RESUMO
The Wnt signalling pathway is a critical regulator of bone mass and quality. Several heterozygous mutations in the LRP5 gene, a Wnt co-receptor, causing high bone mass (LRP5-HBM) have been described to date. The pathogenic mechanism is thought to be a gain-of-function caused by impaired inhibition of the canonical Wnt signalling pathway, thereby leading to increased bone formation. We report the cases of two affected family members, a 53-year-old mother and her 23-year-old daughter, with high bone mass (T-scores mother: lumbar spine 11.4, femoral neck 10.5; T-scores daughter: lumbar spine 5.4, femoral neck 8.7), increased calvarial thickness, and thickened cortices of the long bones but no history of fractures. Whereas the mother did not show any indications of the mutation, the daughter suffered from congenital hearing impairment resulting in cochlear implantation, recurrent facial palsy, and migraine. In addition, she had stenosis of the foramen magnum. In both individuals, we detected a novel heterozygous duplication of six basepairs in the LRP5 gene, resulting in an insertion of two amino acids, very likely associated with a gain-of-function. When the daughter had part of the occipital bone surgically removed, the bone sample was used for the visualization of bone lamellar structure and bone cells as well as the measurement of bone mineralization density distribution (BMDD). The bone sample revealed two distinctly different regions: an intra-cortical region with osteonal remodeling, typical osteonal lamellar orientation, associated with relatively higher heterogeneity of bone matrix mineralization, and another periosteal region devoid of bone remodeling, with parallel bone lamellae and lower heterogeneity of mineralization. In conclusion, we present data on bone tissue and material level from an LRP5-HBM patient with a novel mutation in the LRP5 gene. Our findings indicate normal morphology of osteoclasts and osteoblasts as well as normal mineralization in skull bone in LRP5-HBM.
Assuntos
Densidade Óssea/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Linhagem , Adulto JovemRESUMO
We analyzed the association of proton pump inhibitors (PPIs) with mortality after osteoporosis-related hip fracture in Austria. PPIs were associated with reduced 90-day mortality but elevated mortality after half a year when initiated pre-fracture. Inpatients and discharged patients on PPIs showed lowered in-hospital and 90-day mortality, respectively. INTRODUCTION: We herein investigated use of proton pump inhibitors (PPIs) and mortality among hip fracture patients in a nationwide study in Austria. METHODS: In this retrospective cohort study, data on use of PPIs were obtained from 31,668 Austrian patients ≥50 years with a hip fracture between July 2008 and December 2010. All-cause mortality in patients without anti-osteoporotic drug treatment who had received their first recorded PPI prescription in the study period either before or after fracture was compared with hip fracture patients on neither PPIs nor anti-osteoporotic medication using logistic and Cox regression analysis. RESULTS: With PPI use, 90-day mortality was significantly reduced, both at initiation before (OR 0.66; p < 0.0001) and after hip fracture (OR 0.23; p < 0.0001). 90-day mortality was also reduced when PPIs were prescribed not until after discharge from the last recorded hip fracture-related hospital stay (OR 0.49; p < 0.0001) except for patients aged <70 years. In a sub-cohort of patients beginning PPIs during hospital stay, in-hospital mortality (0.2%) was substantially reduced relative to matched control patients (3.5%) (p < 0.0001). Longer-term mortality significantly increased after half a year post-fracture only among those who started PPI prescription before fracture. CONCLUSIONS: PPI use during and after hospital stay due to hip fracture is associated with a considerable decrease in mortality. These findings could have implications for hip fracture treatment.
