RESUMEN
OBJECTIVE: Treat-to-target in rheumatoid arthritis (RA) recommends targeting remission, with low disease activity (LDA) being an alternative goal. When deciding to target remission or LDA, important considerations are the likelihood of attaining them, and their impacts on function and health-related quality of life (HRQoL). We have addressed this by studying: (a) the frequency of remission and LDA/remission; (b) DAS28-ESR trends after remission; (c) ability of remission vs. LDA to identify patients with normal function (HAQâ¯≤â¯0.5) and HRQoL (EQ-5Dâ¯≥â¯the normal population). METHODS: We studied 571 patients in two clinical trials, and 1693 patients in a 10-year routine care cohort. We assessed the frequency and sustainability of remission and LDA/remission, variability in DAS28-ESR after remission, and sensitivity/specificity of remission and LDA/remission at identifying patients with low disability levels and normal HRQoL using Receiver Operator Characteristic (ROC) curves. RESULTS: Point remission and remission/LDA were common (achieved by 35-58% and 49-74% of patients, respectively), but were rarely sustained (sustained remission and remission/LDA achieved by 5-9% and 9-16% of patients, respectively). Following attaining remission, DAS28-ESR levels varied substantially. Despite this, of those patients attaining point remission, the majority (53-61%) were in remission at study end-points. Whilst remission was highly specific at identifying patients with low disability (85-91%) it lacked sensitivity (51-57%); similar findings were seen for normal HRQoL (specificity 78-86%; sensitivity 52-59%). The optimal DAS28-cut-off to identify individuals with low disability and normal HRQoL was around the LDA threshold. CONCLUSIONS: Our findings support both the treat-to-target goals. Attaining remission is highly specific for attaining low disability and normal HRQoL, although many patients with more active disease also have good function and HRQoL. Attaining a DAS28-ESRâ¯≤â¯3.2 has a better balance of specificity and sensitivity for attaining these outcomes, with the benefit of being more readily achievable. Although sustaining these targets over time is rare, even attaining them on a one-off basis leads to better function and HRQoL outcomes for patients.
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Artritis Reumatoide/diagnóstico , Evaluación de la Discapacidad , Calidad de Vida , Adulto , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Summary Recombinant human binding immunoglobulin protein (BiP) has previously demonstrated anti-inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti-mBiP) or green fluorescent protein (Lenti-GFP) transgene was administered in low- or high-dose studies during early arthritis. Disease activity was assessed by visual scoring, histology, serum cytokine and antibody production measured by cell enzyme-linked immunosorbent assay (ELISA) and ELISA, respectively. Lentiviral vector treatment caused significant induction of interferon (IFN)-γ responses regardless of the transgene; however, further specific effects were directly attributable to the BiP transgene. In both studies Lenti-mBiP suppressed clinical arthritis significantly. Histological examination showed that low-dose Lenti-mBiP suppressed inflammatory cell infiltration, cartilage destruction and significantly reduced pathogenic anti-type II collagen (CII) antibodies. Lenti-mBiP treatment caused significant up-regulation of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4) serum levels and down-regulation of interleukin (IL)-17A production in response to CII cell restimulation. In-vitro studies confirmed that Lenti-mBiP spleen cells could significantly suppress the release of IL-17A from CII primed responder cells following CII restimulation in vitro, and this suppression was associated with increased IL-10 production. Neutralization of CTLA-4 in further co-culture experiments demonstrated inverse regulation of IL-17A production. In conclusion, these data demonstrate proof of principle for the therapeutic potential of systemic lentiviral vector delivery of the BiP transgene leading to immunoregulation of arthritis by induction of soluble CTLA-4 and suppression of IL-17A production.
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Artritis Experimental/prevención & control , Terapia Genética , Vectores Genéticos , Proteínas de Choque Térmico/inmunología , Lentivirus , Transducción Genética , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Progresión de la Enfermedad , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/genética , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Transgenes/inmunologíaRESUMEN
The resolution of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs). RAMPs are released at times of cellular stress and help to counterbalance the inflammatory effects of pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns. We propose that heat shock protein 10 (HSP10), αB-crystallin (αBC), HSP27 and binding immunoglobulin protein (BiP) should be considered founding members of the RAMP family. A greater understanding of RAMP biology may herald the development of novel immunotherapies.
