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OBJECTIVE: To evaluate belimumab addition to the standard of care in patents with refractory idiopathic inflammatory myopathy (IIM). METHODS: We conducted a 40-week multicentre, randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the definition of improvement (DOI) and total improvement score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60-64 weeks. Descriptive statistics, t-test, Fisher's exact test and analysis of variance tests were used. RESULTS: A total of 17 patients were randomized, 15 received five or more doses of belimumab or placebo and were included in the intention-to-treat analysis. More belimumab patients vs placebo attained a TIS ≥40 [55.5% vs 33.3%; P = non-significant (NS)] and achieved the DOI (33.3% vs 16.7%; P = NS) at weeks 40 and 64; the mean TIS was similar among groups. Two patients achieved major responses (TIS = 72.5) after week 40 in the belimumab arm and none in the placebo arm. No improvement in the placebo arm after switching to the open-label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B cells were not reduced, belimumab induced naïve B cell depletion while enhancing the number and frequency memory B cells. CONCLUSION: The study did not meet the primary endpoint and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥40 and reached the DOI. Most patients who received belimumab for >40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (https://clinicaltrials.gov/), NCT02347891.
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Anticuerpos Monoclonales Humanizados , Miositis , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos B , Citometría de Flujo , Miositis/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: It is an understatement to say that drug approvals in systemic lupus erythematosus (SLE), lupus nephritis, and Sjogren's syndrome have lagged far behind those in other autoimmune diseases, such as rheumatoid arthritis and psoriatic arthritis. Reasons for this are multiple and include the molecular and clinical heterogeneity of these conditions; confounding by background medications, especially corticosteroids; and clinical trial endpoints. However, the tides are changing, and there have been several bright spots in our attempts to bring more efficacious drugs to our patients. RECENT FINDINGS: Several positive phase II and phase III trials in SLE and lupus nephritis with drugs such as anifrolumab, voclosporin, belimumab, and obinutuzumab will no doubt eventually generate regulatory approvals for most, if not all, of these drugs. Although early in development, the promising results in Sjogren's syndrome with iscalimab and ianalumab should make the Sjogren's syndrome community quite hopeful of future drug approvals. SUMMARY: In this review, we highlight recent study results in Sjogren's syndrome, SLE, and lupus nephritis, emphasizing investigational therapies in late stage development, but we also provide a glimpse into drugs of the future.
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Productos Biológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Síndrome de Sjögren/tratamiento farmacológico , Humanos , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Síndrome de Sjögren/inmunología , Resultado del TratamientoAsunto(s)
Fallo Renal Crónico , Lupus Eritematoso Sistémico , Insuficiencia Renal Crónica , Humanos , Diálisis Renal , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/terapiaRESUMEN
PURPOSE OF REVIEW: With advancement in our understanding of pathogenic mechanisms in systemic lupus erythematosus (SLE), there is tremendous enthusiasm in examining drugs, old and new, to improve outcomes. This review highlights recent trials' successes and impasses that have come to fore. RECENT FINDINGS: Among B-cell therapies, belimumab continues its run of successes with sustained safety and tolerability documented in a long-term extension as well as the likely approval of a subcutaneous formulation in the near future. With greater antibody-dependent cytotoxicity and less immunogenicity, there is hope for obinituzumab to succeed where its anti-CD 20 predecessors have failed. Drugs targeting type I interferons - sifalimumab and anifrolumab - have been efficacious albeit with an increase in incidence of Herpes zoster infections. There is also renewed interest in evaluating the efficacy of calcineurin inhibitors, specifically tacrolimus in the induction and maintenance of lupus nephritis. Introspection into clinical trial designs have highlighted the effects of entry criteria, end points, background medications and geographical differences on study outcomes. SUMMARY: There are at least 50 drugs and targets being evaluated in SLE. In addition to developing new drugs to treat lupus, future trials have to focus on more effective study designs to improve chances of trial success.
