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1.
Clin Exp Immunol ; 188(1): 174-181, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28076879

RESUMEN

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.


Asunto(s)
Autoanticuerpos/inmunología , Granulomatosis con Poliangitis/inmunología , Inmunoglobulina M/inmunología , Poliangitis Microscópica/inmunología , Mieloblastina/inmunología , Adulto , Anciano , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Biomarcadores , Femenino , Granulomatosis con Poliangitis/diagnóstico , Humanos , Inmunoglobulina G/inmunología , Masculino , Poliangitis Microscópica/diagnóstico , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
2.
Arthritis Rheumatol ; 67(6): 1629-36, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25776953

RESUMEN

OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.


Asunto(s)
Glucocorticoides/uso terapéutico , Granulomatosis con Poliangitis/tratamiento farmacológico , Poliangitis Microscópica/tratamiento farmacológico , Prednisona/uso terapéutico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Autoanticuerpos/inmunología , Azatioprina/uso terapéutico , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Femenino , Granulomatosis con Poliangitis/inmunología , Humanos , Inmunosupresores/uso terapéutico , Quimioterapia de Mantención , Masculino , Poliangitis Microscópica/inmunología , Mieloblastina/inmunología , Peroxidasa/inmunología , Recurrencia , Inducción de Remisión , Rituximab , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
3.
Nephron Clin Pract ; 128(3-4): 216-23, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25401277

RESUMEN

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Productos Biológicos/farmacología , Animales , Humanos
4.
Clin Exp Immunol ; 178(2): 270-8, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25052363

RESUMEN

The objective of this study is to evaluate urinary high mobility group box 1 (HMGB1) levels as markers for active nephritis in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in comparison with urinary CD4(+) effector memory T cells and urinary monocyte chemoattractant protein-1 (MCP-1). Twenty-four AAV patients with active nephritis and 12 healthy controls (HC) were evaluated. In nine patients, samples were also obtained during remission. Urinary levels of HMGB1 were measured by Western blot. CD4(+) T cells and CD4(+) effector memory T cells (CD4(+) CD45RO(+) CCR7(-) ) were determined in urine and whole blood by flow cytometry. Measurement of urinary levels of MCP-1 and serum HMGB1 levels were performed by enzyme-linked immunosorbent assay (ELISA). AAV patients with active nephritis had higher median intensity of HMGB1 in urine than HC [10·3 (7·05-18·50) versus 5·8 (4·48-7·01); P = 0·004]. Both urinary HMGB1 and MCP-1 levels decreased significantly from active nephritis to remission. The urinary MCP-1/creatinine ratio correlated with Birmingham Vasculitis Activity Score (BVAS) (P = 0·042). No correlation was found between the HMGB1/creatinine ratio and 24-h proteinuria, estimated glomerular filtration rate (eGFR), MCP-1/creatinine ratio, BVAS and serum HMGB1. A positive correlation was found between urinary HMGB1/creatinine ratio and CD4(+) T cells/creatinine ratio (P = 0·028) and effector memory T cells/creatinine ratio (P = 0·039) in urine. Urinary HMGB1 levels are increased in AAV patients with active nephritis when compared with HC and patients in remission, and urinary HMGB1 levels are associated with CD4(+) T cells and CD4(+) effector memory T cells in urine. Measurement of urinary HMGB1 may be of additional value in identifying active glomerulonephritis in AAV patients.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Glomerulonefritis/etiología , Glomerulonefritis/orina , Proteína HMGB1/orina , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Biomarcadores , Quimiocina CCL2/orina , Femenino , Glomerulonefritis/sangre , Proteína HMGB1/sangre , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
5.
Arthritis Rheumatol ; 66(11): 3151-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25047592

RESUMEN

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/prevención & control , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Prevención Secundaria/métodos , Azatioprina/uso terapéutico , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Glucocorticoides/uso terapéutico , Humanos , Prednisona/uso terapéutico , Estudios Prospectivos , Recurrencia , Inducción de Remisión/métodos , Rituximab , Factores de Tiempo , Resultado del Tratamiento
6.
Arthritis Rheum ; 65(9): 2441-9, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23754238

