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1.
Rheumatology (Oxford) ; 56(1): 95-102, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27997346

RESUMO

OBJECTIVE: NSAIDs are first-line therapy in axial SpA (axSpA). The proportion of patients responding to NSAIDs and differences between AS and non-radiographic axSpA (nr-axSpA) in this regard have not been studied in detail to date. The aim of this study was to examine the proportion of patients with AS and nr-axSpA responding to NSAIDs according to current treatment recommendations. METHODS: Consecutive anti-TNF-naïve patients with nr-axSpA and AS (n = 50 each) were included if their BASDAI score was ⩾4 without having received maximal NSAID doses. In case of a BASDAI score ⩾4 1 week later, another NSAID was prescribed. For the next 3 weeks, continuous intake of maximal doses was recommended but patients could reduce doses in case of intolerance or improvement. MRI of the SI joints was performed at baseline and week 4. RESULTS: All outcomes except for CRP and MRI scores improved significantly after 4 weeks of NSAIDs, with no difference between axSpA subgroups. An Assessment of SpondyloArthritis international Society 40% (ASAS40) response and partial remission rates were 35 and 16% at week 4, respectively. At the same time point, a BASDAI score ⩾4 was still present in 44% of patients, 30% of which had reduced NSAID doses, partly due to intolerance (38%). Only 13% of all patients had continuously taken NSAIDs at the maximal dosage, but there was no difference in the efficacy outcome compared with those who had taken reduced doses. CONCLUSION: AS and nr-axSpA patients had similar response rates to NSAIDs while objective signs of inflammation did not change over 4 weeks. Only a minority of patients was willing to take maximal doses of NSAIDs, and ⩾40% patients remained candidates for TNF blockers. These results may influence future trial designs.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Proteína C-Reativa/imunologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Radiografia , Articulação Sacroilíaca/diagnóstico por imagem , Espondilartrite/diagnóstico por imagem , Espondilartrite/tratamento farmacológico , Espondilartrite/imunologia , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/imunologia , Resultado do Tratamento
3.
Ann Rheum Dis ; 73(12): 2137-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23956246

RESUMO

OBJECTIVE: To investigate the role of serum vascular endothelial growth factor (VEGF) as a predictor of radiographic spinal progression in patients with axial spondyloarthritis (axSpA). METHODS: Altogether, 172 patients with definite axSpA (95 with ankylosing spondylitis and 77 with non-radiographic axSpA) were included in this study. Spinal radiographs obtained at baseline and after 2 years of follow-up were scored independently by two trained readers in a concealed and randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) scoring system and for the presence of syndesmophytes. Radiographic spinal progression after 2 years was defined as (1) mSASSS worsening by ≥2 units, and (2) new syndesmophyte formation or formation of a bridging syndesmophyte from two single syndesmophytes. Serum VEGF levels were detected at baseline. RESULTS: Mean baseline VEGF values were significantly higher in patients with mSASSS worsening by ≥2 units after 2 years (n=22) than in those without progression (562±357 vs 402±309 pg/mL, respectively, p=0.027) and in patients with syndesmophyte formation (n=18) again as compared with those without new bone formation (579±386 vs 404±307 pg/mL, respectively, p=0.041). VEGF as a predictor of radiographic spinal progression performed especially well in patients who were already at high risk for such a progression due to the presence of syndesmophytes at baseline (n=48). In these patients, a VEGF serum level of >600 pg/mL had a sensitivity of 53%, a specificity of 97% and an OR=36.6 (95% CI 3.9 to 341.5) as a predictor of mSASSS worsening by ≥2 units. For syndesmophyte formation, elevated VEGF demonstrated a sensitivity of 47%, a specificity of 94% and an OR=13.6 (95% CI 2.4 to 78.3). CONCLUSIONS: An elevated serum level of VEGF (>600 pg/mL) is highly specific as a predictor of radiographic spinal progression in patients with axSpA, especially in patients who are at high risk for further progression due to the presence of syndesmophytes.


