Down-regulation of survivin alleviates experimental arthritis

Andersson, Karin; Svensson, Mattias; Erlandsson, Malin C.; Jonsson, I-M; Bokarewa, Maria

doi:10.1189/jlb.3a0714-317r

Cited by 32 publications

(31 citation statements)

References 67 publications

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“…At the preclinical stage of arthritis, serum survivin has been associated with the release of cytokines controlling the formation of Th cell subsets Th1 and Th17 [ 26 , 58 ]. Inhibition of survivin in experimental arthritis proved its intimate relation to the formation of effector T cells and to the system of matrix proteases in the inflamed joints [ 54 , 59 ]. The processes triggering and abrogating survivin release in RA could therefore pave a way to efficient therapeutic control of the disease.…”

Section: Discussionmentioning

confidence: 99%

Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial

Levitsky

Erlandsson

Vollenhoven

et al. 2015

BMC Med

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BackgroundThe identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis.MethodsSerum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF).ResultsAntirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95 % CI 1.12–9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01–3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09–9.10), P = 0.037).DiscussionWe demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients.ConclusionsSurvivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.Trial registrationWHO database at the Karolinska University Hospital: CT20080004; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.

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Section: Discussionmentioning

confidence: 99%

Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial

Levitsky

Erlandsson

Vollenhoven

et al. 2015

BMC Med

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“…It affects 1% of the world population, and recent treatment has been revolutionized by the use of biologic therapies, such as drugs that target cytokines, cells, and signaling pathways. However, half of RA patients display drug resistance to biological therapies, which leads to early mortality and demonstrates our limited knowledge of RA pathogenesis 1 .…”

Section: Introductionmentioning

confidence: 99%

Rheumatoid Arthritis Fibroblast-like Synoviocyte Suppression Mediated by PTEN Involves Survivin Gene Silencing

Chen

Liu

Liú

et al. 2017

Sci Rep

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Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle regulating properties induced by the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In the context of non-cancer pathology, such as rheumatoid arthritis (RA), survivin has emerged as a feature associated with severe joint damage and poor treatment response. Phosphatase and tensin homolog (PTEN) is a phosphatase antagonizing all classes of PI3K. The interplay between survivin oncogenic mechanisms and proliferation suppression networks in RA has remained largely elusive. This study investigated the effect of PTEN on survivin gene expression in rheumatiod arthritis fibroblast-like synoviocyte (RA-FLS). We showed for the first time that the suppression of RA-FLS was mediated by PTEN involving survivin silencing. Considering that survivin suppressants are currently available in clinical trials and clinical use, their effects in RA-FLS support a probably RA therapy to clinical practice.

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“…In the rheumatoid synovia, survivin was found in the areas enriched with macrophages and memory T cells [ 44 – 46 ]. Inhibiting survivin in arthritic mice restored the control over T-cell proliferation, and reduced arthritis [ 47 ]. At early pre-clinical stage of RA, serum levels of survivin correlated with the cytokines predisposing and assuring formation of Th1 and Th17 cells regulating the initial stages of RA pathology [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6

et al. 2015

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Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5+CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5+ Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1+Bcl-6+ subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.

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Down-regulation of survivin alleviates experimental arthritis

Cited by 32 publications

References 67 publications

Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial

Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial

Rheumatoid Arthritis Fibroblast-like Synoviocyte Suppression Mediated by PTEN Involves Survivin Gene Silencing

Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6

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