P-gp expression. Tacrolimus, a P-gp inhibitor, restored IDLs in RA lymphocytes. P-gp overexpression in patients with highly active RA was suppressed by methotrexate but enhanced by corticosteroids. Furthermore, infliximab (3 mg/kg) resulted in improvement of RA disease activity, reduction of P-gp and recovery of IDLs. CONCLUSIONS: P-gp overexpression on lymphocytes might cause efflux of corticosteroids and DMARDs, P-gp substrates, from lymphocytes, resulting in drug resistance in patients with highly active RA. P-gp inhibition/reduction could overcome such drug resistance. Measurement of P-gp expression on lymphocytes could be a potentially useful marker for assessing drug resistance in RA, and may be suitable for selecting infliximab or DMARDs including tacrolimus for RA treatment.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Antirreumáticos/farmacologia , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Subpopulações de Linfócitos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Biomarcadores/sangue , Células Cultivadas , Resistência a Medicamentos , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Infliximab , Subpopulações de Linfócitos/efeitos dos fármacos , Masculino , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Although corticosteroids and immunosuppressants are widely used for the treatments of various autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with SLE who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapies in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by not only genotoxic stresses but also activation stimuli such as cytokines, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that the measurement of P-gp on lymphocytes is a useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Lúpus Eritematoso Sistêmico/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Biomarcadores/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária , Linfócitos/metabolismo , Proteínas Nucleares , Proteína 1 de Ligação a Y-BoxRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoreactive T cells and polyclonally activated B cells that produce autoantibodies. Five SLE patients who failed to respond to conventional immunosuppressants were treated with anti-CD20 antibody (rituximab) and their clinical manifestations and laboratory data were evaluated, including phenotypic analysis of B cells. METHODS: Rituximab (375 mg/m(2)) was administered weekly for 2 weeks in five SLE patients who developed severe manifestations despite intensive treatment. RESULTS: Rituximab resulted in rapid improvement (within several days) in clinical manifestations such as consciousness disorder, seizures, progressive sensory disorder, haemolytic crisis, cardiac function and laboratory data. The effects lasted 20 months in one patient; other patients were in remission for more than 6 months. Flow cytometric analysis revealed down-regulation of CD40 and CD80 expression on CD19-positive B cells 1 week after infusion of rituximab, and such down-regulation was seen for more than 7 months in two patients. CONCLUSIONS: Our pilot study provides sufficient evidence of excellent tolerability and high efficacy of rituximab therapy in refractory SLE. Rituximab not only reduced B-cell number and IgG levels but down-regulated CD40 and CD80 on B cells, suggesting possible disturbance of T-cell activation through these costimulatory molecules. Reduction of both quantity and quality of B cells suggests that rituximab could improve the disease course in patients with refractory SLE.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-1/imunologia , Antígenos CD40/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Linfócitos B/imunologia , Regulação para Baixo/imunologia , Feminino , Humanos , Imunoglobulina G/análise , Lúpus Eritematoso Sistêmico/imunologia , Depleção Linfocítica/métodos , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Rituximab , Resultado do TratamentoAssuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Antineoplásicos/uso terapêutico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/tratamento farmacológico , Adulto , Anticorpos Monoclonais Murinos , Feminino , Humanos , Imunossupressores/uso terapêutico , RituximabRESUMO
We document the first case of a patient who manifested systemic lupus erythematosus (SLE) complicated with multicentric reticulohistiocytosis (MRH). Neither intravenous steroid nor cyclophosphamide (CY) pulse therapies were fully effective against multiple MRH-related tumors that appeared on the left ankle joint and interphalangeal joints of both hands. In contrast, treatment with cyclosporin A (CyA) resulted in a marked regression of these nodules within one month, together with a complete remission of both MRH and lupus nephritis. We propose CyA as an alternative choice for the treatment of MRH.
Assuntos
Antirreumáticos/uso terapêutico , Ciclosporina/uso terapêutico , Histiocitose/complicações , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Feminino , HumanosRESUMO
Abstract This report describes a case of atrophic bladder and bilateral hydroureteronephrosis that occurred in a patient with systemic sclerosis (SSc). A 49-year-old woman who had a 12-year history of SSc was admitted to our hospital because of bilateral hydroureteronephrosis indicated by uroflowmetric and radiological studies. Histological examination of the patient's bladder after biopsy revealed fibrotic replacement of submucosa and infiltration of mononuclear cells, but no deposition of immunoglobulins and complement components were observed. Nephrostomy to relieve the urinary retention was required. There have been few reports regarding SSc complications in hydronephrosis. The association between hydronephrosis and the pathological disorder of SSc is discussed.