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Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Abatacept , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos B/inmunología , Ensayos Clínicos como Asunto , Ciclosporina/uso terapéutico , Herpes Zóster/etiología , Herpes Zóster/inmunología , Humanos , Interferón Tipo I , Lupus Eritematoso Sistémico/inmunología , Quimioterapia de Mantención , Fragmentos de Péptidos/uso terapéutico , Células Plasmáticas/inmunología , Quinolonas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Inducción de Remisión , Linfocitos T/inmunología , Tacrolimus/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: In idiopathic inflammatory myopathies, anti-SSa/SSb and anti-Ro52 are associated with interstitial lung disease (ILD), yet few studies have compared their prognostic utility. Our study analyzes clinical phenotypes associated with anti-SSa/SSb and anti-Ro52 positivity in IIM and their association with ILD. METHODS: We performed a retrospective analysis of IIM patients >18-years-old, seen at Northwell Myositis Center 2007- 2018 who met 2017 EULAR/ACR criteria with available anti-SSa/SSb data. Patients who were anti-SSa/SSb(-) and anti-Ro52(+) were excluded from anti-SSa/SSb subgroup analysis but included in Ro52 subgroup analysis. Organ manifestations, pulmonary function tests (PFTs) and comorbidities were recorded. Statistical analyses included Chi-square, Fisher's Exact, Wilcoxon Rank Sum, McNemar's test. RESULTS: Of 94 patients included in the final analysis, 35% (33/94) were anti-SSa/SSb positive (+). Of 60 patients with anti-Ro52 data, 42% (25/60) were (+). ILD was more common in anti-SSa/SSb (+) versus anti-SSa/SSb negative patients and anti-Ro52(+) versus anti-Ro52 negative patients (58% vs 25%; p = 0.003 and 64% vs.26%; p = 0,004 respectively). Anti-SSa/SSb (+) was not associated with increased ILD severity based on PFTs. Anti-Ro52(+) group had lower DLCO than anti-Ro52(-) (47% vs 68%; p = 0.003). Anti-SSa/SSb positivity did not confer a difference in the frequency of other manifestations. Elevated rates of venous thromboembolism (VTE) (10%-12%) and osteoporosis (13-17%) were observed independent of anti-SSa/SSb or anti-Ro52 status. CONCLUSION: In IIM anti-SSa/SSb or anti-Ro52 positivity is associated with higher ILD rate. Both assays are useful to confer ILD risk, but anti-Ro52 is more predictive of severe ILD. High frequencies of osteoporosis and VTE were observed in all subgroups.
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Enfermedades Pulmonares Intersticiales , Miositis , Osteoporosis , Tromboembolia Venosa , Humanos , Adolescente , Autoanticuerpos , Estudios Retrospectivos , Ribonucleoproteínas , FenotipoRESUMEN
Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.
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Enfermedades Autoinmunes , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Femenino , SARS-CoV-2/inmunología , Masculino , Enfermedades Autoinmunes/inmunología , Persona de Mediana Edad , Adulto , Vacunas contra la COVID-19/inmunología , Inmunosupresores/uso terapéutico , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Vacuna nCoV-2019 mRNA-1273/inmunología , Vacuna nCoV-2019 mRNA-1273/administración & dosificación , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Ácido Micofenólico/uso terapéutico , Anciano , Vacunación , Linfocitos B/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus disease-2019 (COVID-19) infection. The mechanism of liver injury in COVID-19 infection is unclear. However, it has been hypothesized to be a result of direct cytopathic effects of the virus, immune dysfunction and cytokine storm-related multiorgan damage, hypoxia-reperfusion injury and idiosyncratic drug-induced liver injury due to medications used in the management of COVID-19. The favored hypothesis regarding the pathophysiology of liver injury in the setting of COVID-19 is cytokine storm, an aberrant and unabated inflammatory response leading to hyperproduction of cytokines. In the current review, we have summarized the potential pathophysiologic mechanisms of cytokine-induced liver injury based on the reported literature.
