A Translational Study of TNF-Alpha Antagonists as an Adjunctive Therapy for Preventing Hemophilic Arthropathy

Zhang, Feixu; Xu, Mengyang; Yang, Qin; Hua, Baolai; Xia, Binglan; Lin, Zhenyang; Xiao, Xiao; Monahan, Paul E.; Sun, Junjiang

doi:10.3390/jcm9010075

Cited by 9 publications

(4 citation statements)

References 48 publications

(70 reference statements)

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“…TNFα, on the other hand, remained unchanged in the plasma of mice with hemarthrosis and increased only insignificantly in hemophilia patients, which is in line with previous reports. 24 25 Previous data also reinforce a role of IL-6 in the natural history of hemophilic arthropathy as the IL-6/sIL-6Rα complex has been shown to trigger proliferation in synoviocytes and subsequent fibrotic remodeling of the synovia in hemophilia mice. 15 27 Taken together, these findings could be relevant for assessing the effect of bleeding on joint health in hemophilia patients as we found sIL-6Rα to be specifically upregulated in hemophilia patients with recent bleeding in conjunction with IL-6.…”

Section: Discussionmentioning

confidence: 83%

“…22 23 The resulting secretion of IL-1β, IL-6, and TNFα has been strongly implicated in causing typical complications of joint bleeds such as synovitis, cartilage erosion, and bone loss. 15 24 25 26 The association between blood-induced inflammation and arthropathy was reiterated in our mouse model of hemarthrosis, where the fibrous remodeling of the punctured knee joint was preceded by a large increase of plasma IL-6. TNFα, on the other hand, remained unchanged in the plasma of mice with hemarthrosis and increased only insignificantly in hemophilia patients, which is in line with previous reports.…”

Section: Discussionmentioning

confidence: 91%

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Activation of the Acute-Phase Response in Hemophilia

et al. 2023

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To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP) and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) > 30. Subgroup analysis of the remaining non-obese hemophilia patients (BMI 18-29.9) revealed a significant spike of IL-6, CRP and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients that did not experience recent bleeding had IL-6, CRP and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a 4-fold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 91%

Activation of the Acute-Phase Response in Hemophilia

et al. 2023

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“…Zhang et al reported a significant TNF-α accumulation was found in the hemorrhagic tissues of the injured knee and strong TNF-α gene upregulation observed since day 3 up to 30 days after hemarthroses. Elevated TNFα level was found in the synovial fluid and plasma which 6 BioMed Research International TNF-α level in synovial fluids was 5.2-20 folds higher than in plasma (p < 0:05) in PWHA [28].…”

Section: Discussionmentioning

confidence: 91%

Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A

Susanah

Raspati

Sari

et al. 2021

BioMed Research International

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Background. The development of factor VIII (FVIII) inhibitor in patients with hemophilia A (PWHA) is a great challenge for hemophilia care. Both genetic and environmental factors led to complications in PWHA. The development of inhibitory antibodies is usually induced by the immune response. Tumor necrosis factor α (TNF-α), one of the cytokines, might contribute to its polymorphism. In this study, we investigated the clinical factors, level of serum TNF-α, and polymorphism of c . − 308 G > A TNF − α gene in inhibitor development in severe PWHA. Methods. A cross-sectional study was conducted among all PWHA in West Java province. The clinical parameters, FVIII, FVIII inhibitor, and serum TNF-α level were assessed. The genotyping of − 380 G > A TNF-α gene polymorphism was performed using polymerase chain reaction and Sanger sequencing. Results. Among the 258 PWHA, 216 (83.7%) were identified as severe PWHA. The FVIII inhibitor was identified in 90/216 (41.6%) of severe PWHA, consisting of 45 high-titer inhibitors (HTI) and 45 low-titer inhibitors (LTI). There was a significant correlation between serum TNF-α level and the development of HTI ( p = 0.043 ). The cutoff point of serum TNF-α level, which can be used to differentiate between HTI and LTI, was 11.45 pg/mL. The frequency of FVIII replacement therapy was significant only in HTI of severe PWHA regarding serum TNF-α level ( p = 0.028 ). There is no correlation between polymorphisms of − 380 G > A TNF-α gene and inhibitor development ( p = 0.645 ). Conclusions. The prevalence of FVIII inhibitor in severe PWHA in West Java, Indonesia, was 41.6%. The frequency of replacement therapy is a risk factor for inhibitor development. Serum TNF-α level might be used to differentiate between high and low inhibitor levels in severe hemophilia A, and this might support decision making regarding treatment options for inhibitor in severe hemophilia A.

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“…A história natural da hemofilia é marcada por sangramentos articulares espontâneos, cuja recorrência leva à artropatia hemofílica, um processo que combina sinovite, hiperplasia sinovial, destruição da cartilagem e do osso periarticular 36 Resultados preliminares sugerem que o bloqueio da via do TNFα por anticorpos monoclonais pode ser uma alternativa de controlar a sinovite e potencialmente frear a progressão da lesão articular 76,77 .…”

Section: Discussionunclassified

O impacto da terapia gênica na saúde musculoesquelética de pacientes com hemofilia grave

Góes Yamaguti Hayakawa

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Hemophilia is an X-linked hereditary bleeding disorder that presents with absent or insufficient production of factor VIII (FVIII), in hemophilia A, or factor IX (FIX), in hemophilia B. Patients with severe hemophilia (FVIII or FIX < 1%) have recurrent joint bleeding (ankles, knees and elbows), which lead to progressive arthropathy.The best approach to prevent musculoskeletal complications is to prevent hemarthroses, usually with prophylactic replacement of FVIII or FIX concentrates. This treatment requires frequent intravenous infusions and does not guarantee complete control of hemorrhages. In this context, gene therapy is a transformative therapy, with the potential to improve or even normalize hemostasis, with just a single infusion. This prospective study aims to evaluate the impact of gene therapy on the musculoskeletal health of patients with hemophilia A. For this, we analyzed post-gene therapy FVIII expression along with clinical and image evaluation of the musculoskeletal system. Furthermore, the bleeding frequency, the consumption of FVIII concentrate and the musculoskeletal-related biomarkers profile were also assessed, both before and after gene therapy.In this analysis, we included patients with severe hemophilia A who underwent gene therapy with valoctocogene roxaparvovec (AAV5-hFVIII-SQ), at the dose of 6x10 13 vg/kg,

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A Translational Study of TNF-Alpha Antagonists as an Adjunctive Therapy for Preventing Hemophilic Arthropathy

Cited by 9 publications

References 48 publications

Activation of the Acute-Phase Response in Hemophilia

Activation of the Acute-Phase Response in Hemophilia

Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A

O impacto da terapia gênica na saúde musculoesquelética de pacientes com hemofilia grave

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