Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 106
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Biol Chem ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719144

RESUMO

Anti-neutrophil cytoplasmic autoantibodies (ANCAs) are directed against lysosomal components of neutrophils. ANCAs directed to proteinase 3 and myeloperoxidase (MPO) in particular are associated with distinct forms of small vessel vasculitides. MPO is an abundant neutrophil-derived heme protein that is part of the antimicrobial defense system. The protein is typically present in the azurophilic granules of neutrophils, but a large portion may also enter the extracellular space. It remains unclear why MPO is frequently the target of antibody-mediated autoimmune responses. MPO is a homodimeric glycoprotein, post-translationally modified with complex sugars at specific sites. Glycosylation can strongly influence protein function, affecting its folding, receptor interaction, and backbone accessibility. MPO potentially can be heavily modified as it harbors five putative N-glycosylation sites (ten in the mature dimer). Although considered important for MPO structure and function, the full scope and relative abundance of the glycans attached to MPO is unknown. Here, combining bottom-up glycoproteomics and native MS approaches, we structurally characterized MPO from neutrophils of healthy human donors. We quantified the relative occupancy levels of the glycans at each of the five sites and observed complex heterogeneity and site-specific glycosylation. In particular, we detected glycosylation phenotypes uncommon for glycoproteins in the extracellular space, such as a high abundance of phosphorylated high-mannose species and severely truncated small glycans having the size of paucimannose or smaller. We hypothesize that the atypical glycosylation pattern found on MPO might contribute to its specific processing and presentation as a self-antigen by antigen-presenting cells.

2.
Front Immunol ; 10: 1981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507597

RESUMO

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory diseases requiring long-term glucocorticoid treatment. Limited data on dynamics in leukocyte counts before, during and after treatment are available. Leukocyte counts were measured, as cellular markers of inflammation, at fixed time points in our prospectively studied cohort of pre-treatment glucocorticoid-naive GCA (N = 42) and PMR (N = 31) patients. Values were compared with age-matched healthy controls (HCs; N = 51) and infection controls (N = 16). We report that before start of treatment monocyte and neutrophil counts were higher in GCA and PMR patients than in HCs, while NK- and B-cell counts were lower. C-reactive protein (CRP) levels correlated positively with monocyte counts in GCA, and negatively with B-cell and NK-cell counts in PMR. During glucocorticoid treatment, myeloid subsets remained elevated whereas lymphoid subsets tended to fluctuate. Interestingly, erythrocyte sedimentation rate (ESR) outperformed CRP as marker for relapses in GCA. We defined stable treatment-free remission groups in both GCA and PMR. GCA patients in treatment-free remission still demonstrated elevated monocytes, neutrophils, ESR, and platelets. PMR patients in treatment-free remission had normalized levels of inflammation markers, but did have elevated monocytes, lowered CD8+ T-cell counts and lowered NK-cell counts. Finally, we showed that low hemoglobin level was predictive for long-term GC treatment in PMR. Overall, leukocyte composition shifts toward the myeloid lineage in GCA and PMR. This myeloid profile, likely induced by effects of inflammation on hematopoietic stem cell differentiation, persisted during glucocorticoid treatment. Surprisingly, the myeloid profile was retained in treatment-free remission, which may reflect ongoing subclinical inflammation.

3.
Front Immunol ; 10: 1638, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379838

RESUMO

Loss of immune checkpoint (IC) Programmed Death-1 (PD-1) and PD-Ligand1 (PD-L1) expression has been implicated in the immunopathology of Giant Cell Arteritis (GCA). The contribution of the negative immune checkpoint V-domain Immunoglobulin-containing suppressor of T cell activation (VISTA) to GCA pathology has not yet been studied. The aim of our study was to investigate if expression of VISTA and other IC molecules by peripheral blood (PB) immune cells is modulated in GCA and at the site of vascular inflammation. In addition, we assessed the effect of VISTA-Ig engagement on in vitro CD4+ T helper (Th) lineage differentiation. To this end, frequencies of monocytes expressing CD80/86, PD-L1, PD-L2, and VISTA were determined in blood samples from 30 GCA patients and 18 matched healthy controls by flow cytometry. In parallel, frequencies of CD4+ cells expressing CD28, Cytotoxic T-Lymphocyte-associated antigen-4 (CTLA-4), PD-1, and VISTA were determined. Immunohistochemistry was employed to detect VISTA, PD-1, and PD-L1-expressing cells in temporal artery biopsies (TABs) diagnostic of GCA. Furthermore, the effect of VISTA-Ig on in vitro CD4+ Th lineage differentiation in patients and controls was determined. Our study shows that frequencies of CD80/CD86+ and VISTA+ monocytes were decreased in treated GCA patients only. Moreover, proportions of PD-1+ and VISTA+ Th cells were significantly decreased in GCA patients. Clear infiltration of VISTA+, PD1+, and PD-L1+ cells was seen in GCA TABs. Finally, VISTA-Ig engagement failed to suppress Th1, Th17, and Tfh lineage development in GCA. Our results indicate that decreased expression of VISTA may facilitate development of pathogenic Th1 and Th17 cells in GCA.