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Proteínas de Choque Térmico/clasificación , Proteínas de Choque Térmico/fisiología , Homeostasis/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Animales , Humanos , Mediadores de Inflamación/metabolismoRESUMEN
OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor alpha (TNFalpha)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFalpha blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. METHODS: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. RESULTS: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA p = 0.50) and CAP (chi(2) = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. CONCLUSIONS: Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFalpha-blocking therapy.
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Anticuerpos Monoclonales/farmacología , Antirreumáticos/farmacología , Artritis Reumatoide/fisiopatología , Resistencia Vascular/efectos de los fármacos , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Enfermedades de las Arterias Carótidas/etiología , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/patología , Métodos Epidemiológicos , Femenino , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Flujo Pulsátil/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The endoplasmic reticulum chaperone BiP, in addition to its many important intracellular functions, has anti-inflammatory and immunomodulatory properties when present in the extracellular environment by the stimulation of an anti-inflammatory gene programme from human monocytes and by the development of T-cells that secrete regulatory cytokines such as interleukin-10 and interleukin-4. It can both prevent as well as treat ongoing collagen-induced arthritis. It is, therefore, a potential new biologic therapy for rheumatoid arthritis.
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Proteínas de Choque Térmico/fisiología , Factores Inmunológicos/fisiología , Inflamación/metabolismo , Chaperonas Moleculares/fisiología , Animales , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/prevención & control , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Humanos , Factores Inmunológicos/metabolismo , Factores Inmunológicos/farmacología , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Chaperonas Moleculares/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Asma/inducido químicamente , Adalimumab , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To assess the efficacy and safety of the fully human recombinant monoclonal anti-TNF antibody adalimumab in routine clinical practice, including comparison of patients with and without previous anti-TNF exposure. METHODS: We prospectively studied the outcome of 70 rheumatoid arthritis patients treated with adalimumab in normal clinical practice. The primary outcome measures were Disease Activity Score 28 (DAS28), EULAR (European League Against Rheumatism) response and Health Assessment Questionaire (HAQ). RESULTS: Seventy-seven per cent achieved a EULAR response (26% good, 51% moderate) and 19% were in remission. The mean decrease in DAS28 was 2.1 (6.3-4.2; P<0.001). The mean decrease in HAQ score was 0.34 (2.07-1.73; P<0.001), 66% achieving a clinically significant decrease of greater than 0.22. Twenty-three per cent stopped treatment because of side-effects (7%) or failure to respond (16%). Of the 26 patients who had previously tried 29 biologicals, 65% responded to adalimumab. There was no significant difference in the change in mean DAS (P = 0.69) or HAQ (P = 0.88) between groups with and without previous anti-TNF exposure. Of the 13 patients with previous secondary failure to infliximab, 77% responded to adalimumab. Patients with previous secondary failure had significantly better improvement in DAS (P = 0.023) than patients with previous primary failure. CONCLUSION: Our clinical experience confirms that adalimumab is effective and safe in the treatment of RA. It also shows adalimumab is effective in patients with previous biological failures, particularly patients with secondary failure to infliximab.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
The clinical potential of rituximab (MabThera/Rituxan), a selective B-cell-depleting agent, in the treatment of patients with rheumatoid arthritis (RA) is rapidly becoming apparent. The data presented at an official satellite symposium of the European League Against Rheumatism (EULAR) Congress (2003, Lisbon, Portugal), reinforce the rationale for the use of this novel agent in RA and have provided an early indication of its clinical efficacy, safety and tolerability. The symposium presentations were followed by a panel discussion and a question and answer session in which the participants were able to shed further light on specific mechanistic issues relating to effects on B-cell populations based on available data and their own clinical experience of rituximab. Additionally, the implications of current results for longer-term clinical efficacy and safety were discussed. It is becoming clear that rituximab (alone or in combination with disease-modifying anti-rheumatic drugs) is highly efficacious in RA. Extensive data from patients with non-Hodgkin's lymphoma show that early concerns over increased infection rates due to prolonged suppression of B cells have not been realized. The effects of rituximab on long-term RA outcomes, such as joint erosion and duration of response (particularly in patients receiving combination therapy), are eagerly anticipated.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Antígenos CD20/inmunología , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Humanos , Rituximab , Resultado del TratamientoRESUMEN
