Changes in MiRNA-5196 expression as a potential biomarker of anti-TNF-α therapy in rheumatoid arthritis and ankylosing spondylitis Patients

In this study, we analysed the expression level of sera circulating miRNA-5196 in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients before and after tumor necrosis factor (TNF)-α therapy as biomarkers predicting positive treatment outcome. We enrolled 10 RA patients, 13 AS patients, and 12 healthy individuals in the study. The expression of miRNA-5196 was measured by real-time polymerase chain reaction before and after anti-TNF-α therapy. Disease activity of RA patients was assessed using disease activity score 28 (DAS28), whereas ankylosing spondylitis DAS (ASDAS) was used in AS patients. MiRNA-5196 expression was significantly higher in patients with RA and AS before TNF-α therapy than in those following anti-TNF-α therapy and healthy controls. Changes in miRNA-5196 expression positively correlated with delta DAS28 or delta ASDAS, respectively, following TNF-α therapy. In contrast, changes in C-reactive protein (CRP) levels in RA and AS patients did not positively correlate with DAS28 or ASDAS changes. Receiver-operating characteristic analysis showed better diagnostic accuracy of miRNA-5196 expression both in RA (area under curve (AUC) = 0.87, p = 0.055) and AS patients (AUC = 0.90, p = 0.050) compared to CRP levels in RA (AUC = 0.75, p = 0.201) and AS patients (AUC = 0.85, p = 0.086) upon biologic therapy treatment. Finding novel biomarkers, including miRNA-5196 which allow to predict and monitor anti-TNF-α response, would be of clinical value especially during the early phase of RA or AS development

Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria

Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFα levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders

AB0763 Personal approach in axial spondyloarthropathy management

BackgroundSpondyloarthropathies (SpAs) are a group of diseases characterized by arthritis in the spine (axialSpA - axSpA) and peripheral joints, and extra-articular symptoms like uveitis, psoriasis or inflammatory bowel diseases. The onset of the disease is difficult to observe. Due to the lack of a pathognomonic test, diagnosis is based on a combination of physical examination, laboratory test and imaging results. The pathogenesis of SpAs is not fully understood, and genetic, environmental and immunological factors are assumed to play a pivotal role.ObjectivesThe study aimed to evaluate selected polymorphisms (ERAP1 rs2287987, ERAP2 rs2549782, TNF rs1800629, TNFRSF1B rs1061622, FCGR2A rs1801274) as prognostic factors of clinical presentations, and response predictors of anti-TNF treatment in axSpA patients.MethodsThe study enrolled 216 Caucasians: 106 axSpA patients and 110 healthy controls. AS patients were diagnosed according to modified New York criteria, while nr-axSpA patients were diagnosed according to ASAS criteria. Genotyping was performed using LightSNiP assays on the Real-Time PCR Instrument. Clinical data were assessed at baseline, as well as after three and six months of anti-TNF treatment. In addition, information’s about extra-articular symptoms were collected.ResultsThe statistical analysis revealed that TNFRSF1B rs1061622-GG was significantly associated with a higher VAS score at baseline (TT + TG vs GG, p = 0.001), and a higher BASDAI score corrected for the first therapy cycle (X1C BASDAI: TT + TG vs GG, p = 0.005). Moreover, homozygotes were more frequently observed with a lack of BASDAI improvement after six months (X1C BASDAI: TT+GG vs TG, p = 0.045, OR = 2.46, 95%CI 1.00-6.12).ERAP1 rs2287987- GG was more frequently observed with enthesitis (AA vs G+, p = 0.049, OR = 4.636, 95%CI 1.101-21.24). The GG genotype of TNFRSF1B rs1061622 was more common in patients with uveitis than TT variant (GG vs TT, p =0.042, OR = 5, 95%CI 1.08-20).Associations between genetic variants and clinical outcomes were evaluated using laboratory parameters. A lack of the ESR improvement after six months of treatment was more frequently observed within ERAP1 rs2287987-AG (AG vs AA + GG, p = 0.027, OR = 2.72, 95%CI 1.115-6.137) and TNFRSF1B rs1061622- TT (TT vs G+, p = 0.020, OR = 3, 95%CI 1.27-6.9) compared to other genotypes. After three months of therapy, the GG variant of ERAP2 rs2549782 polymorphism was more common among individuals with the lack of ESR improvement than T allele carriers (GG vs T+, p = 0.037, OR = 2.76, 95%CI 1.13-6.72).Differences were also detected between the FCGR2A rs1801274 polymorphism and X1CBASDAI score after six months. The low disease activity (BASDAI &lt; 3) and BASDAI improvement was more frequently observed in patients carrying the A allele than the GG genotype (AA+AG vs GG, p = 0.028, OR = 4.545, 95%CI 1.337-16 and p = 0.012, OR = 6.212, 95%CI 1.683-20.47, respectively). The AG genotype was more common among patients with remission (BASDAI &lt; 2) compared to homozygotes (AG vs AA+GG, p = 0.046, OR = 2.36, 95%CI 1.05-5.13).ConclusionGenetic profiling of patients will help to identify those at risk of high initial disease activity or the presence of extra-articular symptoms. Identifying patients less responsive to treatment may allow selecting a drug with an appropriate efficacy profile.AcknowledgementsThis work was supported by the grant from Wroclaw Medical University (Poland) STM.A270.20.153.Disclosure of InterestsBartosz Bugaj: None declared, Joanna Wielinska: None declared, Jerzy Swierkot Speakers bureau: For Abbvie, Roche, Lilly, Sandoz, Pfizer, Medac, MSD, Novartis, UCB, Katarzyna Bogunia-Kubik: None declared</jats:sec