Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 4/2017

Open Access 01-06-2017 | Review

Future therapeutic targets in rheumatoid arthritis?

Authors: Tommy Tsang Cheung, Iain B. McInnes

Published in: Seminars in Immunopathology | Issue 4/2017

Login to get access

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton’s tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches.
Literature
1.
Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC (2003) Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107(9):1303–1307PubMedCrossRef
2.
Semb AG, Kvien TK, Aastveit AH, Jungner I, Pedersen TR, Walldius G, Holme I (2010) Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) study. Ann Rheum Dis 69(11):1996–2001PubMedCrossRef
3.
Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, McInnes IB, Haentzschel H, Gonzalez-Gay MA, Provan S, Semb A, Sidiropoulos P, Kitas G, Smulders YM, Soubrier M, Szekanecz Z, Sattar N, Nurmohamed MT (2010) EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 69(2):325–331PubMedCrossRef
4.
Meune C, Touze E, Trinquart L, Allanore Y (2009) Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford) 48(10):1309–1313CrossRef
5.
Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59(12):1690–1697PubMedCrossRef
6.
Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, Coster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapaa-Dahlqvist S, Saxne T, Klareskog L (2005) Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 64(10):1421–1426PubMedPubMedCentralCrossRef
7.
Geborek P, Bladstrom A, Turesson C, Gulfe A, Petersson IF, Saxne T, Olsson H, Jacobsson LT (2005) Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 64(5):699–703PubMedPubMedCentralCrossRef
8.
Thomas E, Brewster DH, Black RJ, Macfarlane GJ (2000) Risk of malignancy among patients with rheumatic conditions. Int J Cancer 88(3):497–502PubMedCrossRef
9.
Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compan MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin-Mola E, Nash P, Ostergaard M, Ostor A, Richards P, Sokka-Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15PubMedCrossRef
10.
van Eijk IC, Nielen MM, van der Horst-Bruinsma I, Tijhuis GJ, Boers M, Dijkmans BA, van Schaardenburg D (2012) Aggressive therapy in patients with early arthritis results in similar outcome compared with conventional care: the STREAM randomized trial. Rheumatology (Oxford) 51(4):686–694CrossRef
11.
Schipper LG, Vermeer M, Kuper HH, Hoekstra MO, Haagsma CJ, Den Broeder AA, van Riel P, Fransen J, van de Laar MA (2012) A tight control treatment strategy aiming for remission in early rheumatoid arthritis is more effective than usual care treatment in daily clinical practice: a study of two cohorts in the Dutch Rheumatoid Arthritis Monitoring registry. Ann Rheum Dis 71(6):845–850PubMedCrossRef
12.
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Kerstens PJ, Nielen MM, Vos K, van Schaardenburg D, Speyer I, Seys PE, Breedveld FC, Allaart CF, Dijkmans BA (2010) DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis. Ann Rheum Dis 69(1):65–69PubMedCrossRef
13.
Soubrier M, Lukas C, Sibilia J, Fautrel B, Roux F, Gossec L, Patternotte S, Dougados M (2011) Disease activity score-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis: data from the GUEPARD trial and ESPOIR cohort. Ann Rheum Dis 70(4):611–615PubMedPubMedCentralCrossRef
14.
Gullick NJ, Oakley SP, Zain A, Gibson T, Jones T, Mistlin A, Rees JD, Panayi GS, Kirkham BW (2012) Goal-directed therapy for RA in routine practice is associated with improved function in patients with disease duration up to 15 years. Rheumatology (Oxford) 51(4):759–761CrossRef
15.
Brenol CV, da Chakr RM, Andrade NP, Toni M, Laurindo IM, Brenol JC, Xavier RM (2015) Daily practice feasibility and effectiveness of treating long-standing rheumatoid arthritis to target with synthetic disease-modifying antirheumatic drugs: a prospective cohort study. Clin Rheumatol 34(10):1781–1785PubMedCrossRef
16.