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COVID-19 , Síndrome de Liberación de Citoquinas , Hepatopatías/virología , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/virología , Citocinas , HumanosRESUMEN
BACKGROUND: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment. INTERPRETATION: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.
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Corticoesteroides/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , COVID-19 , Síndrome de Liberación de Citoquinas , Inmunomodulación , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , COVID-19/inmunología , COVID-19/mortalidad , COVID-19/terapia , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/terapia , Síndrome de Liberación de Citoquinas/virología , Reposicionamiento de Medicamentos , Quimioterapia Combinada/métodos , Registros Electrónicos de Salud/estadística & datos numéricos , Humanos , Inmunosupresores/administración & dosificación , Administración del Tratamiento Farmacológico/estadística & datos numéricos , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Estudios Retrospectivos , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.
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Inmunidad Adaptativa/inmunología , COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Inmunidad Innata/inmunología , Síndrome de Dificultad Respiratoria/inmunología , Formación de Anticuerpos , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/sangre , COVID-19/fisiopatología , Inactivadores del Complemento/uso terapéutico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Endotelio Vascular/inmunología , Endotelio Vascular/fisiopatología , Humanos , Inmunidad Humoral/inmunología , Inmunoglobulina G/inmunología , Factores Inmunológicos/uso terapéutico , Memoria Inmunológica , Inmunosupresores/uso terapéutico , Interferones/inmunología , Células Asesinas Naturales/inmunología , Linfopenia/inmunología , Activación de Macrófagos/inmunología , Infiltración Neutrófila/inmunología , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Trombofilia/sangre , Trombofilia/inmunología , Trombosis/sangre , Trombosis/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
OBJECTIVE: To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. METHODS: Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1-3 years to evaluate transition into ACR-classifiable SLE. Individual cell-bound complement activation products (CB-CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme-linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: Of the 92 patients with pSLE enrolled, 74 had one or two follow-up visits 9-35 months after enrollment for a total of 128 follow-up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR-classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow-up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. CONCLUSION: Approximately one-third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.
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OBJECTIVE: To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. METHODS: Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively. RESULTS: The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). CONCLUSION: Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.
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Activación de Complemento/inmunología , Complemento C3/inmunología , Complemento C4b/inmunología , Lupus Eritematoso Sistémico/inmunología , Fragmentos de Péptidos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Linfocitos B/metabolismo , Estudios de Casos y Controles , Complemento C4/inmunología , Complemento C4b/metabolismo , Progresión de la Enfermedad , Eritrocitos/metabolismo , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Estudios Prospectivos , Enfermedades Reumáticas/inmunología , Factor Reumatoide/inmunología , Síndrome de Sjögren/inmunología , Adulto JovenRESUMEN
OBJECTIVES: To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS: All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS: Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p<0.0001). LSI was low (median 5.44, IQR: 4.77-6.93) in patients with no complement abnormality, intermediate in patients with abnormal CB-CAPs (median 6.09, IQR: 5.31-8.20) and high in the group presenting with both abnormal CB-CAPs and low C3 and/or C4 (median 7.85, IQR: 5.51-8.37). Odds of immunosuppressant use was higher in subjects with LSI ≥5.95 compared with subjects with LSI <5.95 (1.60 vs 0.53, p<0.0001 for both). Multivariable regression analysis revealed that higher LSI scores associated with abnormal CB-CAPs-but not low C3/C4-after adjusting for younger age, race and longer disease duration (p=0.0001), which were also independent predictors of disease severity (global R2=0.145). CONCLUSION: Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.
