RESUMO
BACKGROUND: Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. METHODS: In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. RESULTS: A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). CONCLUSIONS: Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Interleucina-2/administração & dosagem , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Progressão da Doença , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Feminino , Fatores de Transcrição Forkhead/metabolismo , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/imunologia , Humanos , Interleucina-2/efeitos adversos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Observação , Adulto JovemAssuntos
Cefaleia/etiologia , Papiledema/diagnóstico , Trombose dos Seios Intracranianos/diagnóstico , Anticoagulantes/uso terapêutico , Feminino , Humanos , Hipertensão Intracraniana/complicações , Hipertensão Intracraniana/diagnóstico , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Papiledema/etiologia , Trombose dos Seios Intracranianos/complicações , Trombose dos Seios Intracranianos/tratamento farmacológico , Varfarina/uso terapêuticoAssuntos
Encéfalo/patologia , Síndrome de Susac/diagnóstico , Adulto , Confusão/etiologia , Diagnóstico Diferencial , Fluoresceína , Cefaleia/etiologia , Perda Auditiva/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/etiologia , Oftalmoscopia , Radiografia , Artéria Retiniana/diagnóstico por imagem , Síndrome de Susac/complicações , Vasculite/diagnósticoRESUMO
BACKGROUND: Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function. METHODS: This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks. RESULTS: Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV1 and FVC remained stable at 48 weeks, but the 6-min walk distance showed a decrease toward baseline. CONCLUSIONS: The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov.
Assuntos
Inibidores Enzimáticos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Imunossupressores/uso terapêutico , Linfangioleiomiomatose/tratamento farmacológico , Sirolimo/uso terapêutico , Adulto , Idoso , Autofagia , Diarreia/induzido quimicamente , Ensaio de Imunoadsorção Enzimática , Feminino , Volume Expiratório Forçado , Cefaleia/induzido quimicamente , Humanos , Linfangioleiomiomatose/sangue , Linfangioleiomiomatose/fisiopatologia , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Resultado do Tratamento , Fator D de Crescimento do Endotélio Vascular/sangue , Capacidade Vital , Teste de CaminhadaRESUMO
We studied the motion perception of a patient, AMG, who had a lesion in the left occipital lobe centered on visual areas V3 and V3A, with involvement of underlying white matter. As shown by a variety of psychophysical tests involving her perception of motion, the patient was impaired at motion discriminations that involved the detection of small displacements of random-dot displays, including local speed discrimination. However, she was unimpaired on tests that required spatial and temporal integration of moving displays, such as motion coherence. The results indicate that she had a specific impairment of the computation of local but not global motion and that she could not integrate motion information across different spatial scales. Such a specific impairment has not been reported before.
Assuntos
Percepção de Movimento/fisiologia , Lobo Occipital/fisiopatologia , Percepção Espacial/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Mapeamento Encefálico , Estudos de Casos e Controles , Percepção de Cores , Sensibilidades de Contraste , Percepção de Profundidade , Feminino , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Occipital/anatomia & histologia , Transtornos da Percepção/fisiopatologia , Psicofísica , Campos VisuaisRESUMO
OBJECTIVE: To characterize the microbiome of the temporal artery in patients with giant cell arteritis (GCA), and to apply an unbiased and comprehensive shotgun sequencing-based approach to determine whether there is an enrichment of candidate pathogens in the affected tissue. METHODS: Temporal artery biopsy specimens were collected from patients at a single institution over a period of 4 years, and unbiased DNA sequencing was performed on 17 formalin-fixed, paraffin-embedded specimens. Twelve of the 17 patients fulfilled the clinical and histopathologic criteria for GCA, and the other 5 patients served as controls. Using PathSeq software, human DNA sequences were computationally subtracted, and the remaining non-human DNA sequences were taxonomically classified using a comprehensive microbial sequence database. The relative abundance of microbes was inferred based on read counts assigned to each organism. Comparison of the microbial diversity between GCA cases and controls was carried out using hierarchical clustering and linear discriminant analysis of effect size. RESULTS: Propionibacterium acnes and Escherichia coli were the most abundant microorganisms in 16 of the 17 samples, and Moraxella catarrhalis was the most abundant organism in 1 control sample. Pathogens previously described to be correlated with GCA were not differentially abundant in cases compared to controls. There was not a significant burden of likely pathogenic viruses. CONCLUSION: DNA sequencing of temporal artery biopsy specimens from GCA cases, in comparison with non-GCA controls, showed no evidence of previously identified candidate GCA pathogens. A single pathogen was not clearly and consistently associated with GCA in this case series.
