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1.
Ann Rheum Dis ; 82(1): 35-47, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35725297

RESUMEN

OBJECTIVES: Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations. METHODS: Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement. RESULTS: In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients. CONCLUSIONS: These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.


Asunto(s)
Antirreumáticos , Enfermedades Autoinmunes , Enfermedades Reumáticas , Adulto , Humanos , Niño , Vacunas Atenuadas/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Vacunación/métodos , Inmunosupresores/efectos adversos , Antirreumáticos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico
2.
Artículo en Inglés | MEDLINE | ID: mdl-37669122

RESUMEN

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis. Most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. OBJECTIVES: To conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. METHODS: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of 3 rounds. In the first two rounds, online list of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. RESULTS: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate, and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side-effect, and preferred the use of biologics over conventional treatment. The role of interleukin-1 and interleukin-6 blocking agents was considered important in the treatment of AOSD. CONCLUSIONS: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

3.
Clin Exp Rheumatol ; 40(11): 2153-2160, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35579081

RESUMEN

OBJECTIVES: We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects. METHODS: We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes. RESULTS: Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02). CONCLUSIONS: Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.


Asunto(s)
Lupus Eritematoso Sistémico , Complicaciones del Embarazo , Embarazo , Humanos , Femenino , Quimerismo , Leucocitos Mononucleares , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
4.
Ann Rheum Dis ; 79(1): 39-52, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31413005

RESUMEN

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.


Asunto(s)
Antirreumáticos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Infecciones Bacterianas/prevención & control , Enfermedades Reumáticas/tratamiento farmacológico , Vacunas/uso terapéutico , Virosis/prevención & control , Composición Familiar , Hepatitis A/prevención & control , Vacunas contra la Hepatitis A/uso terapéutico , Hepatitis B/prevención & control , Vacunas contra Hepatitis B/uso terapéutico , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/uso terapéutico , Humanos , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/prevención & control , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/uso terapéutico , Tétanos/prevención & control , Toxoide Tetánico/uso terapéutico , Vacunas Atenuadas/uso terapéutico
5.
N Engl J Med ; 370(5): 433-43, 2014 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-24350901

RESUMEN

BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).


Asunto(s)
Células Dendríticas/metabolismo , Factor Plaquetario 4/sangre , Esclerodermia Sistémica/sangre , Adulto , Animales , Biomarcadores/sangre , Citocinas/metabolismo , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertensión Pulmonar/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Factor Plaquetario 4/metabolismo , Proteoma , Fibrosis Pulmonar/sangre , ARN Mensajero/metabolismo , Esclerodermia Sistémica/etiología , Piel/patología
6.
Mol Med ; 22: 12-21, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26837069

RESUMEN

High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 µg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

7.
Rheumatology (Oxford) ; 55(12): 2260-2270, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27632996

RESUMEN

OBJECTIVES: Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased HMGB1 levels, as present in SLE, skew macrophage differentiation towards M1-like phenotypes and thereby diminish uptake of apoptotic cells. The aim of this study was to investigate the effect of HMGB1 on macrophage polarization and on phagocytic capacity of differentiated macrophages. METHODS: SLE patients with quiescent disease (SLEDAI ⩽4) and healthy controls (HCs) were included. Monocytes and differentiated M1 and M2 macrophages were assessed for expression of M1 and M2 markers and for phagocytic capacity. HMGB1 was added during differentiation and during phagocytosis. RESULTS: Expression of CD86 (M1) was not different, whereas CD163 (M2) was significantly lower on SLE monocytes. After differentiation, no differences regarding surface receptor expression and phagocytic capacity were observed between M1 and M2 macrophages from SLE patients and HCs. Addition of HMGB1 during M2 differentiation resulted in high IL-6 and TNF-α mRNA expression and reduced phagocytic capacity of apoptotic cells. Furthermore, adding HMGB1 to apoptotic Jurkat cells diminished phagocytosis of these cells. CONCLUSION: Circulating monocytes from SLE patients display an M1-like phenotype compared with HCs, but in vitro differentiation abolishes this difference. HMGB1 skews differentiation of M2-like macrophages towards an M1-like phenotype and, subsequently, reduces phagocytosis of apoptotic cells. These data imply that the phenotype of monocytes or macrophages is determined by their environment, such as the presence of cytokines and HMGB1.


