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OBJECTIVES: To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination. METHODS: This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay. RESULTS: The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3-6 weeks after the second vaccination and 3-6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus. CONCLUSIONS: Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution.
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COVID-19 , Enfermedades Reumáticas , Humanos , Vacunas contra la COVID-19 , Rituximab , Abatacept , Vacuna BNT162 , Estudios de Cohortes , Metotrexato/uso terapéutico , Ácido Micofenólico , Estudios Prospectivos , COVID-19/prevención & control , SARS-CoV-2 , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Vacunación , AnticuerposRESUMEN
OBJECTIVE: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). METHODS: We employed multicenter cohort data collected during 2011-2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. RESULTS: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. CONCLUSION: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Poliangitis Microscópica , Humanos , Glucocorticoides/efectos adversos , Resultado del Tratamiento , Rituximab/uso terapéutico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Anticuerpos Anticitoplasma de Neutrófilos , Inducción de Remisión , Granulomatosis con Poliangitis/tratamiento farmacológicoRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a febrile disease with hyperinflammation characterized by activated macrophages with phagocytosis. The treatment strategy of secondary HLH has not been clearly established. Because of the high mortality rate and poor prognosis of HLH, alternative treatment strategies have been sought in treatment-resistant cases. Recently, there have been several reports that ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor, was effective against secondary HLH. Since the pathogenesis of HLH involves the overproduction of cytokines and JAK transmits a variety of cytokine signals, JAK inhibitors are thought to be effective in HLH. We herein report a case of HLH that was refractory to glucocorticoids, cyclosporine, and etoposide but responded to baricitinib. In the field of rheumatology, treatment-resistant cases of secondary HLH remain unmet needs. This is the first report to show that baricitinib was effective in a case of HLH. The accumulation of more cases in the future may prove that baricitinib is a potent agent for treating HLH.
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Azetidinas , Linfohistiocitosis Hemofagocítica , Humanos , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/etiología , Purinas/uso terapéutico , Azetidinas/uso terapéutico , Sulfonamidas/uso terapéutico , CitocinasRESUMEN
OBJECTIVES: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases. METHODS: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis. RESULTS: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01). CONCLUSIONS: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide.
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COVID-19 , Enfermedades Reumáticas , Humanos , Inmunosupresores/uso terapéutico , Rituximab , Metotrexato/uso terapéutico , Abatacept , Inhibidores de la Calcineurina , Japón , Formación de Anticuerpos , Vacunas contra la COVID-19/uso terapéutico , Estudios Prospectivos , Estudios de Cohortes , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2 , Ácido Micofenólico/uso terapéutico , Ciclofosfamida , Enfermedades Reumáticas/tratamiento farmacológicoRESUMEN
BACKGROUND: To analyse the subsequent clinical course of patients with rheumatoid arthritis (RA) who either continued or discontinued biologic agents after hospitalization for infections. METHODS: We retrospectively reviewed the clinical records of 230 RA patients with 307 hospitalizations for infections under biologic therapy between September 2008 and May 2014 in 15 institutions for up to 18 months after discharge. The risks of RA flares and subsequent hospitalizations for infections from 61 days to 18 months after discharge were evaluated. RESULTS: Survival analyses indicated that patients who continued biologic therapy had a significantly lower risk of RA flares (31.4% vs. 60.6%, P < 0.01) and a slightly lower risk of subsequent infections (28.7% vs. 34.5%, P = 0.37). Multivariate analysis showed that discontinuation of biologic therapy, diabetes, and a history of hospitalization for infection under biologic therapy were associated with RA flares. Oral steroid therapy equivalent to prednisolone 5 mg/day or more and chronic renal dysfunction were independent risk factors for subsequent hospitalizations for infections. CONCLUSIONS: Discontinuation of biologic therapy after hospitalization for infections may result in RA flares. Continuation of biologic therapy is preferable, particularly in patients without immunodeficiency.