4.
Ann Rheum Dis ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270110

RESUMO

BACKGROUND: Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations. METHODS: Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations. RESULTS: Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40-60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons. CONCLUSIONS: We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31292652

RESUMO

OBJECTIVES: PMR frequently co-occurs with GCA. So far, a simple biomarker for detecting concomitant arterial inflammation in PMR patients is lacking. Furthermore, biomarkers predicting disease course in PMR are awaited. We here investigated the diagnostic and prognostic value of acute-phase markers (ESR, CRP, IL-6, serum amyloid A) and angiogenesis markers (VEGF, soluble Tie2, angiopoietin-1, angiopoietin-2) in isolated PMR and PMR/GCA overlap patients. METHODS: We prospectively included 39 treatment-naïve PMR patients, of whom 10 patients also showed evidence of large vessel GCA by PET-CT. Age-matched healthy controls (n = 32) and infection controls (n = 13) were included for comparison. Serum marker levels were measured by an ELISA or Luminex assay. Receiver operating characteristic and Kaplan-Meier analyses were used to asses diagnostic and prognostic accuracy, respectively. RESULTS: All acute-phase and angiogenesis markers, except angiopoietin-1, were higher in isolated PMR patients than in healthy controls. Angiopoietin-2, ESR and soluble Tie-2 were significantly higher in patients with PMR/GCA overlap than in isolated PMR patients. Angiopoeietin-2, but not soluble Tie2, outperformed ESR and CRP in discriminating patients with and without overlapping GCA (area under the curve: 0.90; sensitivity: 100%; specificity: 76%). Moreover, high angiopoietin-2 levels were associated with long-term glucocorticoid requirement. CONCLUSION: Assessment of angiopoietin-2 at baseline may assist diagnosis of concomitant vasculitis in PMR. Moreover, high levels of angiopoietin-2 were associated with an unfavourable disease course in isolated PMR patients. These findings imply that angiopoietin-2 is an interesting diagnostic and prognostic biomarker in PMR.

7.
Arthritis Rheumatol ; 71(8): 1329-1338, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30835950

RESUMO

OBJECTIVE: This study was undertaken to evaluate glucocorticoid dosages and serologic findings in patients with giant cell arteritis (GCA) flares. METHODS: Patients with GCA were randomly assigned to receive double-blind dosing with either subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26-week prednisone taper (TCZ-QW + Pred-26), every-other-week TCZ plus 26-week prednisone taper (TCZ-Q2W + Pred-26), placebo plus 26-week prednisone taper (PBO + Pred-26), or placebo plus 52-week prednisone taper (PBO + Pred-52). Outcome measures were prednisone dosage, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare. RESULTS: One hundred patients received TCZ-QW + Pred-26, 49 received TCZ-Q2W + Pred-26, 50 received PBO + Pred-26, and 51 received PBO + Pred-52. Of the 149 TCZ-treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dosage 2.0 mg/day). Among 101 PBO + Pred-treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dosage 5.0 mg/day). Many flares occurred while patients were taking >10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22%) in the placebo groups. Thirty-three flares (92%) in TCZ-treated groups and 20 (34%) in PBO + Pred-treated groups occurred with normal CRP levels. More than half of the PBO + Pred-treated patients had elevated CRP levels without flares. Benefits of the TCZ and prednisone combination over prednisone alone for remission induction were apparent by 8 weeks. CONCLUSION: Most GCA flares occurred while patients were still receiving prednisone. Acute-phase reactant levels were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control.

