Methotrexate promotes the release of granulocyte-macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling.
Arthritis, Rheumatoid
/ metabolism
Humans
Methotrexate
/ pharmacology
Synoviocytes
/ drug effects
Granulocyte-Macrophage Colony-Stimulating Factor
/ metabolism
Antirheumatic Agents
/ pharmacology
Signal Transduction
/ drug effects
Cells, Cultured
Fibroblasts
/ metabolism
Interleukin-1
/ metabolism
Autocrine Communication
/ drug effects
Coculture Techniques
Synovial Membrane
/ metabolism
Piperidines
Pyrimidines
Anti-rheumatic drugs
Cytokines
Fibroblast-like synoviocyte
Rheumatoid arthritis
Synovitis
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
11 Oct 2024
11 Oct 2024
Historique:
received:
01
05
2024
accepted:
23
09
2024
medline:
12
10
2024
pubmed:
12
10
2024
entrez:
11
10
2024
Statut:
epublish
Résumé
Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators. Primary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations. Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on 'Molecular mechanisms of cancer' and TOFA on 'Interferon signaling'. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte-macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages. MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.
Sections du résumé
BACKGROUND
BACKGROUND
Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.
METHODS
METHODS
Primary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations.
RESULTS
RESULTS
Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on 'Molecular mechanisms of cancer' and TOFA on 'Interferon signaling'. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte-macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages.
CONCLUSIONS
CONCLUSIONS
MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.
Identifiants
pubmed: 39394168
doi: 10.1186/s13075-024-03406-6
pii: 10.1186/s13075-024-03406-6
doi:
Substances chimiques
Methotrexate
YL5FZ2Y5U1
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Antirheumatic Agents
0
Interleukin-1
0
tofacitinib
87LA6FU830
Piperidines
0
Pyrimidines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
178Informations de copyright
© 2024. The Author(s).
Références
Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch MH, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62–8.
pubmed: 24095940
doi: 10.1136/annrheumdis-2013-204223
Murray K, Turk M, Alammari Y, Young F, Gallagher P, Saber T, et al. Long-term remission and biologic persistence rates: 12-year real-world data. Arthritis Res Ther. 2021;23(1):25.
pubmed: 33441191
pmcid: 7807520
doi: 10.1186/s13075-020-02380-z
Aga AB, Lie E, Uhlig T, Olsen IC, Wierod A, Kalstad S, et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010. Ann Rheum Dis. 2015;74(2):381–8.
pubmed: 24285493
doi: 10.1136/annrheumdis-2013-204020
Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol. 2020;16(6):316–33.
pubmed: 32393826
pmcid: 7987137
doi: 10.1038/s41584-020-0413-5
Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570(7760):246–51.
pubmed: 31142839
pmcid: 6690841
doi: 10.1038/s41586-019-1263-7
Floudas A, Smith CM, Tynan O, Neto N, Krishna V, Wade SM, et al. Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis. Ann Rheum Dis. 2022;81:1224–42.
pubmed: 35701153
doi: 10.1136/annrheumdis-2021-221761
Yoshitomi H. Regulation of immune responses and chronic inflammation by fibroblast-like synoviocytes. Front Immunol. 2019;10: 1395.
pubmed: 31275325
pmcid: 6593115
doi: 10.3389/fimmu.2019.01395
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61.
pubmed: 12748655
doi: 10.1038/nature01661
Rosengren S, Corr M, Boyle DL. Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res Ther. 2010;12(2):R65.
pubmed: 20380722
pmcid: 2888219
doi: 10.1186/ar2981
Wang BH, Lu YH, Wu LF, Lu X, Guo W, Deng FY, et al. Evaluation of plasma cytokine protein array profile: the highlighted PDGF-BB in rheumatoid arthritis. Clin Rheumatol. 2020;39(11):3323–30.
pubmed: 32385763
doi: 10.1007/s10067-020-05109-0
Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–7.
pubmed: 20215140
doi: 10.1136/ard.2009.123919
Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993;92(6):2675–82.
pubmed: 8254024
pmcid: 288465
doi: 10.1172/JCI116884
Spurlock CF 3rd, Tossberg JT, Fuchs HA, Olsen NJ, Aune TM. Methotrexate increases expression of cell cycle checkpoint genes via JNK activation. Arthritis Rheum. 2012;64(6):1780–9.
pubmed: 22183962
doi: 10.1002/art.34342
Spurlock CF 3rd, Aune ZT, Tossberg JT, Collins PL, Aune JP, Huston JW 3rd, et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis Rheum. 2011;63(9):2606–16.
pubmed: 21618198
pmcid: 3165146
doi: 10.1002/art.30457
Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS ONE. 2015;10(7): e0130078.
pubmed: 26131691
pmcid: 4489434
doi: 10.1371/journal.pone.0130078
Spurlock CF, 3rd, Gass HMt, Bryant CJ, Wells BC, Olsen NJ, Aune TM. Methotrexate-mediated inhibition of nuclear factor kappaB activation by distinct pathways in T cells and fibroblast-like synoviocytes. Rheumatology (Oxford). 2015;54(1):178-87.
Bergstrom B, Carlsten H, Ekwall AH. Methotrexate inhibits effects of platelet-derived growth factor and interleukin-1beta on rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Res Ther. 2018;20(1):49.
pubmed: 29554943
pmcid: 5859417
doi: 10.1186/s13075-018-1554-7
Hetland ML, Haavardsholm EA, Rudin A, Nordstrom D, Nurmohamed M, Gudbjornsson B, et al. Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ. 2020;371: m4328.
pubmed: 33268527
pmcid: 7708829
doi: 10.1136/bmj.m4328
Sergeant JC, Hyrich KL, Anderson J, Kopec-Harding K, Hope HF, Symmons DPM, et al. Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS). Arthritis Res Ther. 2018;20(1):147.
pubmed: 30005689
pmcid: 6044018
doi: 10.1186/s13075-018-1645-5
Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360–72.
pubmed: 30285183
doi: 10.1001/jama.2018.13103
Tanaka Y, Luo Y, O’Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18(3):133–45.
pubmed: 34987201
pmcid: 8730299
doi: 10.1038/s41584-021-00726-8
Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.
pubmed: 24941177
doi: 10.1056/NEJMoa1310476
Rosengren S, Corr M, Firestein GS, Boyle DL. The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis. 2012;71(3):440–7.
pubmed: 22121136
doi: 10.1136/ard.2011.150284
Bonelli M, Dalwigk K, Platzer A, Olmos Calvo I, Hayer S, Niederreiter B, et al. IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes : JAKinibs suppress the interferon response in RA-FLSs. Exp Mol Med. 2019;51(7):75.
pubmed: 31285419
pmcid: 6802656
doi: 10.1038/s12276-019-0267-6
Sellden T, Mardh CK, Joelsson M, Vikgren J, Johnsson A, Larsson G, et al. Radiographic airway abnormalities in untreated early rheumatoid arthritis are associated with peripheral neutrophil activation. Arthritis Res Ther. 2023;25(1):44.
pubmed: 36941690
pmcid: 10026468
doi: 10.1186/s13075-023-03019-5
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.
pubmed: 20872595
doi: 10.1002/art.27584
Ekwall AK, Eisler T, Anderberg C, Jin C, Karlsson N, Brisslert M, et al. The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis. Arthritis Res Ther. 2011;13(2):R40.
pubmed: 21385358
pmcid: 3132020
doi: 10.1186/ar3274
Cohen S, Zwillich SH, Chow V, Labadie RR, Wilkinson B. Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Br J Clin Pharmacol. 2010;69(2):143–51.
pubmed: 20233177
pmcid: 2824475
doi: 10.1111/j.1365-2125.2009.03570.x
Svensson MND, Zoccheddu M, Yang S, Nygaard G, Secchi C, Doody KM, et al. Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci Adv. 2020;6(26):eaba4353.
pubmed: 32637608
pmcid: 7319753
doi: 10.1126/sciadv.aba4353
Zhang T, Inesta-Vaquera F, Niepel M, Zhang J, Ficarro SB, Machleidt T, et al. Discovery of potent and selective covalent inhibitors of JNK. Chem Biol. 2012;19(1):140–54.
pubmed: 22284361
pmcid: 3270411
doi: 10.1016/j.chembiol.2011.11.010
Umar S, Palasiewicz K, Volin MV, Zanotti B, Al-Awqati M, Sweiss N, et al. IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts. Life Sci. 2021;287: 120114.
pubmed: 34732329
pmcid: 10020992
doi: 10.1016/j.lfs.2021.120114
Chang DM, Chang SY, Yeh MK, Lai JH. The pharmacokinetics of interleukin-1 receptor antagonist in Chinese subjects with rheumatoid arthritis. Pharmacol Res. 2004;50(3):371–6.
pubmed: 15225683
doi: 10.1016/j.phrs.2004.02.002
Kuo D, Ding J, Cohn IS, Zhang F, Wei K, Rao DA, et al. HBEGF(+) macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med. 2019;11(491):eaau8587.
pubmed: 31068444
pmcid: 6726376
doi: 10.1126/scitranslmed.aau8587
Pucino V, Nefla M, Gauthier V, Alsaleh G, Clayton SA, Marshall J, et al. Differential effect of lactate on synovial fibroblast and macrophage effector functions. Front Immunol. 2023;14: 1183825.
pubmed: 37304267
pmcid: 10251493
doi: 10.3389/fimmu.2023.1183825
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Yarwood A, Huizinga TW, Worthington J. The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford). 2016;55(2):199–209.
pubmed: 25239882
doi: 10.1093/rheumatology/keu323
Bergstrom B, Lundqvist C, Vasileiadis GK, Carlsten H, Ekwall O, Ekwall AH. The rheumatoid arthritis risk gene AIRE is induced by cytokines in fibroblast-like synoviocytes and augments the pro-inflammatory response. Front Immunol. 2019;10:1384.
pubmed: 31275320
pmcid: 6591464
doi: 10.3389/fimmu.2019.01384
Whitaker JW, Boyle DL, Bartok B, Ball ST, Gay S, Wang W, et al. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets. PLoS ONE. 2015;10(4): e0124254.
pubmed: 25901943
pmcid: 4406750
doi: 10.1371/journal.pone.0124254
Whitaker JW, Shoemaker R, Boyle DL, Hillman J, Anderson D, Wang W, et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 2013;5(4):40.
pubmed: 23631487
pmcid: 3706831
doi: 10.1186/gm444
Crowley T, O’Neil JD, Adams H, Thomas AM, Filer A, Buckley CD, et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res Ther. 2017;19(1):35.
pubmed: 28187781
pmcid: 5303242
doi: 10.1186/s13075-017-1248-6
Schreck R, Baeuerle PA. NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene. Mol Cell Biol. 1990;10(3):1281–6.
pubmed: 2406568
pmcid: 361021
Cockerill PN, Bert AG, Jenkins F, Ryan GR, Shannon MF, Vadas MA. Human granulocyte-macrophage colony-stimulating factor enhancer function is associated with cooperative interactions between AP-1 and NFATp/c. Mol Cell Biol. 1995;15(4):2071–9.
pubmed: 7891702
pmcid: 230434
doi: 10.1128/MCB.15.4.2071
Thomas RS, Tymms MJ, McKinlay LH, Shannon MF, Seth A, Kola I. ETS1, NFkappaB and AP1 synergistically transactivate the human GM-CSF promoter. Oncogene. 1997;14(23):2845–55.
pubmed: 9190901
doi: 10.1038/sj.onc.1201125
Winkler A, Sun W, De S, Jiao A, Sharif MN, Symanowicz PT, et al. The interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial. Arthritis Rheumatol. 2021;73(12):2206–18.
pubmed: 34423919
pmcid: 8671219
doi: 10.1002/art.41953
Bell AL, Magill MK, McKane WR, Kirk F, Irvine AE. Measurement of colony-stimulating factors in synovial fluid: potential clinical value. Rheumatol Int. 1995;14(5):177–82.
pubmed: 7536953
doi: 10.1007/BF00262295
Wright HL, Bucknall RC, Moots RJ, Edwards SW. Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy. Rheumatology (Oxford). 2012;51(3):451–9.
pubmed: 22179732
doi: 10.1093/rheumatology/ker338
Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 1993;52(12):870–5.
pubmed: 8311538
pmcid: 1005218
doi: 10.1136/ard.52.12.870
Fiehn C, Wermann M, Pezzutto A, Hufner M, Heilig B. Plasma GM-CSF concentrations in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy. Z Rheumatol. 1992;51(3):121–6.
pubmed: 1502858
Altomonte L, Zoli A, Mirone L, Scolieri P, Magaro M. Serum levels of interleukin-1b, tumour necrosis factor-a and interleukin-2 in rheumatoid arthritis. Correlation with disease activity. Clin Rheumatol. 1992;11(2):202–5.