Thiele K, Huscher D, Bischoff S, Spathling-Mestekemper S, Backhaus M, Aringer M, Kohlmann T, Zink A, German Collaborative Arthritis (2013) Performance of the 2011 ACR/EULAR preliminary remission criteria compared with DAS28 remission in unselected patients with rheumatoid arthritis. Ann Rheum Dis 72(7):1194–1199PubMedCrossRef
17.
Provan SA, Semb AG, Hisdal J, Stranden E, Agewall S, Dagfinrud H, Angel K, Atar D, Kvien TK (2011) Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study. Ann Rheum Dis 70(5):812–817PubMedCrossRef
18.
Pavelka K, Chon Y, Newmark R, Lin SL, Baumgartner S, Erondu N (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(6):912–919PubMedCrossRef
19.
Genovese MC, Braun DK, Erickson JS, Berclaz PY, Banerjee S, Heffernan MP, Carlier H (2016) Safety and efficacy of open-label subcutaneous ixekizumab treatment for 48 weeks in a phase II study in biologic-naive and TNF-IR patients with rheumatoid arthritis. J Rheumatol 43(2):289–297PubMedCrossRef
20.
Genovese MC, Greenwald M, Cho CS, Berman A, Jin L, Cameron GS, Benichou O, Xie L, Braun D, Berclaz PY, Banerjee S (2014) 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. Arthritis & Rheumatology 66(7):1693–1704CrossRef
21.
Blanco FJ, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M, Rohrer S, Richards H. (2017) Secukinumab in active rheumatoid arthritis: a randomized, double-blind placebo and active comparator controlled phase 3 study. Arthritis Rheumatol. doi:0.1002/art.40070
22.
Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Aelion JA, Lee SH, Codding CE, Kellner H, Ikawa T, Hugot S, Ligozio G, Mpofu S (2014) 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(3):414–421PubMedCrossRef
23.
Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, Aelion JA, Lee SH, Codding CE, Kellner H, Ikawa T, Hugot S, Mpofu S (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(6):863–869PubMedCrossRef
24.
Senolt L, Leszczynski P, Dokoupilova E, Gothberg M, Valencia X, Hansen BB, Canete JD (2015) Efficacy and safety of anti-interleukin-20 monoclonal antibody in patients with rheumatoid arthritis: a randomized phase IIa trial. Arthritis & Rheumatology 67(6):1438–1448CrossRef
25.
Bussolino F, Wang JM, Defilippi P, Turrini F, Sanavio F, Edgell CJ, Aglietta M, Arese P, Mantovani A (1989) Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 337(6206):471–473PubMedCrossRef
26.
Leizer T, Cebon J, Layton JE, Hamilton JA (1990) Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. Blood 76(10):1989–1996PubMed
27.
Campbell IK, Novak U, Cebon J, Layton JE, Hamilton JA (1991) Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J Immunol 147(4):1238–1246PubMed
28.
Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8(7):533–544PubMedCrossRef
29.
Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW (2008) The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134(3):496–507PubMedCrossRef
30.
Jenkins BJ, Blake TJ, Gonda TJ (1998) Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation. Blood 92(6):1989–2002PubMed
31.
Sato N, Sakamaki K, Terada N, Arai K, Miyajima A (1993) Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J 12(11):4181–4189PubMedPubMedCentral
32.
Fleetwood AJ, Cook AD, Hamilton JA (2005) Functions of granulocyte-macrophage colony-stimulating factor. Crit Rev Immunol 25(5):405–428PubMedCrossRef
33.
Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD (2007) Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178(8):5245–5252PubMedCrossRef
34.
Xu Y, Zhan Y, Lew AM, Naik SH, Kershaw MH (2007) Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol 179(11):7577–7584PubMedCrossRef
35.
Gilliet M, Boonstra A, Paturel C, Antonenko S, Xu XL, Trinchieri G, O’Garra A, Liu YJ (2002) The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J Exp Med 195(7):953–958PubMedPubMedCentralCrossRef
36.
Li BZ, Ye QL, Xu WD, Li JH, Ye DQ, Xu Y (2013) GM-CSF alters dendritic cells in autoimmune diseases. Autoimmunity 46(7):409–418PubMedCrossRef
37.
Conti L, Gessani S (2008) GM-CSF in the generation of dendritic cells from human blood monocyte precursors: recent advances. Immunobiology 213(9–10):859–870PubMedCrossRef
38.
