RESUMO
CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Artrite Reumatoide/sangue , Linfócitos B/patologia , Diferenciação Celular , Movimento Celular , Quimiocina CXCL13/metabolismo , Perfilação da Expressão Gênica , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Fatores Ativadores de Macrófagos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/deficiência , Receptores CXCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Proteínas Repressoras/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Líquido Sinovial/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. KEY POINTS: Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células de Transição/diagnóstico , Granulomatose com Poliangiite/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adrenalectomia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/imunologia , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/métodos , Cistectomia , Diagnóstico Diferencial , Granulomatose com Poliangiite/induzido quimicamente , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/imunologia , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Nefroureterectomia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Prostatectomia , Exacerbação dos Sintomas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologiaAssuntos
Febre de Causa Desconhecida/etiologia , Leiomiossarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Anorexia/etiologia , Biópsia , Tosse/etiologia , Diagnóstico Diferencial , Feminino , Glucocorticoides/uso terapêutico , Humanos , Leiomiossarcoma/complicações , Leiomiossarcoma/patologia , Fígado/patologia , Testes de Função Hepática , Pessoa de Meia-Idade , Dor/etiologia , Tomografia Computadorizada por Raios X , Neoplasias Uterinas/complicações , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). METHODS: This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (≥20 units), anti-MCV negativity (≤70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.
Assuntos
Linfócitos B/imunologia , Plaquetas/imunologia , Eritrócitos/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Fragmentos de Peptídeos/sangue , Receptores de Complemento/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Ativação do Complemento/fisiologia , Complemento C4b , Estudos Transversais , DNA/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Sensibilidade e Especificidade , Vimentina/sangueRESUMO
Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
Assuntos
Artrite Psoriásica , Artrite Reumatoide , Linfócitos T CD8-Positivos , Humanos , Artrite Psoriásica/metabolismo , Líquido Sinovial/metabolismo , Linfócitos T Citotóxicos/metabolismoRESUMO
The objective of the 2010 ACR/European League Against Rheumatism classification criteria for RA was to distinguish patients at high risk for developing persistent erosive and/or inflammatory disease from those with undifferentiated inflammatory arthritis. These criteria were developed for use in clinical trials; in order to implement these criteria most effectively, they need to be validated in real-world settings. The 1987 criteria may have led to underdiagnosis in the case of patients with positive anti-citrullinated peptide antibody values but no evidence of radiographic progression of joint erosion, or overdiagnosis in the case of some patients with FM; similarly, the possibility that the 2010 criteria may result in overdiagnosis cannot be excluded. Prospective validation of the 2010 criteria has been carried out in several cohorts, with reported sensitivities ranging from 0.50 to 0.60 and specificities from 0.88 to 0.97. The sensitivity and specificity of the 2010 criteria were 0.74 and 0.66 when compared against the gold standard of needing MTX therapy in the opinion of experienced clinicians, and 0.69 and 0.72 against the standard of having persistent synovitis despite DMARDs after 1 year. Other comparisons have yielded similar sensitivities and specificities, ranging up to 0.85 for the gold standard of needing MTX therapy. Questions remain concerning the utility of the 2010 criteria for non-arthritis health care practitioners, who may be less than expert in identifying swollen joints and may underestimate the number of joints affected by synovitis. US may be of value in the future, but its role remains to be validated.
