Tumour necrosis factor alpha kinoid(Neovacs)

Whether patients with atrial fibrillation (AF) and liver disease are also prone to cerebrovascular events and respond similarly favorably to antithrombotic therapy remains under-investigated.

Patients ≥18years with newly-diagnosed AF in the period 2005 to 2009 were scrutinized from the "Longitudinal Health Insurance Database 2005" (1 million beneficiaries) of Taiwan's National Health Insurance Institute. Patients were categorized into the Liver (N=433) or the Non-liver (N=3490) cohort according to whether they had a diagnosis of advanced liver disease. Patients were then followed to determine cumulative incidence of hospitalization-requiring cerebrovascular events, preventive effects of antithrombotics, and predictors of cerebrovascular events by Cox regression analysis.

Within a mean follow-up of 3.3±1.4years, ischemic stroke (89.2 vs. 50.3 per 1000 person-years, adjusted HR 1.502, 95% CI 1.207-1.868, p<0.001) and overall cerebrovascular events (102.3 vs. 56.4 per 1000 person-years, adjusted HR 1.535, 95% CI 1.251-1.883, p<0.001) occurred significantly more often in the Liver than in the Non-liver cohort. Cox models identified aging (≥65years), DM, and CHA2DS-VASc score≥2 points as risk factors for overall cerebrovascular events in the Liver cohort, whereas antiplatelet agents (HR 0.932, 95% CI 0.128-6.803, p=NS) and vit-K antagonistic anticoagulants (HR 1.087, 95% CI 0.150-7.862, p=NS) showed no correlation.

AF patients comorbid with advanced liver disease are more vulnerable to ischemic and therein overall cerebrovascular events, especially in those with old age, DM, or high CHA2DS-VASc scores. This propensity to cerebrovascular events, however, can't be altered by antithrombotic therapy.

Passive blockade of tumor necrosis factor-alpha (TNF-α) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, although some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-α. This study sought to demonstrate a long-lasting therapeutic effect on established arthritis of an active immunotherapy to human (h) TNF-α and to evaluate the long-term consequences of an endogenous anti-TNF-α response.

hTNF-α transgenic mice, which spontaneously develop arthritides from 8 weeks of age, were immunized with a heterocomplex (TNF kinoid, or TNF-K) composed of hTNF-α and keyhole limpet hemocyanin after disease onset. We evaluated arthritides by clinical and histological assessment, and titers of neutralizing anti-hTNF-α antibody by enzyme-linked immunosorbent assay and L929 assay.

Arthritides were dramatically improved compared to control mice at week 27. TNF-K-treated mice exhibited high levels of neutralizing anti-hTNF-α antibodies. Between weeks 27 and 45, all immunized mice exhibited symptoms of clinical deterioration and a parallel decrease in anti-hTNF-α neutralizing antibodies. A maintenance dose of TNF-K reversed the clinical deterioration and increased the anti-hTNF-α antibody titer. At 45 weeks, TNF-K long-term efficacy was confirmed by low clinical and mild histological scores for the TNF-K-treated mice. Injections of unmodified hTNF-α did not induce a recall response to hTNF-α in TNF-K immunized mice.

Anti-TNF-α immunotherapy with TNF-K has a sustained but reversible therapeutic efficacy in an established disease model, supporting the potential suitability of this approach in treating human disease.