RESUMEN

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Granulomatosis con Poliangitis/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Poliangitis Microscópica/tratamiento farmacológico , Inducción de Remisión/métodos , Adulto , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Azatioprina/administración & dosificación , Azatioprina/uso terapéutico , Estudios Cruzados , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Masculino , Rituximab , Resultado del Tratamiento
7.
Lupus ; 22(6): 597-606, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23549344

RESUMEN

SUMMARY: Photosensitivity is characteristic of systemic lupus erythematosus (SLE). Upon ultraviolet B (UVB) exposure, patients develop inflammatory skin lesions in the vicinity of sunburn cells (SBCs). High mobility group box 1 (HMGB1) is released from apoptotic and activated cells and exerts inflammatory actions through ligation to its receptors. METHODS: Eleven SLE patients and 10 healthy controls (HCs) were exposed to UVB. Skin biopsies were taken before and at one, three and 10 days after irradiation. Sections were stained for SBC, HMGB1, CD3, CD68, interferon-induced protein MxA and cleaved caspase 3. In vitro experiments with UVB-irradiated keratinocytes were also performed. Higher numbers of cells that had released HMGB1 were seen in the skin of SLE patients compared to HCs before and after irradiation. HMGB1-negative nuclei correlated with the presence of SBCs, and with the number of cleaved caspase 3 positive cells in lupus skin. RESULTS: HMGB1 release is increased in the skin of SLE patients compared to HCs. Upon UVB exposure, HMGB1 release further increases in SLE patients and is related to the number of apoptotic cells. Our data suggest that HMGB1, probably released from apoptotic keratinocytes, contributes to the development of inflammatory lesions in the skin of SLE patients upon UVB exposure.


Asunto(s)
Proteína HMGB1/metabolismo , Inflamación/etiología , Lupus Eritematoso Sistémico/complicaciones , Trastornos por Fotosensibilidad/etiología , Adulto , Apoptosis/efectos de la radiación , Biopsia , Estudios de Casos y Controles , Caspasa 3/metabolismo , Femenino , Humanos , Inflamación/diagnóstico , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Masculino , Persona de Mediana Edad , Trastornos por Fotosensibilidad/diagnóstico , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Factores de Tiempo , Rayos Ultravioleta/efectos adversos
9.
Autoimmun Rev ; 11(12): 909-17, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22495229

RESUMEN

The nuclear protein high mobility group box 1 (HMGB1) has been suggested to be involved in the pathogenesis of several vascular diseases such as systemic vasculitis and atherosclerosis. In systemic vasculitides including ANCA-associated vasculitis and Kawasaki disease, serum HMGB1 levels are higher in patients with active disease compared to healthy controls. In atherosclerotic disease, HMGB1 displays increased expression in nuclei and cytoplasm of macrophages and smooth muscle cells in the atherosclerotic lesions, and is implicated in the progression of the atherosclerotic plaque. Experimental models of acute coronary syndromes and cerebrovascular accidents show that HMGB1 is not only involved in the amplification of the inflammatory response during acute ischemic injury, but also in the recovery and remodeling process after ischemia. Patients with acute coronary syndromes or stroke present significantly higher serum levels of HMGB1 than healthy controls and levels are associated with disease severity and mortality. Here we review clinical and experimental studies dealing with the role of HMGB1 in vascular diseases.


Asunto(s)
Aterosclerosis/inmunología , Biomarcadores/metabolismo , Proteína HMGB1/metabolismo , Vasculitis/inmunología , Animales , Aterosclerosis/diagnóstico , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Proteína HMGB1/inmunología , Humanos , Modelos Animales , Vasculitis/diagnóstico
10.
Lupus ; 21(9): 959-68, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22513366

RESUMEN

OBJECTIVE: Interaction of advanced glycation end products (AGEs) with their receptors (RAGE) plays an important role in inflammation in auto-immune diseases. Several functional polymorphisms of RAGE have been described. In this study we analysed the role of RAGE polymorphisms in disease susceptibility for systemic lupus erythematosus (SLE). In addition, we investigated whether these polymorphisms in SLE are associated with serum levels of soluble RAGE (sRAGE), renal involvement (lupus nephritis (LN)) and its outcome. METHODS: For this cross-sectional study DNA samples of 97 SLE patients, 114 LN patients and 429 healthy controls (HC) were genotyped for four RAGE polymorphisms: -429 T/C, -374 T/A, 2184 A/G and Gly82Ser. Differences in genotype frequencies and allele frequencies were tested between patients and HCs. In SLE patients, sRAGE was measured by enzyme-linked immunosorbent assay (ELISA). In addition, association of genotypes with sRAGE and disease severity in LN was analysed. RESULTS: The C allele of -429 T/C, the T allele of -374 T/A and the G allele of 2184 A/G were significantly more prevalent in SLE and LN compared with HC. In LN, the C allele of RAGE -429 T/C, the A allele of -374 T/A and the G allele of RAGE 2184 A/G polymorphism were significantly associated with more proteinuria and worse renal function during the first two years of treatment. No association of genotype with sRAGE was found. CONCLUSION: RAGE polymorphisms are associated with susceptibility to SLE and LN. In addition, some of these polymorphisms are likely to be associated with disease severity and initial response to treatment in LN.