Lebre MC, Tak PP (2008) Dendritic cell subsets: their roles in rheumatoid arthritis. Acta reumatologica portuguesa 33(1):35–45PubMed
39.
Bell AL, Magill MK, McKane WR, Kirk F, Irvine AE (1995) Measurement of colony-stimulating factors in synovial fluid: potential clinical value. Rheumatol Int 14(5):177–182PubMedCrossRef
40.
Field M, Clinton L (1993) Expression of GM-CSF receptor in rheumatoid arthritis. Lancet 342(8881):1244PubMedCrossRef
41.
Berenbaum F, Rajzbaum G, Amor B, Toubert A (1994) Evidence for GM-CSF receptor expression in synovial tissue. An analysis by semi-quantitative polymerase chain reaction on rheumatoid arthritis and osteoarthritis synovial biopsies. Eur Cytokine Netw 5(1):43–46PubMed
42.
Jang J, Lim DS, Choi YE, Jeong Y, Yoo SA, Kim WU, Bae YS (2006) MLN51 and GM-CSF involvement in the proliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. Arthritis Research & Therapy 8(6):R170CrossRef
43.
Torchinsky MB, Garaude J, Martin AP, Blander JM (2009) Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation. Nature 458(7234):78–82PubMedCrossRef
44.
MacDonald KP, Pettit AR, Quinn C, Thomas GJ, Thomas R (1999) Resistance of rheumatoid synovial dendritic cells to the immunosuppressive effects of IL-10. J Immunol 163(10):5599–5607PubMed
45.
Radstake TR, van Lent PL, Pesman GJ, Blom AB, Sweep FG, Ronnelid J, Adema GJ, Barrera P, van den Berg WB (2004) High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon FcgammaR triggering. Ann Rheum Dis 63(6):696–702PubMedPubMedCentralCrossRef
46.
Tsark EC, Wang W, Teng YC, Arkfeld D, Dodge GR, Kovats S (2002) Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. J Immunol 169(11):6625–6633PubMedCrossRef
47.
Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA (2001) Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res 3(5):293–298PubMedPubMedCentralCrossRef
48.
Cornish AL, Campbell IK, McKenzie BS, Chatfield S, Wicks IP (2009) G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol 5(10):554–559PubMedCrossRef
49.
Avci AB, Feist E, Burmester GR (2016) Targeting GM-CSF in rheumatoid arthritis. Clin Exp Rheumatol 34(4 Suppl 98):39–44PubMed
50.
Burmester GR, Weinblatt ME, McInnes IB, Porter D, Barbarash O, Vatutin M, Szombati I, Esfandiari E, Sleeman MA, Kane CD, Cavet G, Wang B, Godwood A, Magrini F, E.S. Group (2013) Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann Rheum Dis 72(9):1445–1452PubMedCrossRef
51.
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314PubMedPubMedCentralCrossRef
52.
53.
Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063PubMedCrossRef
54.
Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117(Pt 8):1281–1283PubMedCrossRef
55.
56.
Shuai K, Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3(11):900–911PubMedCrossRef
57.
Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O'Shea JJ (2005) Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev 203:127–142PubMedCrossRef
58.
Feist E, Burmester GR (2013) Small molecules targeting JAKs—a new approach in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 52(8):1352–1357CrossRef
59.
Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, Koncz T, Krishnaswami S, Wallenstein GV, Zang C, Zwillich SH, van Vollenhoven RF, Investigators OS (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370(25):2377–2386PubMedCrossRef
60.
van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, Cardiel MH, Cohen S, Nash P, Song YW, Tegzova D, Wyman BT, Gruben D, Benda B, Wallenstein G, Krishnaswami S, Zwillich SH, Bradley JD, Connell CA, Investigators OS (2013) Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 65(3):559–570PubMedCrossRef
61.
Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Soma K, Bradley J, Mebus C, O.S. investigators (2013) Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 381(9865):451–460PubMedCrossRef
62.
van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, Forejtova S, Zwillich SH, Gruben D, Koncz T, Wallenstein GV, Krishnaswami S, Bradley JD, Wilkinson B, Investigators OS (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367(6):508–519PubMedCrossRef
63.
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS, Investigators OS (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367(6):495–507PubMedCrossRef
64.
Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, Isaacs JD, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Riese R, Bradley J (2013) Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 159(4):253–261PubMedCrossRef
65.
Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, Kawabata T, Riese R (2014) Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis & Rheumatology 66(10):2675–2684CrossRef
66.
Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P (2017) Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 76(1):88–95PubMedCrossRef
67.
Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS (2016) Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 374(13):1243–1252PubMedCrossRef
68.
Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CA, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo WL, Rooney T, Macias W, Takeuchi T (2016) Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 69(3):506–517CrossRef
69.
Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich C, Rooney T, Schlichting D, Macias WL, de Bono S, Tanaka Y (2017) Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 376(7):652–662PubMedCrossRef
70.
Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P (2016) Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. doi:10.​1136/​annrheumdis-2016-210104
71.
Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, Greenwald M, Van der Aa A,Vanhoutte F,Tasset C,Harrison P (2016) Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. 10.​1136/​annrheumdis-2016-210105
72.
Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S (2016) Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis & rheumatology 68(12):2857–2866CrossRef
73.
Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S, Keystone EC (2016) A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy. Arthritis & rheumatology 68(12):2867–2877CrossRef
74.
Satterthwaite AB, Li Z, Witte ON (1998) Btk function in B cell development and response. Semin Immunol 10(4):309–316PubMedCrossRef
75.
76.
Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, Christensson B, Berglof A, Vihinen M, Nore BF, Smith CI (2009) Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 228(1):58–73PubMedCrossRef
77.
Khan WN (2001) Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol Res 23(2–3):147–156PubMedCrossRef
78.
Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S et al (1993) Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72(2):279–290PubMedCrossRef
79.
Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG et al (1993) Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science 261(5119):358–361PubMedCrossRef
80.
Mukhopadhyay S, Mohanty M, Mangla A, George A, Bal V, Rath S, Ravindran B (2002) Macrophage effector functions controlled by Bruton’s tyrosine kinase are more crucial than the cytokine balance of T cell responses for microfilarial clearance. J Immunol 168(6):2914–2921PubMedCrossRef
81.
Mukhopadhyay S, George A, Bal V, Ravindran B, Rath S (1999) Bruton’s tyrosine kinase deficiency in macrophages inhibits nitric oxide generation leading to enhancement of IL-12 induction. J Immunol 163(4):1786–1792PubMed
82.
83.
Kleinau S, Martinsson P, Heyman B (2000) Induction and suppression of collagen-induced arthritis is dependent on distinct fcgamma receptors. J Exp Med 191(9):1611–1616PubMedPubMedCentralCrossRef
84.
Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT, Witowski SR, Lounsbury H, Chaturvedi P, Mazdiyasni H, Zhu Z, Nacht M, Freed MI, Petter RC, Dubrovskiy A, Singh J, Westlin WF (2013) Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther 346(2):219–228PubMedCrossRef
85.
Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT (2007) Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem 2(1):58–61PubMedCrossRef
86.
Norman P (2016) Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 25(8):891–899PubMedCrossRef
87.
88.
Foster FM, Traer CJ, Abraham SM, Fry MJ (2003) The phosphoinositide (PI) 3-kinase family. J Cell Sci 116(Pt 15):3037–3040PubMedCrossRef
89.
Okkenhaug K, Vanhaesebroeck B (2003) PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 3(4):317–330PubMedCrossRef
90.
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031–1034PubMed
91.
Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B (2006) The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 177(8):5122–5128PubMedCrossRef
92.
Nashed BF, Zhang T, Al-Alwan M, Srinivasan G, Halayko AJ, Okkenhaug K, Vanhaesebroeck B, Hayglass KT, Marshall AJ (2007) Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation. Eur J Immunol 37(2):416–424PubMedCrossRef
93.
Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, Rowan WC, Sancho S, Walker LS, Vanhaesebroeck B, Okkenhaug K (2006) Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 177(10):6598–6602PubMedCrossRef
94.
Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, Vanhaesebroeck B (2006) Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107(2):642–650PubMedCrossRef
95.
Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, Wang D, Ihle JN (2002) Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 22(24):8580–8591PubMedPubMedCentralCrossRef
96.
Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE, Okkenhaug K (2010) The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal 3(134):ra60PubMedPubMedCentralCrossRef
97.
Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196(6):753–763PubMedPubMedCentralCrossRef
98.
Thomas MS, Mitchell JS, DeNucci CC, Martin AL, Shimizu Y (2008) The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites. J Leukoc Biol 84(3):814–823PubMedPubMedCentralCrossRef
99.
Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG (2004) Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173(4):2236–2240PubMedCrossRef
100.
Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287(5455):1046–1049PubMedCrossRef
101.
Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287(5455):1049–1053PubMedCrossRef
102.
Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, Vanhaesebroeck B, Turner M, Webb L, Wymann MP, Hirsch E, Ruckle T, Camps M, Rommel C, Jackson SP, Chilvers ER, Stephens LR, Hawkins PT (2005) Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106(4):1432–1440PubMedCrossRef
103.
Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A, Sozzani S (2004) Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice. EMBO J 23(17):3505–3515PubMedPubMedCentralCrossRef
104.
Krishnamoorthy N, Oriss TB, Paglia M, Fei M, Yarlagadda M, Vanhaesebroeck B, Ray A, Ray P (2008) Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat Med 14(5):565–573PubMedPubMedCentralCrossRef
105.
Rommel C, Camps M, Ji H (2007) PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 7(3):191–201PubMedCrossRef
106.
Banham-Hall E, Clatworthy MR, Okkenhaug K (2012) The therapeutic potential for PI3K inhibitors in autoimmune rheumatic diseases. Open Rheumatol J 6:245–258PubMedPubMedCentralCrossRef
107.
Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C (2005) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11(9):936–943PubMed
108.
Hayer S, Pundt N, Peters MA, Wunrau C, Kuhnel I, Neugebauer K, Strietholt S, Zwerina J, Korb A, Penninger J, Joosten LA, Gay S, Ruckle T, Schett G, Pap T (2009) PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis. FASEB J 23(12):4288–4298PubMedCrossRef
109.
Zou L, Zhang G, Liu L, Chen C, Cao X, Cai J (2016) Relationship between PI3K pathway and angiogenesis in CIA rat synovium. Am J Transl Res 8(7):3141–3147PubMedPubMedCentral
110.
Sujobert P, Rioufol C, Salles GA (2016) Idelalisib: targeting the PI3 kinase pathway in non-Hodgkin lymphoma. Cancer J 22(1):12–16PubMedCrossRef
111.
Nair KS, Cheson B (2016) The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia. Ther Adv Hematol 7(2):69–84PubMedPubMedCentralCrossRef
112.
Barrientos JC (2016) Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential. Onco Targets Ther 9:2945–2953PubMedPubMedCentralCrossRef
113.
Yang Q, Modi P, Newcomb T, Queva C, Gandhi V (2015) Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res 21(7):1537–1542PubMedPubMedCentralCrossRef
114.
Courtright LJ, Kuzell WC (1965) Sparing effect of neurological deficit and trauma on the course of adjuvant arthritis in the rat. Ann Rheum Dis 24(4):360–368PubMedPubMedCentralCrossRef
115.
Koopman FA, Stoof SP, Straub RH, Van Maanen MA, Vervoordeldonk MJ, Tak PP (2011) Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis. Mol Med 17(9–10):937–948PubMedPubMedCentral
116.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462PubMedCrossRef
117.
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421(6921):384–388PubMedCrossRef
118.
119.
van Maanen MA, Stoof SP, van der Zanden EP, de Jonge WJ, Janssen RA, Fischer DF, Vandeghinste N, Brys R, Vervoordeldonk MJ, Tak PP (2009) The alpha7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: a possible role for a key neurotransmitter in synovial inflammation. Arthritis Rheum 60(5):1272–1281PubMedCrossRef
120.
Westman M, Engstrom M, Catrina AI, Lampa J (2009) Cell specific synovial expression of nicotinic alpha 7 acetylcholine receptor in rheumatoid arthritis and psoriatic arthritis. Scand J Immunol 70(2):136–140PubMedCrossRef
121.
van Maanen MA, Lebre MC, van der Poll T, LaRosa GJ, Elbaum D, Vervoordeldonk MJ, Tak PP (2009) Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum 60(1):114–122PubMedCrossRef
122.
Li T, Zuo X, Zhou Y, Wang Y, Zhuang H, Zhang L, Zhang H, Xiao X (2010) The vagus nerve and nicotinic receptors involve inhibition of HMGB1 release and early pro-inflammatory cytokines function in collagen-induced arthritis. J Clin Immunol 30(2):213–220PubMedCrossRef
123.
van Maanen MA, Stoof SP, Larosa GJ, Vervoordeldonk MJ, Tak PP (2010) Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor alpha7 subunit gene knockout mice. Ann Rheum Dis 69(9):1717–1723PubMedCrossRef
124.
Waldburger JM, Boyle DL, Pavlov VA, Tracey KJ, Firestein GS (2008) Acetylcholine regulation of synoviocyte cytokine expression by the alpha7 nicotinic receptor. Arthritis Rheum 58(11):3439–3449PubMedPubMedCentralCrossRef
125.
Buijs RM, van der Vliet J, Garidou ML, Huitinga I, Escobar C (2008) Spleen vagal denervation inhibits the production of antibodies to circulating antigens. PLoS One 3(9):e3152PubMedPubMedCentralCrossRef
126.
Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ (2008) Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A 105(31):11008–11013PubMedPubMedCentralCrossRef
127.
Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 113(29):8284–8289PubMedPubMedCentralCrossRef
128.
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595–638PubMed
129.
130.
Evrengul H, Dursunoglu D, Cobankara V, Polat B, Seleci D, Kabukcu S, Kaftan A, Semiz E, Kilic M (2004) Heart rate variability in patients with rheumatoid arthritis. Rheumatol Int 24(4):198–202PubMedCrossRef
131.
Baerwald C, Graefe C, Muhl C, Von Wichert P, Krause A (1992) Beta 2-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatic diseases. Eur J Clin Investig 22(Suppl 1):42–46
132.
Straub RH, Harle P (2005) Sympathetic neurotransmitters in joint inflammation. Rheum Dis Clin N Am 31(1):43–59 viii CrossRef
133.
Heijnen CJ, Rouppe van der Voort C, Wulffraat N, van der Net J, Kuis W, Kavelaars A (1996) Functional alpha 1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis. J Neuroimmunol 71(1–2):223–226PubMedCrossRef
134.
Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S, Molinaro C, Lubahn C, Lorton D (2008) Sympathetic modulation of immunity: relevance to disease. Cell Immunol 252(1–2):27–56PubMedPubMedCentralCrossRef
135.
Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annu Rev Immunol 30:1–22PubMedCrossRef
136.
137.
Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A 99(1):351–358PubMedPubMedCentralCrossRef
138.
139.
Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50PubMedCrossRef
140.
Skoberne M, Beignon AS, Larsson M, Bhardwaj N (2005) Apoptotic cells at the crossroads of tolerance and immunity. Curr Top Microbiol Immunol 289:259–292PubMed
141.
Skoberne M, Somersan S, Almodovar W, Truong T, Petrova K, Henson PM, Bhardwaj N (2006) The apoptotic-cell receptor CR3, but not alphavbeta5, is a regulator of human dendritic-cell immunostimulatory function. Blood 108(3):947–955PubMedPubMedCentralCrossRef
142.
Pettit AR, MacDonald KP, O'Sullivan B, Thomas R (2000) Differentiated dendritic cells expressing nuclear RelB are predominantly located in rheumatoid synovial tissue perivascular mononuclear cell aggregates. Arthritis Rheum 43(4):791–800PubMedCrossRef
143.
Martin CA, Carsons SE, Kowalewski R, Bernstein D, Valentino M, Santiago-Schwarz F (2003) Aberrant extracellular and dendritic cell (DC) surface expression of heat shock protein (hsp)70 in the rheumatoid joint: possible mechanisms of hsp/DC-mediated cross-priming. J Immunol 171(11):5736–5742PubMedCrossRef
144.
Lebre MC, Jongbloed SL, Tas SW, Smeets TJ, McInnes IB, Tak PP (2008) Rheumatoid arthritis synovium contains two subsets of CD83-DC-LAMP- dendritic cells with distinct cytokine profiles. Am J Pathol 172(4):940–950PubMedPubMedCentralCrossRef
145.
van Lieshout AW, Barrera P, Smeets RL, Pesman GJ, van Riel PL, van den Berg WB, Radstake TR (2005) Inhibition of TNF alpha during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF alpha blockade in rheumatoid arthritis. Ann Rheum Dis 64(3):408–414PubMedCrossRef
146.
Balanescu A, Radu E, Nat R, Regalia T, Bojinca V, Ionescu R, Balanescu S, Savu C, Predeteanu D (2005) Early and late effect of infliximab on circulating dendritic cells phenotype in rheumatoid arthritis patients. Int J Clin Pharmacol Res 25(1):9–18PubMed
147.
Park JE, Jang J, Choi JH, Kang MS, Woo YJ, Seong YR, Choi CB, Lee HS, Bae SC, Bae YS (2015) DC-based immunotherapy combined with low-dose methotrexate effective in the treatment of advanced CIA in mice. J Immunol Res 2015:834085PubMedPubMedCentral
148.
Ren Y, Yang Y, Yang J, Xie R, Fan H (2014) Tolerogenic dendritic cells modified by tacrolimus suppress CD4(+) T-cell proliferation and inhibit collagen-induced arthritis in mice. Int Immunopharmacol 21(1):247–254PubMedCrossRef
149.
Zhang L, Fu J, Sheng K, Li Y, Song S, Li P, Song S, Wang Q, Chen J, Yu J, Wei W (2015) Bone marrow CD11b(+)F4/80(+) dendritic cells ameliorate collagen-induced arthritis through modulating the balance between Treg and Th17. Int Immunopharmacol 25(1):96–105PubMedCrossRef
150.
151.
152.
Martin E, O'Sullivan B, Low P, Thomas R (2003) Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 18(1):155–167PubMedCrossRef
153.
Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, Fouweather T, MacDonald C, Chadwick T, McColl E, Dunn J, Dickinson AM, Hilkens CM, Isaacs JD (2017) Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis 76(1):227–234PubMedCrossRef
154.
Voigtlander C, Rossner S, Cierpka E, Theiner G, Wiethe C, Menges M, Schuler G, Lutz MB (2006) Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity. J Immunother 29(4):407–415PubMedCrossRef
155.
Lim DS, Kang MS, Jeong JA, Bae YS (2009) Semi-mature DC are immunogenic and not tolerogenic when inoculated at a high dose in collagen-induced arthritis mice. Eur J Immunol 39(5):1334–1343PubMedCrossRef
156.
Ludewig B, Ochsenbein AF, Odermatt B, Paulin D, Hengartner H, Zinkernagel RM (2000) Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med 191(5):795–804PubMedPubMedCentralCrossRef
Metadata
Title
Future therapeutic targets in rheumatoid arthritis?
Authors
Tommy Tsang Cheung
Iain B. McInnes
Publication date
01-06-2017
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 4/2017
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-017-0623-3

Other articles of this Issue 4/2017

Seminars in Immunopathology 4/2017 Go to the issue

Introduction

Rheumatoid arthritis: from basic findings and clinical manifestations to future therapies

Review

Arthritis models: usefulness and interpretation

Review

Epigenetics in the pathogenesis of RA

Review

Genetics of rheumatoid arthritis susceptibility, severity, and treatment response

Review

Synovial cellular and molecular markers in rheumatoid arthritis

Review

Environmental factors and hormones in the development of rheumatoid arthritis

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits