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BackgroundAnti-MDA5 antibody-positive dermatomyositis (anti-MDA5+DM) is a rare autoimmune disease associated with a high mortality rate due to rapid-progressive interstitial lung disease (RP-ILD), particularly in East Asia[1]. MDA5, acts as a cytoplasmic sensor of viral RNA, thus activating antiviral responses including the type I interferon (IFN) signaling pathway[2]. The involvement of type 1 IFN in the pathogenesis of MDA5+DM has been proposed based on the significantly elevated expression of its downstream stimulated genes(ISG) in muscle, skin, lung, and peripheral blood[3;4]. Janus kinase inhibitor, which targets the IFN pathway, combined with glucocorticoid could improve the survival of early-stage MDA5+DM-ILD patients[5]. In clinical practice, there is still an urgent demand for sensitive biomarkers to facilitate clinical risk assessment and precise treatment.ObjectivesThis study aimed to investigate the clinical significance of interferon score, especially IFN-I score, in patients with anti-MDA5+DM.MethodsDifferent subtypes of idiopathic inflammatory myopathy, including anti-MDA5+DM(n=61), anti-MDA5-DM(n=20), antisynthetase syndrome(ASS,n=22),polymyositis(PM,n=6) and immune-mediated necrotizing myopathy(IMNM,n=9), and 58 healthy controls were enrolled.. A multiplex quantitative real-time PCR(RT-qPCR) assay using four TaqMan probes was utilized to evaluate two type I ISGs (IFI44, MX1, which are used for IFN-I score), one type II ISG (IRF1), and one housekeeping gene (HRPT1). Clinical features and disease activity index were compared between high and low IFN-I score groups in 61 anti-MDA5+DM patients. The association between laboratory findings and the predictive value of baseline IFN-I score level for mortality was analyzed.ResultsThe IFN scores were significantly higher in patients with anti-MDA5+DM than in HC (Figure 1A). The IFN-I score correlated positively with serum IFN α(r = 0.335, P =0.008), ferritin (r = 0.302, P = 0.018), and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) score(r=0.426, P=0.001). Compared with patients with low IFN-I scores, patients with high IFN-I scores showed increased MYOACT score, CRP, AST, ferritin, and the percentages of plasma cells (PC%) but decreased lymphocyte count, natural killer cell count, and monocyte count. The 3-month survival rate was significantly lower in patients with IFN-I score > 4.9 than in those with IFN-I score ≤ 4.9(72.9% vs. 100%, P=0.044)(Figure 1B).ConclusionIFN score, especially IFN-I score, detected by multiplex RT-qPCR, can be a valuable biomarker for monitoring disease activity and predicting mortality in anti-MDA5+DM patients.References[1]I.E. Lundberg, M. Fujimoto, J. Vencovsky, R. Aggarwal, M. Holmqvist, L. Christopher-Stine, A.L. Mammen, and F.W. Miller, Idiopathic inflammatory myopathies. Nat Rev Dis Primers 7 (2021) 86.[2]G. Liu, J.H. Lee, Z.M. Parker, D. Acharya, J.J. Chiang, M. van Gent, W. Riedl, M.E. Davis-Gardner, E. Wies, C. Chiang, and M.U. Gack, ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat Microbiol 6 (2021) 467-478.[3]G.M. Moneta, D. Pires Marafon, E. Marasco, S. Rosina, M. Verardo, C. Fiorillo, C. Minetti, L. Bracci-Laudiero, A. Ravelli, F. De Benedetti, and R. Nicolai, Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features. Arthritis Rheumatol 71 (2019) 1011-1021.[4]Y. Ye, Z. Chen, S. Jiang, F. Jia, T. Li, X. Lu, J. Xue, X. Lian, J. Ma, P. Hao, L. Lu, S. Ye, N. Shen, C. Bao, Q. Fu, and X. Zhang, Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications. Nat Commun 13 (2022) 6458.[5]Z. Chen, X. Wang, and S. Ye, Tofacitinib in Amyopathic Dermatomyositis–Associated Interstitial Lung Disease. New England Journal of Medicine 381 (2019) 291-293.AcknowledgementsThis work was supported by the National Natural Science Foundation of China [81974251], and Shanghai Hospital Develop ent Center, Joint Research of New Advanced Technology Project [SHDC12018106]Disclosure of InterestsNone Declared.
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Background: TFV is a nucleotide analogue whose active form, TFV diphosphate (TDP), inhibits reverse transcription of hepatitis B virus (HBV) and is the active metabolite of HBV treatment TFV alafenamide (TAF). NCO-48F is a novel TFV prodrug designed to increase the liver concentration and maximize efficacy and/or potency while reducing drug exposure outside of the liver. NCO-48F is expected to minimize kidney and bone toxicity by reducing systemic exposure of TFV. Method(s): Safety, tolerability, pharmacokinetics (PK), and anti-HBV activity of multiple daily oral doses of 4 and 20 mg of NCO-48F, compared with 25 mg TAF, were evaluated in a randomized, open-label, active-controlled, parallel-assignment study in adult subjects with treatment-naive HBV infection (3 groups of 8 subjects each). Each subject was administered NCO-48F or TAF daily for 28d and followed for 28d after the last dose. Result(s): Preliminary data from 12 subjects (4 subjects/group) were available for analysis. NCO-48F at 4 mg and 20 mg and TAF were safe and well tolerated. No subjects had a serious adverse event (AE) or were discontinued due to an AE. There were no clinically significant or dose-dependent changes in hematology, clinical chemistry, urinalysis, electrocardiograms, or vital signs. One treatment-emergent AE was reported by 1 NCO-48F 4 mg subject (COVID-19 infection) which was not considered drug-related. NCO-48F was orally absorbed with Cmax observed within 30 minutes. NCO-48F was metabolized to TFV and rapidly cleared. Minimal urinary excretion of intact NCO-48F was detected, consistent with conversion to TFV. TFV Cmax was observed within one hour of NCO-48F administration, a faster uptake than observed after TAF administration. TFV elimination kinetics appeared similar after administration of either NCO-48F or TAF. Plasma concentrations of NCO-48F and TFV increased approximately dose proportionately. Over 28d of treatment, declines in serum HBV DNA levels (log10 IU/mL) were observed among all dose groups, and mean changes in HBV DNA at day 28 were -2.12 and -3.29 for NCO48F 4 mg and 20 mg, and -3.27 for TAF. Three subjects treated with NCO48F 20 mg had levels below limit of quantitation during treatment, and recovery of HBV DNA levels was slower during the follow- up period compared to subjects treated with TAF. Conclusion(s): NCO-48F is a promising agent for the treatment of HBV, demonstrating excellent safety and PK properties, and declines in HBV DNA comparable to TAF.