8.
PLoS One ; 14(2): e0211895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30716132

RESUMO

OBJECTIVE: Physical quality of life is reduced in ANCA-associated vasculitis (AAV). This study aims to investigate whether this may be explained by reduced muscle strength and physical activity resulting from disease damage and steroid myopathy. METHODS: Forty-eight AAV patients were sequentially included from the outpatient clinic. Patients in different stages of disease and treatment underwent measurements of muscle strength and anthropometric parameters. Patients filled in physical activity (Baecke) and quality of life questionnaires (RAND-36) and carried an accelerometer for a week. Muscle strength and physical activity were compared to quality of life, prednisolone use and disease duration. RESULTS: Most AAV patients had lower knee extension (76%) and elbow flexion (67%) forces than expected based on healthy norms. Also, physical (P<0.001) and mental (P = 0.01) quality of life were significantly reduced compared to healthy norm values. Lower knee extension force (P = 0.009), younger age <70 (P<0.001) and relapse of vasculitis (P = 0.003) were associated with lower age-adjusted physical quality of life. Lower Baecke index (P = 0.006), higher prednisolone dose (P = 0.005) and ENT involvement (P = 0.006) were associated with lower age-adjusted mental quality of life. Leg muscle strength showed no association with current or cumulative prednisolone use. Disease duration was longer in patients with knee extension force below healthy norms (P = 0.006). CONCLUSION: Knee extension force and physical activity are positively associated with quality of life in AAV. Knee extension force decreases with longer disease duration, suggesting that disease- and treatment-related damage have a cumulative negative effect on muscle strength.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Força Muscular , Músculo Esquelético/fisiopatologia , Qualidade de Vida , Inquéritos e Questionários , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Estudos Transversais , Feminino , Humanos , Perna (Membro)/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos
9.
Front Immunol ; 10: 83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761147

RESUMO

Giant cell arteritis (GCA) can be classified into Cranial(C)-GCA and Large Vessel(LV)-GCA. Based on analysis of temporal arteries, GCA is postulated to be T-cell-mediated. Recently, a disturbed B-cell homeostasis was documented in newly diagnosed GCA patients. In the current study, we assessed the presence of B-cells and their level of ectopic organization in the aorta of LV-GCA patients. Aorta tissue samples of 9 histologically-proven LV-GCA patients and 22 age- and sex-matched atherosclerosis patients who underwent aortic aneurysm surgery were studied by immunohistochemistry. Sections were stained for B-cells, T-cells, follicular dendritic cells, high endothelial venules, germinal center B-cells, proliferating B-cells, macrophages, and plasma cells. Aortas of LV-GCA patients showed massive infiltration of B-cells, which clearly outnumbered T-cells, as opposed to C-GCA patients where, as previously reported, T-cells outnumber B-cells. B-cells were mainly found in the adventitia of the vessel wall and were organized into artery tertiary lymphoid organs. These tertiary lymphoid organs had germinal centers, proliferating B-cells and plasma cell niches. In conclusion, we found massive and organized B-cell infiltrates in the aorta of LV-GCA patients, which is in line with the previously documented decrease of circulating B-cells in active GCA. Our data indicate a role for B-cells in the pathogenesis of GCA and thus evoke further investigation into the factors determining the tissue tropism and organization of B-cells in GCA.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30805622

RESUMO

OBJECTIVE: GCA, a systemic vasculitis, is characterized by an IL-6-dependent acute-phase response. This response is typically suppressed by treatment rendering CRP/ESR unreliable for monitoring vascular inflammation. Also, there are no accurate biomarkers predicting a non-favourable disease course. Here we investigated macrophage products and markers of angiogenesis as biomarkers for prognosis and monitoring of vascular inflammation. METHODS: Forty-one newly diagnosed, glucocorticoid-naive GCA patients were prospectively followed for relapses and glucocorticoid requirement for a median of 30 months (range 0-71). Serum markers at baseline and during follow-up were compared with 33 age-matched healthy controls and 13 infection controls. Concentrations of IL-6, serum amyloid A, soluble CD163, calprotectin, YKL-40, VEGF, angiopoietin-1 and -2 and sTie2 were determined by ELISA/Luminex assay. RESULTS: Serum concentrations of all markers, but not angiopoietin-1, were elevated in GCA patients at baseline when compared with healthy controls. High VEGF (P = 0.0025) and angiopoietin-1 (P = 0.0174) and low YKL-40 (P = 0.0369) levels at baseline were predictive of a short time to glucocorticoid-free remission. Elevated angiopoietin-2 levels were associated with an imminent relapse during treatment (P < 0.05). IL-6 correlated strongly with acute-phase markers and soluble CD163 but not with markers of angiogenesis, YKL-40 or calprotectin. Glucocorticoid treatment down-modulated all markers except for calprotectin and YKL-40. Tissue expression of markers in temporal arteries was confirmed. CONCLUSION: Markers of angiogenesis at baseline and during treatment predict GCA disease course, suggesting utility in patient stratification for glucocorticoid-sparing therapy. Calprotectin and YKL-40 are candidate markers for monitoring vessel wall inflammation.