Assuntos
Artrite Reumatoide/classificação , Artrite Reumatoide/diagnóstico , Padrões de Prática Médica/tendências , Artrite Reumatoide/terapia , Terapia Biológica , Progressão da Doença , Europa (Continente) , Humanos , Sensibilidade e Especificidade , Sociedades Médicas , Estados UnidosRESUMO
As more effective treatments for RA have become available, studies have demonstrated that in patients who attained remission, defined as a simplified disease activity index (SDAI) ≤3.3, not only disease activity but radiographic progression was reduced. The feasibility and the benefit of attaining remission led to the development of the ACR/European League Against Rheumatism (EULAR) 2011 remission criteria. These criteria employ either a Boolean definition, including tender and swollen joint counts ≤1, and CRP ≤1 mg/dl, or an index-based definition, SDAI ≤3.3, in combination with patient-reported outcomes on a scale of 0-10. It is expected that the ACR/EULAR criteria will be used as secondary outcomes in clinical trials. Some questions about the implementation of the new criteria include the availability of CRP values, and the possibility that patient-reported outcomes may skew the outcome if patients cannot distinguish other musculoskeletal conditions from RA. Several issues require further study, including the role of imaging, fatigue and the impact of the involvement of joints other than the 28 counted in the ACR/EULAR criteria.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/classificação , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Artrite Reumatoide/fisiopatologia , Proteína C-Reativa/metabolismo , Europa (Continente) , Humanos , Articulações/fisiopatologia , Indução de Remissão , Sociedades Médicas , Estados UnidosRESUMO
OBJECTIVE: To investigate the efficacy and safety of certolizumab pegol (CZP) in a broad population of patients with active RA. METHODS: In this 12-week, double-blind period of the phase IIIb trial, RA patients with inadequate response to at least one DMARD were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo (every 2 weeks) plus current therapy stratified by previous TNF inhibitor use, concomitant methotrexate use and disease duration (<2 vs ≥2 years). The primary outcome was ACR20 response rate at week 12. RESULTS: Of 1063 patients (CZP = 851; placebo = 212), 37.6% had previous TNF inhibitor use. Baseline mean HAQ Disability Index (HAQ-DI) and DAS 28-joint assessment-ESR [DAS28(ESR)] values were 1.5 and 6.4 in the CZP group, and 1.6 and 6.4 in the placebo group, respectively. The primary endpoint was significant (week 12 ACR20, CZP vs placebo: 51.1 vs 25.9%; P < 0.001); differences were noted at week 2 (31.8 vs 8.5%; P < 0.001). HAQ-DI and DAS28(ESR) change from baseline and ACR50 were significant from week 2. Week 12 ACR20 responses were similar across CZP patient subgroups regardless of concomitant DMARD use at baseline. Adverse and serious adverse events were comparable between CZP and placebo, with no new safety signals. CONCLUSION: CZP was associated with rapid and consistent clinical responses and improved physical function in a diverse group of RA patients, irrespective of concomitant or previous therapy. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00717236.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Certolizumab Pegol , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Resultado do TratamentoRESUMO
Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.
Assuntos
Inflamação/imunologia , Ativação de Macrófagos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Transcriptoma/imunologia , Doença Aguda , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Doença Crônica , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Ativação de Macrófagos/genética , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única/métodos , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Transcriptoma/genéticaRESUMO
T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.
Assuntos
COVID-19 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Granzimas/metabolismo , HumanosRESUMO
Managing lupus patients traditionally involves treating manifestations of active disease with the most effective and least toxic therapies so that "damage" from ongoing disease or treatments can be minimized. Damage in clinical epidemiologic studies is usually defined by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, a validated, organ-specific assessment tool. This review summarizes recent developments regarding organ-specific manifestations and lupus-related damage and their prevention.
Assuntos
Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Avaliação da Deficiência , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/fisiopatologia , Gastroenteropatias/epidemiologia , Gastroenteropatias/fisiopatologia , Indicadores Básicos de Saúde , Humanos , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Pneumopatias/epidemiologia , Pneumopatias/fisiopatologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Vasculite Associada ao Lúpus do Sistema Nervoso Central/epidemiologia , Morbidade , Índice de Gravidade de Doença , Dermatopatias/epidemiologia , Dermatopatias/fisiopatologiaRESUMO
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.
RESUMO
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.
