RESUMO
This report evaluates the effects of blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.
Assuntos
Fadiga/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Proteínas Recombinantes de Fusão/administração & dosagem , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of subcutaneous blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial. METHODS: 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI). RESULTS: Although SRI-5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of blisibimod (200â mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1-6 at baseline, significant reductions in proteinuria were observed with blisibimod. Significant (p<0.01) changes in anti-double stranded DNA antibodies, complement C3 and C4, and reductions in B cells were observed with blisibimod.No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for blisibimod compared with placebo. CONCLUSIONS: This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of blisibimod effect in Phase 3. TRIAL REGISTRATION NUMBER: NCT01162681.
Assuntos
Fatores Imunológicos/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Anticorpos Antinucleares/imunologia , Antimaláricos/uso terapêutico , Complemento C3/imunologia , Complemento C4/imunologia , Método Duplo-Cego , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas Recombinantes de Fusão/uso terapêutico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Serum amyloid protein A (SAA), the precursor of secondary amyloid protein, is elevated in chronic diseases which are associated with an increased incidence of amyloid. However, SAA is also elevated in acute bacterial and viral infections and somes forms of cancer. The murine model of casein-induced amyloidosis was studied to determine the relationship between SAA production and amyloid deposition. SAA levels measured by radioimmunoassay were found to be as high as 200 times the normal level in CBA/J mice receiving daily parenteral casein. After a single injection of casein the SAA level was elevated by 3h and peaked by 12-18 h. Similar levels were found in casein-treated A/J mice, a strain less susceptible to the induction of amyloid. Parenterally administered bovine serum albumin, which has low potential for amyloid induction, gave SAA levels in CBA/J and A/J mice comparable to casein treatment. These data show that, while SAA levels are elevated during chronic antigenic stimulation, there are other factors involved in amyloid formation. These factors may include alterations in the degradation of SAA by the reticuloendothelial system caused by substances such as casein. Nude (athymic) mice were shown to attain high levels of SAA after receiving casein parenterally. Therefore, thymus-derived lymphocytes are not necessary for the synthesis of SAA.
Assuntos
Amiloide/sangue , Amiloidose/sangue , Proteínas Sanguíneas/metabolismo , Amiloide/metabolismo , Amiloidose/etiologia , Animais , Caseínas , Cinética , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Soroalbumina Bovina/farmacologiaRESUMO
The interrelationship among lymphocytes, macrophages, and neutrophils appears to be an important aspect of the synovial inflammation that is characteristic of rheumatoid arthritis. In a study comparing gold sodium aurothiomalate (GST) with auranofin (Au), an orally absorbed compound, both appeared to inhibit the disease process and no difference between parenteral and oral administration was observed. Another study involved two groups of nine patients with severe rheumatoid arthritis. One group underwent plasmapheresis. The second group underwent total lymphoid irradiation. Both agents appeared to inhibit the disease process. Plasmapheresis was better tolerated that irradiation.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/terapia , Auranofina , Aurotioglucose/análogos & derivados , Aurotioglucose/uso terapêutico , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Feminino , Tiomalato Sódico de Ouro/uso terapêutico , Humanos , Linfonodos/efeitos da radiação , Masculino , Monócitos/efeitos dos fármacos , Monócitos/imunologia , PlasmafereseRESUMO
We evaluated T-lymphocyte subsets in 18 patients with active untreated uveitis and in 20 controls by monoclonal OKT (Ortho-Kung-T cell) antibodies. Both OKT4- and OKT8-positive cells were detected in the aqueous humor of patients with uveitis. The percentage of OKT4-positive cells (21.1 +/- 7.4) was larger than that of OKT8-positive cells (15.2 +/- 5.3) and the OKT4-OKT8 ratio was 1.40 +/- 0.3. A comparison of aqueous humor and peripheral blood cells from patients with uveitis showed diminished frequencies of OKT4- and OKT8-positive cells. The OKT4-OKT8 ratios were not significantly different. A comparison of peripheral blood cells from patients with uveitis and from controls showed that patients with uveitis had lower OKT4-OKT8 ratios. Lower percentages of OKT4-positive cells were also observed in the peripheral blood cells of patients with uveitis.