11.
MBio ; 9(5)2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30377277

RESUMO

The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of this citrullinating enzyme, named Porphyromonas peptidylarginine deiminase (PPAD), in the periodontal environment. The results show that PPAD is detectable in the gingiva of patients with periodontitis, and that it literally neutralizes human innate immune defenses at three distinct levels, namely bacterial phagocytosis, capture in neutrophil extracellular traps (NETs), and killing by the lysozyme-derived cationic antimicrobial peptide LP9. As shown by mass spectrometry, exposure of neutrophils to PPAD-proficient bacteria reduces the levels of neutrophil proteins involved in phagocytosis and the bactericidal histone H2. Further, PPAD is shown to citrullinate the histone H3, thereby facilitating the bacterial escape from NETs. Last, PPAD is shown to citrullinate LP9, thereby restricting its antimicrobial activity. The importance of PPAD for immune evasion is corroborated in the infection model Galleria mellonella, which only possesses an innate immune system. Together, the present observations show that PPAD-catalyzed protein citrullination defuses innate immune responses in the oral cavity, and that the citrullinating enzyme of P. gingivalis represents a new type of bacterial immune evasion factor.IMPORTANCE Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3.

12.
Front Immunol ; 9: 1400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29967621

RESUMO

Loss of CD28 is a characteristic feature of T cell aging, but the underlying mechanisms of this loss are elusive. As differential expression of microRNAs (miRNAs) has been described between CD28+ and CD28- T cells, we hypothesized that altered miRNA expression contributes to the age-associated downregulation of CD28. To avoid the confounding effects of age-associated changes in the proportions of T cells at various differentiation stages in vivo, an experimental model system was used to study changes over time in the expression of miRNA associated with the loss of CD28 expression in monoclonal T cell populations at a lower or higher number of population doublings (PDs). This approach allows identification of age-associated miRNA expression changes in a longitudinal model. Results were validated in ex vivo samples. The cumulative number of PDs but not the age of the donor of the T cell clone was correlated with decreased expression of CD28. Principal component analysis of 252 expressed miRNAs showed clustering based on low and high PDs, irrespective of the age of the clone donor. Increased expression of miR-9-5p and miR-34a-5p was seen in clones at higher PDs, and miR-9-5p expression inversely correlated with CD28 expression in ex vivo sorted T-cells from healthy subjects. We then examined the involvement of miR-9-5p, miR-34a-5p, and the members of the miR-23a~24-2 cluster, in which all are predicted to bind to the 3'UTR of CD28, in the IL-15-induced loss of CD28 in T cells. Culture of fresh naive CD28+ T cells in the presence of IL-15 resulted in a gradual loss of CD28 expression, while the expression of miR-9-5p, miR-34a-5p, and members of the miR-23a~24-2 cluster increased. Binding of miR-9-5p, miR-34a-5p, miR-24-3p, and miR-27- 3p to the 3'UTR of CD28 was studied using luciferase reporter constructs. Functional binding to the 3'UTR was shown for miR-24-3p and miR-27a-3p. Our results indicate involvement of defined miRNAs in T cells in relation to specific characteristics of T cell aging, i.e., PD and CD28 expression.