pubmed: 1617893
doi: 10.1007/BF02207957
Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988;2(8613):706–9.
pubmed: 2901567
doi: 10.1016/S0140-6736(88)90185-7
Lewis MJ, Barnes MR, Blighe K, Goldmann K, Rana S, Hackney JA, et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 2019;28(9):2455-70 e5.
pubmed: 31461658
pmcid: 6718830
doi: 10.1016/j.celrep.2019.07.091
Einarsson JT, Willim M, Ernestam S, Saxne T, Geborek P, Kapetanovic MC. Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a nationwide study in Sweden. Rheumatology (Oxford). 2019;58(2):227–36.
pubmed: 29538755
doi: 10.1093/rheumatology/key054
Rivellese F, Surace AEA, Goldmann K, Sciacca E, Cubuk C, Giorli G, et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med. 2022;28(6):1256–68.
pubmed: 35589854
pmcid: 9205785
doi: 10.1038/s41591-022-01789-0
Haupl T, Yahyawi M, Lubke C, Ringe J, Rohrlach T, Burmester GR, et al. Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007;12(3):328–40.
pubmed: 17379860
doi: 10.1177/1087057107299261
Olsen NJ, Spurlock CF 3rd, Aune TM. Methotrexate induces production of IL-1 and IL-6 in the monocytic cell line U937. Arthritis Res Ther. 2014;16(1):R17.
pubmed: 24444433
pmcid: 3978848
doi: 10.1186/ar4444
Weber BN, Giles JT, Liao KP. Shared inflammatory pathways of rheumatoid arthritis and atherosclerotic cardiovascular disease. Nat Rev Rheumatol. 2023;19(7):417–28.
pubmed: 37231248
pmcid: 10330911
doi: 10.1038/s41584-023-00969-7
Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. 2010;3(105):cm1.
pubmed: 20086235
Cavalli G, Colafrancesco S, Emmi G, Imazio M, Lopalco G, Maggio MC, et al. Interleukin 1alpha: a comprehensive review on the role of IL-1alpha in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2021;20(3): 102763.
pubmed: 33482337
doi: 10.1016/j.autrev.2021.102763
Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020;16:145–54.
pubmed: 32066940
doi: 10.1038/s41584-020-0373-9
Gao Y, Gao YN, Wang MJ, Zhang Y, Zhang FQ, He ZX, et al. Efficacy and safety of tofacitinib combined with methotrexate in the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Heliyon. 2023;9(5): e15839.
pubmed: 37215854
pmcid: 10196519
doi: 10.1016/j.heliyon.2023.e15839
Humby F, Lewis M, Ramamoorthi N, Hackney JA, Barnes MR, Bombardieri M, et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Ann Rheum Dis. 2019;78(6):761–72.
pubmed: 30878974
doi: 10.1136/annrheumdis-2018-214539
Greven DE, Cohen ES, Gerlag DM, Campbell J, Woods J, Davis N, et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann Rheum Dis. 2015;74(10):1924–30.
pubmed: 24936585
doi: 10.1136/annrheumdis-2014-205234
Lee KMC, Achuthan AA, Hamilton JA. GM-CSF: a promising target in inflammation and autoimmunity. Immunotargets Ther. 2020;9:225–40.
pubmed: 33150139
pmcid: 7605919
doi: 10.2147/ITT.S262566
Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998;41(12):2196–204.
pubmed: 9870876
doi: 10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2
Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 2003;48(4):927–34.
pubmed: 12687534
doi: 10.1002/art.10870
Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(3):614–24.
pubmed: 11920396
doi: 10.1002/art.10141
Scott IC, Ibrahim F, Simpson G, Kowalczyk A, White-Alao B, Hassell A, et al. A randomised trial evaluating anakinra in early active rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(1):88–93.
pubmed: 26842950
Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582(7811):259–64.
pubmed: 32499639
pmcid: 7841716
doi: 10.1038/s41586-020-2222-z
Smith MH, Gao VR, Periyakoil PK, Kochen A, DiCarlo EF, Goodman SM, et al. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis. Nat Immunol. 2023;24(7):1200–10.
pubmed: 37277655
pmcid: 10307631
doi: 10.1038/s41590-023-01527-9