Assuntos
Coluna Vertebral/diagnóstico por imagem , Espondilite Anquilosante/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Radiografia , Índice de Gravidade de Doença , Espondilartrite/sangue , Espondilartrite/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem
4.
Arthritis Rheum ; 65(6): 1522-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23508523

RESUMO

OBJECTIVE: The interleukin-12 (IL-12) family of cytokines has been suggested to play a critical role in inflammatory autoimmune diseases, and recent studies analyzing peripheral blood and synovial fluid from patients with spondyloarthritides suggest that IL-23 might be a proinflammatory factor in these disorders. This study was undertaken to investigate the presence and source of IL-23 in the spines of patients with ankylosing spondylitis (AS). METHODS: The frequency of IL-23-positive and IL-12-positive cells within the subchondral bone marrow and within fibrous tissue replacing normal bone marrow in facet joints of patients with AS was analyzed by immunohistochemistry. The origin of IL-23-positive cells was determined by double staining of CD163+ macrophages, CD68+ macrophages, CD1a+ dendritic cells, tryptase-positive mast cells, myeloperoxidase-positive cells, CD20+ B cells, and CD3+ T cells. Findings in 28 facet joints from 22 AS patients were compared with those in 20 facet joints from 13 patients with osteoarthritis (OA) and 10 normal control specimens. RESULTS: The frequency of IL-23-positive cells in subchondral bone marrow from the joints of AS patients (mean ± SD 42.50 ± 32.81/high-power field [hpf]) was significantly increased compared to that in subchondral bone marrow from OA patients (OA 15.63 ± 29.90/hpf) (P = 0.0017) or controls (19.36 ± 16.8/hpf) (P = 0.03). Myeloperoxidase-positive cells and, to a lesser extent, macrophages and dendritic cells were found to be the origin of IL-23 in the bone marrow. In AS and OA patients, the frequency of IL-23-positive cells was significantly higher than that of IL-12-positive cells (P < 0.001 in both patient groups). Within fibrous tissue from AS and OA facet joints, IL-23 was predominantly produced by CD163+ macrophages (mean ± SD 0.64 ± 0.59/hpf and 4.36 ± 3.4/hpf, respectively) and CD68+ macrophages (2.3 ± 0.65/hpf and 6.54 ± 4.1/hpf, respectively). CONCLUSION: IL-23 is expressed in the subchondral bone marrow and in fibrous tissue replacing bone marrow in facet joints of patients with AS. It might have a role in inflammatory processes and in chronic changes in AS joints, which makes it an interesting potential therapeutic target in this disease.


Assuntos
Interleucina-12/metabolismo , Interleucina-23/metabolismo , Articulações/imunologia , Macrófagos/imunologia , Coluna Vertebral/patologia , Espondilite Anquilosante/imunologia , Adulto , Idoso , Citocinas , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Coluna Vertebral/imunologia
5.
Ann Rheum Dis ; 71(4): 572-4, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22186710

RESUMO

INTRODUCTION: The molecular mechanisms of syndesmophyte formation in ankylosing spondylitis (AS) are yet to be characterised. Molecules involved in bone formation such as Wnt proteins and their antagonists probably drive syndesmophyte formation in AS. METHODS: This study investigated sequential serum levels of functional dickkopf-1 (Dkk1), a potent Wnt antagonist involved in bone formation in arthritis, by capture ELISA with its receptor LRP6 in 65 AS patients from the German Spondyloarthritis Inception Cohort. Dkk1 levels were then related to structural progression (syndesmophyte formation) as well as sclerostin and C-reactive protein (CRP) levels. RESULTS: Functional Dkk1 levels were significantly (p=0.025) higher in patients with no syndesmophyte growth (6.78 ± 5.48 pg/ml) compared with those with syndesmophyte growth (4.13 ± 2.10 pg/ml). Dkk1 levels were highly correlated to serum sclerostin levels (r=0.71, 95% CI 0.53 to 0.82; p<0.001) but not to CRP (r=0.15, 95% CI -0.10 to 0.38; p=0.23). CONCLUSION: AS patients with no syndesmophyte formation show significantly higher functional Dkk1 levels suggesting that blunted Wnt signalling suppresses new bone formation and consequently syndesmophyte growth and spinal ankylosis. Similar to serum sclerostin levels, the functional Dkk1 level thus emerges as a potential biomarker for structural progression in patients with AS.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/sangue , Osteófito/etiologia , Espondilite Anquilosante/complicações , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Proteína C-Reativa/metabolismo , Progressão da Doença , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Osteófito/sangue , Prognóstico , Radiografia , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico por imagem
6.
Mol Ther Methods Clin Dev ; 21: 288-298, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-33898628