Assuntos
Fraturas do Quadril/mortalidade , Fraturas por Osteoporose/mortalidade , Inibidores da Bomba de Prótons/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Esquema de Medicação , Uso de Medicamentos/estatística & dados numéricos , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
UNLABELLED: We analyzed the association of bisphosphonate therapy with mortality and hip refracture incidence among osteoporosis-related hip fracture patients in Austria. Mortality was lower in primarily female bisphosphonate users, while hip refracture incidence was generally elevated relative to controls, indicating beneficial effects of bisphosphonates other than on bone. INTRODUCTION: The purpose of this study was to analyze mortality and hip refracture risk in osteoporotic hip fracture patients with and without antiosteoporotic medication. METHODS: We retrospectively analyzed data on 31,668 Austrian patients ≥50 years with a hip fracture between July 2008 and December 2010 for antiosteoporotic drug treatment with respect to outcome parameters all-cause mortality, hip refracture incidence, and hip refracture-free days. Outcomes when bisphosphonate (BP) treatment was begun before or after fracture were compared with an age- and sex-matched hip fracture control without antiosteoporotic medication. RESULTS: 27.69 % of patients (33.01 % of women, 13.13 % of men) were prescribed antiosteoporotic medication, primarily BPs. Females having initiated BP treatment before first fracture had lower odds for mortality 1 and 3 year(s) post-fracture, whereas hip refracture incidence under pre-fracture BP initiation was generally higher. Treatment that was started after fracture, however, entailed significantly lower mortality hazards for both genders (HR 0.43, 95 %CI 0.36-0.52, p < 0.0001 after 1 year) but significantly higher hip refracture incidence except for patients aged 50-69 years and more hip refracture free days for females. Hip refractures overall amounted to 29.22/1000 patient years differing significantly between women and men (31.03 vs. 23.89, respectively, p < 0.0001), and longer hip refracture free survival was observed for women than for men (499 vs. 466 median days, respectively, p < 0.0001). CONCLUSIONS: Although BP use is associated with reduced mortality after hip fracture, notably among women, hip refracture incidences are likewise elevated, which is most likely accounted for by a high probability of BP prescription to more comorbid patients suffering from more severe osteoporosis. Concomitantly, through possible effects other than on bone, BPs might be able to curtail mortality. Male hip fracture patients' low treatment frequency in particular reflects underdiagnosis and undertreatment of osteoporosis in Austria.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Fraturas do Quadril/prevenção & controle , Fraturas por Osteoporose/prevenção & controle , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Feminino , Fraturas do Quadril/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/mortalidade , Fraturas por Osteoporose/mortalidade , Recidiva , Estudos Retrospectivos , Medição de Risco/métodos , Distribuição por SexoRESUMO
Hereditary hemochromatosis is a frequent autosomal recessive iron storage disease in northern and western Europe. The classical clinical triad of liver cirrhosis, hyperpigmentation and diabetes is nowadays rare, most probably because of early recognition. The homozygous C282Y mutation in the HFE gene is responsible for most cases of hereditary hemochromatosis, although other much rarer mutations in other genes have been recently identified. Progressive iron overload not only causes liver cirrhosis but also triggers development of a characteristic arthropathy. Bony swelling with intermittent arthritis of the second and third metacarpophalangeal joints is typical as well as occurrence of chondrocalcinosis in wrists and knee joints. The therapy of choice is excess iron removal by phlebotomy. Treatment usually prevents or even reverses liver damage but does not alter the course of hemochromatosis arthropathy.
Assuntos
Hemocromatose/diagnóstico , Hemocromatose/terapia , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Flebotomia/métodos , Medicina Baseada em Evidências , Hemocromatose/complicações , Humanos , Cirrose Hepática/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Gout is the most common inflammatory arthropathy in the Western world. This is mainly due to the high socioeconomic status, sufficient even superfluous nutrition, overweight and alcohol consumption. Despite adequate medication, information and advice on nutrition and lifestyle are one of the cornerstones in the management of these patients. OBJECTIVE: The aim was to provide recommendations on nutrition and lifestyle in cases of gout and hyperuricemia by a group of rheumatologists, based on a review of the most recent literature. MATERIALS AND METHODS: The study group for osteoarthritis and crystal arthropathies of the Austrian Society for Rheumatology and Rehabilitation (ÖGR) carried out a literature search on this topic. The selected papers were listed according to the level of evidence. RESULTS: Based on this literature search nine recommendations were generated and modified via a Delphi approach: four red "don'ts" concerning nutrition and beverages to be avoided, three green "do's" concerning favorable food as well as two blue general lifestyle recommendations. The format of the recommendations is a two-page leaflet with the list of recommendations, level of evidence, strength of recommendation and literature citations on the front page and a colored icon presentation of food and beverages in a circle, matching the colors of the written recommendations, on the reverse. CONCLUSION: For the first time in Austria, nine recommendations on nutrition, beverages and lifestyle for patients with gout and hyperuricemia were defined for everyday practice, as education material for patients and updated information for physicians.
