RESUMO
OBJECTIVE: Several rheumatoid arthritis (RA) susceptibility variants map close to genes involved in the tumor necrosis factor (TNF) signaling pathway, prompting the investigation of RA susceptibility variants in studies of predictors of response to TNF blockade. Based on a previously reported association of RA with the PTPRC genetic locus, the present study was undertaken to test established RA susceptibility variants, including PTPRC, in the prediction of response to TNF blockade in a large cohort of patients from the UK. METHODS: DNA was extracted from the blood of 1,115 UK patients with RA who were receiving anti-TNF biologic therapy. Samples were analyzed for 29 single-nucleotide polymorphisms (SNPs) previously established as RA susceptibility variants. In the primary analysis, the effect of each SNP on treatment response was assessed by linear regression, using an additive model, in which absolute change in the Disease Activity Score in 28 joints at 6 months of followup was the outcome measure. In a secondary analysis, logistic regression models were used to compare patients with a good treatment response (n = 274) to those with a poor response (n = 195), as defined using the European League Against Rheumatism response criteria. Results were combined with those from previous studies to confirm the findings by meta-analysis. RESULTS: The PTPRC rs10919563 SNP was associated with improved treatment response in both the primary analysis (regression coefficient 0.19, 95% confidence interval [95% CI] 0.09, 0.37; P = 0.04) and secondary analysis (odds ratio 0.62, 95% CI 0.40, 0.95; P = 0.03). A meta-analysis combining these data with the results from a previous study strengthened the evidence for association with the PTPRC SNP (P = 5.13 × 10(-5) ). No convincing association of the treatment response with other candidate loci was detected. CONCLUSION: Presence of the rs10919563 RA susceptibility variant at the PTPRC gene locus predicts improved response to anti-TNF biologic therapy. Fine-mapping studies are required to determine whether this SNP or another variant at the locus provides the greatest predictive accuracy for treatment response.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Estudo de Associação Genômica Ampla , Antígenos Comuns de Leucócito/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Nível de Saúde , Humanos , Articulações/patologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transdução de Sinais , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo , Reino Unido/epidemiologiaRESUMO
A middle-aged man presented to emergency services with central vision loss in the setting of flu-like illness with fever. A striking subfoveal abscess was observed in the right fundus. Focal acute chorioretinal inflammation was noted in the asymptomatic fellow eye. Staphylococcus aureus septicaemia was subsequently diagnosed. He presented with undiagnosed HIV infection and latent syphilis. Serial high-definition multimodal retinal imaging showcased resolution of the dome-shaped subretinal abscess following treatment with intravenous flucloxacillin. A chorioretinal scar swiftly replaced the subfoveal abscess. Peripheral right vision and full left vision was retained. Vision loss due to endogenous endophthalmitis in systemic sepsis is an emergency requiring prompt multidisciplinary care. Sight and life are at risk-thus this is not a diagnosis to miss! Early recognition is paramount to health and in retaining vision. We briefly review relevant literature and portray how multimodal imaging guided response to treatment of acute subretinal abscess.
