The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Abstract Background Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown. Methods The expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot. Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays. The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay. The level of phosphorylated-p65 was examined by Western blot. The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Results HAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway. Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p. Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown. HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs. Conclusion MSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.

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AB0138 A MOLECULAR SIGNATURE RESPONSE CLASSIFIER STRATIFIES SEROPOSITIVE RHEUMATOID ARTHRITIS PATIENTS BASED ON THEIR LIKELIHOOD OF INADEQUATE RESPONSE TO TNF INHIBITOR THERAPIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3307 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1096.3-1097

Author(s):

S. Cohen ◽

V. Strand ◽

E. Connolly-Strong ◽

J. Withers ◽

L. Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Targeted Therapy ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Molecular Signature ◽

Inadequate Response ◽

Tnf Inhibitor ◽

Odds Ratios ◽

Selection For ◽

Necrosis Factor

Background:There is an urgent need for precision medicine in targeted therapy selection for the treatment of rheumatoid arthritis (RA). TNF inhibitor (TNFi) therapies are the most prescribed targeted therapy for RA patients, yet the majority of patients fail to achieve a clinically meaningful response using this medication class. A blood-based molecular signature test evaluates RNA and clinical metrics to stratify RA patients based on their likelihood of having an inadequate response to TNFi therapies.1 Patients unlikely to respond to TNFi therapies can be directed to a different treatment option such as a JAK inhibitor, thus reducing the time needed to identify an effective therapy, improving confidence in and adherence to treatment, and increasing the patients’ chance of reaching treat-to-target goals.Objectives:High-titers of anti-cyclic citrillunated protein (anti-CCP) have been independently associated with reduced response to TNFi therapy;2 thus, we evaluated the ability of a blood-based molecular signature response classifier (MSRC) test to stratify RA patients by their likelihood of inadequate response to TNFi therapies – regardless of their positive or negative anti-CCP status.Methods:A subset of patients enrolled in the Network-04 prospective observational trial evaluating the ability of a molecular signature response classifier to stratify patients were subdivided into two groups based upon whether they were positive (N = 72) or negative (N = 74) for anti-CCP. The odds of inadequate response to TNFi therapies were calculated based on whether or not a patient had a molecular signature of non-response to TNFi therapy at baseline before the start of treatment. Odds ratios and confidence intervals were calculated3,4 to represent the strength of association between detecting the molecular signature of non-response and the patient’s failure to achieve ACR50 at 6 months.Results:The odds that a patient with a molecular signature of non-response failed to meet ACR50 criteria at 6 months was approximately three times greater than among those patients who lacked the signal (Table 1). No significant difference in odds ratios was observed between patients who were positive or negative for anti-CCP.Table 1.The odds of patients with a molecular signature of non-response failing to achieve an ACR50 response 6 months after TNF inhibitor therapy initiationOdds ratio (95% confidence interval)Anti-CCP positive3.5 (1.3-9.7)Anti-CCP negative3.1 (1.2-8.3)Conclusion:The MSRC test evaluates RA disease biology and accurately stratifies patients based on their likelihood of having an inadequate response to TNFi therapies, regardless of being negative or positive for anti-CCP autoantibodies. Rheumatologists can use the results of the MSRC test to inform targeted therapy selection for RA patients, instead of their anti-CCP serostatus, eliminating the variability inherent to the anti-CCP measurement and its inability to consistently predict TNFi therapy incompatibility. With the MSRC test, providers can rely on a more predictable and accurate assessment of TNFi therapy success or failure when coordinating patient management.References:[1]Mellors, T. et al. Clinical Validation of a Blood-Based Predictive Test for Stratification of Response to Tumor Necrosis Factor Inhibitor Therapies in Rheumatoid Arthritis Patients. Network and Systems Medicine3, 91-104, doi:10.1089/nsm.2020.0007 (2020).[2]Braun-Moscovici, Y. et al. Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis. J Rheumatol33, 497-500 (2006).[3]Szumilas, M. Explaining odds ratios. J Can Acad Child Adolesc Psychiatry19, 227-229 (2010).[4]Sperandei, S. Understanding logistic regression analysis. Biochem Med (Zagreb) 24, 12-18, doi:10.11613/BM.2014.003 (2014).Disclosure of Interests:Stanley Cohen: None declared, Vibeke Strand Consultant of: Abbvie, Amgen, Arena, BMS, Boehringer Ingelheim, Celltrion, Galapagos, Genentech/Roche, Gilead, GSK, Ichnos, Inmedix, Janssen,Kiniksa, Lilly,Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Setpoint, UCB, Erin Connolly-Strong Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Johanna Withers Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Lixia Zhang Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Ted Mellors Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Viatcheslav Akmaev Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation

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Remission of anti‐tumor necrosis factor‐α antibody‐induced palmoplantar pustulosis with the Janus kinase inhibitor baricitinib in a patient with rheumatoid arthritis

The Journal of Dermatology ◽

10.1111/1346-8138.15860 ◽

2021 ◽

Author(s):

Shinichi Imafuku ◽

Akira Maeyama

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Kinase Inhibitor ◽

Janus Kinase ◽

Palmoplantar Pustulosis ◽

Janus Kinase Inhibitor ◽

Factor Α ◽

Necrosis Factor

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