Assuntos
Humor Aquoso/citologia , Linfócitos T/classificação , Uveíte/imunologia , Doença Aguda , Anticorpos Monoclonais , Humor Aquoso/imunologia , Humanos , Contagem de Leucócitos , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores , Uveíte/sangueRESUMO
In an ongoing study patients with severe rheumatoid arthritis (RA) who had previously failed conventional therapy including gold salts and penicillamine were randomly assigned on an open basis to a plasma exchange or fractionated total lymphoid irradiation protocol. Nine patients (eight female, one male) with erosive RA of long duration exchanged 40 ml/kg of plasma over a period of two to four weeks. Nine patients (eight female, one male) with similar characteristics, received 2,000 rads to lymphoid tissues in fractionated doses (200 rads each) over 4 to 5 weeks. Treatment was completed in all patients and follow-up ranged from two to twelve months for plasma exchange and eight to sixteen months for radiation. Results of the study showed subjective and objective improvement including morning stiffness, joint score, and pertinent laboratory evaluation in six patients admitted to plasmapheresis with duration of remission lasting as long as seven weeks. Three patients failed to show any improvement in the activity of the disease. Eight patients on the radiation protocol showed a marked decrease in disease activity which has been maintained until the present time. Side effects for the plasma exchange group included mild febrile reactions during the exchange and one non-A non-B Hepatitis. In the radiation group occipital alopecia, loss of appetite and nausea was seen in all patients and severe leucopenia in one (WBC 500/mm3). The present results suggest that both procedures can reduce disease activity in severe RA. Plasma exchange efficacy appears to be short-lived when compared to total lymphoid radiation. The latter was poorly tolerated by all patients submitted to the program.
Assuntos
Artrite Reumatoide/terapia , Artrite Reumatoide/radioterapia , Humanos , Tecido Linfoide/efeitos da radiação , PlasmafereseRESUMO
We studied the levels of membrane-bound and soluble-form interleukin 2 (IL-2) receptors in forty patients with rheumatoid arthritis. Levels of IL-2 receptors in the sera and synovial fluid of patients with rheumatoid arthritis were elevated when compared to values observed in normal sera and synovial fluid derived from the osteoarthritic joint. Simultaneous elevation of IL-2 receptor expression in blood and synovial fluid lymphoid cells was also detected, but no correlation was found between the two parameters nor between serum IL-2 receptor levels and the hemosedimentation rate. We conclude that measurement of serum concentrations of soluble IL-2 receptors should be used with caution as an index of disease activity, but may be useful when used in conjunction with other parameters in the management of patients with rheumatoid arthritis.
Assuntos
Artrite Reumatoide/metabolismo , Receptores de Interleucina-2/metabolismo , Líquido Sinovial/metabolismo , Artrite Reumatoide/sangue , Humanos , Membranas/metabolismo , Valores de Referência , SolubilidadeRESUMO
OBJECTIVE: Adult onset Still's disease (AOSD) is an inflammatory disorder with elevated serum acute phase proteins. Interleukin-6 is a major contributor to the acute phase response. We therefore examined the serum levels of CRP, SAA and interleukin-6 in active and inactive AOSD. RESULTS: Active patients had significantly elevated CRP, SAA, and interleukin-6 values. After steroid treatment a marked reduction was observed in all three parameters. There was a close kinetics on the fluctuations of CRP and SAA, but not on IL-6. CONCLUSION: Acute phase proteins and IL-6 are useful markers of disease activity in AOSD.
Assuntos
Biomarcadores/sangue , Interleucina-6/sangue , Doença de Still de Início Tardio/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas/metabolismo , Proteína C-Reativa/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/metabolismoRESUMO
Lymphocyte subsets in the peripheral blood of 10 patients with RA were studied using monoclonal antibodies. The mean percentages of total T, T helper, T suppressor and TAR in the peripheral blood of RA patients were not different from those observed in normal controls. In the synovial fluid the mean percentages of T suppressor cells were present in increased numbers associated with a decreased number of autorosette T cells. We conclude that patients with rheumatoid arthritis present distinct immunoregulatory abnormalities in the synovial fluid not present in the peripheral blood. These changes may be related to the immune abnormalities present and related to the etiology of RA.
