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PURPOSE: Testicular cancer survivors (TCS) exposed to chemotherapy have an increased expression of CDKN2A/p16INK4a and a lymphocyte phenotype associated with immunosenescence. We seek to define whether the immunosenescent phenotype is associated with chemotherapy. METHODS: Case-control study of TCS, disease-free ≥3 months and stratified by primary treatment modality into orchiectomy only, chemotherapy, or bone marrow transplant (BMT). Each group was compared with age-matched healthy controls (HC). We measured the relative proportions of lymphocyte subpopulations using flow cytometry, levels of C-reactive protein, and relative expression of CDKN2A/p16INK4a quantified by qPCR. RESULTS: We included 65 patients; 19 were treated with orchiectomy only, 35 received different doses of chemotherapy, and 11 underwent BMT. The chemotherapy and BMT groups had decreased naïve CD4 cells compared to HC. The chemotherapy group showed increased central and effector memory CD4 cells, as well as effector and terminally differentiated CD8 cells, compared to HC. Chemotherapy (chemotherapy 1.84 vs. HC 0.92; p < 0.01) and BMT (BMT 6.96 vs. HC 1.25; p < 0.005) groups had higher expression of CDKN2A/p16INK4a compared to HC. The orchiectomy group showed no significant difference with HC (orchiectomy 1.73 vs. HC 1.01; p = 0.17). CRP levels were higher in all groups when compared with HC; in the orchiectomy group, they were only marginally increased (chemotherapy 0.22 vs. HC 0.06; p < 0.01; BMT 0.26 vs. HC 0.06; p < 0.01; orchiectomy 0.09 vs. HC 0.07; p < 0.01). CONCLUSIONS: Among TCS, only patients exposed to cytotoxic agents developed an immunosenescent phenotype. This finding supports the attribution of this alteration to the cytotoxic treatment.
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Supervivientes de Cáncer , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Orquiectomía , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/terapia , Estudios de Casos y Controles , Adulto , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Persona de Mediana Edad , Trasplante de Médula Ósea , Inmunosenescencia , Envejecimiento , Adulto JovenRESUMEN
The mechanisms that drive systemic lupus erythematosus (SLE) patients to achieve remission are unknown; one possible explanation might be T cell exhaustion. The aim of the present study was to measure CD4+ and CD8+ T cell exhaustion in SLE patients in prolonged remission (PR-SLE) and compared them with patients with active SLE (Act-SLE) and healthy subjects. We included 15 PR-SLE patients, 15 Act-SLE and 29 healthy subjects. T cell exhaustion was determined by flow cytometry according to the expression of programmed cell death 1 (PD)-1, T cell immunoglobulin and mucin 3 (Tim-3), natural killer cell receptor (2B4), eomesodermin (EOMES) and T-box transcription factor TBX21 (T-bet) in CD4+ and CD8+ T cells. Dimensionality reduction using the T-distributed stochastic neighbor-embedding algorithm and clustering analysis was used for the identification of relevant populations. Percentages of CD3+ , CD4+ and CD8+ T cells were similar among groups. We identified five subpopulations of CD8+ and seven of CD4+ cells. The CD4+ T-bet+ CD45RO+ cells identified in the unsupervised analysis were significantly increased in PR-SLE versus Act-SLE [median = 0·20, interquartile range (IQR) = 1·74-30·50 versus 1·68, IQR = 0·4-2·83; P < 0·01]. CD4+ EOMES+ cells were also increased in PR-SLE versus Act-SLE (5·24, IQR = 3·38-14·70 versus 1·39, IQR = 0·48-2·87; P < 0·001). CD8+ EOMES+ cells were increased in PR-SLE versus Act-SLE (37·6, IQR = 24·9-53·2 versus 8·13, IQR = 2·33-20·5; P < 0·001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patients versus healthy subjects. Some subpopulations of T cells expressing markers associated with exhaustion are increased in patients in remission, supporting T cell exhaustion as a tolerance mechanism in SLE. Exhaustion of specific populations of T cells might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission in these patients.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Biomarcadores/sangre , Estudios Transversales , Femenino , Citometría de Flujo/métodos , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana EdadRESUMEN
The original published version of the above article contained errors in Key Points and Conclusion sections.
