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1.
Lancet Haematol ; 7(2): e157-e167, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32004485

RESUMEN

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre/efectos adversos , Manejo de la Enfermedad , Monitoreo de Drogas , Resistencia a Medicamentos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresión/métodos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Trasplante de Células Madre/métodos , Acondicionamiento Pretrasplante/métodos
2.
Lancet Haematol ; 7(2): e100-e111, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31958417

RESUMEN

BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60-7·60]; p=0·0016. At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9-23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9-25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2-29·2) versus 31·3% (21·9-40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5-35·1) in the anti-thymocyte globulin group and 41·3% (31·3-51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 53·3% (95% CI 42·8-62·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 70.6% (95% CI 60·6-78·6) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35-0·90]; p=0·017. Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient died of Epstein-Barr virus hepatitis. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including a decrease in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin could be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Inmunosupresores/uso terapéutico , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Adolescente , Adulto , Anciano , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresores/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Medición de Resultados Informados por el Paciente , Linfocitos T/inmunología , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Donante no Emparentado , Adulto Joven
3.
Medicine (Baltimore) ; 98(50): e18415, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31852165

RESUMEN

RATIONALE: Urinary obstruction are relatively rare complications of autoimmune diseases including systemic lupus erythematosus and systemic vasculitis. It has never been reported in rheumatoid arthritis (RA). PATIENT CONCERNS: We report a case of a female patient with seropositive RA who presented with gross hematuria associated with worsening joint symptoms, found to have acute kidney injury (AKI), bilateral hydronephrosis with bilateral renal pelvis, and ureteral wall thickening. Uroscopy with biopsy demonstrated inflammation without evidence of malignancy. DIAGNOSES: Rheumatoid arthritis related inflammation and obstruction of the urinary tract. INTERVENTIONS: Prednisone 50 mg daily (tapering began 1 month later), iguratimod 50 mg daily, and leflunomide 20 mg daily were prescribed. OUTCOMES: The patient responded well to steroids and immunosuppressive therapy with complete resolution of hematuria, renal injury, and hydronephrosis. LESSONS: Our case showed that RA might cause local inflammation involving the urinary tract which leads to obstruction and AKI.


Asunto(s)
Artritis Reumatoide/complicaciones , Obstrucción Ureteral/etiología , Antiinflamatorios/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Hematuria/etiología , Humanos , Hidronefrosis/etiología , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Prednisona/uso terapéutico , Obstrucción Ureteral/tratamiento farmacológico
4.
Clin Exp Rheumatol ; 37 Suppl 121(6): 98-104, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31856935

RESUMEN

OBJECTIVES: The aim of this multicentre study was to understand patients' needs and to evaluate the oral ulcer activity with the Composite Index (CI), according to different treatment modalities in Behçet's syndrome (BS). METHODS: BS patients (n=834) from 12 centres participated in this cross-sectional study. Oral ulcer activity (active vs. inactive) and the CI (0: inactive vs. 1-10 points: active) were evaluated during the previous month. The effects of treatment protocols [non-immunosuppressive: non-IS vs. immunosuppressive: (ISs)], severity (mild vs. severe), disease duration (<5 years vs. ≥5 years) and smoking pattern (non-smoker vs. current smoker) were analysed for oral ulcer activity. RESULTS: Oral ulcer activity was observed in 65.1% of the group (n=543). In both genders, the activity was higher in mild disease course with non-IS treatment group compared to severe course with ISs (p<0.05). As a resistant group, patients with mild disease course whose mucocutaneous symptoms were unresponsive to non-IS medications were treated with ISs in a limited period and achieved the highest CI scores in females. Oral ulcer activity and poor CI score were associated with disease duration less than 5 years compared to others in male patients (p<0.05). CONCLUSIONS: Oral ulcer activity pattern is affected by both the combination of disease course, treatment protocols and disease duration. CI scores reflected the oral clinical activity and CI might be a candidate scale to evaluate the efficacy of treatments during the follow-up of oral ulcer activity in BS.