The role of T cells in the pathogenesis of RA is well established, whereas to date the precise contribution of B cells is less well defined. B cells have many potential key roles: they can act as antigen-presenting cells, secrete pro-inflammatory cytokines (including tumour necrosis factor-alpha), produce rheumatoid factor (RF) and other autoantibodies and activate T cells. B cells act as antigen-presenting cells by processing and presenting antigenic peptides to T cells, which become activated, proliferate and exert pro-inflammatory activities. RF may also play a role in perpetuating B-cell activation and antigen presentation to T cells, thus leading to sustained production of RF. This, combined with RF immune-complex-mediated complement activation, may contribute to the sustained inflammatory response. Studies have shown that the use of an anti-CD20 monoclonal antibody in RA depletes circulating B cells, resulting in improvement in disease activity for up to 1 yr. It is thus evident that B cells play a central role in the pathophysiology of RA and therefore merit further investigation as a therapeutic target.
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Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Humanos , Activación de Linfocitos/inmunología , Cooperación Linfocítica/inmunología , Factor Reumatoide/inmunología , Linfocitos T/inmunologíaAsunto(s)
Anticuerpos/análisis , Artritis Juvenil/inmunología , Proteínas de Choque Térmico/inmunología , Chaperonas Moleculares/inmunología , Adolescente , Adulto , Biomarcadores/análisis , Niño , Preescolar , Chaperón BiP del Retículo Endoplásmico , Humanos , Lactante , Factor Reumatoide/inmunologíaRESUMEN
OBJECTIVES: The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA. METHODS: An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls. RESULTS: We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartile range 1.1-4.7) before symptoms of joint disease, the sensitivity for anti-BiP antibodies was 45% and the specificity was 65% for the development of RA. CONCLUSION: Antibodies to BiP are found in the sera of patients with RA and in sera antedating the onset of RA.
Asunto(s)
Formación de Anticuerpos/inmunología , Artritis Reumatoide/inmunología , Proteínas de Choque Térmico/inmunología , Chaperonas Moleculares/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/análisis , Especificidad de Anticuerpos/inmunología , Chaperón BiP del Retículo Endoplásmico , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Artropatías/inmunología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: We have reported that synovial fluid T cells from patients with rheumatoid arthritis (RA) proliferate in response to the endoplasmic reticulum molecular chaperone immunoglobulin binding protein (BiP). The aim of the present work was to clone and define T cells responding to this protein. METHODS: T-cell clones were generated from the peripheral blood of an individual known to respond to BiP by limiting dilution of BiP-stimulated peripheral blood mononuclear cells. T-cell receptor usage of BiP-responsive clones was determined by monoclonal antibody staining followed by flow cytometric analysis. Cytokine production by the BiP-responsive clones was determined by analysis of post-stimulation supernatants by ELISA. Additional phenotyping was performed by flow cytometry. RESULTS: Of 49 clones isolated, six were shown to proliferate in response to BiP. Proliferation was low but consistent. One clone expressed CD4 and five were CD8-positive. Three clones, all CD8(+), grew strongly and were investigated further. T-cell receptor usage was determined in two clones (Vbeta 7.1 and Vbeta 12); the Vbeta element of the remaining clone was not recognized by the panel of antibodies used. All three clones produced interleukin 10 (IL-10) (80-380 pg/ml) and two of them produced IL-4 (10-80 pg/ml) and IL-5 (>5000 pg/ml). One clone produced both IL-10 and interferon gamma (>5000 pg/ml). Additional phenotyping of these clones showed them to express CD25, CD28, CD80 and 86 but not CD56 or 57. One clone constitutively expressed CTLA-4 cytoplasmically. CONCLUSIONS: This study demonstrates that a population of CD8(+) T cells with the cytokine profile of Tc2 cells can be stimulated by the chaperone BiP. These cells may perform a regulatory role in the normal response to inflammation. The increase in response to this antigen in the synovial joint in RA may indicate an attempt to regulate the ongoing inflammation.