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Artritis Reumatoide , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Terapia Biológica , Hospitalización , Humanos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Trastornos Linfoproliferativos/tratamiento farmacológico , Metotrexato/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quinasas Janus/antagonistas & inhibidores , Estimación de Kaplan-Meier , Linfoma no Hodgkin/mortalidad , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Prednisona/administración & dosificación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
OBJECTIVE: We investigated the association of airway comorbidities with the clinical phenotypes and outcomes of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-positive ANCA-associated vasculitis (AAV). METHODS: An AAV patient multicenter cohort trial was established in 13 hospitals in western Japan between 2012 and 2018. We examined 143 of the new-onset MPO-ANCA-positive AAV patients. Their clinical characteristics and comorbidities at disease onset were compared based on clinical phenotypes. Multivariate analysis was performed to identify factors predictive of remission and death. RESULTS: Twenty-seven cases with granulomatosis with polyangiitis (GPA), 10 with eosinophilic GPA (EGPA), 81 with microscopic polyangiitis (MPA), and 25 with unclassified AAV were identified. The average age of MPO-ANCA-positive patients was 71.4 years. Comorbidity (87.4%) and airway comorbidity (70.6%) were frequently observed in these patients. Examination of the clinical phenotypes revealed that the cases of GPA were frequently accompanied by infectious airway comorbidity (upper airway disease, bronchiectasis, pulmonary infections), and most of the cases of MPA and unclassified AAV were accompanied by fibrotic interstitial lung disease (fILD) or emphysema. Among MPO-ANCA-positive patients, infectious airway comorbidity was predictive of both remission (HR 1.58, P = 0.03) and mortality (HR 2.64, P = 0.04), and fILD was predictive of mortality (HR 7.55, P = 0.008). The combination of infectious airway comorbidities and fILD caused the worst survival outcomes in patients. CONCLUSION: MPO-ANCA-positive AAV was frequently accompanied by airway comorbidities. In addition to fILD, infectious airway comorbidities were closely associated with those clinical phenotypes and outcomes.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/epidemiología , Anticuerpos Anticitoplasma de Neutrófilos , Comorbilidad , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/epidemiología , Humanos , Mieloblastina , Peroxidasa , FenotipoRESUMEN
OBJECTIVES: We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety. RESULTS: We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = .122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group. CONCLUSION: RTX maintenance therapy could be effective and safe in Japanese GPA patients.
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Antirreumáticos/uso terapéutico , Rituximab/uso terapéutico , Adulto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Rituximab/administración & dosificación , Rituximab/efectos adversosRESUMEN
Rheumatoid arthritis (RA) and diabetes mellitus (DM) are associated with inflammation. We tried to investigate the influence of tumor necrosis factor inhibitors (TNFi) and tocilizumab (TCZ) on the glucose metabolism of RA patients. RA patients in whom treatment with TNFi or TCZ was initiated from 2008 to 2015 were studied based on their medical records. We analyzed patients whose glycosylated hemoglobin (HbA1c) levels were measured both before and 3 months after the initiation of these biologic agents. The association between HbA1c reduction and the treatment was evaluated. From 971 cases treated with these biologic agents, 221 cases whose medical records of HbA1c were available, were included (TNFi, n = 154; TCZ, n = 67). Both the TNFi and TCZ groups had significantly lower HbA1c values at 1 month and 3 months after the initiation of treatment (TNFi, p<0.001; TCZ, p<0.001). Although the pretreatment HbA1c values did not differ (TNFi, 6.2%; TCZ, 6.2%; p = 0.532), the 3-month treatment HbA1c values were lower (TNFi, 6.1%; TCZ, 5.8%; p = 0.010) and the changes in HbA1c (ΔHbA1c) were greater (TNFi, 0.1%; TCZ, 0.4%; p<0.001) in the TCZ group. The reduction of HbA1c-defined by the achievement of a ΔHbA1c of ≥0.5%-was associated with baseline diagnosis of diabetes mellitus, baseline diabetes treatment, hospitalization, medical change during the observation period, and TCZ. In the multivariate logistic regression analysis, TCZ was associated with the reduction of HbA1c in comparison to TNFi (adjusted OR = 5.59, 95% CI = 2.56-12.2; p<0.001). The HbA1c levels in RA patients were significantly lower after the initiation of TNFi or TCZ. Our study suggests that TCZ decreases the HbA1c levels in RA patients to a greater extent than TNFi.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Hemoglobina Glucada/análisis , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Complicaciones de la Diabetes/diagnóstico , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Retrospectivos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We studied the clinico-pathological differences among PR3-ANCA-positive granulomatosis with polyangiitis (PR3-GPA), MPO-ANCA-positive GPA (MPO-GPA) and microscopic polyangiitis (MPA). ANCA-associated vasculitis (AAV) was classified using the European Medicines Agency classification. We retrospectively analyzed 38 patients with GPA and 41 with MPA treated in eight hospitals in Japan. Of the patients with GPA, 17 were positive for MPO-ANCA, and 15 for PR3-ANCA. All patients with MPA were MPO-ANCA positive. The mean ages of those with MPO-GPA were 69.6 years old, 10 years older than those with PR3-GPA. The majority (82 %) of patients with MPO-GPA were woman, a significantly greater proportion than for PR3-GPA. We also found that ear, nose and throat (ENT), nervous system involvement were significantly more common in MPO-GPA, but renal function was less impaired than those with MPA. Both PR3-GPA and MPO-GPA relapsed more frequently than MPA, but overall survival was significantly better (P < 0.01 and P < 0.05, respectively). Univariate analysis identified the following factors as predictors of a poor prognosis: MPA (P < 0.01), pulmonary UIP pattern (P < 0.005) Cr ≥ 1.7 mg/dl (P < 0.01) and absence of ENT involvement (P < 0.05), which were characteristics of MPA. In our cohort, MPO-GPA was most likely to affect older women and was associated with otitis media, nervous system involvement, mild renal impairment and more favorable outcome. It is clinically useful to differentiate MPO-GPA from MPA and PR3-GPA in patients with AAV.