Asunto(s)
Proteína HMGB1/fisiología , Macrófagos/fisiología , Fagocitosis/fisiología , Adulto , Apoptosis/fisiología , Biomarcadores/metabolismo , Diferenciación Celular/fisiología , Femenino , Proteína HMGB1/farmacología , Humanos , Técnicas In Vitro , Células Jurkat/fisiología , Leucocitos Mononucleares/fisiología , Activación de Macrófagos/fisiología , Masculino , Persona de Mediana Edad , Necrosis , Fagocitosis/efectos de los fármacos , ARN Mensajero/metabolismo , Adulto Joven
8.
Rheumatology (Oxford) ; 55(5): 939-48, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26748351

RESUMEN

OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.


Asunto(s)
Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Receptores de IgG/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Nefritis Lúpica/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex/métodos , Sistemas de Lectura Abierta
9.
Rheumatology (Oxford) ; 54(7): 1257-61, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25587178

RESUMEN

OBJECTIVE: The incidence of cardiovascular disease (CVD) is increased in RA. This study was designed to evaluate whether a reduction in disease activity influences early markers of CVD. METHODS: In a prospective longitudinal study, 58 newly diagnosed RA patients and 58 age- and sex-matched healthy controls (HCs) were included. Endothelial dysfunction was measured by small artery elasticity (SAE) and endothelial cell activation was assessed by measuring soluble vascular cellular activation molecule 1(sVCAM-1) and von Willebrand factor (vWF). Advanced glycation end products (AGEs) were quantified by skin autofluorescence. After 1 year, measurements were repeated in all RA patients. RESULTS: At entry, SAE was decreased in RA vs HCs [median 3.4 ml/mmHg100 (range 1.2-9.0) vs 6.1 (range 5.0-15.3), P < 0.0001] and sVCAM-1 and vWF were increased: 391 ng/ml (range 256-680) vs 341 (range 223-691) (P = 0.0015) and 120 ng/ml (range 26.5-342) vs 99 (range 22-298) (P = 0.02), respectively. SAE was inversely correlated with the 28-joint DAS (DAS28; r = -0.31, P = 0.016). AGEs were increased by 2.55 arbitrary units (range 1.29-4.65) vs 2.12 (range 1.32-3.82) in HCs (P = 0.003). In multivariate analysis, the presence of RA, age and systolic blood pressure were independently and inversely related to SAE. After 1 year, SAE had significantly improved in RA, from 3.4 (range 1.2-9.0) to 3.8 (range 1.5-10.3) (P = 0.03). CONCLUSION: Endothelial dysfunction is present in newly diagnosed RA patients, independently of traditional risk factors and is inversely correlated with disease activity. By reducing disease activity, endothelial dysfunction improves, although not to normal values. Also, a reduction in disease activity targeting traditional risk factors remains important in preventing CVD in RA.


Asunto(s)
Artritis Reumatoide/complicaciones , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Productos Finales de Glicación Avanzada/sangre , Índice de Severidad de la Enfermedad , Molécula 1 de Adhesión Celular Vascular/sangre , Factor de von Willebrand/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Biomarcadores/sangre , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/fisiopatología , Estudios de Casos y Controles , Elasticidad/fisiología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto Joven
10.
Rheumatology (Oxford) ; 54(12): 2151-5, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26170374

RESUMEN

OBJECTIVES: High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released into the extracellular milieu. HMGB1 is a biomarker of active disease in several systemic autoimmune diseases. Behçet's disease (BD) is a systemic inflammatory disorder with a waxing/waning course. The objective of this study is to evaluate serum HMGB1 levels as a possible biomarker for disease activity in BD. METHODS: A cross-sectional study measuring serum HMGB1 levels was performed in 26 BD patients and 20 healthy controls. The Brazilian version of the simplified BD Current Activity Form (BR-BDCAFs) was used to measure disease activity. RESULTS: Serum HMGB1 levels were higher in patients with active disease [3.82 (2.54-6.11) ng/ml], in patients with BD without active disease but still on therapy [2.76 (1.89-5.78) ng/ml] and in patients in remission without treatment [2.66 (1.86-4.70) ng/ml] than in healthy controls [0.96 (0.59-1.39) ng/ml], P < 0.001. Levels were comparable between BD patients with active disease, BD without active disease but still on therapy and those in remission without treatment (P = 0.432). There was no correlation between serum HMGB1 levels and BR-BDCAF(s) (ρ = 0.195; P = 0.339). No association could be found between serum HMGB1 levels and specific disease involvement or therapy. So serum HMGB1 levels cannot be used as a biomarker in BD. CONCLUSION: Serum HMGB1 levels are increased in patients with BD as compared with healthy controls. However, no association was found with disease activity, specific organ involvement or therapy in BD.


Asunto(s)
Síndrome de Behçet/sangre , Proteína HMGB1/sangre , Adulto , Azatioprina/uso terapéutico , Síndrome de Behçet/tratamiento farmacológico , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Índice de Severidad de la Enfermedad
11.
Mol Med ; 20: 72-9, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24531837

RESUMEN

High-mobility group box 1 (HMGB1) is an important molecule for several nuclear processes. Recently, HMGB1 has gained much attention as a damage-associated molecular pattern (DAMP) and has been implicated in the pathogenesis of several (auto)-immune diseases, in particular, systemic lupus erythematosus (SLE). A main pathogenic feature in SLE is the accumulation of apoptotic cells. Since HMGB1 is released from apoptotic cells it has been hypothesized that HMGB1 might fuel the inflammatory processes, as seen in this disease, and play a fundamental role in the pathogenesis. In this review, we discuss evidence in support of the theory that HMGB1 is an important mediator in SLE and may be considered a new autoantigen.


Asunto(s)
Proteína HMGB1/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Enfermedades Reumáticas/metabolismo , Animales , Proteína HMGB1/sangre , Proteína HMGB1/inmunología , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Fagocitosis , Enfermedades Reumáticas/sangre , Enfermedades Reumáticas/inmunología
12.
Arthritis Rheum ; 65(9): 2368-79, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23740801

RESUMEN

OBJECTIVE: To investigate the efficacy and safety of ocrelizumab in patients with class III/IV lupus nephritis (LN). METHODS: Patients were randomized 1:1:1 to receive placebo, 400 mg ocrelizumab, or 1,000 mg ocrelizumab given as an intravenous infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter, accompanied by background glucocorticoids plus either mycophenolate mofetil (MMF) or the Euro-Lupus Nephritis Trial (ELNT) regimen (cyclophosphamide followed by azathioprine). The study was terminated early due to an imbalance in serious infections in ocrelizumab-treated patients versus placebo-treated patients. We report week 48 efficacy data for patients receiving ≥32 weeks of treatment (n = 223) and safety results for all treated patients (n = 378). RESULTS: The overall renal response rate was 54.7%, 66.7%, 67.1%, and 66.9% in the placebo-treated, 400 mg ocrelizumab-treated, 1,000 mg ocrelizumab-treated, and combined ocrelizumab-treated groups, respectively. The associated treatment difference versus placebo for the combined ocrelizumab-treated groups was 12.7% (95% confidence interval [95% CI] -0.8, 26.1) (P = 0.065), with similar differences observed for both ocrelizumab-treated groups. Ocrelizumab versus placebo treatment differences were apparent in patients receiving the background ELNT regimen, but not in those receiving background MMF. A numerically greater proportion of ocrelizumab-treated patients had a ≥50% reduction in the urinary protein:urinary creatinine ratio at 48 weeks compared with placebo-treated patients (placebo-treated patients, 58.7%; 400 mg ocrelizumab-treated patients, 70.7%; 1,000 mg ocrelizumab-treated patients, 68.5%). Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab-treated patients, and 22.0% of 1,000 mg ocrelizumab-treated patients. Corresponding serious infection rates (events/100 patient-years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen. CONCLUSION: In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Azatioprina/administración & dosificación , Azatioprina/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Resultado del Tratamiento
13.
Autoimmun Rev ; 23(1): 103426, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37634680

RESUMEN

Timing of vaccination and its relationship with concomitant immunosuppressive therapy has been a matter of debate in the field of AutoImmune Inflammatory Rheumatic Diseases (AIIRD). Vaccination is crucial in the prevention of infections, which, in the setting of AIIRD, are known risk factors for disease flare and expose patients to increase risk of complications and mortality. As evidenced from real-life studies, vaccines do not significantly affect disease activity. Conversely, disease activity (especially in Systemic Lupus Erythematosus) may predict for vaccine response: high disease activity correlates with decreased seroconversion. For this reason, according to the EULAR 2019 recommendation, vaccination should preferably be administered during quiescent AIIRD. Beside disease activity, background immunosuppressive therapy should be considered when performing vaccination, as different Disease Modifying Anti-Rheumatic Drugs (DMARDs) decrease vaccine immunogenicity. AIIRD patients should be vaccinated, independently from the vaccine type, before starting immunosuppression. If the patient is on active immunosuppressive therapy, the best window of opportunity to boost vaccine response is during AIIRD quiescence, as low disease activity increases seroconversion and allows safe immunosuppressant spacing. In conclusion, the majority of AIIRD patients should receive vaccination, preferably during quiescent disease and taking into consideration immunosuppressant spacing.


Asunto(s)
Antirreumáticos , Enfermedades Autoinmunes , Enfermedades Reumáticas , Vacunación , Humanos , Antirreumáticos/administración & dosificación , Inmunosupresores/administración & dosificación , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/tratamiento farmacológico
14.
Curr Opin Rheumatol ; 25(2): 254-9, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23249831

RESUMEN

PURPOSE OF REVIEW: High-mobility group box 1 (HMGB1) is a molecule that has gained much attention in the last couple of years as an important player in innate immune responses and modulating factor in several (auto)immune diseases. Furthermore, advancements have been made in identifying the diverse functions that HMGB1 can play in the body by studying its receptors, pathways and effects. This review will focus on the modulation of HMGB1 in animal models of (auto)immune diseases. RECENT FINDINGS: In different disease models like sepsis, ischemia-reperfusion and arthritis, HMGB1-blocking therapies have been tested and the disease course was shown to be ameliorated. SUMMARY: These findings indicate that HMGB1 is an important mediator in innate immunity, inflammation and sterile injury. Furthermore, HMGB1 might be a new therapeutic target in inflammation and autoimmune diseases, which may be translated to the clinic.


Asunto(s)
Enfermedades Autoinmunes/terapia , Proteína HMGB1/antagonistas & inhibidores , Animales , Artritis Reumatoide/inmunología , Artritis Reumatoide/terapia , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Endotoxemia/inmunología , Endotoxemia/terapia , Proteína HMGB1/sangre , Proteína HMGB1/inmunología , Humanos , Inmunidad Innata , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Daño por Reperfusión/inmunología , Daño por Reperfusión/terapia , Sepsis/inmunología , Sepsis/terapia , Transducción de Señal/inmunología
15.
Ann Rheum Dis ; 71(6): 966-73, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22128082

RESUMEN

OBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluate the predictive value of clinical, laboratory and renal biopsy parameters regarding renal outcome. METHODS: 87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality. RESULTS: After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome. CONCLUSION: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.


Asunto(s)
Azatioprina/administración & dosificación , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Adolescente , Adulto , Antiinflamatorios/administración & dosificación , Creatinina/sangre , Femenino , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/prevención & control , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/sangre , Proteinuria/tratamiento farmacológico , Proteinuria/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
16.
Res Pract Thromb Haemost ; 6(8): e12839, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36397932

RESUMEN

Background: Recurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. Aim: To determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares. Methods: A multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. Results: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE. Conclusion: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk.

17.
Front Pediatr ; 10: 910026, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35874582

RESUMEN

Background: In 2011, the first European League Against Rheumatism (EULAR) vaccination recommendations for pediatric patients with autoimmune inflammatory rheumatic diseases (pedAIIRD) were published. The past decade numerous new studies were performed to assess the safety, efficacy and immunogenicity of vaccinations in pedAIIRD. A systematic literature review (SLR) was therefore performed to serve as the basis for the updated 2021 EULAR/PRES recommendations. Methods: An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Primary outcomes were efficacy, immunogenicity and safety of vaccination in pedAIIRD. The search was performed in Medline, Embase and the Cochrane Library and included studies published from November 2010 until July 2020. Results: The SLR yielded 57 studies which were included for critical appraisal and data extraction. Only 8 studies described the occurrence of vaccine-preventable infections after vaccination (efficacy), none of these studies were powered to assess efficacy. The majority of studies assessed (humoral) immune responses as surrogate endpoint for vaccine efficacy. Studies on non-live vaccines showed that these were safe and in general immunogenic. Biologic disease-modifying antirheumatic drugs (bDMARDs) in general did not significantly reduce seroprotection rates, except for B-cell depleting therapies which severely hampered humoral responses. Four new studies on human papilloma virus vaccination showed that this vaccine was safe and immunogenic in pedAIIRD. Regarding live-attenuated vaccinations, level 1 evidence of the measles mumps rubella (MMR) booster vaccination became available which showed the safety of this booster for patients treated with methotrexate. In addition, level 3 evidence became available that suggested that the MMR and varicella zoster virus (VZV) vaccination for patients on low dose glucocorticosteroids and bDMARDs might be safe as well. Conclusions: The past decade, knowledge on the safety and immunogenicity of (live-attenuated) vaccines in pedAIIRD significantly increased. Data on efficacy (infection prevention) remains scarce. The results from this SLR are the basis for the updated EULAR/PRES vaccination recommendations in pedAIIRD.

18.
Clin Immunol ; 141(2): 197-204, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21920821

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by disturbed T-cell homeostasis. Dysbalance of T-helper-cell (Th) subsets (Th1/Th2/Th17) and regulatory T-cells (T(regs)) is suggested to contribute to the pathogenesis of SLE. Recent reports suggest functional deviation of T(regs) in terms of producing IL-17A, a process that may be aberrant in SLE. Therefore, we analyzed these T-cell subsets in SLE to test the hypothesis that aberrant T-cell subset skewing is present in SLE-patients. We investigated simultaneously the intracellular cytokines IFN-γ, IL-4 and IL-17A in CD4(+)T-cells as well as in T(regs). Skewing of T-cell subsets towards Th17 cells was observed in SLE-patients. Although the proportion of T(regs) was similar between SLE-patients and healthy controls, the ability of T(regs) to express IFN-γ and IL17A was impaired in SLE-patients. Even in quiescent SLE-patients T-cell homeostasis is aberrant in terms of skewing towards IL-17 producing T-cells.


Asunto(s)
Lupus Eritematoso Sistémico/inmunología , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/patología , Células TH1/patología , Células Th17/patología , Células Th2/patología , Adulto , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/sangre , Homeostasis/inmunología , Humanos , Inmunofenotipificación , Interferón gamma/sangre , Interleucina-17/sangre , Interleucina-4/sangre , Líquido Intracelular/química , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/patología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/química , Linfocitos T Reguladores/química , Células TH1/química , Células Th17/química , Células Th2/química
19.
Clin Immunol ; 141(2): 161-8, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21889412

RESUMEN

Influenza-specific cell-mediated immune (CMI) responses can protect from influenza, but may be decreased in CVID-patients since defects in CMI responses have been demonstrated in CVID-patients. Therefore CMI responses were evaluated in 15 CVID-patients and 15 matched healthy controls (HC) by determining frequencies of interferon (IFN)γ-producing PBMC, and frequencies of IFNγ-, interleukin (IL)-2- and tumour necrosis factor (TNF)α-producing CD4+ and CD8+ T-cells before and after influenza vaccination using IFNγ enzyme-linked immunospot (IFNγ-ELISpot) and flow cytometry. Humoral responses were determined using haemagglutination inhibition assay. In CVID-patients the number of spotforming PBMC in the IFNγ-ELISpot did not increase following influenza vaccination, in contrast to HC. In flow cytometry, the frequencies of IFNγ-producing T-cells decreased in CVID-patients after influenza vaccination, while in HC the frequencies of IFNγ-production flow cytometry increased. Concluding, CMI responses following influenza vaccination are hampered in CVID-patients compared to HC. Additional protective strategies against influenza other than vaccination are warranted.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Inmunidad Celular , Vacunas contra la Influenza/inmunología , Vacunación , Adulto , Anciano , Anticuerpos Antivirales/biosíntesis , Relación CD4-CD8 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Ensayo de Immunospot Ligado a Enzimas , Femenino , Citometría de Flujo , Pruebas de Inhibición de Hemaglutinación , Humanos , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/biosíntesis , Vacunas de Productos Inactivados/inmunología , Vacunas de Subunidad/inmunología
20.
Rheumatology (Oxford) ; 50(4): 665-73, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21131273

RESUMEN

OBJECTIVE: To investigate whether serum levels of endothelial cell activation markers in early RA patients can serve as biomarkers for inflammation and disease activity, and are associated with radiological progression and development of cardiovascular disease (CVD). METHODS: Serum levels of VEGF, soluble vascular cell adhesion molecule (sVCAM)-1 and angiopoietin-2 (Angpt-2) were measured by ELISA in 176 patients with recent-onset RA, at the time of diagnosis and after 2 years. Markers of inflammation and disease activity were assessed, as well as radiological damage of hands and feet, at diagnosis and after 2 years. Prevalence of CVD of all patients after 12.5 years disease duration was retrieved from medical records. RESULTS: Patients with RA had higher levels of VEGF and Angpt-2 at disease onset compared with healthy controls, which correlated with markers of inflammation, but were not predictive of radiological progression after 2 years. Angpt-2 levels, moreover, significantly correlated with measures of disease activity. Nearly 18% of RA patients developed CVD after an average of 12.5 years of disease, and these patients had a significantly higher level of Angpt-2 at the onset of RA compared with patients who did not develop CVD. CONCLUSIONS: In early RA, markers of endothelial activation are highly correlated with inflammation and disease activity, but not with radiological progression. Angpt-2 could be predictive for the development of CVD since Angpt-2 levels were significantly higher in CVD patients than in non-CVD patients.


Asunto(s)
Angiopoyetina 2/sangre , Artritis Reumatoide/sangre , Artritis Reumatoide/fisiopatología , Enfermedades Cardiovasculares/epidemiología , Progresión de la Enfermedad , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/diagnóstico por imagen , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Pie/diagnóstico por imagen , Mano/diagnóstico por imagen , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Radiografía , Estudios Retrospectivos , Factores de Riesgo , Molécula 1 de Adhesión Celular Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/sangre
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