• This record comes from PubMed

High cumulative glucocorticoid dose is associated with increased levels of inflammation-related mediators in active rheumatoid arthritis

. 2024 ; 15 () : 1505615. [epub] 20241218

Language English Country Switzerland Media electronic-ecollection

Document type Journal Article

INTRODUCTION: Glucocorticoids (GCs) are widely used as a treatment for rheumatoid arthritis (RA), leading to high cumulative doses in long-term treated patients. The impact of a high cumulative GC dose on the systemic inflammatory response in RA remains poorly understood. METHODS: We investigated long-treated patients with RA (n = 72, median disease duration 14 years) through blood counts and the serum levels of 92 inflammation-related proteins, and disease activity was assessed using the Simple Disease Activity Index (SDAI). Patients were grouped based on the cumulative GC dose, with a cut-off value of 20 g (low/high, n = 49/23). RESULTS AND DISCUSSION: Patients with a high cumulative GC dose within the active RA group had elevated serum levels in 23 inflammation-related proteins compared with patients with a low dose (cytokines/soluble receptors: CCL3, CCL20, CCL25, IL-8, CXCL9, IL-17A, IL-17C, IL-18, sIL-18R1, IL-10, sIL-10RB, OSM and sOPG; growth factors: sTGFα and sHGF; other inflammatory mediators: caspase 8, STAMBP, sCDCP1, sirtuin 2, 4E-BP1, sCD40, uPA and axin-1; pcorr < 0.05). In non-active RA, the high and low GC groups did not differ in analysed serum protein levels. Moreover, patients with active RA with a high GC dose had an increased white blood cell count, increased neutrophil-lymphocyte and platelet-lymphocyte ratios and a decreased lymphocyte-monocyte ratio compared with the low dose group (p < 0.05). This is the first study to report elevated serum levels in inflammation-related proteins and deregulated blood counts in patients with active RA with a high cumulative GC dose. The elevated systemic inflammation highlights the importance of improving care for patients receiving high cumulative GC doses.

See more in PubMed

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. Ann Rheum Dis. (2010) 69:1580–8. doi: 10.1136/ard.2010.138461 PubMed DOI

Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD Open. (2020) 6:e000536. doi: 10.1136/rmdopen-2017-000536 PubMed DOI PMC

Cutolo M, Paolino S, Gotelli E. Glucocorticoids in rheumatoid arthritis still on first line: the reasons. Expert Rev Clin Immunol. (2021) 17:417–20. doi: 10.1080/1744666X.2021.1903319 PubMed DOI

Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. . American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheumatol. (2008) 59:762–84. doi: 10.1002/art.23721 PubMed DOI

Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. (2020) 79:685–99. doi: 10.1136/annrheumdis-2019-216655 PubMed DOI

Šenolt L, Mann H, Závada J, Pavelka K, Vencovský J. 2017 recommendations of the Czech Society for Rheumatology for the pharmacological treatment of rheumatoid arthritis [in Czech. Česká revmatologie. (2017) 25:8–24.

Petrackova A, Smrzova A, Gajdos P, Schubertova M, Schneiderova P, Kromer P, et al. . Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay. Clin Proteomics. (2017) 14:32. doi: 10.1186/s12014-017-9167-8 PubMed DOI PMC

Schneiderova P, Pika T, Gajdos P, Fillerova R, Kromer P, Kudelka M, et al. . Serum protein fingerprinting by PEA immunoassay coupled with a pattern–recognition algorithms distinguishes MGUS and multiple myeloma. Oncotarget. (2016) 8:69408–21. doi: 10.18632/oncotarget.11242 PubMed DOI PMC

Haringman JJ, Ludikhuize J, Tak PP. Chemokines in joint disease: the key to inflammation? Ann Rheum Dis. (2004) 63:1186–94. doi: 10.1136/ard.2004.020529 PubMed DOI PMC

McInnes IB, Liew FY, Gracie JA. Interleukin–18: a therapeutic target in rheumatoid arthritis? Arthritis Res Ther. (2005) 7:38–41. doi: 10.1186/ar1497 PubMed DOI PMC

Panezai J, Ali A, Ghaffar A, Benchimol D, Altamash M, Klinge B, et al. . Upregulation of circulating inflammatory biomarkers under the influence of periodontal disease in rheumatoid arthritis patients. Cytokine. (2020) 131:155117. doi: 10.1016/j.cyto.2020.155117 PubMed DOI