Assuntos
Abscesso/diagnóstico , Infecções Oculares Bacterianas/diagnóstico , Imagem Multimodal/métodos , Retina/diagnóstico por imagem , Sepse/diagnóstico , Infecções Estafilocócicas/diagnóstico , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Administração Intravenosa , Antibacterianos/uso terapêutico , Diagnóstico Diferencial , Diagnóstico Precoce , Endoftalmite/complicações , Infecções Oculares Bacterianas/tratamento farmacológico , Floxacilina/administração & dosagem , Floxacilina/uso terapêutico , Infecções por HIV/diagnóstico , Humanos , Masculino , Retina/microbiologia , Doenças Retinianas/microbiologia , Sepse/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/isolamento & purificação , Sífilis/diagnóstico , Resultado do Tratamento , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologiaRESUMO
Tendon ruptures are common injuries that are often treated surgically. Growth Differentiation Factor-5 (GDF-5) has been shown to accelerate tendon healing with varying degrees of success. We used a novel technique to apply recombinant human GDF-5 (rhGDF-5) to suture and hypothesized that controlled, local delivery of rhGDF-5 can be used to enhance tendon repair. Tendons of 92 rats were transected and repaired with sutures. All researchers were blinded to the following treatment groups (24 rats in each group): 0 rhGDF (control), 24 ng/cm rhGDF, 55 ng/cm rhGDF, and 556 ng/cm rhGDF. Rats were euthanized at 3 weeks (n = 48) and at 6 weeks (n = 48). Sutures were coated with rhGDF-5 using a novel dip-coat technique. Enzyme-linked immunosorbent assay confirmed consistent and reproducible delivery of rhGDF-5. Within each group, 8 were tested biomechanically, and 4 were assessed histologically. Histologic grading at 3 weeks showed improved healing in tendons repaired with coated suture versus controls. By 6 weeks, there were no significant differences. At 3 weeks, minimal isolated cartilage formation was observed; 6-week samples showed more extensive presence, typically surrounding suture fibers. At 3 weeks, tendons repaired with rhGDF-5-coated sutures resulted in significantly higher ultimate tensile load and stiffness compared with control sutures (P < .05) At 6 weeks, there were no significant differences in the mechanical properties of repaired tendons. At 3 weeks, rhGDF-5 induced significant tendon hypertrophy that was more pronounced than at 6 weeks. In addition, tendons repaired with rhGDF-5 showed an increased rate of healing versus control repairs at 3 weeks. This study showed that a novel dip-coating technique can be used to deliver growth factors in varying concentrations to local repair sites to accelerate tendon healing.
Assuntos
Proteínas Morfogenéticas Ósseas/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Traumatismos dos Tendões/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Fenômenos Biomecânicos , Materiais Revestidos Biocompatíveis , Modelos Animais de Doenças , Fator 5 de Diferenciação de Crescimento , Masculino , Ratos , Ratos Sprague-Dawley , Método Simples-Cego , Suturas , Traumatismos dos Tendões/patologia , Traumatismos dos Tendões/cirurgiaRESUMO
BACKGROUND: Transplantation of composite-tissue allograft (CTA) such as the human hand recently became a clinical reality. The high risks associated with the use of lifelong immunosuppression have been the prohibiting factor in the routine use of the CTA transplants. In this article, we present a new approach of inducing long-term, donor-specific tolerance to CTAs without recipient preconditioning and need for chronic immunosuppression. METHODS: We have developed a clinically applicable 35-day protocol that induces donor-specific tolerance in a rat hindlimb-transplantation model across major histocompatibility complex (MHC) barrier [Lewis-Brown-Norway (LBN, RT1 -->F1) to Lewis (LEW, RT1 ) by using cyclosporine A (CsA) and a mouse monoclonal antibody against rat alphabeta-T-cell receptor (TCR) to systemically eliminate alloresponsive cells. Standard skin grafting, flow cytometry (FC), and mixed lymphocyte reaction (MLR) were used to assess efficacy of immunodepletion and confirm donor-specific tolerance and chimerism. RESULTS: Under this protocol long-term tolerance (>720 days) was induced in all (n=5) CTA recipients across the MHC barrier without further need for immunosuppression. Tolerance was confirmed in all limb-allograft recipients by skin grafting in vivo and by MLR in vitro. The animals rejected third-party grafts, indicating immunocompetence. CONCLUSIONS: In this CTA model, combined protocol of alphabeta-TCR monoclonal antibody and CsA resulted in induction of donor-specific tolerance across the MHC barrier without recipient conditioning. We believe that our findings will foster development of new therapeutic strategies and expand clinical applications for composite-tissue transplantation.