Assuntos
Artrite Reumatoide/patologia , Líquido Sinovial/citologia , Linfócitos T Auxiliares-Indutores/classificação , Linfócitos T Reguladores/classificação , Anticorpos Monoclonais , Artrite Reumatoide/sangue , Humanos , Formação de Roseta , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/patologiaRESUMO
Previous work from our laboratory has demonstrated a marked inhibitory activity of Auranofin (Au) and Gold Sodium Aurothiomalate (GST) on monocyte-macrophage function and an important role for macrophages in the pathogenesis of casein-induced experimental amyloidosis. In the present study we have looked at the in vivo effect of Au and GST on the inhibition of casein-induced macrophage activation and serum SAA levels. Au and GST markedly inhibited casein-induced macrophage activation while only Au reduced serum SAA levels to a significant degree. The present data raises the possibility that Au may be helpful in the treatment of secondary amyloid disease.
Assuntos
Caseínas/farmacologia , Ouro/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Proteína Amiloide A Sérica/sangue , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Complemento C3/metabolismo , Camundongos , Receptores Fc/metabolismoRESUMO
OBJECTIVES: To investigate the serum levels of VEGF in patients with rheumatoid arthritis of long duration. METHODS: Serum VEGF levels were measured in 118 patients with long-standing rheumatoid arthritis according to the ACR criteria (mean duration 12 years). The disease activity score was evaluated by the method of van der Heijde et al. RESULTS: Serum levels of VEGF in patients with RA were significantly higher than in healthy controls. VEGF levels showed no correlation with CRP, SAA amyloid protein, or the disease activity score. CONCLUSIONS: Our findings suggest that, contrary to the results reported in patients with early onset RA, where VEGF appears to play an active part in joint inflammation, in long-standing RA elevated VEGF serum levels may be an independent marker although its significance remain to be established.
Assuntos
Artrite Reumatoide/sangue , Fatores de Crescimento Endotelial/sangue , Linfocinas/sangue , Adulto , Amiloide/sangue , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Previous work at our laboratory has shown that Piroxicam is a potent inhibitor of neutrophil cell migration "in vitro". We have now extended these observations by comparing the effect of Piroxicam "in vivo" on neutrophil and monocyte chemotactic activity as well as comparing the findings with those obtained with Auranofin, a novel oral gold salt preparation. The data presented support the notion that Piroxicam appears to be an inhibitor of neutrophil cell function while Auranofin predominantly affects monocyte cell migration.
Assuntos
Anti-Inflamatórios/farmacologia , Aurotioglucose/análogos & derivados , Quimiotaxia de Leucócito/efeitos dos fármacos , Ouro/análogos & derivados , Tiazinas/farmacologia , Adulto , Idoso , Artrite Reumatoide/sangue , Auranofina , Aurotioglucose/farmacologia , Inibição de Migração Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , PiroxicamRESUMO
Our objective was to assess the prevalence of autoantibodies in patients with leprosy. Forty-one cases of lepromatous leprosy were studied. For the detection of autoantibodies we used the Elisa technique using the following purified antigens in an Elisa assay: dsDNA, ssDNA, histone, mitochondria, RNA, RNP, SS-A, SS-B, Sm, Scl-70, Anca C, Anca P and the cardiolipin complex. As a "cut off" point we used values shown on previous studies to differentiate normal from elevated values. Antibodies to SS-B, mitochondria and cardiolipin were the most prevalent in our study. Antimitochondrial antibodies distinct from those seen in primary biliary cirrhosis and antiphospholipid antibodies with variable ligand activity to B2GIP are frequent in the sera of leprosy patients.
Assuntos
Autoanticorpos/sangue , Hanseníase/imunologia , Autoanticorpos/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , PrevalênciaRESUMO
A patient with amyloidosis secondary to polyarticular gout is presented in whom amyloid protein A (AA) was demonstrated in the kidney with a monoclonal antibody against protein A. The rarity of this association is discussed and a pathogenetic mechanism proposed.
