Introduction The altered expression of miRNAs is involved in the pathophysiology of inflammatory conditions. Moreover, circulating miRNAs appear promising therapeutic and prognostic biomarkers. Objectives To investigate the effect of anti-TNF therapy on the levels of circulating miRNAs in patients with ankylosing spondylitis (AS). Methods Our study included 19 AS patients. Clinical and laboratory parameters of disease activity were assessed at baseline (M0) and after 3 (M3) and 12 months (M12) of therapy. Total RNA from plasma was isolated using miRNeasy Serum/ Plasma Kit (Qiagen). First, a comprehensive analysis of miRNAs was performed using TaqMan Low Density Array (TLDA) in 3 patients. Next, single assays were used for validation of selected miRNAs. dCt method was used for relative quantification. Data were analysed using ANOVA with Bonferroni corrections and Spearman's correlation coefficient. Results All AS patients had high disease activity at baseline and had a good therapeutic response to anti TNF therapy at M3 and M12 (BASDAI p<0.001, ASDAS p<0.001).Out of all 380 miRNAs analysed by TLDA, 125 miRNAs were detected in all samples, 148 miRNAs were detected at M0, 154 at M3 and 151 at M12. Validation of 17 selected miRNAs confirmed significant downregulation of miR-145 at M3 (TLDA 1.59-change; single assays 1.62-change, p=0.024), but the downregulation did not reach statistical significance at M12 (TLDA 1.46-change; single assays 1.11-change, p>0.05).The decrease in miR-145 expression from M0 to M3 significantly correlated with disease activity improvement over time from M3 to M12 as per BASDAI (r=0.672, p=0.002) and ASDAS scores (r=0.607, p=0.006) and VAS at M12 (r=0.515, p=0.024). Although the overall clinical efficacy of anti-TNF therapy sustained, 6 patients revealed some ASDAS worsening at M12. This may have resulted to correlation of higher miR-145 levels at M3 with disease activity worsening as per increase in ASDAS from M3 to M12 (r=0.593, p=0.007) and higher ASDAS (r=0.533, p=0.019) and VAS (r=0.564, p=0.012) at M12. Conclusions We propose that an early change in miR-145 levels may be a predictor for the future outcome of AS patients as it's early decrease after anti-TNF initiation correlated with further disease activity improvement. These data suggest the potential to use circulating miRNAs as biomarkers of treatment response in AS.
Career situation of first and presenting authorPost-doctoral fellow.IntroductionAs the IL17/IL23 axis has proven pathogenic for many inflammatory conditions like rheumatoid arthritis, psoriasis, IBD, multiple sclerosis (MS) and others, IL17 inhibition is an attractive target for the treatment of these diseases. Indeed, biologics targeting human IL17 (hIL17) have recently proven a successful treatment for psoriasis with similar therapeutics being currently under development for this and other diseases.ObjectivesTo describe novel preclinical platforms based on a hIL17A transgenic mouse model for the efficacy evaluation of human therapeutics, targeting psoriasis and MS.MethodsHuman IL17A transgenic mice were generated using as transgene a 170 kb genomic DNA fragment comprising hIL17A intron exon sequences flanked by extended 5’ and 3’ regulatory regions. These mice were further crossed with IL17AKO1 resulting in a mouse line (TghIL17) that exclusively expresses hIL17A. We standardized IMQ-induced psoriasis and MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) induction protocols in these mice and characterized their response to anti hIL17 treatment. Disease severity was evaluated using established clinical and histopathological scoring scales.ResultsTghIL17 mice have no overt pathology, and express hIL17A upon induction. IMQ- induced psoriasis induction in TghIL17 mice resulted in the development of skin pathology characterized clinically by skin erythema, thickening and scaling and histopathologically by acanthosis, hyperkeratosis and lymphocytic infiltration. Treatment with secukinumab resulted in alleviation of both clinical and histopathological psoriasis hallmarks to levels comparable to those observed in the IL17KO mice. MOG-induced EAE in TghIL17 mice resulted in clinical symptoms comparable to the ones observed in WT mice that involved, at the peak of the disease, paraplegia with forelimb weakness or paralysis. Treatment of EAE-affected TghIL17 mice with secukinumab ameliorated the pathological findings to a level similar to the one observed in IL17KO mice.ConclusionsTghIL17 mice upon induction develop pathologies similar to WT animals demonstrating that human IL17A efficiently replaces its mouse counterpart. Using these mice with standardized IMQ-induced psoriasis and MOG-induced EAE protocols we established and validateed with commercially approved anti-hIL17 biologics, preclinical platforms that allow the efficient and reproducible evaluation of anti-hIL17 therapeutics.ReferenceNakae S, et al. Antigen-specific T cell sensitization is impaired in Il-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002.Disclosure of InterestNone declared.
BackgroundPatients with RA exhibit an increased risk of developing multiple extraarticular pathologies. The link between co-manifested pathologies and RA at the level of common molecular and cellular mechanisms remains to be further elucidated.ObjectivesWe aimed to identify comorbidities developing in models of TNF-driven chronic polyarthritis and further explore their aetiopathogenesis.MethodsThrough detailed phenotyping, clinical, histopathological and functional analysis we investigated the development of comorbidities in the Tg197 and TnfΔARE/+ mouse models that overexpress respectively human and mouse TNF and develop spontaneous chronic polyarthritis with the concomitant development of Crohn's-like IBD in the case of the TnfΔARE/+ animals. Targeting mesenchymal origin cells, ex vivo cellular analyses and RNA sequencing expression profiling allowed us to further explore the key cellular instigators of RA related comorbidities.ResultsHistopathological evaluation and echocardiography assessment of both arthritis models showed thickening of the aortic valve and cardiac dysfunction characterized by mild decreased fractional shortening, decreased heart rate and increased velocities in ascending aorta hinting towards aortic valve disease. The aortic valve pathology, similarly to arthritis, was ameliorated with anti-TNF treatment. The thickening of the aortic valve leaflets was due to fibrosis which consisted almost entirely of mesenchymal origin Valve Interstitial Cells (VICs). VICs from mutant mice expressed high levels of TNF and exhibited a proliferative and migratory phenotype resembling the activated phenotype of pathogenic Synovial Fibroblasts (SFs) isolated from the joints of the same mice. RNA-seq analysis further supported a significant correlation between pathogenic SFs and VICs highlighting a common cellular mechanism linking RA and aortic valve pathology. Furthermore, we show that TNF deregulation leads to additional RA related comorbidities, as described in human disease, including periodontitis with early onset alveolar bone loss and pulmonary inflammation with mild to severe bronchus-associated lymphoid tissue (BALT).ConclusionsSimilarly to human RA patients, TNF-driven arthritis models develop multiple RA-associated comorbidities, offering novel insights into potential molecular and cellular mechanisms commonly underlying these complex pathologies.References Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).Kontoyiannis, D. et al. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–7 (2008). Disclosure of InterestNone declared
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