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Activación de Complemento/inmunología , Complemento C3/análisis , Complemento C4/análisis , Lupus Eritematoso Sistémico/inmunología , Adolescente , Adulto , Linfocitos B/química , Linfocitos B/inmunología , Estudios de Casos y Controles , Complemento C3/metabolismo , Complemento C4/metabolismo , Estudios Transversales , Eritrocitos/química , Eritrocitos/inmunología , Etnicidad , Femenino , Citometría de Flujo/métodos , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: We compared the physician-assessed diagnostic likelihood of SLE resulting from standard diagnosis laboratory testing (SDLT) to that resulting from multianalyte assay panel (MAP) with cell-bound complement activation products (MAP/CB-CAPs), which reports a two-tiered index test result having 80% sensitivity and 86% specificity for SLE. METHODS: Patients (n=145) with a history of positive antinuclear antibody status were evaluated clinically by rheumatologists and randomised to SDLT arm (tests ordered at the discretion of the rheumatologists) or to MAP/CB-CAPs testing arm. The primary endpoint was based on the change in the physician likelihood of SLE on a five-point Likert scale collected before and after testing. Changes in pharmacological treatment based on laboratory results were assessed in both arms. Statistical analysis consisted of Wilcoxon and Fisher's exact tests. RESULTS: At enrolment, patients randomised to SDLT (n=73, age=48±2 years, 94% females) and MAP/CB-CAPs testing arms (n=72, 50±2 years, 93% females) presented with similar pretest likelihood of SLE (1.42±0.06 vs 1.46±0.06 points, respectively; p=0.68). Post-test likelihood of SLE resulting from randomisation in the MAP/CB-CAPs testing arm was significantly lower than that resulting from randomisation to SDLT arm on review of test results (-0.44±0.10 points vs -0.19±0.07 points) and at the 12-week follow-up visit (-0.61±0.10 points vs -0.31±0.10 points) (p<0.05). Among patients randomised to the MAP/CB-CAPs testing arm, two-tiered positive test results associated significantly with initiation of prednisone (p=0.034). CONCLUSION: Our data suggest that MAP/CB-CAPs testing has clinical utility in facilitating SLE diagnosis and treatment decisions.
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The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.
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There has long been a need for biomarkers of disease activity in lupus nephritis (LN). Such markers ideally would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy thus obviating the need for serial renal biopsies. Since urine can be readily obtained it lends itself as an obvious biological sample. Much of the focus has been on the measurement of urinary chemokines and cytokines in patients with LN. Elevations in urinary IL-6 and IL-10 had initially been reported to be associated with disease activity in LN but these markers have proven to be less reliable in larger studies. We and others have recently reported that MCP-1, a key chemokine involved in monocyte chemotaxis can be consistently found at high levels in the urine of patients with active LN. Moreover urinary MCP-1 levels decline with treatment of nephritis. In contrast urinary IL-8, a chemokine involved primarily in neutrophil chemotaxis is not a good predictor of disease activity in LN. Further longitudinal studies with larger numbers of patients are needed to determine the utility of urinary biomarkers such as MCP-1 which may act as surrogates of ongoing inflammation in LN.
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Biomarcadores/orina , Quimiocina CCL2/orina , Nefritis Lúpica/orina , Biomarcadores/análisis , Quimiocina CCL4 , Interleucina-10/orina , Interleucina-6/orina , Interleucina-8/orina , Proteínas Inflamatorias de Macrófagos/orinaRESUMEN
Screening for disease-specific autoantibodies may be useful in asymptomatic ANA-positive individuals as a means of evaluating the risk of developing a systemic autoimmune disease such as systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), scleroderma (SSc), Sjögren's syndrome (SS), rheumatoid arthritis (RA), or primary biliary cirrhosis (PBC) in the future. In patients with known or suspected systemic autoimmune disease, a panel of disease-specific markers may help to establish a diagnosis and to assess the prognosis. The great strides in autoantibody testing over the last 20 years make it feasible to use specific autoantibody markers to improve diagnostic accuracy in systemic autoimmune disease. New technology enabling screening for multiple autoantibodies may further enhance the clinical usefulness of autoantibody testing, making it possible to diagnose autoimmune disease in its earliest stages and to intervene before serious end organ damage occurs.