RESUMO

While virus-specific antibodies are broadly recognized as correlates of protection, virus-specific T cells are important for direct clearance of infected cells. Failure to generate hepatitis B virus (HBV)-specific antibodies is well-known in patients with end-stage renal disease. However, whether and to what extent HBV-specific cellular immunity is altered in this population and how it influences humoral immunity is not clear. To address it, we analyzed HBV-reactive T cells and antibodies in hemodialysis patients post vaccination. 29 hemodialysis patients and 10 healthy controls were enrolled in a cross-sectional study. Using multiparameter flow cytometry, HBV-reactive T cells were analyzed and functionally dissected based on granzyme B, interferon-γ (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), and IL-4 expression. Importantly, HBV-reactive CD4+ T cells were detected not only in all patients with sufficient titers but also in 70% of non-responders. Furthermore, a correlation between the magnitude of HBV-reactive CD4+ T cells and post-vaccination titers was observed. In summary, our data showed that HBV-reactive polyfunctional T cells were present in the majority of hemodialysis patients even if humoral immunity failed. Further studies are required to confirm their in vivo antiviral capacity. The ability to induce vaccine-reactive T cells paves new ways for improved vaccination and therapy protocols.

8.
Curr Rheumatol Rep ; 10(5): 356-63, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18817638

RESUMO

Ankylosing spondylitis (AS) is characterized by two key pathologic findings: sacroiliac joint and spinal inflammation and new bone formation with possible bone fusion, usually in the axial skeleton. Thus, structural damage in AS must be viewed differently than that in rheumatoid arthritis. Tumor necrosis factor blockers effectively inhibit inflammation, as shown by signs and symptoms, function, C-reactive protein, and MRI, and will probably prevent erosive structural damage. However, the ossification of already-damaged bone cannot be influenced by tumor necrosis factor blockade, because these drugs do not inhibit osteoblasts. It remains to be seen whether additional targeting of new bone formation is clinically meaningful in advanced AS. The most important action to prevent structural damage is probably an early diagnosis and effective anti-inflammatory treatment of AS.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Espondilite Anquilosante , Anti-Inflamatórios/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Osteogênese/efeitos dos fármacos , Radiografia , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/patologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/fisiopatologia , Espondilite Anquilosante/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
Nat Clin Pract Rheumatol ; 4(11): 578-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18839009

RESUMO

In light of the impressive efficacy of tumor necrosis factor blockers in the treatment of ankylosing spondylitis, particularly in patients with short disease duration, defining outcome parameters to monitor the structural damage of the disease has become more pertinent. In this Viewpoint the authors explore the relevance of osteoproliferation amongst other outcome parameters.


Assuntos
Osteogênese , Espondilite Anquilosante/fisiopatologia , Humanos , Osteogênese/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral
10.
J Clin Invest ; 112(6): 831-42, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12975468

RESUMO

Containment of hepatitis C virus (HCV) and other chronic human viral infections is associated with persistence of virus-specific CD4 T cells, but ex vivo characterization of circulating CD4 T cells has not been achieved. To further define the phenotype and function of these cells, we developed a novel approach for the generation of tetrameric forms of MHC class II/peptide complexes that is based on the cellular peptide-exchange mechanism. HLA-DR molecules were expressed as precursors with a covalently linked CLIP peptide, which could be efficiently exchanged with viral peptides following linker cleavage. In subjects who spontaneously resolved HCV viremia, but not in those with chronic progressive infection, HCV tetramer-labeled cells could be isolated by magnetic bead capture despite very low frequencies (1:1,200 to 1:111,000) among circulating CD4 T cells. These T cells expressed a set of surface receptors (CCR7+CD45RA-CD27+) indicative of a surveillance function for secondary lymphoid structures and had undergone significant in vivo selection since they utilized a restricted Vbeta repertoire. These studies demonstrate a relationship between clinical outcome and the presence of circulating CD4 T cells directed against this virus. Moreover, they show that rare populations of memory CD4 T cells can be studied ex vivo in human diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos HLA-DR/imunologia , Hepacivirus/imunologia , Memória Imunológica , Animais , Linfócitos T CD4-Positivos/metabolismo , Genes MHC da Classe II , Hepatite C/imunologia , Humanos , Peptídeos/química , Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Viremia/imunologia
11.
RMD Open ; 3(2): e000541, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29435361

RESUMO

BACKGROUND: Imaging has an essential role in the new spondyloarthritis (SpA) classification criteria for axial but not for peripheral manifestations. We evaluated the impact of imaging findings for identification and treatment decisions in patients with peripheral spondyloarthritis (pSpA) and controls (non-SpA). METHODS: Patients with pSpA (Assessment of SpA international Society criteria, n=30) and non-SpA (n=30), aged <45 years, with painful heels or knees, were recruited. Conventional radiography, grey-scale ultrasound including power Doppler (US/PDUS) and MRI of symptomatic areas were performed to assess inflammatory and structural changes. Mann-Whitney U test was used for group comparisons. RESULTS: In total, 105 painful entheses (71 heels, 34 knees) in 60 patients were examined. Differences between diagnoses were found for symptom duration (pSpA: 17.2±27.5 vs non-SpA: 4.4±4.3 months), human leucocyte antigen B27 prevalence (67% vs 13%) and gender distribution (53.3% vs 20% male, respectively), all P<0.05. Logistic regression analysis for baseline differences showed that chronic changes (erosions and calcification) in the heel were more frequent in pSpA versus non-SpA by US/PDUS (62.5% vs 28.6% patients and 59.5% vs 26.5% entheses, P<0.05). Inflammatory changes in heel or knee by US/PDUS and MRI could not differentiate between non-SpA and pSpA. CONCLUSIONS: Differentiation between pSpA and non-SpA was only possible based on structural but not inflammatory changes in the heels and knees of symptomatic patients. US/PDUS was superior to MRI for this purpose. These findings imply that pSpA is associated with erosive changes at enthesitic sites, while inflammation and susceptibility are of minor influence for the development of erosions and calcification to pSpA.

12.
Arthritis Rheumatol ; 68(10): 2456-65, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27111225

RESUMO

OBJECTIVE: We previously suggested that fibroblast-rich granulation tissue eroding the subchondral bone is instrumental in the joint remodeling that occurs in ankylosing spondylitis (AS). The purpose of this study was to determine if this granulation tissue also carries bone-forming capabilities, which we approached by searching for bone-forming cells (hypertrophic chondrocytes, osteoblasts) in its vicinity. We also assessed adipogenic tissue transformation, which has been suggested to be an intermediate feature in AS bone formation based on imaging studies. METHODS: The facet joints of AS patients, osteoarthritis (OA) patients, and autopsy subjects (controls) were screened for subchondral granulation tissue. We searched for hypertrophic chondrocytes by assessing RUNX-2, type X collagen, and matrix metalloproteinase 13 (MMP-13) expression, for osteoblasts by analyzing RUNX-2, CD56, and type I collagen expression, as well as for signs of new bone formation. Adipocytes and lipid accumulation were assessed in Safranin O-stained sections. RESULTS: In the joints of AS and OA patients, RUNX-2-positive cells were found to be lining the granulation tissue. These cells coexpressed type I collagen but lacked type X collagen and MMP-13 expression, confirming their osteoblastic nature. In 91% of AS joints and in 20% of OA joints (P < 0.05), we observed foci of new bone formation at contact zones between the granulation tissue and the cartilage. Joints containing bony spots showed greater replacement of the adjacent bone marrow by granulation tissue than did joints without bone formation (P < 0.05). The granulation tissue often contained adipocytes and lipid accumulations. Replacement of the subchondral bone marrow by fat tissue was also frequently found but was not associated with new bone formation. CONCLUSION: The subchondral granulation tissue carries osteoblasts, which promote new bone formation, leading to intraarticular ankylosis of the facet joints in AS.


Assuntos
Condrócitos/patologia , Tecido de Granulação/patologia , Osteoartrite da Coluna Vertebral/patologia , Osteoblastos/patologia , Osteogênese , Coluna Vertebral/patologia , Espondilite Anquilosante/patologia , Articulação Zigapofisária/patologia , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Estudos de Casos e Controles , Condrócitos/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo X/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Tecido de Granulação/metabolismo , Humanos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite da Coluna Vertebral/metabolismo , Osteoblastos/metabolismo , Coluna Vertebral/metabolismo , Espondilite Anquilosante/metabolismo , Articulação Zigapofisária/metabolismo
14.
Arthritis Res Ther ; 17: 170, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26123554

RESUMO

INTRODUCTION: In ankylosing spondylitis (AS), joint remodeling leading to joint ankylosis involves cartilage fusion. Here, we analyzed whether chondrocyte hypertrophy is involved in cartilage fusion and subsequent joint remodeling in AS. METHODS: We assessed the expression of chondrocyte hypertrophy markers runt-related transcription factor 2 (Runx2), type X collagen (COL10), matrix metalloproteinase 13 (MMP13), osteocalcin and beta-catenin and the expression of positive bone morphogenic proteins (BMPs) and negative regulators (dickkopf-1 (DKK-1)), sclerostin, (wingless inhibitory factor 1 (wif-1)) of chondrocyte hypertrophy in the cartilage of facet joints from patients with AS or osteoarthritis (OA) and from autopsy controls (CO) by immunohistochemistry. Sex determining region Y (SRY)-box 9 (Sox9) and type II collagen (COL2) expression was assessed as indicators of chondrocyte integrity and function. RESULTS: The percentage of hypertrophic chondrocytes expressing Runx2, COL10, MMP13, osteocalcin or beta-catenin was significantly increased in OA but not in AS joints compared to CO joints. Frequencies of sclerostin-positive and DKK-1-positive chondrocytes were similar in AS and CO. In contrast, wif-1- but also BMP-2- and BMP-7-expressing and Sox9-expressing chondrocytes were drastically reduced in AS joints compared to CO as well as OA joints whereas the percentage of COL2-expressing chondrocytes was significantly higher in AS joints compared to CO joints. CONCLUSIONS: We found no evidence for chondrocyte hypertrophy within hyaline cartilage of AS joints even in the presence of reduced expression of the wnt inhibitor wif-1 suggesting that chondrocyte hypertrophy is not a predominant pathway involved in joint fusion and remodeling in AS. In contrast, the reduced expression of Sox9, BMP-2 and BMP-7 concomitantly with induced COL2 expression rather point to disturbed cartilage homeostasis promoting cartilage degeneration in AS.


Assuntos
Doenças das Cartilagens/diagnóstico , Cartilagem Articular/patologia , Condrócitos/patologia , Espondilite Anquilosante/diagnóstico , Articulação Zigapofisária/patologia , Adulto , Idoso , Doenças das Cartilagens/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/metabolismo , Articulação Zigapofisária/metabolismo
15.
Clin Rheumatol ; 23(5): 435-40, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15459815