Asunto(s)
Síndrome de Behçet , Inmunosupresores/uso terapéutico , Úlceras Bucales , Síndrome de Behçet/clasificación , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Úlceras Bucales/clasificación , Recurrencia , Índice de Severidad de la Enfermedad
5.
Clin Exp Rheumatol ; 37 Suppl 121(6): 3-17, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31856939

RESUMEN

Several epidemiologic studies report on the prevalence of Behçet's syndrome (BS) and demographic and clinical findings in patients from different countries and ethnicities. Although these studies point out geographic differences in disease course, methodologic differences make it difficult to compare the results of these studies. Recent data suggest that neutrophil extracellular trap levels are elevated in patients with BS, and that it may be a potential therapeutic target for the reduction or prevention of BS-associated thrombotic risk. Details on the mode of functioning of ERAP have been delineated and further epigenetic data reported. Wall thickness of lower extremity veins is increased among BS patients without any apparent clinical involvement. Magnetic resonance (MR) venography and Doppler ultrasonography (USG) were comparable in the diagnosis of chronic deep vein thrombosis, while MR venography is more effective in detecting collateral formations. Results were also collected on some dietary and non-dietary factors in triggering oral ulcers, while smoking seems to have a protective role. With regards to the therapy, it has been demonstrated that endovascular interventions carry the risk of inducing pathergy phenomenon. Apremilast has been convincingly shown to be useful for oral ulcers of BS and classical immunosuppressives are effective as first line therapy in more than half of patients with uveitis. While infliximab and adalimumab seem to be equally effective in the treatment of refractory uveitis of BS, the combination of adalimumab and immunosuppressives appears to be superior to immunosuppressives alone for venous thrombosis of the extremities. In addition, tocilizumab might be an alternative to anti-TNF agents for patients with arterial involvement refractory to immunosuppressives. On the other hand, the place of IL-17 inhibition in the treatment of BS still remains questionable.


Asunto(s)
Síndrome de Behçet , Inmunosupresores/uso terapéutico , Adalimumab , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamiento farmacológico , Predisposición Genética a la Enfermedad , Humanos , Úlceras Bucales/etiología , Prevalencia , Factor de Necrosis Tumoral alfa/uso terapéutico , Uveítis/etiología , Trombosis de la Vena/etiología
6.
N Engl J Med ; 381(22): 2114-2124, 2019 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-31774956

RESUMEN

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti-aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. The efficacy of satralizumab added to immunosuppressant treatment in patients with NMOSD is unclear. METHODS: In a phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with NMOSD who were seropositive or seronegative for AQP4-IgG to receive either satralizumab, at a dose of 120 mg, or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary end point was the first protocol-defined relapse in a time-to-event analysis. Key secondary end points were the change from baseline to week 24 in the visual-analogue scale (VAS) pain score (range, 0 to 100, with higher scores indicating more pain) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicating more fatigue). Safety was also assessed. RESULTS: A total of 83 patients were enrolled, with 41 assigned to the satralizumab group and 42 to the placebo group. The median treatment duration with satralizumab in the double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%) receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38; 95% confidence interval [CI], 0.16 to 0.88). Multiple imputation for censored data resulted in hazard ratios ranging from 0.34 to 0.44 (with corresponding P values of 0.01 to 0.04). Among 55 AQP4-IgG-seropositive patients, relapse occurred in 11% of those in the satralizumab group and in 43% of those in the placebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28 AQP4-IgG-seronegative patients, relapse occurred in 36% and 43%, respectively (hazard ratio, 0.66; 95% CI, 0.20 to 2.24). The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, -8.44 to 16.61); the between-group difference in the change in the mean FACIT-F score was -3.10 (95% CI, -8.38 to 2.18). The rates of serious adverse events and infections did not differ between groups. CONCLUSIONS: Among patients with NMOSD, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo but did not differ from placebo in its effect on pain or fatigue. (Funded by Chugai Pharmaceutical; ClinicalTrials.gov number, NCT02028884.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/inmunología , Receptores de Interleucina-6/inmunología , Recurrencia , Adulto Joven
8.
Mayo Clin Proc ; 94(11): 2199-2208, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685150

