AN OPEN-LABEL, EXPLORATORY STUDY TO ESTABLISH THE EFFICACY AND SAFETY OF 1-YEAR CANAKINUMAB TREATMENT IN BEHÇET’S DISEASE PATIENTS WITH NEUROLOGIC OR VASCULAR INVOLVEMENT

Background: Previous observations in Behcet’ s disease (BD) patients receiving anti-IL 1 therapies suggested that dosage and route of administration may be critical in controlling disease manifestations. This was supported by favorable observations with infliximab infusions reaching higher serum trough levels in refractory BD patients compared to other anti-TNF agents. Objectives: The primary objective was to evaluate the safety and efficacy of intravenous (IV) canakinumab (CAN) on the clinical and inflammatory findings of BD patients with neurologic and vascular involvement. Methods: Biologic-naïve BD patients, who had a recent attack of large vessel vascular or parenchymal neurologic disease within the last month were enrolled and all received 300 mg CAN IV without a change in other medications. Response was assessed on day 30 as the primary objective; partial responders were able to take the 2nd 300 mg IV on day 30 and continued the treatment with monthly 150 mg IV 4 times. Others continued the treatment with 150 mg IV monthly. At month 6, patients were able to switch to SC injections or continue 150 mg IV for 6 months. Non-responder patients were dropped out. Prednisolone dosage was ≤20 mg at baseline and not increased during the trial. Complete response was defined as full clinical recovery to pre-attack state, disappearance of MRI lesions, normalization of CSF findings; partial response was defined as partial improvement in clinical findings, which were still worse than pre-attack state, with MRI lesions becoming smaller with no or less enhancement, and a decrease in CSF cell count. Complete response of vascular findings was defined as ≥50% improvement in patient’s and physician’s global assessments, ≥50% reduction in CRP; along with stable or ≥20% reduced aneurysm size or stable or ≥20% reduced calf swelling; and partial response was an improvement between 20-49% in global assessments, 20-49% reduction in CRP; stable or ≤20% reduced aneurysm size or ≤20% reduced calf swelling. Results: 9 subjects were screened, and 8 male subjects (5 vascular, 3 neurologic) aged 27.3 ± 2.3 years entered the study. No new attack or worsening of manifestations was observed, and at least a partial response was obtained in all patients on day 30. Two vascular patients (2/5, 40%) and 1 neurologic patient (1/3, 33%) received another 300 mg infusion on day 30; one of them left the study on day 120 because of safety concerns after noticing the use of illicit drugs, and the other required 150 mg IV CAN after day 180 and discontinued the study because of the worsening of pulmonary artery aneurysm, despite favorable response in venous findings. The remaining 3 patients (3/5, 60%) with deep vein thrombosis completed the study with clinical and radiological improvement. 2 patients with parenchymal involvement had lesions in the brain stem and showed complete improvement of clinical findings between 1-3 months and radiologic findings between 3-6 months. Clinical findings of 1 patient with sinus thrombosis improved within 2 months, and the last cranial MRI showed that the vein thrombus was recanalized. Patients experienced other mild manifestations of BD following a switch to SC administration. BD, % Healthy, % P Arterial hypertension 22,1 13,3 ns Smoked 29,5 24,4 ns Diabetes mellitus 0 0 ns Lipid abnormalities 76,8 64,4 ns Total cholesterol 5,0 ±1,40 5,3 ±0,96 ns TGs 0,91 ±0,65 0,90 ±0,68 ns HDL 1,18 ±0,39 1,26 ±0,29 ns LDL 3,40 ±1,46 3,47 ±0,90 ns Hs CRP 2,42 ±21,0 0,3 ±0,63 <0,00 Mean IMT carotid artery 0,68 ±0,09 0,64 ±0,09 ns IMT <0,5 mm 31,6 6,6 <0,00 IMT > 0,5-0,89 mm 49,5 86,6 ns IMT - 0,9 – 1,2 mm 13,68 6,6 ns IMT > 1,2 mm (plaques) 5,7 0 ns The mean carotid IMT in BD pts was similar with controls. In pts thinning IMT and concentration of hsCRP was significantly higher compared with controls. IMT correlated with age of pts, concentration of total cholesterol, LDL and hsCRP but did not correlated with clinical manifestation and disease duration. Carotid atherosclerotic plaques were found in 5 pts with BD – mean age 40,0±8,1, who had traditional cardiovascular risk factors (high body masse index, hypertension) and received long time therapy with glucocorticoids. Conclusion: Response to CAN without high-dose methylprednisolone treatment suggests that IL-1 antagonism plays a role in acute exacerbations of neurologic and vascular manifestations of BD, and no new safety signal was recorded with IV use. Favorable responses during the early months of the study and development of clinical and laboratory findings after switching to SC administration may suggest that achievement of higher serum trough levels may be critical, and up-titration of the dosages may provide better results in individual patients with higher inflammatory activity. REFERENCES: NA Acknowledgments : This study was supported by Novartis. Disclosure of Interests: Ahmet Gül: None declared, Murat Kurtuncu Grant/research support from: Travel, symposia speaker and Honoraria grants (Novartis, Bayer, Teva, Ali Raif, Gen), Consultant of: (Novartis, Bayer, Teva, Ali Raif, Gen), Speakers bureau: (Novartis, Bayer, Teva, Ali Raif, Gen), Murat Erdugan: None declared, Emin Oguz: None declared, Tuncay Gunduz: None declared, Gulsen Akman Demir Grant/research support from: Novartis, Consultant of: Novartis, Serhan Sevgi Employee of: Novartis, Soner Turgay Employee of: Novartis, Ersen Acar Employee of: Novartis Citation: Ann Rheum Dis, volume 79, supplement 1, year 2020, page 1533Session: Vasculitis (Abstracts Accepted for Publication)