RESUMO

A relative high secretion level of IL-10 and a low secretion of TNF-alpha has been described in the synovial fluid and peripheral blood of patients with reactive arthritis (ReA), possibly contributing to the persistence of bacteria. The role of TGF-beta is less clear. We investigated these cytokines in the synovial membrane of patients with ReA and rheumatoid arthritis (RA) and tried to identify their cellular source. We used sections from the synovial membrane of 4 ReA and 4 RA patients which were double stained with immunofluorescence antibodies against cell surface markers for T cells (CD3), macrophages (CD68) and B cells (CD20) in combination with antibodies against intracellular cytokines TNF-alpha, IFN-gamma, TGF-beta, IL-4 and IL-10, and quantified these using a fluorescence microscope. A lower number of TNF-alpha-secreting cells were found in ReA compared to RA: CD3+: 1.78 +/- 0.54% versus 5.02% +/- 0.47% (p = 0.034). CD68+: 2.86 +/- 0.52 versus 5.37 +/- 0.53% (p = 0.034), CD20+ : 3.02 +/- 0.42% versus 3.58 +/- 0.48% (p > 0.05). A higher number of IL-10 positive cells were found in ReA compared to RA: CD3+: 3.27 +/- 1.5% versus 1.13 +/- 0.50% (p = 0.034), CD68+ 1.23 +/- 0.75% versus 0.83 +/- 0.35% (p > 0.05), CD20+: 3.70 +/- 1.6% versus 1.6 +/- 1.1% (p > 0.05). A difference between ReA and RA was also found for TGF-beta+ T cells: CD3+ 7.86 + 1.5% versus 1.78 + 0.35% (p = 0.032); CD20+: 7.91 + 2.1% versus 2.1 + 2.8% (p > 0.05), CD68+: 7.81% + 1.24% versus 2.12 + 0.28% (p = 0.032). In conclusion, we saw a different cytokine secretion pattern in the synovial membrane of ReA and RA. For T cells in ReA we found a cytokine secretion profile typical for T regulatory cells 1 (Tr1), with an elevated level of IL-10- and TGF-beta-secreting cells. Whether this is due to a more general difference in TNF-alpha, IL-10 or TGF-beta production which is genetically determined or regulated by T cells remains to be determined.


Assuntos
Artrite Infecciosa/imunologia , Artrite Reumatoide/imunologia , Citocinas/metabolismo , Linfócitos/metabolismo , Macrófagos/metabolismo , Membrana Sinovial/metabolismo , Antígenos CD/metabolismo , Artrite Infecciosa/metabolismo , Artrite Infecciosa/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Contagem de Células , Feminino , Humanos , Imuno-Histoquímica , Interleucina-10/metabolismo , Linfócitos/patologia , Macrófagos/patologia , Masculino , Proibitinas , Membrana Sinovial/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Crescimento Transformador beta/metabolismo
16.
Arthritis Rheumatol ; 66(7): 1745-54, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24574301

RESUMO

OBJECTIVE: To unravel the mechanisms that control bony ankylosis in ankylosing spondylitis (AS). METHODS: Histomorphologic and histomorphometric analyses were performed on zygapophyseal joints obtained from 18 patients with AS, 9 patients with osteoarthritis (OA), and 10 cadaver donors without a rheumatic disease (controls). The proteoglycan content of the cartilage was determined by Safranin O staining and the chondrocyte apoptosis according to caspase 3 expression. RESULTS: AS joints were categorized into 3 groups according to the morphology of the joint surfaces and joint space: group 1 were joints with an open joint space, group 2 were joints with cartilaginous fusion, and group 3 were joints with bony fusion of the joint surfaces. Progressive loss of the joint space from group 1 joints to group 3 joints suggests that this grouping corresponds to sequential stages of joint remodeling. Cartilage thickness and subchondral bone plate thickness declined from group 1 to group 3 (P < 0.01). Increased chondrocyte apoptosis rates were found in groups 1 and 2 (P < 0.05), while in group 3, a reduction in the proteoglycan content was found (P < 0.001). Bone marrow replacement and invasion of the subchondral bone plate by fibrous tissue was found predominantly in AS joints in group 2. CONCLUSION: Cartilage degeneration, indicated by cartilage thinning, enhanced chondrocyte apoptosis, and proteoglycan loss, and subchondral bone thinning, promoted by invasion of the subchondral bone plate by a fibrous tissue originating from the bone marrow, are hallmarks of joint remodeling in AS.


Assuntos
Condrócitos/patologia , Osteoblastos/patologia , Espondilite Anquilosante/patologia , Articulação Zigapofisária/patologia , Idoso , Apoptose/fisiologia , Medula Óssea/patologia , Cadáver , Cartilagem/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Proteoglicanas/metabolismo , Espondilite Anquilosante/metabolismo , Espondilite Anquilosante/fisiopatologia , Articulação Zigapofisária/metabolismo
17.
Open Rheumatol J ; 5: 123-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22279511

RESUMO

Recent studies using magnetic resonance imaging have suggested that the subchondral bone marrow and the entheses are the sites which are primarily involved in the peripheral and axial inflammation found in patients with spondyloarthritides. Histopathological analyses indicated that the typical morphological features at these sites reflect an inflammation (osteitis) at the bone cartilage interface and in the subchondral bone marrow. This finding implies that synovitis may be of minor importance, especially in comparison to other inflammatory joint diseases such as rheumatoid arthritis. Here, we summarize current available knowledge on synovial involvement in inflammatory processes related to SpA.