RESUMEN

OBJECTIVE: To evaluate the impact of the sequence of treatment with rituximab and/or splenectomy on time to relapse for patients with steroid-refractory immune thrombocytopenia (ITP). PATIENTS AND METHODS: Patients 18 years or older with steroid-refractory immune thrombocytopenia who underwent treatment with splenectomy or rituximab from January 1, 2002, through December 31, 2015, at Mayo Clinic. Evaluation included freedom from relapse (FFR) and response rates after treatment with rituximab or splenectomy as single or sequential interventions. RESULTS: A total of 218 eligible patients with ITP who were treated according to standard of care were included in this analysis. Patients failing steroids treated with splenectomy had a higher 5-year FFR than did those treated with rituximab (67.4% vs 19.2%; P<.001, propensity-score matched). Patients who failed splenectomy and were then treated with rituximab had a 2-year FFR similar to that of patients who failed rituximab and were then treated with splenectomy (73.4% vs 59.9%; P=.52). Patients treated with rituximab after splenectomy had a longer 2-year FFR than did patients treated with rituximab as a second-line treatment (73.4% vs 29.0%; P<.001). CONCLUSION: For patients with ITP that relapse after treatment with steroids, splenectomy provides longer FFR than rituximab as a second-line therapy. Among patients who fail second-line treatment with splenectomy or rituximab, those who end up receiving sequential splenectomy-rituximab or rituximab-splenectomy therapy seem to derive similar benefit in the long term. Patients who received rituximab after splenectomy seem to derive superior benefit than do those who are treated with rituximab with an intact spleen.


Asunto(s)
Inmunosupresores/uso terapéutico , Púrpura Trombocitopénica Idiopática/terapia , Rituximab/uso terapéutico , Esplenectomía/métodos , Esteroides/uso terapéutico , Adulto , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/fisiopatología , Análisis de Supervivencia , Resultado del Tratamiento
9.
BMC Neurol ; 19(1): 263, 2019 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-31672142

RESUMEN

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rapidly developing demyelinating disease in the cerebral white matter and is often caused by JC polyomavirus (JCV). PML after lung transplantation is rare and has a poor prognosis, with no established therapies. Reducing the patient's immunosuppressant doses, thereby restoring immunity, could be used to treat PML. However, some patients develop immune reconstitution inflammatory syndrome (IRIS) with this treatment, an immune-induced inflammatory response to JCV that results in serious neuronal damage. We herein report a case of a 60-year-old female who suffered from PML 5 years after lung transplantation, had worsened brain lesions thought to be related to PML-IRIS at the time of immunosuppressant reduction, and missed treatment opportunities. CASE PRESENTATION: A 60-year-old female developed PML 5 years after lung transplantation. Fluid-attenuated inversion recovery and diffusion-weighted brain magnetic resonance imaging (MRI) revealed multiple high-signal lesions, mainly in the cerebral white matter. Polymerase chain reaction found 0.32 million copies/mL of JCV in the cerebrospinal fluid. Thus, she was given a diagnosis of PML. Mycophenolate mofetil and tacrolimus dosages were reduced, and CD4-positive cell counts and the blood concentration of each immunosuppressant were monitored. Mefloquine was also orally administered at a daily dose of 275 mg for 3 days and was then administered at a dose of 275 mg per week. Although the patient's CD4-positive cell counts increased and her immune system recovered, her symptoms and brain MRI findings worsened. We suspected PML progression or a transition to PML-IRIS. Steroid pulse therapy to suppress the inflammatory lesions was not possible but was retrospectively indicated. The patient rapidly began to exhibit akinetic mutism and died 4 months after the onset of neurologic symptoms. CONCLUSIONS: When neurologic symptoms and abnormal brain MRI findings are noted during immune recovery, it is often difficult to distinguish between progressed PML and PML-IRIS. However, the pathogenesis of brain lesions usually involves inflammation and immune-reactive mechanisms for JCV. Steroid pulse therapy, which can reduce inflammation, should thus be administered in organ transplantation cases with differential diagnoses including PML-IRIS.