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Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Granulomatosis con Poliangitis/inmunología , Mieloblastina/inmunología , Peroxidasa/inmunología , Factores de Edad , Anciano , Femenino , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/mortalidad , Humanos , Japón , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Otitis Media/etiología , Recurrencia , Estudios Retrospectivos , Factores Sexuales , Vasculitis del Sistema Nervioso Central/etiologíaRESUMEN
OBJECTIVES: The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. METHODS: We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy. RESULTS: PCP developed within 26 weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥65 years [hazard ratio (HR) 3.35, p = 0.037], coexisting lung disease (HR 4.48, p = 0.009), and concomitant methotrexate treatment (HR 4.68, p = 0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p < 0.001 for patients with two or more risk factors vs. those with no risk factor, and p = 0.001 for patients with one risk factor vs. those with no risk factor). CONCLUSION: Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present.
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Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Inmunoglobulina G/efectos adversos , Infecciones Oportunistas/inducido químicamente , Pneumocystis carinii/aislamiento & purificación , Neumonía por Pneumocystis/microbiología , Adulto , Anciano , Antifúngicos/uso terapéutico , Antirreumáticos/uso terapéutico , Estudios de Casos y Controles , Etanercept , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/tratamiento farmacológico , Neumonía por Pneumocystis/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Estudios RetrospectivosRESUMEN
Objectives The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. Methods We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy. Results PCP developed within 26 weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥ 65 years [hazard ratio (HR) 3.35, p = 0.037], coexisting lung disease (HR 4.48, p = 0.009), and concomitant methotrexate treatment (HR 4.68, p = 0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p < 0.001 for patients with two or more risk factors vs. those with no risk factor, and p = 0.001 for patients with one risk factor vs. those with no risk factor). Conclusion Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present.
RESUMEN
A 56-year-old woman who had been treated for mixed connective tissue disease (MCTD) noticed a skin ulcer on the lower leg. There was no history of trauma. X-rays of the lower legs showed extensive calcification in the soft tissue. Biopsied tissue from the ulcer showed marked calcium deposition with necrosis. Laboratory findings revealed normal serum calcium and phosphate levels and normal parathyroid function. On the basis of these findings, we diagnosed skin ulcer due to subcutaneous dystrophic calcification associated with MCTD. The ulcer was gradually reduced in size and epithelialized by treatment with local debridement and antibiotics.
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Calcinosis/patología , Enfermedad Mixta del Tejido Conjuntivo/patología , Calcinosis/complicaciones , Femenino , Humanos , Pierna , Persona de Mediana Edad , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Úlcera Cutánea/etiología , Úlcera Cutánea/patología , Úlcera Cutánea/terapiaRESUMEN
OBJECTIVE: Identification of the association of killer cell immunoglobulin-like receptor (KIR) genes with SLE and accompanying infections. METHODS: Presence or absence of all 14 KIR genes was studied for association with SLE by case-control studies. A total of 417 SLE cases, 72 RA cases and 256 controls, all of Japanese descent, were enrolled. RESULTS: The carrier frequency of KIR2DL5 was significantly decreased in SLE patients compared with healthy controls [39.3 vs 50.4%; odds ratio (OR) = 0.64; 95% CI 0.36, 0.92; P = 0.005). When the prevalence of severe infections was analysed in 184 SLE patients, whose medical records were available, KIR2DL5 carriers were at an increased risk of overall infection and viral infection (crude OR = 2.66; 95% CI 1.43, 4.92; P = 0.017 and crude OR = 2.31; 95% CI 1.15, 4.62; P = 0.017, respectively). After adjusting for methylprednisolone pulse and/or cyclophosphamide pulse therapy, KIR2DL5 carriers were at significantly greater risk of infectious events overall (adjusted OR = 2.45; 95% CI 1.24, 4.81; P = 0.0095). However, KIR2DL5 carriers were marginally associated with an increased risk of viral infectious events (adjusted OR = 2.03; 95% CI 0.94, 4.41; P = 0.0718). CONCLUSION: KIR2DL5 was significantly associated with a decreased risk of SLE as well as an increased risk of infectious events overall in SLE patients. Our data suggest a further role of KIRs in the pathogenesis of autoimmune diseases and infection.