Assuntos
Dietoterapia/normas , Gota/terapia , Hiperuricemia/terapia , Política Nutricional , Reumatologia/normas , Comportamento de Redução do Risco , Áustria , Humanos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
Assuntos
Adenoma/patologia , Adenoma/prevenção & controle , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Suplementos Nutricionais , Caracteres Sexuais , Vitamina D/administração & dosagem , Vitamina D/sangue , Adenoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/farmacologiaRESUMO
The differential diagnosis of swelling of the small finger joints is broad. We report on two young men presenting with progressive painless swelling of the proximal interphalangeal (PIP) joints where the physical examination was otherwise inconspicuous. Laboratory investigations including auto- antibodies were all normal, x-rays and magnetic resonance imaging (MRI) revealed no joint pathologies but only increased skin thickening. Skin biopsy demonstrated hyperkeratosis and acanthosis without tissue inflammation. We thus diagnosed pachydermodactyly in both cases. This rare disease predominantly affects young males, can affect one or both hands and is often associated with mechanical stress due to repetitive movements in patients with obsessive-compulsive disorders. Occupational exposure by monotonous actions (e.g. poultry processing) may also be a cause. A specific therapy is unnecessary in most cases but may include intralesional steroid administration or surgical resection. Cessation of mechanical stress can significantly improve pachydermodactyly.
Assuntos
Fibroma/diagnóstico , Fibroma/prevenção & controle , Dedos/patologia , Deformidades da Mão/diagnóstico , Deformidades da Mão/prevenção & controle , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/prevenção & controle , Adolescente , Diagnóstico Diferencial , Humanos , Masculino , Síndrome , Adulto JovemRESUMO
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA) is a systemic small-vessel vasculitis associated with asthma and eosinophilia. Histology of EGPA shows tissue eosinophilia, necrotizing vasculitis, and eosinophil-rich granulomatous inflammation. EGPA commonly presents with upper airway tract and lung involvement, peripheral neuropathy, cardiac and skin lesions. Antineutrophil cytoplasmic antibodies (ANCA) are positive in ~40% of the cases and more often in patients with clinical manifestations due to small-vessel vasculitis. The pathogenesis of EGPA is multifactorial: the disease can be triggered by exposure to allergens or drugs, but a genetic background has also been recognized, particularly an association with HLA-DRB4. Th2 responses are prominent, with up-regulation of IL-4, IL-13, and IL-5; however, Th1 and Th17 responses are not negligible. Eosinophils are activated, have a prolonged lifespan and probably cause tissue damage by releasing their granule proteins; their tissue recruitment can be regulated by chemokines such as eotaxin-3 and CCL17. Humoral immunity is also dysregulated, as demonstrated by prominent IgG4 and IgE responses. EGPA promptly responds to glucocorticoid therapy, although combinations of glucocorticoids and immunosuppressants (e.g., cyclophosphamide, azathioprine) are eventually required in most cases. Newer therapeutic options include the anti-IL5 antibody mepolizumab, whose efficacy has been described in small clinical trials, and the B-cell-depleting agent rituximab, reported in several case series.