Asunto(s)
Síndrome Inflamatorio de Reconstitución Inmune , Leucoencefalopatía Multifocal Progresiva , Trasplante de Pulmón , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Huésped Inmunocomprometido , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Virus JC , Persona de Mediana Edad
10.
Presse Med ; 48(11 Pt 2): 328-337, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31703956

RESUMEN

Anti-glomerular basement membrane (GBM) disease is a rare autoimmune vasculitis characterised by antibodies directed against the non collagenous (NC1) domain of the α3 chain of type 4 collagen (α3(IV)NC1). Clinical features are typically of a rapidly progressive glomerulonephritis (RPGN) with or without pulmonary haemorrhage. Treatment aims to rapidly remove circulating autoantibodies with plasma exchange and prevent further antibody production and suppress inflammation using immunosuppression and corticosteroids. Retrospective studies have shown that this combination of treatment results in good renal outcomes compared to historical controls. Disease relapse is uncommon and, unless patients have a co-existing antineutrophil cytoplasm antibody, maintenance treatment is not required.


Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Intercambio Plasmático , Corticoesteroides/uso terapéutico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/complicaciones , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/diagnóstico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Autoantígenos/inmunología , Biopsia , Colágeno Tipo IV/inmunología , Terapia Combinada/métodos , Glomerulonefritis/complicaciones , Humanos , Inmunosupresores/uso terapéutico , Inflamación/tratamiento farmacológico , Riñón/patología , Estudios Retrospectivos
11.
Transplant Proc ; 51(9): 2917-2920, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31711577

RESUMEN

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.


Asunto(s)
Citocromo P-450 CYP3A/genética , Inmunosupresores/metabolismo , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Tacrolimus/metabolismo , Tacrolimus/uso terapéutico , Adulto , Anciano , Monitoreo de Drogas , Femenino , Genotipo , Rechazo de Injerto/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Medicina de Precisión/métodos , Estudios Retrospectivos
12.
Transplant Proc ; 51(9): 3181-3185, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31711586

RESUMEN

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.


Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Intestinos/trasplante , Femenino , Enfermedad de Hirschsprung/cirugía , Humanos , Complicaciones Posoperatorias/tratamiento farmacológico , Embarazo , Adulto Joven
13.
Medicine (Baltimore) ; 98(46): e18005, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31725670

RESUMEN

RATIONALE: Multiple system atrophy is a late-onset rare neurodegenerative movement disorder which results in debilitating disease. Fever frequently ensues in the context of infections which can be associated with significant morbidity and mortality, but among alternative diagnostic possibilities neoplasms and autoimmune disorders should be considered. PATIENT CONCERNS: We describe a case of a prolonged febrile syndrome in a 55-year-old female patient with onset of multiple system atrophy two years before presentation. Patient history and symptoms were not contributive to guide the diagnostic work-up. DIAGNOSIS: Initial evaluation provided no specific findings. Repeat testing of auto-antibodies revealed positive antinuclear and anti-ds DNA antibodies coupled with low complement which in conjunction with renal biopsy substantiated the diagnosis of systemic lupus erythematosus flare. INTERVENTION: Pending the biopsy result, treatment with hydroxychloroquine and corticosteroids was initiated. Due to failure to achieve remission, azathioprine was added, but symptoms persisted. Following the diagnosis of lupus nephritis, azathioprine was discontinued and induction treatment with cyclophosphamide in accordance with the Euro-Lupus regimen was initiated and upon completion followed by maintenance therapy with mycophenolate mofetil. OUTCOMES: The patient achieved remission after cyclophosphamide was added to treatment with corticosteroids and has not experienced new flares during the next two years. The neurological syndrome has remained stable during this period. LESSONS: To our knowledge, we report the first case of concurrent systemic lupus erythematosus and multiple system atrophy. Prolonged fever presents unique challenges in patients with rare diseases.


Asunto(s)
Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad
14.
BMC Infect Dis ; 19(1): 974, 2019 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-31744480

RESUMEN

BACKGROUND: Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN. METHODS: All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4+ and CD8+ T cells, after stimulation with large-T antigen (LT) and viral capsid protein 1 (VP1), were performed both at the time of diagnosis and after adjustment of immunosuppression. RESULTS: We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4+ T cells to LT at a median of 3 (IQR: 1-4) months after adjustment of immunosuppression compared with at the time of diagnosis (0.004 vs. 0.015; p = 0.047). However, the difference between the median percentage of IFN-γ-producing CD4+ T cells to VP1 and CD8+ T cells to LT and VP1 did not reach statistical significance. Four (33%) patients achieved plasma BKPyV DNA clearance, and the remaining eight (67%) patients had persistent BKPyV DNAemia. Although eight (67%) patients developed allograft dysfunction, none required hemodialysis. CONCLUSIONS: We observed a marginal trend of BKPyV-specific CD4+ T cell recovery after adjustment of immunosuppression in KT recipients diagnosed with BKPyVAN. A further study would be benefited to confirm and better assess BKPyV-specific immune response after KT.