Assuntos
Membro Posterior/transplante , Tolerância ao Transplante , Animais , Permeabilidade Capilar , Quimera , Citometria de Fluxo , Sobrevivência de Enxerto , Hemodinâmica , Membro Posterior/irrigação sanguínea , Imunocompetência , Terapia de Imunossupressão , Teste de Cultura Mista de Linfócitos , Masculino , Microcirculação , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Recuperação de Função Fisiológica , Transplante de Pele , Doadores de Tecidos , Transplante HomólogoRESUMO
BACKGROUND: This study assessed the ability of antilymphocyte serum (ALS) and cyclosporine A (CsA) to induce tolerance for hind limb composite tissue allograft in rats without chronic immunosuppression. METHODS: Hind limb transplantations were performed in Lewis-Brown-Norway (LBN, RT1(1+n)) and Lewis (LEW, RT1(1)) rats. Treatment consisted of ALS only (0.4 mL/kg), CsA only (16 mg/kg), and a combination of CsA and ALS, and it was administered 12 hr before surgery at three different intervals (7, 14, and 21 days). Long-term survivors were tested for tolerance by standard skin grafting from the recipient (LEW), the donor (LBN), and the third party (ACI, RT1 ) 60 days after cessation of the treatment and by mixed lymphocyte reaction at 100 days. T-cell lines were analyzed with flow cytometry. RESULTS: Single use of ALS in all treatment intervals did not prolong allograft survival. Single use of CsA extended survival up to 23 days in the 21-day protocol group. CsA and ALS caused indefinite survival in two of six rats in the 14-day protocol and in all six rats in the 21-day protocol (>420 days). The six long-term survivors in the 21-day protocol accepted the skin grafts from the donor (LBN) and the recipient (LEW) and rejected third-party grafts (ACI). Tolerant animals showed a donor-specific hematopoietic chimerism of 35% to 42% in the peripheral blood. Mixed lymphocyte reaction assay demonstrated tolerance to the host and donor alloantigens and increased response to the third party. CONCLUSIONS: Administration of CsA and ALS for 21 days induced donor-specific tolerance in the recipients of the rat hind limb composite tissue allografts. The mechanism of tolerance should be investigated further.
Assuntos
Soro Antilinfocitário/administração & dosagem , Ciclosporina/administração & dosagem , Membro Posterior/transplante , Tolerância Imunológica , Transplante de Rim/imunologia , Animais , Transplante de Medula Óssea , Citometria de Fluxo , Sobrevivência de Enxerto , Teste de Cultura Mista de Linfócitos , Masculino , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo , Quimeras de Transplante , Transplante HomólogoRESUMO
OBJECTIVE: The Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components. METHODS: A cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression. RESULTS: Total DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count. CONCLUSION: One of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs.
Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/psicologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores Farmacológicos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Estudos de Associação Genética , Humanos , Infliximab , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Composite tissue allograft (CTA) transplantation became a clinical reality despite major side effects associated with the administration of chronic immunosuppression. Development of new treatment modalities eliminating life-long immunosuppression is essential for the future of CTA transplantation. In this study, combined use of cyclosporine A (CsA) and antilymphocyte serum (ALS) was tested for the potential to induce tolerance in the rat hind-limb allograft recipients across a major histocompatibility (MHC) barrier (Lewis-Brown-Norway [LBN, RT1(l+n)] to Lewis [LEW, RT1(l)] rats). Thirty transplantations were performed in 5 experimental groups. Animals received CsA and ALS 12 hours before surgery for 21 days thereafter. Although the allograft controls rejected their limbs at day 7 combined treatment of CsA and ALS resulted in indefinite survival (over 420 d) in all allograft recipients. Long-term survivors showed 35% to 42% of donor-specific chimerism in the peripheral blood. Clinical tolerance was confirmed by acceptance of the donor-specific skin grafts and immunocompetence was confirmed by rejection of the third-party grafts. Mixed lymphocyte reaction revealed suppressed response against donor-type antigens and increased response to third-party antigens. Donor-specific tolerance across MHC barrier was induced in CTA allografts under 21 days protocol of ALS/CsA.