Assuntos
Síndrome de Churg-Strauss , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/etiologia , Síndrome de Churg-Strauss/terapia , Meio Ambiente , Humanos , Doenças RarasRESUMO
Primary osteoarthritis (OA) of peripheral joints is a common disease mainly occurring after the age of 50. It is important to distinguish primary from secondary OA. Younger age at disease onset, rapid progression, unusual disease manifestations and co-morbidities are signs of secondary OA. This review outlines an important group of secondary OA. Hereditary metabolic diseases can exhibit joint involvement. For some of these diseases, correct diagnosis is critical, since appropriate therapy influences not only joint function and quality of life, but can also prevent relevant end-organ damage.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Osteoartrite/congênito , Osteoartrite/diagnóstico , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Osteoartrite/genéticaRESUMO
Primary osteoarthritis (OA) of peripheral joints is a common disease mainly occurring after the age of 50. It is important to distinguish primary from secondary OA. Younger age at disease onset, rapid progression, unusual disease manifestations and co-morbidities are signs of secondary OA. This review outlines an important group of secondary OA. Hereditary metabolic diseases can exhibit joint involvement. For some of these diseases, correct diagnosis is critical, since appropriate therapy influences not only joint function and quality of life, but can also prevent relevant end-organ damage.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Osteoartrite/diagnóstico , Osteoartrite/genética , Adulto , Alcaptonúria/diagnóstico , Alcaptonúria/epidemiologia , Alcaptonúria/genética , Animais , Criança , Condrocalcinose/diagnóstico , Condrocalcinose/epidemiologia , Condrocalcinose/genética , Estudos Transversais , Diagnóstico Diferencial , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/epidemiologia , Síndrome de Gitelman/genética , Hemocromatose/diagnóstico , Hemocromatose/epidemiologia , Hemocromatose/genética , Proteína da Hemocromatose , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/epidemiologia , Degeneração Hepatolenticular/genética , Antígenos de Histocompatibilidade Classe I/genética , Homozigoto , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Recém-Nascido , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/epidemiologia , Ocronose/diagnóstico , Ocronose/epidemiologia , Ocronose/genética , Osteoartrite/epidemiologia , PenetrânciaRESUMO
OBJECTIVE: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints. METHODS: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, beta-catenin and DKK-1 was assessed by immunohistochemistry. RESULTS: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints. CONCLUSION: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.
Assuntos
Anticorpos Monoclonais/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Articulação Sacroilíaca , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/metabolismo , Artrite Experimental/fisiopatologia , Colágeno Tipo X/metabolismo , Imuno-Histoquímica , Infliximab , Camundongos , Camundongos Transgênicos , beta Catenina/metabolismoRESUMO
OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. METHODS: To determine whether TNF directly triggers bone loss or requires IL1, human TNFalpha mice (hTNFtg) were crossed with mice lacking IL1alpha and IL1beta (IL1(-/-)hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. RESULTS: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1(-/-)hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. CONCLUSIONS: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.
Assuntos
Artrite Experimental/complicações , Artrite Reumatoide/complicações , Doenças Ósseas Metabólicas/etiologia , Interleucina-1/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biomarcadores/sangue , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Reabsorção Óssea/fisiopatologia , Tomografia com Microscopia Eletrônica , Feminino , Interleucina-1/deficiência , Camundongos , Camundongos Transgênicos , Osteoblastos/patologia , Osteoclastos/patologia , Tíbia/ultraestruturaRESUMO
While one of the major achievements of the 20th century was prolonging life expectancy in developed countries, the main challenge of the 21st century is to improve the quality of life of the aging population. Aging is associated with a progressive reduction of organ system function. Therefore, regenerative medicine will be one of the major developing fields of medicine. This new medical field does not only apply to aging but also to all degenerative diseases, such as arthritis and degenerative joint disease, which lead to progressive degeneration of mesenchymal tissues such as bone and cartilage. The discovery of pluripotent mesenchymal stem cells (MSCs) offers a promising alternative to surgery for non-invasive regenerative therapies of mesenchymal tissues. This review focuses on the characterization and potential application of MSCs in the regeneration of damaged joints.
Assuntos
Artrite Reumatoide/terapia , Transplante de Células-Tronco Mesenquimais , Osteoartrite/terapia , Animais , Artrite Reumatoide/imunologia , Diferenciação Celular/imunologia , Condrócitos/citologia , Humanos , Técnicas In Vitro , Osteoartrite/imunologia , Regeneração/fisiologia , Alicerces TeciduaisRESUMO
OBJECTIVE: Churg-Strauss Syndrome (CSS) is characterized by excessive eosinophil accumulation in peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. The contribution of eosinophil-chemotactic cytokines (eotaxin family) to eosinophilia and disease activity in CSS is unknown. Thus, we compared serum levels of the eotaxin family members in CSS patients with healthy and disease controls. METHODS: Forty patients with CSS diagnosed according to ACR 1990 criteria, 30 healthy controls (HC) and 57 disease controls (28 asthma, 20 small vessel vasculitis, 9 hypereosinophilic syndrome) were studied. Clinical data were collected and serum levels of eotaxin-1, -2 and -3 were determined by ELISA. Further, immunohistochemistry was applied to identify eotaxin-3 expression in tissue biopsies from patients with CSS. RESULTS: In contrast to eotaxin-1 and -2, eotaxin-3 was highly elevated in serum samples of active CSS patients and correlated highly significantly with eosinophil counts, total immunoglobulin E (IgE) levels and acute-phase parameters. Moreover, eotaxin-3 was not elevated in other eosinophilic and vasculitic diseases. Immunohistochemical analysis revealed strong expression of eotaxin-3 in endothelial and inflammatory cells in affected tissues of active CSS patients. CONCLUSIONS: This study reveals the specific association of elevated eotaxin-3 expression with high disease activity and eosinophilia in CSS patients. Eotaxin-3 might thus be a pathogenic player, biomarker and potential therapeutic target in CSS.