Assuntos
Arterite de Células Gigantes/microbiologia , Arterite de Células Gigantes/patologia , Microbiota , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , DNA Bacteriano/genética , Escherichia coli/genética , Infecções por Escherichia coli/complicações , Feminino , Infecções por Bactérias Gram-Positivas/complicações , Humanos , Masculino , Moraxella catarrhalis/genética , Infecções por Moraxellaceae/complicações , Propionibacterium acnes/genéticaAssuntos
Mucormicose/patologia , Doenças Orbitárias/patologia , Idoso , Idoso de 80 Anos ou mais , Cegueira/etiologia , Encéfalo/patologia , Artéria Carótida Interna/patologia , Diagnóstico Diferencial , Seio Etmoidal/patologia , Evolução Fatal , Feminino , Testes Hematológicos , Humanos , Infecções/diagnóstico , Imageamento por Ressonância Magnética , Mucorales/isolamento & purificação , Mucormicose/complicações , Mucormicose/diagnóstico , Doenças Orbitárias/complicações , Doenças Orbitárias/diagnóstico , Pancitopenia/complicações , Seio Esfenoidal/patologia , Punção EspinalAssuntos
Antirreumáticos/efeitos adversos , Hidroxicloroquina/efeitos adversos , Retina/efeitos dos fármacos , Transtornos da Visão/induzido quimicamente , Transtornos da Visão/diagnóstico , Campos Visuais/efeitos dos fármacos , Humanos , Testes de Função Renal , Testes de Função Hepática , Testes de Campo VisualRESUMO
OBJECTIVE: To describe the clinical course and management of patients with a pathologic diagnosis of "healed" giant cell arteritis (GCA), and to determine whether previously published histological descriptions of healed arteritis can identify patients with a greater likelihood of clinically significant arteritis. METHODS: All temporal artery biopsy reports between 1994 and 2003 were examined for a diagnosis of "healed arteritis." Two rheumatologists abstracted the medical record for presenting features, physical findings, comorbid conditions, and data on treatment and outcomes. One pathologist, blinded to the clinical data, reviewed all specimens and reinterpreted the biopsies according to published histological descriptions of healed arteritis. RESULTS: Forty-seven patients with an initial pathologic diagnosis of healed arteritis were identified. In 54% of these patients, corticosteroid therapy did not change after the diagnosis of healed arteritis was documented in the pathology report. Seventy percent were ultimately treated with no corticosteroids or low-moderate corticosteroid regimens. Only 32% of the initial cases were confirmed upon review of the biopsies using standardized histological criteria. Patients with confirmed healed arteritis were more likely to have a documented history of polymyalgia rheumatica/GCA and a longer duration of corticosteroid treatment before biopsy. These patients were not more likely to have adverse outcomes. CONCLUSION: In this case series, the diagnosis of healed arteritis had little effect on treatment decisions. In most cases, the initial pathologic diagnosis of healed arteritis was not confirmed when biopsies were reviewed by a single pathologist using uniform histological criteria.
Assuntos
Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/patologia , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimialgia Reumática/diagnósticoRESUMO
B cells may be implicated in the pathophysiology of chronic graft-versus-host disease (GVHD), as evidenced by antibody production against sex-mismatched, Y chromosome-encoded minor HLA antigens in association with chronic GVHD. We therefore designed a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twenty-one patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events. The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period. We conclude that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroidrefractory chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00136396.