13.
Front Immunol ; 9: 752, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725326

RESUMO

Immune-aging is associated with perturbed immune responses in the elderly. CD161-expressing T cells, i.e., the previously described subsets of CD161+ CD4+ T cells, CD161high CD8+ T cells, and CD161int CD8+ T cells, are highly functional, pro-inflammatory T cells. These CD161-expressing T cells are critical in immunity against microbes, while possibly contributing to autoimmune diseases. So far, little is known about the impact of aging on the frequency, phenotype, and function of these CD161-expressing T cells. In the current study, we investigated the impact of aging on CD161+ CD4+ T cells, CD161high CD8+ T cells, and CD161int CD8+ T cells in peripheral blood samples of 96 healthy subjects (age 20-84). Frequencies of CD161+ CD4+ T cells and CD161int CD8+ T cells were stable with aging, whereas frequencies of CD161high CD8+ T cells declined. Although CD161high CD8+ T cells were mostly T cell receptor-Vα7.2+ mucosal-associated invariant T cells, CD161 expressing CD4+ and CD8+ T cells showed a limited expression of markers for gamma-delta T cells or invariant natural killer (NK) T cells, in both young and old subjects. In essence, CD161-expressing T cells showed a similar memory phenotype in young and old subjects. The expression of the inhibitory NK receptor KLRG1 was decreased on CD161+ CD4+ T cells of old subjects, whereas the expression of other NK receptors by CD161-expressing T cells was unaltered with age. The expression of cytotoxic effector molecules was similar in CD161high and CD161int CD8+ T cells of young and old subjects. The ability to produce pro-inflammatory cytokines was preserved in CD161high and CD161int CD8+ T cells of old subjects. However, the percentages of IFN-γ+ and interleukin-17+ cells were significantly lower in CD161+ CD4+ T cells of old individuals than those of young individuals. In addition, aging was associated with a decrease of nonclassic T helper 1 cells, as indicated by decreased percentages of CD161-expressing cells within the IFN-γ+ CD4+ T cell compartment of old subjects. Taken together, aging is associated with a numerical decline of circulating CD161high CD8+ T cells, as well as a decreased production of pro-inflammatory cytokines by CD161+ CD4+ T cells. These aging-associated changes could contribute to perturbed immunity in the elderly.

14.
Autoimmun Rev ; 17(7): 715-726, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29729443

RESUMO

Macrophages are key players in the pathogenesis of large-vessel vasculitis (LVV) and may serve as a target for diagnostic imaging of LVV. The radiotracer, 18F-FDG has proven to be useful in the diagnosis of giant cell arteritis (GCA), a form of LVV. Although uptake of 18F-FDG is high in activated macrophages, it is not a specific radiotracer as its uptake is high in any proliferating cell and other activated immune cells resulting in high non-specific background radioactivity especially in aging and atherosclerotic vessels which dramatically lowers the diagnostic accuracy. Evidence also exists that the sensitivity of 18F-FDG PET drops in patients upon glucocorticoid treatment. Therefore, there is a clinical need for more specific radiotracers in imaging GCA to improve diagnostic accuracy. Numerous clinically established and newly developed macrophage targeted radiotracers for oncological and inflammatory diseases can potentially be utilized for LVV imaging. These tracers are more target specific and therefore may provide lower background radioactivity, higher diagnostic accuracy and the ability to assess treatment effectiveness. However, current knowledge regarding macrophage subsets in LVV lesions is limited. Further understanding regarding macrophage subsets in vasculitis lesion is needed for better selection of tracers and new targets for tracer development. This review summarizes the development of macrophage targeted tracers in the last decade and the potential application of macrophage targeted tracers currently used in other inflammatory diseases in imaging LVV.


Assuntos
Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/patologia , Macrófagos/patologia , Humanos , Imagem Molecular , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único
15.
PLoS One ; 13(4): e0196281, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29689112

RESUMO

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are regarded as the cornerstone of conventional treatment for AS. However little is known about concomitant NSAID use during treatment (with TNF-α inhibitors) in daily clinical practice. METHODS AND FINDINGS: Consecutive patients from the GLAS cohort were included. NSAID use and ASAS-NSAID index were evaluated at group level and at individual patient level during 52 weeks of follow-up. Analyses were stratified for treatment regimen. Generalized estimating equations (GEE) was used to evaluate NSAID use in relation to assessments of disease activity over time. In patients starting TNF-α inhibitors (n = 254), 79% used NSAIDs at baseline and this proportion decreased significantly to 38% at 52 weeks. ASAS-NSAID index also decreased significantly from median 65 to 0. In patients on conventional treatment (n = 139), 74% used NSAIDs at baseline with median ASAS-NSAID index of 50 and this remained stable during follow-up. At each follow-up visit, approximately half of the patients changed their type or dose of NSAIDs. GEE analysis over time showed that NSAID use was associated with AS disease activity score (p<0.05). This relation was more pronounced in patients treated with TNF-α inhibitors compared to conventional treatment (B = 0.825 vs. B = 0.250). CONCLUSIONS: In this observational cohort of established AS patients, there was no difference in baseline NSAID use between patients with and without indication for TNF-α inhibitors. NSAID use decreased significantly after starting TNF-α inhibitors. During conventional treatment, NSAID use remained stable at group level. However, NSAID use changed frequently at individual patient level and was significantly associated with disease activity.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Estudos de Coortes , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Índice de Gravidade de Doença , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/patologia
16.
Arthritis Rheumatol ; 70(9): 1366-1376, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29648680