Assuntos
Quimiocinas CC/sangue , Síndrome de Churg-Strauss/sangue , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Biópsia , Quimiocina CCL11/sangue , Quimiocina CCL24/sangue , Quimiocina CCL26 , Quimiocinas CC/metabolismo , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patologia , Eosinofilia/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vasculite/sangueRESUMO
Churg-Strauss syndrome is a systemic ANCA-associated vasculitis arising almost exclusively in patients with a pre-existent asthma. Common clinical manifestations are marked blood eosinophilia, asthma, chronic sinusitis, cardiomyopathy, pulmonary infiltrates, gastrointestinal complaints and a multiplex neuropathy. The morphological substrate is an eosinophilic necrotizing vasculitis. Other eosinophilic disorders such as parasitic diseases, allergies and idiopathic hyper-eosinophilic syndrome have to be excluded. The mainstay of therapy is high-dose corticosteroids with the addition of cytotoxic drugs in patients with poor prognosis.
Assuntos
Corticosteroides/uso terapêutico , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Citotoxinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Alemanha , Humanos , Guias de Prática Clínica como Assunto , Padrões de Prática MédicaRESUMO
OBJECTIVE: To investigate the presence and regulation of lymphatic vessels in inflamed joints of mice with experimental arthritis as well as patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: Lymphatic vessels and blood vessels were assessed in synovial tissue of human tumour necrosis factor transgenic (TNFtg) mice and synovial biopsies from patients with RA and SpA by immunohistochemistry for podoplanin and CD31, respectively. Assessments were performed before and after TNF blockade in all biopsies. RESULTS: Lymphatic vessels were abundantly present in the synovial tissue of hTNFtg mice as well as patients with RA and SpA. The number of lymphatic vessels was positively related to the severity of synovial inflammation. Treatment with infliximab led to an increase in the formation of lymphatic vessels in murine and human inflammatory tissue. CONCLUSIONS: This study shows that TNF blockade promotes the proliferation of lymphatic vessels in the inflamed synovium of RA and SpA. This finding leads to the assumption that promotion of lymphangiogenesis may play an important part in efflux of cells and fluid out of the inflamed tissue.
Assuntos
Artrite/patologia , Linfangiogênese/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite/tratamento farmacológico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Biópsia , Feminino , Humanos , Infliximab , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Espondilartrite/tratamento farmacológico , Espondilartrite/patologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
CTLA-4 is a regulator of co-stimulation and inhibits the activation of T cells through interfering with the interaction of CD80/86 on antigen-presenting cells with CD28 on T cells. CTLA-4 binds to the surface of antigen-presenting cells, such as dendritic cells and monocytes through CD80/86. Monocytes can differentiate in osteoclasts, the primary bone resorbing cells. Herein, we investigated whether the binding of CTLA-4 affects the differentiation of monocytes into osteoclasts in vitro and vivo. We show that CTLA-4 dose-dependently inhibits RANKL- as well as tumour necrosis factor (TNF)-mediated osteoclastogenesis in vitro without the presence of T cells. Furthermore, CTLA-4 was effective in inhibiting TNF-induced osteoclast formation in a non-T cell dependent TNF-induced model of arthritis as well as the formation of inflammatory bone erosion in vivo. These data suggest that CTLA-4 is an anti-osteoclastogenic molecule that directly binds osteoclast precursor cells and inhibits their differentiation. These findings are an attractive explanation for the anti-erosive effect of abatacept, a CTLA-4 immunoglobulin fusion protein used for the treatment of rheumatoid arthritis.