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OBJECTIVE: To describe the clinical and serological characteristics of patients with SLE who reached a state of sustained remission for more than 10 years in the absence of treatment. METHODS: From a retrospective cohort of 2121 patients, 44 cases with sustained remission (PtRem) were identified and compared with 88 patients whose course has been chronically active (PtAct).The clinical and serological characteristics were analyzed, as well as the treatment of each group at the beginning of the disease and during its evolution. RESULTS: Older age at disease onset was associated with a tendency to reach a state of prolonged remission. These patients also had a higher frequency of thrombocytopenia at the beginning of the disease 34.1% vs 10.2% (p < 0.001). PtAct had a significantly higher initial SLEDAI compared with cases (10.4 ± 5.6 vs 14.1 ± 5.8; p < 0.001). PtRem had a higher initial frequency of anti-ß2 GP1 IgG antibodies. Also, 25% of these patients were serologically active. We did not find differences in the initial treatment between both groups. The accumulated damage measured by SLICC/ACR damage index at the end of the study was significantly less in the patients who remained in prolonged remission. CONCLUSIONS: Although patients with SLE who achieve prolonged remission have some different characteristics at baseline compared with PtAct, it is not possible to identify a characteristic phenotype for the former. Achieving a state of prolonged remission should always be the goal in patients with SLE. Key Points ⢠SLE patients can reach a very prolonged state of remission, free of treatment, including antimalarials, for at least 10 years. ⢠Venous thromboembolism and thrombocytopenia are commonly present in patients that achieved remission. ⢠The presence of serological markers of activity, even after 10 years in remission, is a risk factor for relapse.
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Lupus Eritematoso Sistémico , Anciano , Estudios de Cohortes , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Inducción de Remisión , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Background and objective Pneumonia remains the main cause of mortality in patients with systemic lupus erythematosus (SLE). The aim of the study was to establish the clinical characteristics, microbiology and risk factors for poor prognosis in patients with SLE and pneumonia. Methods We reviewed medical records of patients with SLE (American College of Rheumatology criteria) and pneumonia who attended the emergency room in a single tertiary care center (January 2010-March 2015). We collected demographics, treatment and disease activity (SLEDAI-2K) data. Severity scales of pneumonia (CURB-65 (acronym for risk factors measured: confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older) and Pneumonia Severity Index (PSI)) were obtained. A negative composite outcome was defined as need for mechanical ventilation, septic shock or death secondary to pneumonia up to 30 days after discharge. We conducted a univariate and multivariable analysis. Results We studied 158 patients (76% women) with 187 episodes of pneumonia. There were no differences in age, SLE duration, SLE activity, treatment or comorbidities between patients with negative composite outcome vs the other group. In 53 episodes, patients presented with a negative composite outcome. Of these, 46 (24.6%) required intubation, 13 (7%) developed shock and 12 (6.4%) died. The most common bacteria isolated was S. aureus, and we observed a high percentage of nonhabitual microorganisms. Fifteen percent of patients who presented with a negative outcome had low values on CURB-65 and PSI scales. Conclusion Patients with SLE and pneumonia have a high risk of complications and present with a high percentage of nonhabitual microorganisms. Severity scales for pneumonia can misclassify as low risk SLE patients with poor prognosis.