18.
J Rheumatol ; 38(11): 2445-51, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21921098

RESUMO

OBJECTIVE: Regulatory T cells are characterized by expression of the transcription factor FoxP3 and are thought to be involved in the pathogenesis of autoimmune diseases. We determined the frequency and phenotypic characteristics of CD4+FoxP3+ T cells in the blood and synovial fluid (SF) of patients with inflammatory joint diseases. METHODS: SF from 10 patients with ankylosing spondylitis (AS), 20 patients with other spondyloarthritides or with peripheral arthritis (pSpA), and 12 patients with rheumatoid arthritis (RA), and peripheral blood (PB) from 22 patients with AS, 19 with pSpA, 15 with RA, and 12 healthy controls were stained for CD4, FoxP3, CD25, and CD127 and different effector cytokines and then analyzed by flow cytometry. Methylation pattern of the Treg-specific demethylated region (TSDR) was determined after bisulfite treatment by quantitative polymerase chain reaction. RESULTS: In all groups of patients we observed higher frequencies of Foxp3+ cells/CD4+ T cells within SF compared to PB. The frequency of synovial Foxp3+ cells/CD4+ T cells was significantly higher in patients with pSpA (18.79% ± 6.41%) compared to patients with AS (9.69% ± 4.11%) and patients with RA (5.95% ± 2.21%). CD4+FoxP3+ T cells were CD25+ and CD127- and lacked effector cytokine production in any of the different patient groups. The majority of the CD4+CD25+CD127- T cells showed demethylation of the TSDR within the Foxp3 locus, confirming its regulatory phenotype. CONCLUSION: Our data show accumulation of Foxp3+ T cells within inflamed joints. These Foxp3+ T cells are mainly of stable T regulatory phenotype. The high frequency of Foxp3+ T cells in pSpA might contribute to the spontaneous resolution and remitting course of arthritis in pSpA as compared to the more persistent joint inflammation in RA.


Assuntos
Artrite Reumatoide/patologia , Células Sanguíneas/patologia , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Espondilartrite/patologia , Espondilite Anquilosante/patologia , Líquido Sinovial/citologia , Linfócitos T/patologia , Adulto , Idoso , Artrite Psoriásica/metabolismo , Artrite Psoriásica/patologia , Artrite Reativa/metabolismo , Artrite Reativa/patologia , Artrite Reumatoide/metabolismo , Células Sanguíneas/metabolismo , Estudos de Casos e Controles , Contagem de Células , Citocinas/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Pessoa de Meia-Idade , Fenótipo , Espondilartrite/metabolismo , Espondilite Anquilosante/metabolismo , Líquido Sinovial/metabolismo , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
19.
Arthritis Res Ther ; 13(3): R95, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21689402

RESUMO

INTRODUCTION: In this study, we analysed the number of IL-17(+) cells in facet joints, in the peripheral blood (PB) and synovial fluid (SF) of spondyloarthritis (SpA) patients and compared these results with those of patients with other rheumatic diseases and controls. METHODS: Immunohistochemical analysis of IL-17(+) cells was performed in facet joints of 33 ankylosing spondylitis (AS) patients and compared with data from 20 osteoarthritis (OA) patients. The frequency of IL-17(+)CD4(+) T cells in PB and SF of SpA patients (PB n = 30, SF n = 11), rheumatoid arthritis (RA) patients (PB n = 14, SF n = 7), OA patients (PB n = 10) and healthy controls (PB n = 12) was analysed after stimulation with Staphylococcus aureus Enterotoxin B and phorbol 12-myristate 13-acetate/ionomycin and quantified by flow cytometry. RESULTS: In AS facet joints, the frequency of IL-17-secreting cells was significantly higher than in samples obtained from OA patients (P < 0.001), with a slight predominance of IL-17(+) cells among the mononuclear cells (61.5% ± 14.9%) compared to cells with polysegmental nuclei. Immunofluorescence microscopy revealed that the majority of IL-17(+) cells were myeloperoxidase-positive (35.84 ± 13.06/high-power field (HPF) and CD15(+) neutrophils (24.25 ± 10.36/HPF), while CD3(+) T cells (0.51 ± 0.49/HPF) and AA-1(+) mast cells (2.28 ± 1.96/HPF) were less often IL-17-positive. The frequency of IL-17(+)CD4(+) T cells in the PB and SF of SpA patients did not differ significantly compared to RA patients, OA patients or healthy controls. CONCLUSIONS: Our data suggest an important role for IL-17 in the inflammatory processes in AS. However, the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response.


