Hypoxia and angiogenesis in rheumatoid arthritis

Taylor, Peter; Sivakumar, Branavan

doi:10.1097/01.bor.0000155361.83990.5b

Cited by 169 publications

(129 citation statements)

References 60 publications

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“…One pathophysiologic condition in RA synovial tissue that could be implicated in BCRP expression is its hypoxic environment. It is well recognized that synovial infiltrating cells suffer from hypoxic stress (34). Given the notion that BCRP transcription is induced by hypoxia via the hypoxia-inducible transcription factor complex hypoxia-inducible factor 1␣ (HIF-1␣) (35), and that HIF-1␣ is particularly expressed in synovial tissue …”

Section: Discussionmentioning

confidence: 99%

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Arthritis & Rheumatism

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Objective. To determine whether multidrugresistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).Methods. Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n ‫؍‬ 17) or LEF (n ‫؍‬ 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.Results. BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P ‫؍‬ 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.Conclusion. These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

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Section: Discussionmentioning

confidence: 99%

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Arthritis & Rheumatism

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“…The possibility of systemic production is supported by the increased serum levels of VEGF in our patients with myositis. High serum levels of VEGF have also been recorded in other autoimmune diseases (35)(36)(37). The source of serum VEGF in these conditions is still not clarified but may be platelets (38), inflammatory cells (39), or endothelial cells (35).…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis

Grundtman¹,

Tham²,

Ulfgren³

et al. 2008

Arthritis & Rheumatism

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Objective. To investigate the expression of vascular endothelial growth factor (VEGF) in muscle biopsy specimens and serum from patients with polymyositis and patients with dermatomyositis compared with that in healthy control subjects.Methods. Muscle biopsy specimens from 33 patients with polymyositis or dermatomyositis and 15 healthy control subjects and serum samples from 56 patients and 56 healthy control subjects were analyzed. Patients were categorized into 3 groups, depending on disease duration and the presence or absence of inflammatory infiltrates. The expression of VEGF and the vessel marker CD31 in muscle was analyzed by immunohistochemistry, the expression of VEGF messenger RNA (mRNA) was analyzed by in situ hybridization, and serum levels of VEGF were determined by enzymelinked immunosorbent assay.Results. Patients with polymyositis or dermatomyositis in the early or chronic phase without inflammatory infiltrates had a decreased total number of capillaries compared with healthy individuals. In patients with early disease without inflammatory infil-

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“…Its capacity to stimulate the production and secretion of pro-inflammatory cytokines, regulate the expression of adhesion molecules on endothelial cells, control the migration of leucocytes to sites of inflammation, increase the production of metalloproteinases from synovial macrophages and inhibit the production of proteoglycans has been well demonstrated to date [3]. Moreover, TNFα stimulates neovascularisation of synovial tissue, a phenomenon which correlates with the level of local inflammatory activity [4]. In essence, TNFα represents a key molecule in the activation and perpetuation of the inflammatory process within joints and systemically in RA, leading subsequently to joint erosion and permanent structural damage [5].…”

Section: Introductionmentioning

confidence: 99%

Etanercept in the treatment of rheumatoid arthritis: clinical follow-up over one year by ultrasonography

et al. 2007

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We evaluated clinically and sonographically the effects of etanercept therapy in patients with rheumatoid arthritis (RA) over 12 months of treatment. Eighteen patients affected by RAwho were non-responders or partial responders to disease modifying therapy were commenced on Etanercept treatment. Before starting therapy (T0) and at 12 months (T1), the following parameters were evaluated: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS) for pain, number of painful and swollen joints, health assessment questionnaire (HAQ) and disease activity score in 28 joints (DAS 28). Musculoskeletal ultrasound (US) was performed in the following joints: second and fifth metacarpophalangeal, third interphalangeal, wrist and knee joints and a semiquantitative score (0-3) calculated and used to indicate the presence of a localised inflammatory process (synovitis, tenosynovitis, bursitis) and/or structural damage (bone erosion and cartilaginous change). An overall score was calculated based on the sum of the single scores to obtain a comprehensive score indicative of the global pathological change. The US global scores significantly reduced between T0 and T1 (p<0.0001). The following laboratory and clinical parameters also significantly reduced: ESR (p<0.0001), CRP (p<0.02), VAS (p<0.001), number of total swollen joints (p<0.001), number of total painful joints (p<0.01), HAQ scores (p<0.05) and DAS 28 (p< 0.0001). A positive response to treatment with Etanercept was demonstrated both by US examination of several joints and by clinical evaluation of several parameters. US is a useful tool in the monitoring of biologic therapy in RA, assessing both inflammatory and destructive changes.

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Hypoxia and angiogenesis in rheumatoid arthritis

Cited by 169 publications

References 60 publications

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis

Etanercept in the treatment of rheumatoid arthritis: clinical follow-up over one year by ultrasonography

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