Assuntos
Amiloidose/diagnóstico , Gota/complicações , Proteína Amiloide A Sérica/análise , Amiloidose/complicações , Anticorpos Anti-Idiotípicos , Anticorpos Monoclonais , Humanos , Técnicas Imunoenzimáticas , Rim/análise , Masculino , Pessoa de Meia-IdadeRESUMO
1. We have shown that nonsteroidal anti-inflammatory drugs are potent inhibitors of neutrophil activation. Tenoxicam is a new compound of the oxicam family which has been shown to be effective for routine clinical use. 2. In the present study we examined the immune pharmacological effects of this compound on lymphocyte function by determining its effect on the expression of IL-2 receptors, on monocyte function by looking at chemotaxis and IL-1 release and on neutrophil function by evaluating the chemotactic response to a standard stimulus. 3. The data show that Tenoxicam inhibits the neutrophil and monocyte functional chemotactic response in vitro, and to some extent in vivo for monocytes, but has no effect on the expression of IL-2 receptors or IL-1 release. Tenoxicam inhibits the mobilization of neutrophils and monocytes to inflammatory sites, even though this effect was not clearly demonstrable when cells were tested after oral use.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Linfócitos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Piroxicam/análogos & derivados , Receptores de Interleucina-2/metabolismo , Quimiotaxia/efeitos dos fármacos , Humanos , Técnicas In Vitro , Linfócitos/metabolismo , Monócitos/metabolismo , Neutrófilos/metabolismo , Piroxicam/farmacologiaRESUMO
Recent data suggest that the clinical course of reactional states in leprosy is closely related to the cytokine profile released locally or systemically by the patients. In the present study, patients with erythema nodosum leprosum (ENL) were grouped according to the intensity of their clinical symptoms. Clinical and immunological aspects of ENL and the impact of these parameters on bacterial load were assessed in conjunction with patients' in vitro immune response to mycobacterial antigens. In 10 out of the 17 patients tested, BI (bacterial index) was reduced by at least 1 log from leprosy diagnosis to the onset of their first reactional episode (ENL), as compared to an expected 0.3 log reduction in the unreactional group for the same MDT (multidrug therapy) period. However, no difference in the rate of BI reduction was noted at the end of MDT among ENL and unreactional lepromatous patients. Accordingly, although TNF-alpha (tumor necrosis factor) levels were enhanced in the sera of 70.6% of the ENL patients tested, no relationship was noted between circulating TNF-alpha levels and the decrease in BI detected at the onset of the reactional episode. Evaluation of bacterial viability of M. leprae isolated from the reactional lesions showed no growth in the mouse footpads. Only 20% of the patients demonstrated specific immune response to M. leprae during ENL. Moreover, high levels of soluble IL-2R (interleukin-2 receptor) were present in 78% of the patients. Circulating anti-neural (anti-ceramide and anti-galactocerebroside antibodies) and anti-mycobacterial antibodies were detected in ENL patients' sera as well, which were not related to the clinical course of disease. Our data suggest that bacterial killing is enhanced during reactions. Emergence of specific immune response to M. leprae and the effective role of TNF-alpha in mediating fragmentation of bacteria still need to be clarified.
Assuntos
Eritema Nodoso/imunologia , Hanseníase Virchowiana/imunologia , Mycobacterium leprae/crescimento & desenvolvimento , Receptores de Interleucina-2/sangue , Adolescente , Adulto , Idoso , Animais , Contagem de Colônia Microbiana , Eritema Nodoso/sangue , Eritema Nodoso/microbiologia , Feminino , Humanos , Interferon gama/sangue , Hanseníase Virchowiana/sangue , Hanseníase Virchowiana/microbiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/análiseRESUMO
Serum samples were analysed for interleukin-2 receptors levels (sIL-2R) in 26 patients with definite multiple sclerosis as defined by Poser and col. Three groups of patients form the basis of this study: group I, with 14 patients with clinical evidence of active disease; group II, with 12 patients with clinically stable multiple sclerosis; and group III, with 8 patients with other neurological diseases. Blood was collected by venipuncture and centrifuged. All samples were stored at -20 degrees C until testing. The assay used monoclonal antibodies against epitopes of interleukin-2 receptors. In the wells of a microtiter plate coated with anti-soluble interleukin-2 receptors (Immunotech SA) samples to be measured or standards are incubated in the presence of a second monoclonal antibody conjugated with alkaline phosphatase. The amount of bound enzyme-conjugate is measured by adding a chromogenic substrate. The intensity of the resulting colour is proportional to the sIL-2R concentration present in the sample. Increased serum levels of sIL-2R were found in 7 of 14 patients with active multiple sclerosis (50%), in only 1 of the 12 patients with clinically stable multiple sclerosis and in none of the patients with other neurological diseases.
Assuntos
Esclerose Múltipla/sangue , Receptores de Interleucina-2/análise , Adolescente , Adulto , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/fisiologia , Linfócitos T/metabolismoRESUMO
The articular manifestations of the intestinal diseases can be quite variable affecting primarily either the pripheral joints, or sacroiliac areas and the spine. The presence of the haplotype HLA-B27 is associated in the majority of cases with the presence of spinal involvement. The treatment of the arthritis does not usually follow the natural history of the inflammatory bowel disease.