Asunto(s)
Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Polimorfismo Genético , Receptores Inmunológicos/genética , Adulto , Anciano , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Receptor para Productos Finales de Glicación Avanzada
11.
Int J Rheumatol ; 2011: 417813, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21977038

RESUMEN

Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors. Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded. Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68 ± 0.58 a.u. versus 1.63 ± 0.41 a.u., P = 0.684). Skin AF-EEMS in SSc patients was associated with levels of CRP (r = 0.44, P = 0.004), Medsger's severity scale (r = 0.45, P = 0.006), and use of agents intervening in the renin-angiotensin system (r = 0.33, P = 0.027). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS. Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients.

12.
Clin Exp Immunol ; 164 Suppl 1: 1-3, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21447120

RESUMEN

Enormous progress has been made during the last 25 years in our understanding of the aetiopathogenesis of the anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). This has led to improvements in early diagnosis, treatment and secondary prevention of these diseases. Nevertheless, there are still unmet needs in the AAV. With respect to diagnosis and follow-up, sensitive biomarkers that reflect disease activity, also during smouldering disease, are needed. In the field of aetiopathogenesis, genetic and epigenetic studies are being performed not only directed at the autoimmune response but also at the expression of, possibly modified, autoantigens. Environmental factors, in particular microbial factors, are also being explored. This will enable analysis of gene-environment interactions in the AAV, so elucidating further their aetiopathogenesis. Explaining the differences in clinical presentation between proteinase 3 (PR3)-associated AAV and myeloperoxidase (MPO)-associated AAV requires an adequate animal model for PR3-ANCA disease, which is currently lacking. Although many large randomized controlled trials have built a base for a rational therapeutic approach in the AAV, late morbidity and mortality is still significant. The availability of new biologicals and the development of sensitive biomarkers for disease activity could further improve prognosis for patients suffering from AAV.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/etiología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/fisiopatología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Biomarcadores/metabolismo , Humanos , Mieloblastina/metabolismo , Peroxidasa/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto
13.
Neth J Med ; 69(1): 5-13, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21325695

RESUMEN

Among immunocompromised patients morbidity and mortality due to vaccine-preventable infections is high. Although vaccination seems indicated, controversy exists about which vaccines should be offered, at what moment, and to whom. Guidelines are needed as the number of immunocompromised individuals increases due to the wider use of immunosuppressive drugs and, in particular, because since the introduction of biological agents, the spectrum of immunosuppressive drugs is rapidly expanding. In this review we will highlight controversies about vaccination in immunocompromised patients and will discuss indications for the several vaccines available to prevent infectious diseases with the focus on patients with autoimmune-inflammatory diseases.


Asunto(s)
Enfermedades Autoinmunes/prevención & control , Huésped Inmunocomprometido/inmunología , Inflamación/prevención & control , Vacunación , Enfermedades Autoinmunes/inmunología , Humanos , Inflamación/inmunología , Factores de Riesgo , Factores de Tiempo , Vacunación/efectos adversos
15.
Ann Rheum Dis ; 70(3): 414-22, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21131643

RESUMEN

OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD). METHODS: A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force. RESULTS: Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. CONCLUSION: Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.


Asunto(s)
Enfermedades Autoinmunes/complicaciones , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/prevención & control , Enfermedades Reumáticas/complicaciones , Vacunación , Enfermedades Autoinmunes/tratamiento farmacológico , Técnica Delphi , Medicina Basada en la Evidencia/métodos , Humanos , Inmunosupresores/efectos adversos , Enfermedades Reumáticas/tratamiento farmacológico
16.
Autoimmun Rev ; 10(6): 341-52, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21182987

RESUMEN

OBJECTIVES: To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD). METHODS: AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible. RESULTS: Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive. CONCLUSION: Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.


