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.

Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA.

This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection.

The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not.

TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement.

ClinicalTrials.gov NCT01040715.