Assuntos
Ativação do Complemento/imunologia , Complemento C3/imunologia , Complemento C4b/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fragmentos de Peptídeos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antiproteína Citrulinada/imunologia , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Complemento C4/imunologia , Complemento C4b/metabolismo , Progressão da Doença , Eritrócitos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Doenças Reumáticas/imunologia , Fator Reumatoide/imunologia , Síndrome de Sjogren/imunologia , Adulto JovemRESUMO
As tumor necrosis factor (TNF)-alpha inhibitors gain wider use in clinical practice, it is becoming increasingly evident that these potent immunosuppressants can also induce inflammatory reactions. We present two cases of lichen planus-like eruptions after infliximab and adalimumab therapy for psoriasis, and review the literature on this phenomenon. Eleven cases of lichen planus or lichenoid drug eruptions have been previously reported in patients taking TNF-alpha inhibitors, in addition to several cases of psoriasiform eruptions with a lichenoid histology. Because TNF-alpha has been implicated in the pathogenesis of lichen planus, induction of lichenoid reactions by TNF-alpha inhibition is somewhat unexpected. We consider potential immunologic mechanisms, and suggest that TNF-alpha inhibition may precipitate lichenoid reactions through disruption of a delicate balance between TNF-alpha and interferon-alpha in susceptible patients.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Erupções Liquenoides/induzido quimicamente , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Anticorpos Monoclonais Humanizados , Toxidermias/imunologia , Feminino , Humanos , Infliximab , Interferon-alfa/imunologia , Líquen Plano/induzido quimicamente , Erupções Liquenoides/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation, which if left untreated leads to progressive disability and joint destruction. A combination of antiinflammatory agents, steroids, disease-modifying antirheumatic drugs, and biological agents are used to treat RA. Beyond the use of conventional measures of disease activity, such as American College of Rheumatology (ACR) response rates, the importance of patient-reported outcomes (PROs) in assessing therapeutic benefits is gaining increasing emphasis in clinical trials of RA and other chronic illnesses. Clinical trials testing new RA therapeutics generally include health-related quality of life (HRQoL) measures and assessments of function and disability. Abatacept, a costimulation modulator that selectively targets the activation of T cells and downregulates the immune response, has been approved by the US Food and Drug Administration for the treatment of RA, with or without methotrexate. OBJECTIVE: The aim of this review was to summarize the clinical outcomes and PROs in published trials of abatacept. METHODS: A literature search was performed using the MEDLINE, EMBASE, and BIOSIS databases (restricted to articles posted between January 2000 and September 2007) with the search terms CTLA-4Ig, abatacept, and Orencia to identify published trials of abatacept. Primary clinical trial publications in patients with RA were selected. The ACR response and PROs data presented in the identified publications are summarized in this review. RESULTS: Our search identified 6 studies that met our selection criteria, which included 1 Phase IIa study, 2 Phase IIb studies, and 3 Phase III studies. The Phase IIa study found that abatacept was more effective than placebo and that physical function improved in treated patients compared with placebo. The 2 Phase IIb studies in 339 patients with RA previously treated with methotrexate found statistically significant improvements in HRQoL with abatacept at 6 months and 1 year. Similar findings were noted in the published Phase III trials. Across clinical trials, abatacept has been associated with clinically meaningful and statistically significant improvements in conventional measures of disease activity, HRQoL, and physical function. CONCLUSIONS: These 6 published trials found that abatacept was associated with significant improvements in both conventional measures of disease activity and PROs. Continued assessment of these outcomes will be required to further support the findings of the Phase II and III abatacept clinical trial literature reviewed here.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Imunoconjugados/uso terapêutico , Abatacepte , Nível de Saúde , Humanos , Projetos Piloto , Qualidade de Vida , Resultado do TratamentoRESUMO
High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10-3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27- HLA-DR+ cells were associated with RA (meta-analysis P = 2.3 × 10-4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27- HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27- HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with T helper 1 (TH1)- and cytotoxicity-associated features and produced abundant interferon-γ (IFN-γ) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Transcriptoma/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