Assuntos
Imunidade Adaptativa/imunologia , Interleucina-17/imunologia , Espondilite Anquilosante/imunologia , Células Th17/imunologia , Articulação Zigapofisária/imunologia , Adulto , Idoso , Especificidade de Anticorpos , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Humanos , Interleucina-17/metabolismo , Vértebras Lombares/imunologia , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Pessoa de Meia-Idade , Osteoartrite/imunologia , Receptores CCR6/imunologia , Receptores CCR6/metabolismo , Espondilite Anquilosante/metabolismo , Espondilite Anquilosante/patologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Células Th17/metabolismo , Adulto Jovem , Articulação Zigapofisária/metabolismo , Articulação Zigapofisária/patologia
20.
PLoS One ; 6(8): e24048, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21887369

RESUMO

INTRODUCTION: This study examines the expression of IL-17A-secreting cells within the inflamed synovium and the relationship to in vivo joint hypoxia measurements. METHODS: IL-17A expression was quantified in synovial tissue (ST), serum and synovial fluid (SF) by immunohistochemistry and MSD-plex assays. IL-6 SF and serum levels were measured by MSD-plex assays. Dual immunofluorescence for IL-17A was quantified in ST CD15+ cells (neutrophils), Tryptase+ (mast cells) and CD4+ (T cells). Synovial tissue oxygen (tpO(2)) levels were measured under direct visualisation at arthroscopy. Synovial infiltration was assessed using immunohistochemistry for cell specific markers. Peripheral blood mononuclear and polymorphonuclear cells were isolated and exposed to normoxic or 3% hypoxic conditions. IL-17A and IL-6 were quantified as above in culture supernatants. RESULTS: IL-17A expression was localised to mononuclear and polymorphonuclear (PMN) cells in inflamed ST. Dual immunoflourescent staining co-localised IL-17A expression with CD15+ neutrophils Tryptase+ mast cells and CD4+T cells. % IL-17A positivity was highest on CD15+ neutrophils, followed by mast cells and then CD4+T-cells. The number of IL-17A-secreting PMN cells significantly correlated with sublining CD68 expression (r = 0.618, p<0.01). IL-17A SF levels correlated with IL-6 SF levels (r = 0.675, p<0.01). Patients categorized according to tp0(2)< or >20 mmHg, showed those with low tp0(2)<20 mmHg had significantly higher IL-17A+ mononuclear cells with no difference observed for PMNs. Exposure of mononuclear and polymorphonuclear cells to 3% hypoxia, significantly induced IL-6 in mononuclear cells, but had no effect on IL-17A expression in mononuclear and polymorphonuclear cells. CONCLUSION: This study demonstrates IL-17A expression is localised to several immune cell subtypes within the inflamed synovial tissue, further supporting the concept that IL-17A is a key mediator in inflammatory arthritis. The association of hypoxia with Il-17A expression appears to be indirect, probably through hypoxia-induced pro-inflammatory pathways and leukocyte influx within the joint microenvironment.


Assuntos
Movimento Celular/imunologia , Inflamação/patologia , Interleucina-17/análise , Leucócitos Mononucleares/química , Neutrófilos/química , Membrana Sinovial/patologia , Artrite , Humanos , Hipóxia , Articulações/metabolismo , Líquido Sinovial
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