Asunto(s)
Virus BK/inmunología , Linfocitos T CD8-positivos/inmunología , Trasplante de Riñón/efectos adversos , Nefritis Intersticial/diagnóstico , Infecciones por Polyomavirus/diagnóstico , Adulto , Virus BK/genética , Virus BK/aislamiento & purificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , ADN Viral/sangre , Femenino , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Nefritis Intersticial/etiología , Nefritis Intersticial/virología , Infecciones por Polyomavirus/etiología , Infecciones por Polyomavirus/virología , Tacrolimus/uso terapéutico , Trasplante Homólogo , Proteínas Virales/inmunología
15.
Internist (Berl) ; 60(12): 1251-1269, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31754753

RESUMEN

Systemic sclerosis (SSc) is a rare fibrosing rheumatic multi-systemic disease involving many medical specialties. The mortality of SSc is determined by lung fibrosis, pulmonary arterial hypertension and cardiac involvement. With early and intensive treatment, the disease can be stabilized and symptoms relieved. This review summarizes insights into pathophysiology, disease classification, clinical manifestations and successful therapies, as well as recent studies on new immunosuppressant, biological and vasoactive therapies.


Asunto(s)
Hipertensión Pulmonar/fisiopatología , Fibrosis Pulmonar/fisiopatología , Esclerodermia Sistémica/fisiopatología , Humanos , Hipertensión Pulmonar/etiología , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/etiología , Fibrosis Pulmonar/etiología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/terapia
16.
Surg Clin North Am ; 99(6): 1083-1094, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31676049

RESUMEN

Patients with ulcerative colitis and Crohn's disease often present to surgery malnourished and on combination immunosuppression. These factors affect operation selection and postoperative outcomes. Corticosteroids have a well-established detrimental effect on postoperative outcomes, whereas the impact of biologic agents is more controversial. In a patient exposed to these medications, and in the presence of other risk factors, temporary intestinal diversion is likely the best choice. Enteral nutrition may help optimize malnourished patients at high risk of adverse postoperative outcomes.


Asunto(s)
Corticoesteroides/uso terapéutico , Productos Biológicos/uso terapéutico , Colectomía/métodos , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Progresión de la Enfermedad , Toma de Decisiones Clínicas , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/cirugía , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/cirugía , Nutrición Enteral/métodos , Femenino , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/cirugía , Masculino , Desnutrición/terapia , Periodo Preoperatorio , Pronóstico , Resultado del Tratamiento
17.
Medicine (Baltimore) ; 98(45): e17658, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31702617

RESUMEN

Patients with idiopathic membranous nephropathy (IMN) can be categorized into phospholipase A2 receptor (PLA2R)-associated and non-PLA2R-associated cases, according to serum PLA2R antibody status. The present study aimed to determine whether clinical features differed between these.A total of 89 patients with IMN were retrospectively recruited for the present study. Serum PLA2R-Ab levels were determined by time-resolved fluoroimmunoassay. Furthermore, the relationship between serum PLA2R antibody levels and their responses to immunosuppressants among patients with a complete follow-up period, which was defined as at least 1 year, was analyzed.Among these enrollees, 71 (80.0%) patients were positive for serum PLA2R antibody. Furthermore, patients with PLA2R-associated IMN had significantly higher age (with vs without, 54.31 ±â€Š14.03 vs 46.67 ±â€Š13.30 years old; P = .04), proteinuria (4.32 ±â€Š1.84 vs 3.29 ±â€Š1.90 g/d, P = .039), and serum albumin (25.33 ±â€Š9.60 vs 31.38 ±â€Š9.52 g/L, P = .019), but had lower serum immunoglobulin G (6.83 ±â€Š2.89 vs 8.72 ±â€Š2.95 g/L, P = .016) and erythrocyte sedimentation rate (47.31 ±â€Š32.11 vs 26.33 ±â€Š27.94, P = .013), when compared to IMN patients without PLA2R. Furthermore, IMN patients without PLA2R exhibited a better response to immunosuppressants, when compared to patients with PLA2R-associated IMN (without vs with, 66.7% vs 62.5% at 6 months and 100% vs 87.5% at 12 months), but the difference was not statistically significant.Patients with PLA2R-associated IMN had higher disease severity than IMN patients without PLA2R. Furthermore, PLA2R negative patients had a better response to immunosuppressive therapies than PLA2R-positive patients, but the difference was not statistically significant.