INTRODUCTION: The effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) was investigated in 1063 patients with rheumatoid arthritis (RA) from the REALISTIC trial (double-blind, placebo-controlled to week 12, open-label to week 28; randomized 4:1 [CZP:placebo]). Correlations between PROs and RA signs and symptoms, and the relative efficacy of these measures, were examined. METHODS: Adults with RA and an inadequate response to at least one disease-modifying antirheumatic drug were enrolled. PROs assessed included physical function (using the Health Assessment Questionnaire-Disability Index), pain, fatigue, sleep disturbance, Patient Global Assessment of Disease Activity (PtGA), Routine Assessment of Patient Index Data 3 (RAPID3), and Rheumatoid Arthritis Disease Activity Index (RADAI). RESULTS: Early significant and clinically meaningful improvements in all PROs were observed to week 12 with CZP vs. placebo and were maintained to the end of the trial (week 28). At week 12, up to one-third more CZP patients showed improvements compared with placebo that were greater than or equal to the minimal clinically important difference (MCID) in fatigue, sleep problems, pain, PtGA, RADAI, and RAPID3. The changes in PROs were correlated with clinical measures of disease activity, including the Disease Activity Score in 28 joints using C-reactive protein as well as tender and swollen joint counts. CONCLUSIONS: Rapid improvements in PROs were seen in patients with RA treated with CZP. The magnitude of improvement exceeded the MCID in multiple domains and demonstrated that CZP improves aspects of health-related quality of life that are meaningful to patients and superior to placebo. PROs provide information complementary to clinical outcomes in assessment of treatment benefits. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00717236 . Registered on 15 July 2008.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. METHODS: SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. RESULTS: Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3 , or high-dose vitamin D3 ) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns. CONCLUSION: Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes.
Assuntos
Antígenos/sangue , Proteínas de Transporte/sangue , Colecalciferol/farmacologia , Proteínas do Citoesqueleto/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/sangue , Proteínas de Resistência a Myxovirus/sangue , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Anticorpos Anti-Idiotípicos/sangue , Antígenos/genética , Proteínas de Transporte/genética , Colecalciferol/administração & dosagem , Proteínas do Citoesqueleto/genética , DNA/imunologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus/genética , Estudos Prospectivos , Proteínas de Ligação a RNA , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Infection with B. burgdorferi can cause a large joint inflammatory arthritis in patients who have not been treated for early Lyme disease; the knee is the most common joint affected. The diagnosis depends on a history of known exposure to the spirochete, characteristic clinical features, and serologic studies (ELISA and Western blot) confirming exposure to the spirochete. In most patients, antibiotic therapy is curative, but in a smaller percentage of patients, the presence of the HLA-DR beta 1*0401 haplotype can trigger treatment-resistant arthritis, in which antibiotic therapy is ineffective; in these instances, remittive agents, such as hydroxychloroquine and methotrexate, are indicated. Arthroscopic synovectomy may be considered when antibiotic therapy is not curative. Fibromyalgia can follow infection with B. burgdorferi but is unresponsive to antibiotic therapy; it is treated with tricyclic antidepressants and an exercise program. Lyme arthritis is the only chronic inflammatory arthritis in which the specific cause is known and can be cured. As such, it serves as an excellent model with which to study the pathogenesis of more common inflammatory arthritides, such as rheumatoid arthritis.
Assuntos
Artrite Infecciosa/microbiologia , Doença de Lyme/diagnóstico , Doença de Lyme/tratamento farmacológico , Adulto , Antibacterianos/uso terapêutico , Artrite Infecciosa/complicações , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/tratamento farmacológico , Borrelia burgdorferi/isolamento & purificação , Diagnóstico Diferencial , Feminino , Fibromialgia/microbiologia , Humanos , Doença de Lyme/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
The relationship between inflammation and insulin resistance is complex and not fully understood. Patients with rheumatoid arthritis are at increased risk of mortality from cardiovascular disease, which is known to be associated with insulin resistance. In the previous issue of Arthritis Research & Therapy, Ormseth and colleagues report the results of an 8-week trial of pioglitazone, an agent commonly used to treat type 2 diabetes mellitus, upon the DAS-28 (disease activity score using 28 joint counts). Modest improvements in the DAS-28 CRP (DAS-28 C-reactive protein) were shown, with no effect on DAS-28 ESR (DAS-28 erythrocyte sedimentation rate). Other variables that improved with pioglitazone were the CRP, IL-6, and patient-reported assessment of global health. The authors discuss the contribution of insulin resistance to the inflammation noted in rheumatoid arthritis.