Asunto(s)
Autoanticuerpos/análisis , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Anticuerpos Antinucleares/análisis , Anticuerpos Antinucleares/sangre , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Humanos , Pruebas Inmunológicas , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/inmunología , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Polimiositis/diagnóstico , Polimiositis/inmunología , Pronóstico , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/inmunología , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/inmunologíaRESUMEN
BACKGROUND: Most individuals with autoimmune and other immune disorders undergo initial evaluation in the community setting. Since misdiagnosis of systemic autoimmune diseases can have serious consequences, we evaluated community physicians' accuracy in diagnosing autoimmune diseases and the consequences of misdiagnosis. METHODS: We studied the patients referred to our Autoimmune Disease Center for 13 months (n = 476). We estimated the degree of agreement with the final diagnosis (kappa statistic) and the accuracy indexes (sensitivity, specificity, and predictive values) of the referring physicians' diagnoses. RESULTS: We found a 49% agreement between the referring and final diagnoses (kappa = 0.36). Of 263 patients referred with a presumptive diagnosis of systemic lupus erythematosus (SLE), 125 received a diagnosis of other conditions (kappa = 0.34). Of those referred with SLE, 76 (29%) were seropositive for antinuclear antibodies but did not have autoimmune disease. The degree of agreement for referring rheumatologists (kappa = 0.55) was better than that for nonrheumatologists (kappa = 0.32). Stepwise logistic regression indicated that rheumatologists were 4 times more likely to make an accurate diagnosis of SLE than were nonrheumatologists (P<.003). Thirty-nine patients who were seropositive for antinuclear antibodies but had no autoimmune disease had been treated with corticosteroids at dosages as high as 60 mg/d. CONCLUSIONS: Many patients with a positive antinuclear antibody test are incorrectly given a diagnosis of SLE and sometimes treated with toxic medications. The data support the importance of continuing medical education for community physicians in screening for autoimmune diseases and identifying patients who may benefit from early referral to a specialist.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Lupus Vulgar/diagnóstico , Corticoesteroides/uso terapéutico , Anticuerpos Antinucleares/sangre , Enfermedades Autoinmunes/tratamiento farmacológico , Errores Diagnósticos , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Valor Predictivo de las Pruebas , Derivación y Consulta , Reumatología , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: The high-affinity receptor for IgG Fcgamma/CD64 is critical for the development of lupus nephritis (LN). Cross-linking Fc receptor on recruited monocytes by IgG-containing immune complexes is a key step in immune-complex-mediated nephritis in systemic lupus erythematosus (SLE). The goal of this study was to determine whether expression of Fc receptor (FcgammaR) I on circulating monocytes is associated with systemic inflammation and renal disease in SLE patients. METHODS: We studied 205 SLE patients (132 with LN and 73 without LN) along with 74 healthy control individuals. Surface expression of CD14 (monocytes), FcgammaRI/CD64, FcgammaRII/CD32, and FcgammaRIII/CD16 was evaluated by flow cytometry. Monocyte function was assessed by determining the migratory capacity and the ability to produce CCL2 (monocyte chemotractic protein 1). High-sensitivity C-reactive protein, C3 and C4 were measured by nephelometry. RESULTS: There was little difference in the expression of FcgammaRIII/CD16 or FcgammaRIII/CD32 on circulating monocytes between patients with SLE and control individuals. In contrast, FcgammaRI/CD64 expression was significantly higher in SLE patients and even higher in patients with LN. FcgammaRI/CD64 expression was positively associated with serum creatinine and indicators of systemic inflammation. Monocytes from patients with high FcgammaRI/CD64 expression also exhibited increased chemotaxis and capacity to produce monocyte chemotractic protein 1. CONCLUSIONS: Increased FcgammaRI/CD64 expression on circulating monocytes parallels systemic inflammation and renal disease in SLE patients. We propose that circulating monocytes activated by immune complexes and/or proinflammatory mediators upregulate surface expression of FcgammaRI/CD64 in SLE. The enhanced chemotactic and inflammatory potential of the activated monocytes may participate in a vicious cycle of immune cell recruitment and renal injury in SLE.