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Lupus Eritematoso Sistémico/genética , Receptores KIR2DL5/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lupus Eritematoso Sistémico/inmunología , Polimorfismo Genético , Receptores KIR2DL5/inmunología , Análisis de RegresiónRESUMEN
OBJECTIVES: To perform a case-control study of a functional M196R polymorphism of tumour necrosis factor receptor type 2 (TNF-RII) in a Japanese population and a meta-analysis of all published reports on the polymorphism to investigate the association of the M196R polymorphism of TNF-RII with systemic lupus erythematosus (SLE). METHODS: The functional M196R polymorphism of TNF-RII was genotyped by using polymerase chain reaction combined with the subsequent single-strand conformation polymorphism (PCR-SSCP) analysis for screening, followed by nucleotide sequencing for confirmation. A total of 331 patients and 359 controls were subjected to a case-control study. A meta-analysis of the available case-control studies including all published data as well as our own data was performed to investigate the association of the functional M196R polymorphism of TNF-RII with SLE. RESULTS: Our case-control study did not show any significant association of a functional M196R polymorphism of TNF-RII with SLE, although there was a trend towards association. A meta-analysis of seven case-control studies in eight different ethnic populations including our own showed that 196M/R and 196R/R genotypes combined was significantly associated with an increased risk of SLE (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.04 to 1.60; p = 0.02). Stratification by ethnicity showed a more significant association in Asians, including Japanese, Korean and Vietnamese (OR 1.40, 95% CI 1.10 to 1.78; p = 0.006). The effect of the 196R allele on SLE was not clear in Caucasians. CONCLUSIONS: The 196R allele of the functional M196R polymorphism of TNF-RII is a risk factor for SLE, especially in the Asian population.
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Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lupus Eritematoso Sistémico/etnologíaRESUMEN
Membrane TNF-alpha is a precursor form of soluble TNF-alpha and exerts pro-inflammatory functions in a cell-to-cell contact manner. We showed that membrane TNF-alpha is induced upon activation on the cell surface of CD4+ T cells and CD8+ T cells. In patients with systemic lupus erythematosus (SLE), the percentage of membrane TNF-alpha-bearing CD8+ T cells (41.5+/-12.3%) was significantly higher compared with those of healthy controls (26.7+/-3.9%) (p=0.007) or patients with rheumatoid arthritis (29.8+/-15.4%) (p=0.038). Membrane TNF-alpha-bearing CD8+ T cells from SLE patients displayed cytotoxic activity against L929 cells. It is possible that membrane TNF-alpha may be involved in the increased apoptosis and the generation of autoantigens in SLE.
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Linfocitos T CD8-positivos/metabolismo , Lupus Eritematoso Sistémico/sangre , Glicoproteínas de Membrana/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citotoxicidad Inmunológica , Relación Dosis-Respuesta a Droga , Humanos , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos , Glicoproteínas de Membrana/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84bp). A single base substitution (AG to GG) in the 3'-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Delta(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Delta(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3.
Asunto(s)
Complemento C3/deficiencia , Lupus Eritematoso Sistémico/genética , Adulto , Animales , Secuencia de Bases , Células COS , Complemento C3/genética , Cartilla de ADN , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell-specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay. RESULTS: We identified a glutamic acid-proline-glutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. CONCLUSION: These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.
Asunto(s)
Proteínas Sanguíneas/genética , Elementos Transponibles de ADN , Ácido Glutámico/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético/genética , Prolina/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Linfocitos B , Secuencia de Bases , Estudios de Casos y Controles , Línea Celular , ADN , ADN Complementario , Femenino , Frecuencia de los Genes , Genoma Humano , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , TransfecciónRESUMEN
Cyclosporin A (CsA) has various adverse effects including neurotoxicity. We report the case of a 49-year-old Japanese woman with dermatomyositis who showed CsA-induced cortical blindness. The patient demonstrated cortical blindness despite having a normal blood concentration of CsA. The risk factors of CsA-induced cortical blindness include the use of corticosteroids and vascular injury, which are frequently observed in patients with systemic autoimmune diseases. Clinicians should consider CsA neurotoxicity when using CsA for patients with systemic autoimmune diseases.