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Artritis Reumatoide/inmunología , Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteínas Portadoras/inmunología , Proteínas de Choque Térmico , Interleucina-10/biosíntesis , Chaperonas Moleculares/inmunología , Técnicas de Cultivo de Célula/métodos , División Celular/inmunología , Separación Celular/métodos , Células Clonales/inmunología , Chaperón BiP del Retículo Endoplásmico , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Líquido Sinovial/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. RESULTS: Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. CONCLUSION: This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.
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Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Interleucina-6/inmunología , Reacción de Fase Aguda , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Artritis Reumatoide/fisiopatología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Placebos , Resultado del TratamientoRESUMEN
OBJECTIVE: Results of an earlier open-label pilot study showed that 4162W94 was a relatively non-depleting anti-CD4 monoclonal antibody that induced >80% down-modulation of CD4 molecules from the surface of T lymphocytes. This placebo-controlled repeat-cycle study was conducted in active rheumatoid arthritis (RA) patients to determine the duration of CD4 blockade required to achieve lasting clinical benefit. METHODS: Following DMARD washout, 48 patients (i.e. three cohorts of 16 patients) with ACR-defined RA were to be dosed with 1 (cohort 1), 2 (cohort 2) or 3 (cohort 3) cycles of 5x300 mg 4162W94 or placebo (12 and 4 patients per cohort respectively) at monthly intervals. There was at least 3 months of follow-up after dosing. Clinical outcome was assessed in evaluable patients (receiving at least 80% of each dose course) using ACR20 criteria (required on two consecutive visits). CD4 lymphocyte counts and adverse events were also monitored. RESULTS: Sixteen patients were dosed in each of the first two cohorts; however, the dose was reduced in cohort 3 after five patients had received up to two dose cycles due to accumulating evidence of a high frequency of skin rash. These patients were analysed according to the number of cycles received. A further eight patients received 5x100 mg for one to three cycles prior to stopping the study for administrative reasons. Four of 13 (P=0.119 vs placebo) and 7/13 (P=0.015 vs placebo) in cohorts 1 and 2 respectively achieved ACR20 response on at least two consecutive occasions. No patient receiving 5x100 mg/day or placebo achieved ACR20. Four patients were still responding at the end of the 3-month follow-up period. CD4 lymphocyte suppression (<0.2x10(9)/l on at least two successive occasions) occurred in 11/34 patients who received 4162W94 vs none on placebo. Rash occurred in 21/34 monoclonal antibody-treated patients, including one case of biopsy-confirmed cutaneous vasculitis and 1/11 placebo patients. CONCLUSION: 4162W94 demonstrated significant clinical efficacy in this study. However, because of unacceptable CD4 lymphopenia and rash, the original hypothesis that prolonged CD4 blockade would give lasting clinical benefit was not tested.