RESUMO

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.

17.
Cancer Immunol Immunother ; 67(6): 925-933, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29546435

RESUMO

The biological behavior of melanoma is unfavorable in the elderly when compared to young subjects. We hypothesized that differences in T-cell responses might underlie the distinct behavior of melanoma in young and old melanoma patients. Therefore, we investigated the circulating T-cell compartment of 34 patients with metastatic melanoma and 42 controls, which were classified as either young or old. Absolute numbers of CD4+ T cells were decreased in young and old melanoma patients when compared to the age-matched control groups. Percentages of naive and memory CD4+ T cells were not different when comparing old melanoma patients to age-matched controls. Percentages of memory CD4+ T cells tended to be increased in young melanoma patients compared to young controls. Proportions of naive CD4+ T cells were lower in young patients than in age-matched controls, and actually comparable to those in old patients and controls. This was accompanied with increased percentages of memory CD4+ T cells expressing HLA-DR, Ki-67, and PD-1 in young melanoma patients in comparison to the age-matched controls, but not in old patients. Proportions of CD45RA-FOXP3high memory regulatory T cells were increased in young and old melanoma patients when compared to their age-matched controls, whereas those of CD45RA+FOXP3low naive regulatory T cells were similar. We observed no clear modulation of the circulating CD8+ T-cell repertoire in melanoma patients. In conclusion, we show that CD4+ T cells of young melanoma patients show signs of activation, whereas these signs are less clear in CD4+ T cells of old patients.

18.
Front Immunol ; 9: 315, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29520282

RESUMO

Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system.

19.
Rheumatology (Oxford) ; 57(5): 818-825, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29444331

RESUMO

Objectives: To validate the ACR-EULAR classification criteria for primary SS (pSS), and compare them to the American-European Consensus Group (AECG) and ACR criteria in a Dutch prospective diagnostic cohort. Methods: Consecutive patients (n = 129) referred for suspicion of pSS underwent a multidisciplinary evaluation, including a labial and/or parotid gland biopsy. Patients with an incomplete work-up (n = 8) or associated systemic auto-immune disease (n = 7) were excluded. The ACR-EULAR classification was compared with expert classification, AECG and ACR classification. Additionally, the accuracy of individual ACR-EULAR items in discriminating pSS from non-pSS was evaluated. The validity of criteria sets was described separately using parotid or labial gland biopsy results for classification. Results: Of the 114 evaluated patients, the expert panel classified 34 (30%) as pSS and 80 (70%) as non-pSS. Using labial gland biopsy results, ACR-EULAR classification showed 87% absolute agreement (κ = 0.73) with expert classification, with a sensitivity of 97% and specificity of 83%. Using the parotid gland biopsy results, the ACR-EULAR criteria performed excellently as well. Focus score, anti-SSA titre and ocular staining score showed good to excellent accuracy, whereas unstimulated whole saliva and Schirmer's test had poor accuracy. The ACR-EULAR and AECG criteria had equal validity. Compared with ACR classification, ACR-EULAR classification showed higher sensitivity but lower specificity. Conclusion: The ACR-EULAR criteria showed good agreement with expert classification, but some patients may be misclassified as pSS. Unstimulated whole saliva and Schirmer's test showed poor discriminative value. The ACR-EULAR criteria performed equally to the AECG criteria, and had higher sensitivity but lower specificity than the ACR criteria.


Assuntos
Consenso , Grupos Étnicos , Glândula Parótida/patologia , Reumatologia/métodos , Síndrome de Sjogren/classificação , Biópsia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/etnologia , Fatores de Tempo
20.
Ann Rheum Dis ; 77(5): 636-643, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29358285

RESUMO

To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA