Current and novel therapeutic targets in the treatment of rheumatoid arthritis

Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949. https://doi.org/10.1038/ni1496CrossRefPubMed

Afuwape AO, Feldmann M, Paleolog EM (2003) Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther 10:1950–1960. https://doi.org/10.1038/sj.gt.3302104CrossRefPubMed

Ahmed S (2010) Green tea polyphenol epigallocatechin 3-gallate in arthritis: progress and promise. Arthritis Res Ther 12:208. https://doi.org/10.1186/ar2982CrossRefPubMedPubMedCentral

Ahmed S, Pakozdi A, Koch AE (2006) Regulation of interleukin-1beta-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 54:2393–2401. https://doi.org/10.1002/art.22023CrossRefPubMed

Al-Saadany HM, Hussein MS, Gaber RA, Zaytoun HA (2016) Th-17 cells and serum IL-17 in rheumatoid arthritis patients: correlation with disease activity and severity. Egypt Rheumatol 38:1–7. https://doi.org/10.1016/j.ejr.2015.01.001CrossRef

Alzabin S, Abraham SM, Taher TE et al (2012) Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. Ann Rheum Dis 71:1741–1748. https://doi.org/10.1136/annrheumdis-2011-201024CrossRefPubMed

Amarasekara DS, Yun H, Kim S et al (2018) Regulation of osteoclast differentiation by cytokine networks. Immune Netw 18:e8. https://doi.org/10.4110/in.2018.18.e8CrossRefPubMedPubMedCentral

Banerjee S, Biehl A, Gadina M et al (2017) JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs 77:521–546. https://doi.org/10.1007/s40265-017-0701-9CrossRefPubMedPubMedCentral

Bechman K, Subesinghe S, Norton S et al (2019) A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis. Rheumatol (Oxford) 58:1755–1766. https://doi.org/10.1093/rheumatology/kez087CrossRef

Begovich AB, Carlton VEH, Honigberg LA et al (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337. https://doi.org/10.1086/422827CrossRefPubMedPubMedCentral

Beringer A, Noack M, Miossec P (2016) IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med 22:230–241. https://doi.org/10.1016/j.molmed.2016.01.001CrossRefPubMed

Boyle DL, Soma K, Hodge J et al (2015) The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis 74:1311–1316. https://doi.org/10.1136/annrheumdis-2014-206028CrossRefPubMed

Brouwer E, Gouw ASH, Posthumus MD et al (2009) Hypoxia inducible factor-1-alpha (HIF-1alpha) is related to both angiogenesis and inflammation in rheumatoid arthritis. Clin Exp Rheumatol 27:945–951PubMed

Burmester GR, Durez P, Shestakova G et al (2016) Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis. Rheumatology 55:49–55. https://doi.org/10.1093/rheumatology/kev258CrossRefPubMed

Burmester GR, Kremer JM, Van den Bosch F et al (2018) Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391:2503–2512. https://doi.org/10.1016/S0140-6736(18)31115-2CrossRefPubMed

Chabaud M, Garnero P, Dayer JM et al (2000) Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. Cytokine 12:1092–1099. https://doi.org/10.1006/cyto.2000.0681CrossRefPubMed

Chandran B, Goel A (2012) A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res 26:1719–1725. https://doi.org/10.1002/ptr.4639CrossRefPubMed

Charbonneau M, Harper K, Grondin F et al (2007) Hypoxia-inducible factor mediates hypoxic and tumor necrosis factor alpha-induced increases in tumor necrosis factor-alpha converting enzyme/ADAM17 expression by synovial cells. J Biol Chem 282:33714–33724. https://doi.org/10.1074/jbc.M704041200CrossRefPubMed

Chen D-Y, Chen Y-M, Chen H-H et al (2011) Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy. Arthritis Res Ther 13:R126. https://doi.org/10.1186/ar3431CrossRefPubMedPubMedCentral

Choulaki C, Papadaki G, Repa A et al (2015) Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther 17:257. https://doi.org/10.1186/s13075-015-0775-2CrossRefPubMedPubMedCentral

Clark JD, Flanagan ME, Telliez J-B (2014) Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases: miniperspective. J Med Chem 57:5023–5038. https://doi.org/10.1021/jm401490pCrossRefPubMed

Cohen S, Radominski SC, Gomez-Reino JJ et al (2014a) Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis: all-cause mortality and infection rates in studies of tofacitinib. Arthritis Rheumatol 66:2924–2937. https://doi.org/10.1002/art.38779CrossRefPubMed

Cohen S, Radominski SC, Gomez-Reino JJ et al (2014b) Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol 66:2924–2937. https://doi.org/10.1002/art.38779CrossRefPubMed

Cohen SB, Tanaka Y, Mariette X et al (2017) Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis 76:1253–1262. https://doi.org/10.1136/annrheumdis-2016-210457CrossRefPubMedPubMedCentral

Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657CrossRef

D’Ignazio L, Bandarra D, Rocha S (2016) NF-κB and HIF crosstalk in immune responses. FEBS J 283:413–424. https://doi.org/10.1111/febs.13578CrossRefPubMed

Daha NA, Kurreeman FAS, Marques RB et al (2009) Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 60:1255–1260. https://doi.org/10.1002/art.24503CrossRefPubMed

Dai Q, Zhou D, Xu L, Song X (2018) Curcumin alleviates rheumatoid arthritis-induced inflammation and synovial hyperplasia by targeting mTOR pathway in rats. Drug Des Devel Ther 12:4095–4105. https://doi.org/10.2147/DDDT.S175763CrossRefPubMedPubMedCentral

de Aquino SG, Abdollahi-Roodsaz S, Koenders MI et al (2014) Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. J Immunol 192:4103–4111. https://doi.org/10.4049/jimmunol.1301970CrossRefPubMed

Dhaouadi T, Chahbi M, Haouami Y et al (2018) IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis. PLoS One 13:e0194883. https://doi.org/10.1371/journal.pone.0194883CrossRefPubMedPubMedCentral

Elhewala AE, Soliman S, Labib A et al (2015) Interleukin-17 level in rheumatoid arthritis patients and its relation to disease activity: a clinical and ultrasound study. Egypt Rheumatol Rehabil 42:183. https://doi.org/10.4103/1110-161X.168164CrossRef

Elshabrawy HA, Chen Z, Volin MV et al (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18:433–448. https://doi.org/10.1007/s10456-015-9477-2CrossRefPubMedPubMedCentral

Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665. https://doi.org/10.1056/NEJMra0910283CrossRefPubMedPubMedCentral

Ema M, Taya S, Yokotani N et al (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 94:4273–4278. https://doi.org/10.1073/pnas.94.9.4273CrossRefPubMedPubMedCentral

Fleischmann R, Wollenhaupt J, Takiya L et al (2017a) Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies. RMD Open 3:e000491. https://doi.org/10.1136/rmdopen-2017-000491CrossRefPubMedPubMedCentral

Fleischmann RM, Wagner F, Kivitz AJ et al (2017b) Safety, tolerability, and pharmacodynamics of ABT-122, a tumor necrosis factor- and interleukin-17-targeted dual variable domain immunoglobulin, in patients with rheumatoid arthritis. Arthritis Rheumatol 69:2283–2291. https://doi.org/10.1002/art.40319CrossRefPubMed

Fragoulis GE, McInnes IB, Siebert S (2019) JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology 58:i43–i54. https://doi.org/10.1093/rheumatology/key276CrossRefPubMed

Gadina M, Le MT, Schwartz DM et al (2019) Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology 58:i4–i16. https://doi.org/10.1093/rheumatology/key432CrossRefPubMed

Genovese MC, Durez P, Richards HB et al (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72:863–869. https://doi.org/10.1136/annrheumdis-2012-201601CrossRefPubMed

Genovese MC, Durez P, Richards HB et al (2014a) One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 41:414–421. https://doi.org/10.3899/jrheum.130637CrossRefPubMed

Genovese MC, Greenwald M, Cho C-S et al (2014b) A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors: ixekizumab in biologics-naive and TNF inadequate responder RA patients. Arthritis Rheumatol 66:1693–1704. https://doi.org/10.1002/art.38617CrossRefPubMed

Genovese MC, Weinblatt ME, Aelion JA et al (2018) ABT-122, a bispecific dual variable domain immunoglobulin targeting tumor necrosis factor and interleukin-17A, in patients with rheumatoid arthritis with an inadequate response to methotrexate: a randomized, double-blind study. Arthritis Rheumatol 70:1710–1720. https://doi.org/10.1002/art.40580CrossRefPubMedPubMedCentral

Genovese MC, Kalunian K, Gottenberg J-E et al (2019) Effect of filgotinib vs placebo on clinical response in patients with moderate to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy: the FINCH 2 randomized clinical trial. JAMA 322:315–325. https://doi.org/10.1001/jama.2019.9055CrossRefPubMedPubMedCentral

Genovese MC, Smolen JS, Takeuchi T et al (2020) Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol 2:e347–e357. https://doi.org/10.1016/S2665-9913(20)30032-1CrossRef

Glatt S, Taylor PC, McInnes IB et al (2019) Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: a proof-of-concept study. Ann Rheum Dis 78:1033–1040. https://doi.org/10.1136/annrheumdis-2018-214943CrossRefPubMedPubMedCentral

Göschl L, Müller L, Saferding V, et al (2018) P116 Histone deacetylase 1: a novel therapeutic target for patients with rheumatoid arthritis. Ann Rheum Dis 77:A63

Greer SN, Metcalf JL, Wang Y, Ohh M (2012) The updated biology of hypoxia-inducible factor. EMBO J 31:2448–2460. https://doi.org/10.1038/emboj.2012.125CrossRefPubMedPubMedCentral

Gullick NJ, Evans HG, Church LD et al (2010) Linking power doppler ultrasound to the presence of Th17 cells in the rheumatoid arthritis joint. PLoS One 5:e12516. https://doi.org/10.1371/journal.pone.0012516CrossRefPubMedPubMedCentral

Guo C, Fu R, Wang S et al (2018) NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin Exp Immunol 194:231–243. https://doi.org/10.1111/cei.13167CrossRefPubMedPubMedCentral

Ha M-K, Song YH, Jeong S-J et al (2011) Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic rheumatoid synoviocytes. Biol Pharm Bull 34:1432–1437. https://doi.org/10.1248/bpb.34.1432CrossRefPubMed

Hagen KB, Byfuglien MG, Falzon L et al (2009) Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD006400.pub2CrossRefPubMedPubMedCentral

Hamilton JL, Nagao M, Levine BR et al (2016) Targeting VEGF and Its receptors for the treatment of osteoarthritis and associated pain. J Bone Miner Res 31:911–924. https://doi.org/10.1002/jbmr.2828CrossRefPubMedPubMedCentral

Hardy W, Wright F, Hawtree S et al (2014) OP0296 hypoxia-inducible factor 2a regulates macrophage function in rheumatoid arthritis. Ann Rheum Dis 73:1742–2174. https://doi.org/10.1136/annrheumdis-2014-eular.4257CrossRef

Harigai M (2019) Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatol (Oxford) 58:i34–i42. https://doi.org/10.1093/rheumatology/key287CrossRef

Harrington LE, Hatton RD, Mangan PR et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132. https://doi.org/10.1038/ni1254CrossRefPubMed

Hitchon C, Wong K, Ma G et al (2002) Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 46:2587–2597. https://doi.org/10.1002/art.10520CrossRefPubMed

Hu C-J, Wang L-Y, Chodosh LA et al (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23:9361–9374. https://doi.org/10.1128/mcb.23.24.9361-9374.2003CrossRefPubMedPubMedCentral

Hu F, Mu R, Zhu J et al (2014) Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis. Ann Rheum Dis 73:928–936. https://doi.org/10.1136/annrheumdis-2012-202444CrossRefPubMed

Hu F, Liu H, Xu L et al (2016) Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis. Eur J Immunol 46:742–751. https://doi.org/10.1002/eji.201545784CrossRefPubMed

Hua S, Dias TH (2016) Hypoxia-inducible factor (HIF) as a target for novel therapies in rheumatoid arthritis. Front Pharmacol 7:184. https://doi.org/10.3389/fphar.2016.00184CrossRefPubMedPubMedCentral

Huang F, Luo Z-C (2018) Risk of adverse drug events observed with baricitinib 2 mg versus baricitinib 4 mg once daily for the treatment of rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. BioDrugs Clin Immunother Biopharm Gene Ther 32:415–423. https://doi.org/10.1007/s40259-018-0304-3CrossRef

Huang X, Pan Q, Mao Z et al (2018) Kaempferol inhibits interleukin-1β stimulated matrix metalloproteinases by suppressing the MAPK-associated ERK and P38 signaling pathways. Mol Med Rep 18:2697–2704. https://doi.org/10.3892/mmr.2018.9280CrossRefPubMedPubMedCentral

Hueber AJ, Asquith DL, Miller AM et al (2010) Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol 184:3336–3340. https://doi.org/10.4049/jimmunol.0903566CrossRefPubMed

Hwang J-K, Noh E-M, Moon S-J et al (2013) Emodin suppresses inflammatory responses and joint destruction in collagen-induced arthritic mice. Rheumatol (Oxford) 52:1583–1591. https://doi.org/10.1093/rheumatology/ket178CrossRef

Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345:105–120. https://doi.org/10.1007/82_2010_74CrossRefPubMedPubMedCentral

Islam MA, Alam F, Solayman M et al (2016) Dietary phytochemicals: natural swords combating inflammation and oxidation-mediated degenerative diseases. Oxid Med Cell Longev 2016:5137431. https://doi.org/10.1155/2016/5137431CrossRefPubMedPubMedCentral

Ivashkiv LB, Hu X (2003) The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arthritis Rheum 48:2092–2096. https://doi.org/10.1002/art.11095CrossRefPubMed

Iwakura Y, Ishigame H, Saijo S, Nakae S (2011) Functional specialization of interleukin-17 family members. Immunity 34:149–162. https://doi.org/10.1016/j.immuni.2011.02.012CrossRefPubMed

Joosten LAB, Abdollahi-Roodsaz S, Heuvelmans-Jacobs M et al (2008) T cell dependence of chronic destructive murine arthritis induced by repeated local activation of toll-like receptor–driven pathways: crucial role of both interleukin-1β and interleukin-17. Arthritis Rheum 58:98–108. https://doi.org/10.1002/art.23152CrossRefPubMed

Jorgensen I, Miao EA (2015) Pyroptotic cell death defends against intracellular pathogens. Immunol Rev 265:130–142. https://doi.org/10.1111/imr.12287CrossRefPubMedPubMedCentral

Kabbinavar F, Irl C, Zurlo A, Hurwitz H (2008) Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk. Oncology 75:215–223. https://doi.org/10.1159/000163850CrossRefPubMed

Kellner H (2013) Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskelet Dis 5:141–152. https://doi.org/10.1177/1759720X13485328CrossRefPubMedPubMedCentral

Kennedy A, Ng CT, Biniecka M et al (2010) Angiogenesis and blood vessel stability in inflammatory arthritis. Arthritis Rheum 62:711–721. https://doi.org/10.1002/art.27287CrossRefPubMed

Kerlan-Candon S, Combe B, Vincent R et al (2001) HLA-DRB1 gene transcripts in rheumatoid arthritis. Clin Exp Immunol 124:142–149CrossRef

Khojah HM, Ahmed S, Abdel-Rahman MS, Elhakeim EH (2018) Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. Clin Rheumatol 37:2035–2042. https://doi.org/10.1007/s10067-018-4080-8CrossRefPubMed

Kim SY, Choi YJ, Joung SM et al (2010) Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology 129:516–524. https://doi.org/10.1111/j.1365-2567.2009.03203.xCrossRefPubMedPubMedCentral

Kim GW, Lee NR, Pi RH et al (2015a) IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res 38:575–584. https://doi.org/10.1007/s12272-015-0569-8CrossRefPubMed

Kim H-R, Kim K-W, Kim B-M et al (2015b) The effect of vascular endothelial growth factor on osteoclastogenesis in rheumatoid arthritis. PLoS One 10:e0124909. https://doi.org/10.1371/journal.pone.0124909CrossRefPubMedPubMedCentral

Kim HW, Kwon Y-J, Park BW et al (2017) Differential expressions of NOD-like receptors and their associations with inflammatory responses in rheumatoid arthritis. Clin Exp Rheumatol 35:630–637PubMed

Kloesch B, Becker T, Dietersdorfer E et al (2013) Anti-inflammatory and apoptotic effects of the polyphenol curcumin on human fibroblast-like synoviocytes. Int Immunopharmacol 15:400–405. https://doi.org/10.1016/j.intimp.2013.01.003CrossRefPubMed

Koenders MI, van den Berg WB (2015) Novel therapeutic targets in rheumatoid arthritis. Trends Pharmacol Sci 36:189–195. https://doi.org/10.1016/j.tips.2015.02.001CrossRefPubMed

Konisti S, Kiriakidis S, Paleolog EM (2012) Hypoxia–a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat Rev Rheumatol 8:153–162. https://doi.org/10.1038/nrrheum.2011.205CrossRefPubMed

Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517. https://doi.org/10.1146/annurev.immunol.021908.132710CrossRefPubMed

Kubo S, Yamaoka K, Kondo M et al (2014) The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis 73:2192–2198. https://doi.org/10.1136/annrheumdis-2013-203756CrossRefPubMed

Kumar P, Banik S (2013) Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 6:35–43. https://doi.org/10.4137/CMAMD.S5558CrossRefPubMedPubMedCentral

Kummar S, Raffeld M, Juwara L et al (2011) Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin Cancer Res 17:5123–5131. https://doi.org/10.1158/1078-0432.CCR-11-0682CrossRefPubMedPubMedCentral

Kunwar S, Dahal K, Sharma S (2016) Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int 36:1065–1075. https://doi.org/10.1007/s00296-016-3480-9CrossRefPubMed

Lavocat F, Maggi L, Annunziato F, Miossec P (2016) T-cell clones from Th1, Th17 or Th1/17 lineages and their signature cytokines have different capacity to activate endothelial cells or synoviocytes. Cytokine 88:241–250. https://doi.org/10.1016/j.cyto.2016.09.019CrossRefPubMed

Lee H-S, Korman BD, Le JM et al (2009) Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum 60:364–371. https://doi.org/10.1002/art.24245CrossRefPubMedPubMedCentral

Lee EB, Fleischmann R, Hall S et al (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370:2377–2386. https://doi.org/10.1056/NEJMoa1310476CrossRefPubMed

Li J, Gang D, Yu X et al (2013a) Genistein: the potential for efficacy in rheumatoid arthritis. Clin Rheumatol 32:535–540. https://doi.org/10.1007/s10067-012-2148-4CrossRefPubMed

Li S, Yu Y, Yue Y et al (2013b) Microbial infection and rheumatoid arthritis. J Clin Cell Immunol. https://doi.org/10.4172/2155-9899.1000174CrossRefPubMedPubMedCentral

Li A-N, Li S, Zhang Y-J et al (2014) Resources and biological activities of natural polyphenols. Nutrients 6:6020–6047. https://doi.org/10.3390/nu6126020CrossRefPubMedPubMedCentral

Li G, Qin Y, Du P (2015) Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling. Life Sci 136:67–72. https://doi.org/10.1016/j.lfs.2015.06.019CrossRefPubMed

Li S, Yin H, Zhang K et al (2017) Effector T helper cell populations are elevated in the bone marrow of rheumatoid arthritis patients and correlate with disease severity. Sci Rep 7:4776. https://doi.org/10.1038/s41598-017-05014-8CrossRefPubMedPubMedCentral

Lu J, Kasama T, Kobayashi K et al (2000) Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol 164:5922–5927. https://doi.org/10.4049/jimmunol.164.11.5922CrossRefPubMed

Lubberts E, Joosten LA, Oppers B et al (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167:1004–1013CrossRef

Ma X, Xu S (2013) TNF inhibitor therapy for rheumatoid arthritis. Biomed Rep 1:177–184. https://doi.org/10.3892/br.2012.42CrossRefPubMed

Malemud CJ (2013) Intracellular signaling pathways in rheumatoid arthritis. J Clin Cell Immunol 4:160. https://doi.org/10.4172/2155-9899.1000160CrossRefPubMedPubMedCentral

Malmström V, Catrina AI, Klareskog L (2017) The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol 17:60–75. https://doi.org/10.1038/nri.2016.124CrossRefPubMed

Mangan MSJ, Olhava EJ, Roush WR et al (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 17:588CrossRef

Marrelli A, Cipriani P, Liakouli V et al (2011) Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? Autoimmun Rev 10:595–598. https://doi.org/10.1016/j.autrev.2011.04.020CrossRefPubMed

McAllister MJ, Chemaly M, Eakin AJ et al (2018) NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis Cartilage 26:612–619. https://doi.org/10.1016/j.joca.2018.02.901CrossRefPubMed

McInnes IB, Kavanaugh A, Gottlieb AB et al (2013) Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382:780–789. https://doi.org/10.1016/S0140-6736(13)60594-2CrossRefPubMed

Metawi SA, Abbas D, Kamal MM, Ibrahim MK (2011) Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol 30:1201–1207. https://doi.org/10.1007/s10067-011-1737-yCrossRefPubMed

Mileo AM, Nisticò P, Miccadei S (2019) Polyphenols: immunomodulatory and therapeutic implication in colorectal cancer. Front Immunol. https://doi.org/10.3389/fimmu.2019.00729CrossRefPubMedPubMedCentral

Moran EM, Mullan R, McCormick J et al (2009) Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-α, Oncostatin M and response to biologic therapies. Arthritis Res Ther 11:R113. https://doi.org/10.1186/ar2772CrossRefPubMedPubMedCentral

Moreland LW, Baumgartner SW, Schiff MH et al (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141–147. https://doi.org/10.1056/NEJM199707173370301CrossRefPubMed

Moreland LW, O’Dell JR, Paulus HE et al (2012) A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of early aggressive rheumatoid arthritis trial. Arthritis Rheum 64:2824–2835. https://doi.org/10.1002/art.34498CrossRefPubMedPubMedCentral

Morinobu A (2020) JAK inhibitors for the treatment of rheumatoid arthritis. Immunol Med. https://doi.org/10.1080/25785826.2020.1770948CrossRefPubMed

Mueller H, Popp, et al (2019) Effectiveness, tolerability, and safety of tofacitinib in rheumatoid arthritis: a retrospective analysis of real-world data from the St Gallen and Aarau cohorts. J Clin Med 8:1548. https://doi.org/10.3390/jcm8101548CrossRefPubMedCentral

Nakagawa M, Kaneda T, Arakawa T et al (2000) Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett 473:161–164CrossRef

Ndongo-Thiam N, Clement A, Pin J-J et al (2016) Negative association between autoantibodies against IL-17, IL-17/anti-IL-17 antibody immune complexes and destruction in rheumatoid arthritis. Ann Rheum Dis 75:1420–1422. https://doi.org/10.1136/annrheumdis-2016-209149CrossRefPubMed

O’Shea JJ, Kontzias A, Yamaoka K et al (2013) Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 72:ii111–ii115. https://doi.org/10.1136/annrheumdis-2012-202576CrossRefPubMedPubMedCentral

Olivera PA, Lasa JS, Bonovas S et al (2020) Safety of Janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis. Gastroenterology 158:1554–1573.e12. https://doi.org/10.1053/j.gastro.2020.01.001CrossRefPubMed

Oliviero F, Scanu A, Zamudio-Cuevas Y et al (2018) Anti-inflammatory effects of polyphenols in arthritis. J Sci Food Agric 98:1653–1659. https://doi.org/10.1002/jsfa.8664CrossRefPubMed

Orr C, Vieira-Sousa E, Boyle DL et al (2017) Synovial tissue research: a state-of-the-art review. Nat Rev Rheumatol 13:463–475. https://doi.org/10.1038/nrrheum.2017.115CrossRefPubMed

Paek SY, Frieder J, Kivelevitch D, Menter MA (2018) IL-17 inhibitors for psoriasis. Semin Cutan Med Surg 37:148–157. https://doi.org/10.12788/j.sder.2018.051CrossRefPubMed

Pavelka K, Chon Y, Newmark R et al (2015) A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J Rheumatol 42:912–919. https://doi.org/10.3899/jrheum.141271CrossRefPubMed

Phillips RM (2016) Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother Pharmacol 77:441–457. https://doi.org/10.1007/s00280-015-2920-7CrossRefPubMedPubMedCentral

Rajaei E, Mowla K, Ghorbani A et al (2015) The effect of omega-3 fatty acids in patients with active rheumatoid arthritis receiving dmards therapy: double-blind randomized controlled trial. Glob J Health Sci 8:18–25. https://doi.org/10.5539/gjhs.v8n7p18CrossRefPubMedPubMedCentral

Ramadan G, Al-Kahtani MA, El-Sayed WM (2011) Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officinale (ginger) rhizomes in rat adjuvant-induced arthritis. Inflammation 34:291–301. https://doi.org/10.1007/s10753-010-9278-0CrossRefPubMed

Rapisarda A, Uranchimeg B, Scudiero DA et al (2002) Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res 62:4316–4324PubMed

Rathore B, Ali Mahdi A, Nath Paul B et al (2007) Indian herbal medicines: possible potent therapeutic agents for rheumatoid arthritis. J Clin Biochem Nutr 41:12–17. https://doi.org/10.3164/jcbn.2007002CrossRefPubMedPubMedCentral

Reardon S (2014) Microbiome therapy gains market traction. Nature 509:269–270. https://doi.org/10.1038/509269aCrossRefPubMed

Reich K, Puig L, Paul C et al (2014) One-year safety and efficacy of ustekinumab and results of dose adjustment after switching from inadequate methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe plaque psoriasis. Br J Dermatol 170:435–444. https://doi.org/10.1111/bjd.12643CrossRefPubMed

Remmers EF, Plenge RM, Lee AT et al (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357:977–986. https://doi.org/10.1056/NEJMoa073003CrossRefPubMedPubMedCentral

Reoma LB, Trindade CJ, Monaco MC et al (2019) Fatal encephalopathy with wild-type JC virus and ruxolitinib therapy. Ann Neurol 86:878–884. https://doi.org/10.1002/ana.25608CrossRefPubMed

Rider P, Carmi Y, Cohen I (2016) Biologics for targeting inflammatory cytokines, clinical uses, and limitations. Int J Cell Biol 2016:9259646. https://doi.org/10.1155/2016/9259646CrossRefPubMedPubMedCentral

Rivellese F, Lobasso A, Barbieri L et al (2018) Novel therapeutic approaches in rheumatoid arthritis: role of Janus kinases inhibitors. Curr Med Chem. https://doi.org/10.2174/0929867325666180209145243CrossRef

Rizzi M, Lorenzetti R, Fischer K et al (2017) Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J Autoimmun 77:55–66. https://doi.org/10.1016/j.jaut.2016.10.005CrossRefPubMed

Robert M, Miossec P (2019) IL-17 in rheumatoid arthritis and precision medicine: from synovitis expression to circulating bioactive levels. Front Med. https://doi.org/10.3389/fmed.2018.00364CrossRef

Rosillo MÁ, Alcaraz MJ, Sánchez-Hidalgo M et al (2014) Anti-inflammatory and joint protective effects of extra-virgin olive-oil polyphenol extract in experimental arthritis. J Nutr Biochem 25:1275–1281. https://doi.org/10.1016/j.jnutbio.2014.07.006CrossRefPubMed

Ross E, Smallie T, Naylor A et al (2015) A8.1 Tristetraprolin is a novel therapeutic target for rheumatoid arthritis. Ann Rheum Dis 74:A81.1–A81. https://doi.org/10.1136/annrheumdis-2015-207259.186CrossRef

Rudan I, Sidhu S, Papana A et al (2015) Prevalence of rheumatoid arthritis in low- and middle-income countries: a systematic review and analysis. J Glob Health 5:010409. https://doi.org/10.7189/jogh.05.010409CrossRefPubMedPubMedCentral

Ruscitti P, Cipriani P, Di Benedetto P et al (2015) Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol 182:35–44. https://doi.org/10.1111/cei.12667CrossRefPubMedPubMedCentral

Ryu J-H, Chae C-S, Kwak J-S et al (2014) Hypoxia-inducible factor-2α is an essential catabolic regulator of inflammatory rheumatoid arthritis. PLoS Biol 12:e1001881. https://doi.org/10.1371/journal.pbio.1001881CrossRefPubMedPubMedCentral

Santangelo C, Vari R, Scazzocchio B et al (2017) Anti-inflammatory activity of extra virgin olive oil polyphenols: which role in the prevention and treatment of immune-mediated inflammatory diseases? Endocr Metab Immune Disord Drug Targets. https://doi.org/10.2174/1871530317666171114114321CrossRef

Sarkar A, Tripathi VD, Sahu RK (2017) Anti-inflammatory and anti-arthritis activity of flavonoids fractions isolated from Centipeda minima leaves extracts in rats. Clin Exp Pharmacol. https://doi.org/10.4172/2161-1459.1000231CrossRef

Schulze-Koops H, Strand V, Nduaka C et al (2017) Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Rheumatology 56:46–57. https://doi.org/10.1093/rheumatology/kew329CrossRefPubMed

Schwartz DM, Kanno Y, Villarino A et al (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 16:843CrossRef

Schwartz DM, Kanno Y, Villarino A et al (2018) Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78–78. https://doi.org/10.1038/nrd.2017.267CrossRef

Shankar J, Thippegowda PB, Kanum SA (2009) Inhibition of HIF-1alpha activity by BP-1 ameliorates adjuvant induced arthritis in rats. Biochem Biophys Res Commun 387:223–228. https://doi.org/10.1016/j.bbrc.2009.01.086CrossRefPubMed

Shen H-H, Yang Y-X, Meng X et al (2018) NLRP3: a promising therapeutic target for autoimmune diseases. Autoimmun Rev 17:694–702. https://doi.org/10.1016/j.autrev.2018.01.020CrossRefPubMed

Siloşi I, Boldeanu MV, Cojocaru M et al (2016) The relationship of cytokines IL-13 and IL-17 with autoantibodies profile in early rheumatoid arthritis. J Immunol Res 2016:3109135. https://doi.org/10.1155/2016/3109135CrossRefPubMedPubMedCentral

Singh AK, Umar S, Riegsecker S et al (2016) Regulation of transforming growth factor β-activated kinase activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts: suppression of K(63)-linked autoubiquitination of tumor necrosis factor receptor-associated factor 6. Arthritis Rheumatol 68:347–358. https://doi.org/10.1002/art.39447CrossRefPubMedPubMedCentral

Smolen JS, Genovese MC, Takeuchi T et al (2019) Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 46:7–18. https://doi.org/10.3899/jrheum.171361CrossRefPubMed

Soeken KL, Miller SA, Ernst E (2003) Herbal medicines for the treatment of rheumatoid arthritis: a systematic review. Rheumatol (Oxford) 42:652–659. https://doi.org/10.1093/rheumatology/keg183CrossRef

Strietholt S, Maurer B, Peters MA et al (2008) Epigenetic modifications in rheumatoid arthritis. Arthritis Res Ther 10:219. https://doi.org/10.1186/ar2500CrossRefPubMedPubMedCentral

Su L-C, Huang A-F, Jia H et al (2017) Role of microRNA-155 in rheumatoid arthritis. Int J Rheum Dis 20:1631–1637. https://doi.org/10.1111/1756-185X.13202CrossRefPubMed

Taams LS (2020) Interleukin-17 in rheumatoid arthritis: trials and tribulations. J Exp Med 217:e20192048. https://doi.org/10.1084/jem.20192048CrossRefPubMedPubMedCentral

Tanaka Y, McInnes IB, Taylor PC et al (2018) Characterization and changes of lymphocyte subsets in baricitinib-treated patients with rheumatoid arthritis: an integrated analysis. Arthritis Rheumatol 70:1923–1932. https://doi.org/10.1002/art.40680CrossRefPubMedPubMedCentral

Taylor PC, Sivakumar B (2005) Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol 17:293–298CrossRef

Taylor PC, Weinblatt ME, Burmester GR et al (2019) Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol 71:1042–1055. https://doi.org/10.1002/art.40841CrossRefPubMedPubMedCentral

Tian J, Chen J, Gao J et al (2013) Resveratrol inhibits TNF-α-induced IL-1β, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatol Int 33:1829–1835. https://doi.org/10.1007/s00296-012-2657-0CrossRefPubMed

Tobón GJ, Youinou P, Saraux A (2010) The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. J Autoimmun 35:10–14. https://doi.org/10.1016/j.jaut.2009.12.009CrossRefPubMed

van Vollenhoven RF (2009) Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med 7:12. https://doi.org/10.1186/1741-7015-7-12CrossRefPubMedPubMedCentral

van Vollenhoven R, Choy E, Lee EB et al (2016) THU0199 tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: changes in lymphocytes and lymphocyte subset counts and reversibility after up to 8 years of tofacitinib treatment. Ann Rheum Dis 75:1–258. https://doi.org/10.1136/annrheumdis-2016-eular.2134CrossRef

van Vollenhoven R, Lee EB, Strengholt S et al (2019) Evaluation of the short-, mid-, and long-term effects of tofacitinib on lymphocytes in patients with rheumatoid arthritis. Arthritis Rheumatol 71:685–695. https://doi.org/10.1002/art.40780CrossRefPubMedPubMedCentral

Walker JG, Smith MD (2005) The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 32:1650–1653PubMed

Wang J, Zhang Q, Jin S et al (2008) Genistein modulate immune responses in collagen-induced rheumatoid arthritis model. Maturitas 59:405–412. https://doi.org/10.1016/j.maturitas.2008.04.003CrossRefPubMed

Warnecke C, Zaborowska Z, Kurreck J et al (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J 18:1462–1464. https://doi.org/10.1096/fj.04-1640fjeCrossRefPubMed

Wei M, Duan D (2016) Efficacy and safety of monoclonal antibodies targeting interleukin-17 pathway for inflammatory arthritis: a meta-analysis of randomized controlled clinical trials. Drug Des Devel Ther 10:2771–2777. https://doi.org/10.2147/DDDT.S91374CrossRefPubMedPubMedCentral

Westra J, Brouwer E, van Roosmalen IAM et al (2010) Expression and regulation of HIF-1alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. BMC Musculoskelet Disord 11:61. https://doi.org/10.1186/1471-2474-11-61CrossRefPubMedPubMedCentral

Wiens A, Correr CJ, Venson R et al (2010) A systematic review and meta-analysis of the efficacy and safety of adalimumab for treating rheumatoid arthritis. Rheumatol Int 30:1063–1070. https://doi.org/10.1007/s00296-009-1111-4CrossRefPubMed

Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169. https://doi.org/10.1016/j.pharmthera.2016.04.009CrossRefPubMed

Winthrop KL (2017) The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol 13:234–243. https://doi.org/10.1038/nrrheum.2017.23CrossRefPubMed

Winthrop KL, Park S-H, Gul A et al (2016) Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis 75:1133–1138. https://doi.org/10.1136/annrheumdis-2015-207319CrossRefPubMed

Wolfe AM, Kellgren JH, Masi AT (1968) The epidemiology of rheumatoid arthritis: a review. II. Incidence and diagnostic criteria. Bull Rheum Dis 19:524–529PubMed

Wollenhaupt J, Silverfield J, Lee EB et al (2014) Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol 41:837–852. https://doi.org/10.3899/jrheum.130683CrossRefPubMed

Wollenhaupt J, Lee E-B, Curtis JR et al (2019) Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther 21:89. https://doi.org/10.1186/s13075-019-1866-2CrossRefPubMedPubMedCentral

Xie W, Huang Y, Xiao S et al (2019a) Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 78:1048–1054. https://doi.org/10.1136/annrheumdis-2018-214846CrossRefPubMed

Xie W, Xiao S, Huang Y et al (2019b) Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials. Ther Adv Musculoskelet Dis. https://doi.org/10.1177/1759720X19895492CrossRefPubMedPubMedCentral

Xuzhu G, Komai-Koma M, Leung BP et al (2012) Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 71:129–135. https://doi.org/10.1136/ard.2011.149831CrossRefPubMed

Yao Z, Painter SL, Fanslow WC et al (1995) Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483–5486PubMed

Yoon H-Y, Lee E-G, Lee H et al (2013) Kaempferol inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. Int J Mol Med 32:971–977. https://doi.org/10.3892/ijmm.2013.1468CrossRefPubMed

Zhang Y, Zheng Y, Li H (2016) NLRP3 inflammasome plays an important role in the pathogenesis of collagen-induced arthritis. Mediators Inflamm 2016:9656270. https://doi.org/10.1155/2016/9656270CrossRefPubMedPubMedCentral

Zheng Z, Sun Y, Liu Z et al (2015) The effect of curcumin and its nanoformulation on adjuvant-induced arthritis in rats. Drug Des Devel Ther 9:4931–4942. https://doi.org/10.2147/DDDT.S90147CrossRefPubMedPubMedCentral

Zhu M, Yuan K, Lu Q et al (2019) Emodin ameliorates rheumatoid arthritis by promoting neutrophil apoptosis and inhibiting neutrophil extracellular trap formation. Mol Immunol 112:188–197. https://doi.org/10.1016/j.molimm.2019.05.010CrossRefPubMed

At a glance: The STEP trials

Springer Medicine

Current and novel therapeutic targets in the treatment of rheumatoid arthritis

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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