Asunto(s)
Enfermedades Autoinmunes/complicaciones , Medicina Basada en la Evidencia , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/prevención & control , Enfermedades Reumáticas/complicaciones , Vacunación , Adulto , Antirreumáticos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/complicaciones , Humanos , Inmunización Secundaria/estadística & datos numéricos , Factores Inmunológicos/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Vacunación/economía , Vacunación/estadística & datos numéricos , Vacunas/administración & dosificación , Vacunas/efectos adversos , Vacunas/normas
17.
Osteoporos Int ; 22(5): 1431-9, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-20603707

RESUMEN

SUMMARY: Osteoporosis is a well recognized complication of ankylosing spondylitis (AS). This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis, and that bone turnover markers (BTM) are valuable markers to detect bone loss in AS. INTRODUCTION: The aim of this study was to elucidate the pathophysiology of AS-related osteoporosis by investigating the relation between bone mineral density (BMD), BTM, vitamin D, and clinical assessments of disease activity and physical function, as well as to identify parameters that are related to low BMD (osteopenia or osteoporosis) in AS patients with active disease. METHODS: One hundred twenty-eight consecutive Dutch AS outpatients were included in this cross-sectional study. Bath AS Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), C-reactive protein, ASAS-endorsed disease activity score (ASDAS), Bath AS Functional Index (BASFI), bone formation markers procollagen type 1 N-terminal peptide (PINP) and osteocalcin (OC), bone resorption marker serum C-telopeptides of type I collagen (sCTX), 25-hydroxyvitamin D (25OHvitD), lumbar spine and hip BMD, and vertebral fractures were assessed. Z-scores of BTM were calculated using matched 10-year cohorts of a Dutch reference group to correct for the normal influence that age and gender have on bone turnover. RESULTS: sCTX Z-score, OC Z-score, BASDAI, age, and gender were independently related to low BMD. In addition, PINP Z-score, ESR, 25OHvitD, age, and gender were independently related to sCTX and/or OC Z-score. CONCLUSIONS: This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis. Furthermore, sCTX and OC Z-scores seem to be valuable markers to detect bone loss in AS patients in daily clinical practice where BMD of the lumbar spine, measured by DXA, may be overestimated due to osteoproliferation in patients with advanced AS.


Asunto(s)
Osteoporosis/etiología , Espondilitis Anquilosante/complicaciones , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangre , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Colágeno Tipo I/sangre , Estudios Transversales , Femenino , Articulación de la Cadera/fisiopatología , Humanos , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Osteoporosis/sangre , Osteoporosis/fisiopatología , Péptidos/sangre , Factores de Riesgo , Fracturas de la Columna Vertebral/sangre , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/fisiopatología , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/fisiopatología , Vitamina D/sangre
18.
Clin Exp Rheumatol ; 28(5): 661-8, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20822711

RESUMEN

OBJECTIVES: To investigate the influence of antibody formation to TNF-α blocking agents on the clinical response in AS patients treated with infliximab (IFX), etanercept (ETA), or adalimumab (ADA), and to investigate the development of ANA, ANCA, and anti-dsDNA antibodies in association with the formation of antibodies to TNF-α blocking agents. METHODS: Consecutive AS outpatients with active disease who started treatment with IFX (n=20), ETA (n=20), or ADA (n=20) were included in this longitudinal observational study. Clinical data were collected prospectively at baseline and after 3, 6, and 12 months of anti-TNF-α treatment. At the same time points, serum samples were collected. In these samples, antibodies to TNF-α blocking agents, serum TNF-α blocker levels, and ANA, ANCA, and anti-dsDNA antibodies were measured retrospectively. RESULTS: Anti-IFX, anti-ETA, and anti-ADA antibodies were induced in 20%, 0%, and 30% of patients, respectively. Although ANA, ANCA, and anti-dsDNA antibodies were detected during anti-TNF-α treatment, no significant association was found between the presence of these autoantibodies and the formation of antibodies to TNF-α blocking agents. Patients with anti-IFX or anti-ADA antibodies had significantly lower serum TNF-α blocker levels compared to patients without these antibodies. Furthermore, significant negative correlations were found between serum TNF-α blocker levels and assessments of disease activity. CONCLUSIONS: This study indicates that antibody formation to IFX or ADA is related to a decrease in efficacy and early discontinuation of anti-TNF-α treatment in AS patients. Furthermore, autoantibody formation does not seem to be associated with antibody formation to TNF-α blocking agents.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Autoanticuerpos/inmunología , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adalimumab , Adulto , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Antirreumáticos/inmunología , Etanercept , Femenino , Estado de Salud , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/uso terapéutico , Infliximab , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Índice de Severidad de la Enfermedad , Espondilitis Anquilosante/fisiopatología
19.
Autoimmun Rev ; 9(10): 661-5, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20546955

RESUMEN

The chromatin non-histone DNA binding protein high mobility group box one (HMGB1) has recently been extensively studied in autoimmune diseases. In addition to its nuclear functions, HMGB1 has been identified as alarmin that can 'alarm' both innate and adaptive immunity. HMGB1 can amplify inflammation and enhance immune responses by interacting with the receptor for Advanced Glycation End Products (RAGE) and Toll-like receptors 2,4 and 9 (TLRs) . Release of HMGB1 occurs during cell activation as well as cell death. Cells die by apoptosis and eventually necrosis which both are thought to lead to release of HMGB1 into the microenvironment. In the past years disturbed apoptosis or clearance of apoptotic cells has been put forward as a major pathophysiological feature in autoimmune diseases such as Systemic Lupus Erythematosus (SLE), which is a prototypic autoimmune disease that affects many organs. Accumulation of apoptotic cells has been found in SLE. Also, elevated levels of HMGB1 have been detected in the serum of SLE patients and increased expression of HMGB1 was demonstrated in skin lesions of lupus patients. In this review the general characteristics and activities of HMGB1 are highlighted and its role in SLE will be discussed with special attention to its involvement in the pathogenesis of skin lesions.


Asunto(s)
Proteína HMGB1/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Piel/metabolismo , Receptores Toll-Like/metabolismo , Animales , Apoptosis/inmunología , Cromatina/genética , Cromatina/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/inmunología , Histonas/metabolismo , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Lupus Eritematoso Sistémico/fisiopatología , Fagocitosis/inmunología , Unión Proteica , Piel/patología
20.
Clin Exp Immunol ; 161(2): 268-75, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20456419

RESUMEN

Leucocyte transendothelial migration is strictly regulated to prevent undesired inflammation and collateral damage of endothelial cells by activated neutrophils/monocytes. We hypothesized that in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) patients' dysregulation of this process might underlie vascular inflammation. Peripheral blood mononuclear cells (PBMC) and neutrophils from AAV patients (n = 12) and healthy controls (HC, n = 12) were isolated. The influence of human umbilical vein endothelial cells (HUVEC) on neutrophil/monocytes function was tested by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP)- and phorbol 12-myristate 13-acetate (PMA)-mediated ROS production, degranulation and interleukin (IL)-8 production. In addition, the ability of lipopolysaccharide (LPS)-stimulated PBMC to produce tumour necrosis factor (TNF)-alpha in the presence or absence of HUVEC was tested. HUVEC inhibited ROS production dose-dependently by fMLP-stimulated neutrophils but did not influence degranulation. No differences between neutrophils from HC and AAV were found. However, in only one active patient was degranulation inhibited significantly by HUVEC only before cyclophosphamide treatment, but not 6 weeks later. Co-cultures of HUVEC with LPS-stimulated neutrophils/monocytes increased IL-8 production while TNF-alpha production was inhibited significantly. There was no apparent difference between AAV patients and HC in this respect. Our findings demonstrate that HUVEC are able to inhibit ROS and modulate cytokine production upon stimulation of neutrophils or monocytes. Our data do not support the hypothesis that endothelial cells inhibit ROS production of neutrophils from AAV patients inadequately. Impaired neutrophil degranulation may exist in active patients, but this finding needs to be confirmed.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Células Endoteliales/metabolismo , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adenosina Desaminasa/farmacología , Adenosina-5'-(N-etilcarboxamida)/farmacología , Comunicación Celular/efectos de los fármacos , Comunicación Celular/inmunología , Degranulación de la Célula/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Humanos , Interleucina-8/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Peroxidasa/metabolismo , Estallido Respiratorio/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
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