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Anticuerpos Monoclonales/administración & dosificación , Artritis Reumatoide/terapia , Antígenos CD4/inmunología , Inmunoglobulinas/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Artritis Reumatoide/inmunología , Recuento de Linfocito CD4 , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulinas/efectos adversos , Inmunofenotipificación , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Placebos , Resultado del TratamientoRESUMEN
BACKGROUND: Current disease management in rheumatoid arthritis (RA) has moved towards "inverting the therapeutic pyramid" by introducing disease-modifying anti-rheumatic drugs (DMARDs) early. Despite the logic of early DMARD therapy, there is a dearth of supportive evidence for this approach. We report a randomised controlled trial comparing sulphasalazine monotherapy with diclofenac monotherapy in early RA. The primary aim was to provide unequivocal evidence that early DMARDs prevent erosive damage. The secondary aim was to evaluate if sulphasalazine used alone has comparable symptomatic benefits to NSAIDs. METHODS: 117 patients with RA for under 12 months of diagnosis (mean 2 months) were randomised (62 sulphasalazine; 55 diclofenac). Sulphasalazine patients comprised 76% women, and 58% were rheumatoidfactor positive. Diclofenac patients comprised 74% women, and 54% were seropositive. 36% completed 12 months of therapy (16 sulphasalazine; 26 diclofenac); sulphasalazine was given for a mean period of 21 weeks and diclofenac for a mean period of 33 weeks. Results were analysed on an intention to treat basis. RESULTS: After 12 months the mean number of new erosions in patients randomised to receive sulphasalazine was 2.0 (95%CI 0.9, 3.1) and in patients randomised to receive diclofenac was 7.5 (95%CI 4.1, 10.9; p = 0.002 by Student's unpaired t-test). An analysis of valid compliant completers showed the mean number of new erosions in patients who received 12 months therapy with sulphasalazine was 2.3 (95%CI 0.6, 4.0) and in patients who received 12 months diclofenac was 10.5 (95%CI 5.0, 15.9; p = 0.018 by Student's unpaired t-test). The Ritchie articular index, swollen joint counts and pain scores decreased with both sulphasalazine and diclofenac, with mean falls in both groups of 15-20% at 2 weeks and 30-40% at 4 and 8 weeks. There were no differences between treatments. Disease activity scores showed similar highly significant mean decreases within both treatment groups (P < 0.001 in all cases) of 0.5 at 2 weeks and 1.0 at 4 weeks; at 12 and 26 weeks they were significantly lower with sulphasalazine (p = 0.036 and 0.045). 75% of the patients given sulphasalazine and 65% of those given diclofenac had one or more adverse events with no major differences between treatments. CONCLUSIONS: These results show that an accelerated dosing schedule of sulphasalazine has identical effects to diclofenac in reducing symptoms, indicating it is a rapidly effective DMARD. They also provide unequivocal evidence, analysed on an intention to treat basis, that early treatment with sulphasalazine significantly reduces the extent of radiological progression in active RA.
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Antiinflamatorios no Esteroideos/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Diclofenaco/administración & dosificación , Sulfasalazina/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/diagnóstico por imagen , Sedimentación Sanguínea/efectos de los fármacos , Diclofenaco/efectos adversos , Método Doble Ciego , Femenino , Humanos , Articulaciones/patología , Masculino , Persona de Mediana Edad , Radiografía , Índice de Severidad de la Enfermedad , Sulfasalazina/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: Adhesion mechanisms play a central role in the recruitment of leukocytes which characteristically infiltrate rheumatoid synovium. Therefore, we adapted an animal model, in which human rheumatoid synovium was transplanted into severe combined immunodeficient (SCID) mice, to study the effects of Tumor Necrosis Factor-alpha (TNF-alpha) in modulatine leukocyte migration and to investigate the chemotactic potential of Stromal Derived Factor-1 alpha (SDF-1 alpha). MATERIALS AND METHODS: Human synovium samples, obtained from patients undergoing joint replacement, were divided into two parts. One was analysed by immunohistology and the other was implanted subcutaneously into SCID mice under general anaesthesia. Four weeks post-transplantation, grafts were injected with optimal dose of SDF-1, TNF-alpha or saline (negative control). At the same time, animals were injected iv with fluorescently labelled cells. 48 hours later mice were sacrificed and grafts removed for cryo-hystology. The number of cells migrating to the grafts was determined by UV-microscopy and the results expressed as cells per high power field. RESULTS AND CONCLUSIONS: In these studies we provide the evidence that: 1) the animal model, in which human tissues are grafted into SCID mice, can be used to study cell migration under controlled experimental conditions; 2) direct intragraft injection of TNF-alpha increases lymphocytes migration and up-regulates the expression of human adhesion molecules (CAMs) and 3) SDF-1 alphainjected intragraft increases the migration of the pro-myelo-monocytic U937 cells to synovial transplants, even more efficiently than TNF-alpha, but without modifications of CAMs' expression.