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Lupus Eritematoso Sistémico/complicaciones , Neumonía/mortalidad , Staphylococcus aureus/aislamiento & purificación , Adulto , Servicio de Urgencia en Hospital , Femenino , Humanos , Modelos Logísticos , Lupus Eritematoso Sistémico/microbiología , Masculino , México , Análisis Multivariante , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Centros de Atención Terciaria , Adulto JovenRESUMEN
Objective The purpose of this study was to describe the clinical characteristics of acute transverse myelitis, including the time of their presentation, and to evaluate their effect on accrual damage in patients with systemic lupus erythematosus (SLE). Methods Patients with SLE who were hospitalized because of incident, noninfectious myelitis at our institute between January 1997 and December 2013 were identified. As a control group, we selected for each of the patients in the study group one SLE patient hospitalized at the closest date to the case due to other severe non-neuropsychiatric (NP) SLE manifestation, with no history of NP manifestations or noninfectious disease. Clinical characteristics, laboratory results, treatment, disease activity (SLEDAI-2K), and damage (SLICC/ACR-DI) were collected from medical charts at the index hospitalization and one year after hospitalization. Results Demographics and SLE characteristics, including age at SLE diagnosis and time since SLE diagnosis to hospitalization, were comparable in patients with myelitis and controls. At hospitalization, disease activity and cumulative damage were similar in both groups. Patients with myelitis received more aggressive treatment than controls. One year after hospitalization, two of the 15 patients who completed follow-up had symptom improvement without neurologic sequelae, and 13 of them had some improvement of symptoms with neurologic sequelae. Four patients died in the myelitis group, three of them of infectious diseases, and one of alveolar hemorrhage. No patient died because of myelopathy and in the control group no patient died, although three were lost during the follow-up. Disease activity and treatment did not differ between both groups. However, cumulative damage was higher among the patients with myelitis than controls (1.9 ± 0.9 vs 0.75 ± 0.9; p = 0.003). Conclusion Patients with myelitis have clinical characteristics similar to those observed in non-NP SLE and receive more aggressive treatment. Furthermore, myelitis is associated with a significant increase in accrual damage compared with severe non-NP manifestations.
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Encéfalo/diagnóstico por imagen , Vasculitis por Lupus del Sistema Nervioso Central/complicaciones , Vasculitis por Lupus del Sistema Nervioso Central/tratamiento farmacológico , Mielitis Transversa/diagnóstico por imagen , Mielitis Transversa/tratamiento farmacológico , Adulto , Líquido Cefalorraquídeo/virología , Ciclofosfamida/uso terapéutico , Femenino , Hospitalización , Humanos , Imagen por Resonancia Magnética , Masculino , Metilprednisolona/uso terapéutico , México , Fármacos Neuroprotectores/uso terapéutico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to assess the utility of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in serum and cerebrospinal fluid (CSF) as a biomarker in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Thirty three NPSLE patients were evaluated at hospitalization and six months later. As controls, five SLE patients with septic meningitis, 51 hospitalized SLE patients without a history of neuropsychiatric (NP) manifestations and without infections, 16 SLE patients without NP manifestations (surgical-SLE), four patients with primary neuropsychiatric disorders, and 25 patients with non-autoimmune diseases were also studied. Serum and CSF samples were drawn at hospitalization, except non-NPSLE patients, in whom only serum was studied, and six months later in 19 NPSLE and 27 non-NPSLE patients. Serum and CSF TWEAK levels were measured by ELISA; values are expressed in pg/mL. RESULTS: The mean ± SD age of NPSLE patients was 31 ± 13.1 years, which was similar across study groups (p = 0.54). TWEAK levels in serum were not different across the study groups. In CSF, TWEAK levels were higher in NPSLE, surgical-SLE and primary neuropsychiatric groups than in non-autoimmune patients: median (IQR) 159.2 (94.1-374.9), 172.3 (125.3-421.9), 371.3 (143-543) vs. 122.1 (76.1-212.4), respectively; all p < 0.05. Six months later, when the neuropsychiatric manifestations were clinically in remission, serum or CSF TWEAK did not vary from baseline in NPSLE patients. CONCLUSIONS: TWEAK levels are slightly elevated in CSF in SLE patients compared with non-autoimmune controls, irrespective of the presence of NP manifestations. TWEAK levels in serum and CSF do not seem to be a useful biomarker of CNS involvement in SLE.
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Lupus Eritematoso Sistémico/diagnóstico , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Factores de Necrosis Tumoral/sangre , Factores de Necrosis Tumoral/líquido cefalorraquídeo , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Citocina TWEAK , Ensayo de Inmunoadsorción Enzimática , Femenino , Hospitalización , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/líquido cefalorraquídeo , Lupus Eritematoso Sistémico/terapia , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Adulto JovenRESUMEN
OBJECTIVE: To define the cytokine and chemokine profile in cerebrospinal fluid (CSF) from patients with neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Forty-two SLE patients who had been hospitalized because of NP manifestations were studied. Patients were evaluated at hospitalization and 6 months later; a CSF sample was obtained at each evaluation. As controls, CSF from 6 SLE patients with septic meningitis, 16 SLE patients with no history of NP manifestations (non-NPSLE), and 25 patients with nonautoimmune diseases were also studied. Soluble molecules, including cytokines (interleukin-2 [IL-2], IL-4, IL-6, IL-10, tumor necrosis factor alpha [TNFalpha], and interferon-gamma [IFNgamma]) and chemokines (monocyte chemotactic protein 1 [MCP-1], RANTES, IL-8, monokine induced by IFNgamma [MIG], and interferon-gamma-inducible 10-kd protein [IP-10]), were measured with the use of cytometric bead array kits. RESULTS: CSF levels of the following molecules were significantly increased in NPSLE patients as compared with non-NPSLE and nonautoimmune diseases control patients, respectively: IL-6 (32.7 versus 3.0 and 2.96 pg/ml), IL-8 (102.8 versus 29.97 and 19.7 pg/ml), IP-10 (888.2 versus 329.7 [P not significant] and 133.6 pg/ml), RANTES (3.8 versus 2.5 and 2.2 pg/ml), MCP-1 (401.7 versus 257.9 [P not significant] and 136.9 pg/ml), and MIG (35.4 versus 11.4 and 3.5 pg/ml). Low levels of IL-2, IL-4, IL-10, TNFalpha, and IFNgamma were found in all groups. All cytokines and chemokines, except TNFalpha, were significantly higher among the SLE patients with septic meningitis than among the NPSLE patients. Six months later and in the absence of NP manifestations, all elevated molecule levels, except RANTES, in patients with NPSLE had decreased significantly, and no differences were noted between the NPSLE and non-NPSLE groups. CONCLUSION: A central nervous system response composed of IL-6 and chemokines, but not Th1/Th2 cytokines, is associated with NP manifestations in SLE patients.
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Quimiocinas/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Adulto , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Masculino , Meningitis Bacterianas/líquido cefalorraquídeo , Índice de Severidad de la EnfermedadRESUMEN
CD55 and CD59 are glycophosphatidylinositol-anchored proteins with complement inhibitory properties. Lymphopenia in systemic lupus erythematosus (SLE) has been associated with autoantibodies targeting nuclear antigens. The aim of this study was to evaluate the surface density of CD55 and CD59 in T and B lymphocytes from patients with SLE and lymphopenia and its possible correlation with the presence of common SLE autoantibodies. Flow cytometric analyses were performed on CD55 and CD59 stained CD3+ and CD19+ cells from 40 SLE patients, 30 with lymphopenia and 10 without it, and 25 healthy controls. Autoantibodies were detected in the sera by enzyme linked immunosorbent assay. The mean fluorescence intensity of CD55 and CD59 in T and B cells was significantly diminished in SLE patients with lymphopenia when compared with healthy subjects. Interestingly, the opposite was found in T and B cells from non-lymphopenic SLE patients. Although there was no correlation between CD55 and CD59 surface density and the presence of any specificity of the autoantibodies tested, higher titres of anti-dsDNA, anti-SM and anti-ribosomal p antibodies were significantly associated with lymphopenia. The deficiency of CD55 and CD59 expression may play a role in the pathophysiology of lymphopenia, most likely by increasing the susceptibility of cells to complement mediated cytolysis.