Asunto(s)
Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Receptores de Fosfolipasa A2/sangre , Adulto , Anciano , Sedimentación Sanguínea , Femenino , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/metabolismo , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Albúmina Sérica/metabolismo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
18.
Nat Commun ; 10(1): 4779, 2019 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-31636267

RESUMEN

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.


Asunto(s)
Linfohistiocitosis Hemofagocítica/genética , Proteínas de Unión al ARN/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Animales , Codón sin Sentido , Consanguinidad , Ciclosporina/uso terapéutico , Eosinofilia/genética , Eosinofilia/inmunología , Homocigoto , Humanos , Inmunofenotipificación , Inmunosupresores/uso terapéutico , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/inmunología , Masculino , Ratones , Monocitos/inmunología , Receptores OX40/genética , Receptores OX40/inmunología , Receptores OX40/metabolismo , Recurrencia , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Ubiquitina-Proteína Ligasas/inmunología
19.
Cancer Immunol Immunother ; 68(12): 1949-1958, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31637474

RESUMEN

Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia , Neoplasias del Colon/terapia , Ciclofosfamida/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Neoplasias Experimentales/terapia , Partículas alfa , Animales , Antígenos de Neoplasias/inmunología , Células Cultivadas , Femenino , Humanos , Inmunidad , Memoria Inmunológica , Ratones , Ratones Endogámicos BALB C , Poli I-C/administración & dosificación , Inducción de Remisión
20.
BMJ ; 367: l5553, 2019 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-31641045

RESUMEN

Sarcoidosis is a highly variable granulomatous multisystem syndrome. It affects individuals in the prime years of life; both the frequency and severity of sarcoidosis are greater in economically disadvantaged populations. The diagnosis, assessment, and management of pulmonary sarcoidosis have evolved as new technologies and therapies have been adopted. Transbronchial needle aspiration guided by endobronchial ultrasound has replaced mediastinoscopy in many centers. Advanced imaging modalities, such as fluorodeoxyglucose positron emission tomography scanning, and the widespread availability of magnetic resonance imaging have led to more sensitive assessment of organ involvement and disease activity. Although several new insights about the pathogenesis of sarcoidosis exist, no new therapies have been specifically developed for use in the disease. The current or proposed use of immunosuppressive medications for sarcoidosis has been extrapolated from other disease states; various novel pathways are currently under investigation as therapeutic targets. Coupled with the growing recognition of corticosteroid toxicities for managing sarcoidosis, the use of corticosteroid sparing anti-sarcoidosis medications is likely to increase. Besides treatment of granulomatous inflammation, recognition and management of the non-granulomatous complications of pulmonary sarcoidosis are needed for optimal outcomes in patients with advanced disease.


Asunto(s)
Glucocorticoides/uso terapéutico , Hipertensión Pulmonar/prevención & control , Inmunosupresores/uso terapéutico , Fibrosis Pulmonar/prevención & control , Sarcoidosis Pulmonar/diagnóstico , Biomarcadores/sangre , Broncoscopía/métodos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Fluorodesoxiglucosa F18/administración & dosificación , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/mortalidad , Incidencia , Pulmón/diagnóstico por imagen , Pulmón/patología , Tomografía de Emisión de Positrones/métodos , Pronóstico , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/mortalidad , Sarcoidosis Pulmonar/complicaciones , Sarcoidosis Pulmonar/tratamiento farmacológico , Sarcoidosis Pulmonar/epidemiología , Resultado del Tratamiento
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