Asunto(s)
Artritis Reumatoide/etiología , Movimiento Celular , Quimiocinas CXC/farmacología , Factores Quimiotácticos/farmacología , Membrana Sinovial/patología , Factor de Necrosis Tumoral alfa/farmacología , Animales , Artritis Reumatoide/patología , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Síndrome de Chediak-Higashi/genética , Quimiocina CXCL12 , Regulación de la Expresión Génica/efectos de los fármacos , Vida Libre de Gérmenes , Humanos , Péptidos y Proteínas de Señalización Intracelular , Linfocitos/patología , Macrófagos/patología , Ratones , Ratones Mutantes , Ratones SCID , Proteínas/genética , Proteínas/fisiología , Membrana Sinovial/metabolismo , Membrana Sinovial/trasplante , Trasplante Heterólogo , Células U937/citología , Células U937/efectos de los fármacos , Proteínas de Transporte VesicularRESUMEN
OBJECTIVE: In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HuRAg). METHODS: The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF-alpha monoclonal antibody (mAb, 100 microg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 microg of recombinant TNF-alpha or IL-6 (0.6 microg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control. RESULTS: Synovial inflammatory cells were significantly decreased after the anti-TNF-alpha mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-alpha administration. The levels of both IL-6 and TNF-alpha in sera were significantly increased by recombinant TNF-alpha administration, while TNF-alpha levels were unchanged by IL-6 administration. This suggests that TNF-alpha controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-alpha. CONCLUSION: This study provides strong evidence that TNF-alpha is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-alpha regulates IL-6 production. However, other inflammatory pathways independent of TNF-alpha may contribute to the bone and cartilage damage seen in RA.
Asunto(s)
Artritis Reumatoide/metabolismo , Membrana Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Artritis Reumatoide/patología , Células Cultivadas , Quimera , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Interleucina-6/farmacología , Masculino , Ratones , Ratones SCID , Proteínas Recombinantes/uso terapéutico , Organismos Libres de Patógenos Específicos , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/trasplante , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
OBJECTIVE: The mechanisms by which monocyte/macrophage cells migrate to the joint involve a series of integrated adhesion and signaling events in which chemokines and their receptors are strongly implicated. This study was undertaken to investigate the hypothesis that stromal cell-derived factor 1 (SDF-1), a CXC chemokine (CXCL12), plays a critical role in monocyte/macrophage localization to synovium. METHODS: SDF-1 and CXC receptor 4 (CXCR4) expression in rheumatoid arthritis (RA) and osteoarthritis synovium and graft SDF-1, tumor necrosis factor alpha (TNF alpha), and human and murine vascular markers were examined by immunohistochemistry and double-immunofluorescence. The functional capacity of SDF-1 to modulate monocyte migration into joints was investigated by examining the localization of pro-myelomonocytic U937 cells into synovial tissue transplanted into SCID mice. SDF-1, TNF alpha, or saline was injected into graft sites and response determined by the number of fluorescently labeled U937 cells (injected intravenously) detected in grafts by ultraviolet microscopy. RESULTS: SDF-1 and CXCR4 were highly expressed in CD68+ cells in the RA synovium. SDF-1 induced U937 cell migration in vitro and in vivo in a dose-dependent manner and, in vivo, SDF-1 was more effective than TNF alpha. In contrast to TNF alpha, SDF-1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF-1 did not up-regulate TNF alpha, or vice versa. CONCLUSION: This study demonstrates, for the first time, that SDF-1 is functional in vivo when injected into synovial grafts. In addition, SDF-1 is more potent than TNF alpha, and its mechanisms of action appear to be autonomous. Therefore, SDF-1 may be an important TNF-independent molecule involved in the migration to and retention of inflammatory effector cells in the joint.