ObjectivesTo evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX).MethodsIn this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12.ResultsOverall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported.ConclusionsOver 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated.Trial registration numberNCT01894516.
The American cutaneous forms of leishmaniasis include immune-responder individuals with localised cutaneous leishmaniasis (LCL) and non-responder individuals with diffuse cutaneous leishmaniasis (DCL). Patients with intermediate or chronic cutaneous leishmaniasis (ICL) have increased morbidity due to the length of their illness, atypical forms and areas of compromise. In the present study, we evaluated the expression of the leukocyte antigens (CD4, CD8, CLA: cutaneous lymphocyte antigen, CD69, CD83 and CD1a) and cytokines (IFN-gamma, IL-4, IL-10 and TGF-beta 1) in the lesions of patients with ICL (n = 18) using an immunocytochemical procedure. ICL results were compared with the information for LCL (n = 19) and DCL (n = 4). The numbers of CD4+ and CD8+ T cells in ICL were similar to those of LCL lesions, but significantly different (P < or = 0.05) from DCL lesions. LCL lesions have about half the numbers of early activated CD69+ cells as ICL, but most are CLA+ skin homing memory T cells, whereas ICL lesions have the highest number of CD69+ T cells, but about one-third of these cells expressed CLA. This suggests that the granuloma of ICL patients contains many activated T cells that are unprimed to cutaneous-launched antigens, thus contributing to an aberrant immune response. In contrast, DCL granulomas presented the lowest numbers of activated CD69+ and CLA+ cells, associated with the characteristic tolerogenic state of these patients. The immunolocalisation of cytokines showed a mixed cytokine pattern in ICL lesions with many positive cells for IL-10, TGF-beta 1, IL-4 and IFN-gamma, with a preponderance of the first two, and different from the prevalent Th1 and Th2 responses associated with LCL and DCL lesions, respectively. CD1a+ Langerhans cells were decreased (P < or = 0.05) in both ICL (271 +/- 15 cells/mm2) and DCL (245 +/- 19 cells/mm2) as compared to LCL (527 +/- 54 cells/mm2) epidermis. The percentage of IL-10+ epidermal Langerhans cells in ICL (33.69), from the total CD1a+ population, was higher than in LCL (17.45). In addition, fewer CD83+ primed Langerhans cells were present in ICL epidermis. The diminished participation of epidermal Langerhans cells, causing a defective signalling by the epidermis, in ICL lesions may account for the tissue-damaging state observed in these patients.
Morphological studies have hypothesized different origins for the precursors of the vascular smooth muscle cells (SMCs). The intriguing possibility that intimal SMCs may arise from the endothelium has newly emerged. As a first step towards understanding of the possible mechanisms involved in the transdifferentiation of endothelium into smooth muscle cells, we characterized the in vivo phenotype of the cells located in the aortic wall (distal to the aortic arches). This was accomplished using advanced stages of chicken embryo development. Furthermore, we investigated whether the cells present at the intimal thickening derive from the endothelial cell transdifferentiation. Immunolabeling of serial cryosections suggested that mesenchymal cells observed in the intimal thickening may arise from the endothelium. These cells may persist either as non-muscle throughout the development or possibly convert to cells expressing smooth muscle alpha-actin (SM alpha-actin). To determine whether endothelial cells may actually transdifferentiate into mesenchymal cells, aortic explants from 14-day-old chicken embryos (stage 40) were used. We found that explanted endothelial cells lose their cobblestone-appearance and migrate toward cell-free area. Some of these cells maintain the vWf immunoreactivity, whereas other cells coordinately lose vWf and gain SM alpha-actin expression (transitional cells). Taken together these findings strongly support the possibility that embryonic aortic endothelial transdifferentiate into mesenchymal cells, some of which express SM alpha-actin. Since TGFbeta-3 is considered an essential factor during epithelial to mesenchymal transitions in earlier chicken heart development, we also investigated the distribution of this growth factor at day 14. Our observations indicated that the immunoreactivity for TGFbeta-3 in this stage may be associated with migrating mesenchymal cells and that this immunoreactivity appears to decrease as cell differentiation advances. Therefore, the present study provides evidence that could help to explain 1) the presence of cells displaying a phenotype reminiscent of fetal-like cells in the normal chicken aorta and in the intimal region of the human aorta; 2) the SM lineage diversity in the chicken embryo reported by others; 3) a subpopulation of immature cells in the subendothelial region of the main pulmonary arteries of fetal, neonatal and adult bovines; and 4) the presence of intimal cushions, intimal pads, eccentric and diffuse intimal thickening that are observed in mammalian and avian vessels at birth.
BackgroundFilgotinib (GLPG0634) is a novel oral, selective JAK1 inhibitor that was evaluated in a 24-week phase 2B study as monotherapy in active rheumatoid arthritis (RA) with inadequate response to methotrexate. The primary endpoint of proportion of patients achieving ACR20 response after 12 weeks of treatment was met.ObjectivesTo present the results of the 24-week analysis.MethodsPatients with active RA were randomized 1:1:1:1 in a double blinded manner to receive either placebo (PBO) or one of three doses of filgotinib (50mg, 100mg or 200mg) as a once daily regimen for 24 weeks (DARWIN 2 study). At Week 12 all patients on PBO and on 50mg daily whose tender and swollen joint counts did not improve by at least 20% (non-responders (NR)) were reassigned to 100mg daily.ResultsOf 283 randomized and treated patients, mean duration of RA of 9 years and DAS28(CRP) at baseline between 6.0–6.2. At Week 12, a statistically significant higher ACR20, ACR50, ACR70, DAS28(CRP) and CDAI response versus PBO was observed in filgotinib groups. These responses were similar or continued to improve through 24 weeks (Table 1). Increase in filgotinib dose from Week 12 improved efficacy in PBO and 50mg NR groups (at Week 24 ACR20 55% and 60% respectively). Serious Adverse Events and Treatment-Emergent Adverse Events (TEAE) were distributed over the dose groups including PBO: TEAE 39% PBO and 41% filgotinib groups. Infections occurred in 10% PBO and 19% filgotinib groups. No opportunistic infections, cancers or deaths occurred. In filgotinib groups, for the first 4 weeks, a dose dependent decrease in mean neutrophil and a small reduction in platelet counts was seen; mild increase in mean creatinine was apparent. These changes subsequently plateaued and remained stable up to Week 24. A dose dependent increase in haemoglobin was seen during the first 12 weeks and levels remained stable up to Week 24. Over 24 weeks no meaningful difference in transaminase changes was apparent.Table 1.Summary of the efficacy responses after 12 and 24 weeks treatmentPlacebo50mg100mg200mg(n=72)(n=72)(n=70)(n=69)12 weeks ACR20, NRI1, %2967***66***73** ACR50, NRI, %1135**37***44*** ACR70, NRI, %3819**13* DAS28(CRP), LOCF3, mean change from BL2−1.0−1.8***−2.0***−2.3*** CDAI4 mean change from BL, LOCF−12−21***−24***−25***24 weeks ACR20, NRI, %n/a577967 ACR50, NRI, %n/a333945 ACR70, NRI, %n/a192625 DAS28(CRP), LOCF, mean change from BLn/a−2.0−2.6−2.6 CDAI mean change from BL, LOCFn/a−22−30−28*p<0.05 vs. placebo; **p<0.01 vs. placebo; ***p<0.001 vs. placebo. ACR scores based on ITT analysis. 1Non-responder imputation. 2Baseline. 3Last observation carried forward. 4Clinical Disease Activity Index.ConclusionsSignificant improvement in signs and symptoms of active RA was observed after 12 weeks treatment with filgotinib monotherapy. Efficacy responses were sustained or increased at Week 24. The safety profile was acceptable.Disclosure of InterestA. Kavanaugh Grant/research support from: Galapagos, Pfizer, AbbVie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, Cons...
Background:Filgotinib (FIL) is an orally administered, selective inhibitor of Janus Kinase 1 (JAK1) in Phase 3 development for the treatment of rheumatoid arthritis (RA).Objectives:Assess the long-term safety and efficacy of FIL in the DARWIN 3 open-label extension study.Methods:Two 24-week Phase 2b studies were completed in patients (pts) with moderately to severely active RA (DARWIN 1, DARWIN 2; Ref 1, 2). Following study completion, pts were offered FIL in the ongoing DARWIN 3 extension study: 100 mg QD (US males), 200 mg QD, or 100 mg BID. This report summarizes safety data from the first dose of FIL in the DARWIN program to 11 Oct 2017 and efficacy data from the DARWIN 3 baseline visit to Week 108, which all ongoing pts have completed.Results:Of 877 pts, 790 (90%) completed DARWIN 1/2, and 739 (84%) enrolled in DARWIN 3; 603 (82%) were female, mean age 53 years. At analysis, 491/739 (66%) were on study. Cumulative patient years of exposure (PYE) was 1931, median time on study drug was 1072 days. Key data are summarized in table 1. 87%, 68%, and 48% of pts achieved ACR20/50/70, respectively, and 72% achieved DAS28-CRP≤3.2 (by observed case analysis).Table 1Key Safety Events and Lab Abnormalities per 100 PYE** Treatment groups with fewer than 10 subjects were omitted for clarity; †Non-melanoma skin cancer; ‡Single patient DVT leading to PEConclusions:Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile.References[1]Westhovens R, et al. Ann Rheum Dis2017;76:998–1008.[2]Kavanaugh A, et al. Ann Rheum Dis2017;76:1009–1019.Disclosure of Interest:R. Westhovens Grant/research support from: Galapagos and Celltrion, Roche and BMS, Consultant for: Galapagos and Celltrion, Roche and BMS, R. Alten Grant/research support from: Galapagos/Gilead, K. Winthrop Consultant for: Pfizer, Lilly, Galapagos, Gilead, AbbVie, M. Greenwald Grant/research support from: Gilead, L. Ponce: None declared, F. Enriquez-Sosa: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, N. Mozaffarian Shareholder of: Gilead, Employee of: Gilead, J. Greer Shareholder of: Gilead, Employee of: Gilead, R. Kunder Shareholder of: Gilead, Employee of: Gilead, D. An Shareholder of: Gilead, Employee of: Gilead, P. Harrison Shareholder of: Galapagos, Employee of: Galapagos, A. Van der Aa Shareholder of: Galapagos, Employee of: Galapagos, A. Kavanaugh Consultant for: Galapagos, M. Genovese Consultant for: Gilead, Galapagos, Abbvie, Lilly, Pfizer
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