Geusens P. The role of RANK ligand/osteoprotegerin in rheumatoid arthritis. Ther Adv Musculoskelet Dis. (2012) 4:225–33. doi: 10.1177/1759720X12438080 PubMed DOI PMC

Du H, Wang Y, Zeng Y, Huang X, Liu D, Ye L, et al. . Tanshinone IIA suppresses proliferation and inflammatory cytokine production of synovial fibroblasts from rheumatoid arthritis patients induced by TNF–α and attenuates the inflammatory response in AIA mice. Front Pharmacol. (2020) 11:568. doi: 10.3389/fphar.2020.00568 PubMed DOI PMC

Tsunemi S, Iwasaki T, Kitano S, Matsumoto K, Takagi-Kimura M, Kubo S, et al. . Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis. Arthritis Res Ther. (2013) 15:R75. doi: 10.1186/ar4252 PubMed DOI PMC

Ansalone C, Ainsworth RI, Nygaard G, Ai R, Prideaux EB, Hammaker D, et al. . Caspase–8 variant G regulates rheumatoid arthritis fibroblast–like synoviocyte aggressive behavior. ACR Open Rheumatol. (2022) 4:288–99. doi: 10.1002/acr2.11384 PubMed DOI PMC

van de Garde MD, Martinez FO, Melgert BN, Hylkema MN, Jonkers RE, Hamann J. Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction. J Immunol. (2014) 192:1196–208. doi: 10.4049/jimmunol.1302138 PubMed DOI

Zijlstra GJ, Fattahi F, Rozeveld D, Jonker MR, Kliphuis NM, van den Berge M, et al. . Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium. Eur Respir J. (2014) 44:361–70. doi: 10.1183/09031936.00209513 PubMed DOI

Wang L, Yang M, Wang X, Cheng B, Ju Q, Eichenfield DZ, et al. . Glucocorticoids promote CCL20 expression in keratinocytes. Br J Dermatol. (2021) 185:1200–8. doi: 10.1111/bjd.v185.6 PubMed DOI PMC

Conti B, Sugama S, Kim Y, Tinti C, Kim H, Baker H, et al. . Modulation of IL–18 production in the adrenal cortex following acute ACTH or chronic corticosterone treatment. Neuroimmunomodulation. (2000) 8:1–7. doi: 10.1159/000026445 PubMed DOI

He M, Wang J, Wang G, Tian Y, Jiang L, Ren Z, et al. . Effect of glucocorticoids on osteoclast function in a mouse model of bone necrosis. Mol Med Rep. (2016) 14:1054–60. doi: 10.3892/mmr.2016.5368 PubMed DOI PMC

Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant. (2001) 16:479–82. doi: 10.1093/ndt/16.3.479 PubMed DOI

Corrado A, Rotondo C, Mele A, Cici D, Maruotti N, Sanpaolo E, et al. . Influence of glucocorticoid treatment on trabecular bone score and bone remodeling regulators in early rheumatoid arthritis. Arthritis Res Ther. (2021) 23:180. doi: 10.1186/s13075-021-02562-3 PubMed DOI PMC

Shah OJ, Kimball SR, Jefferson LS. Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle. Am J Physiol Endocrinol Metab. (2000) 278:E76–82. doi: 10.1152/ajpendo.2000.278.1.E76 PubMed DOI

Gu L, Xie L, Zuo C, Ma Z, Zhang Y, Zhu Y, et al. . Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E–BP1 null Burkitt Lymphoma. BMC Cancer. (2015) 15:529. doi: 10.1186/s12885-015-1535-z PubMed DOI PMC

Torres L, Klingberg E, Nurkkala M, Carlsten H, Forsblad-d'Elia H. Hepatocyte growth factor is a potential biomarker for osteoproliferation and osteoporosis in ankylosing spondylitis. Osteoporos Int. (2019) 30:441–9. doi: 10.1007/s00198-018-4721-4 PubMed DOI PMC

Marchetti MC, Di Marco B, Cifone G, Migliorati G, Riccardi C. Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Blood. (2003) 101:585–93. doi: 10.1182/blood-2002-06-1779 PubMed DOI

Jenkins E, Louw I, Balog A, Van Duuren E, Horowitz DL, Jaworski J, et al. . Op0036 efficacy, safety, and pharmacokinetics of anti-cd40 antibody abiprubart (Kpl-404) in patients with rheumatoid arthritis: A phase 2, randomized, placebo-controlled 12-week-treatment proof-of-concept study. Ann Rheum Dis. (2024) 83:81–2. doi: 10.1136/annrheumdis-2024-eular.1536 DOI

Yang YL, Li XF, Song B, Wu S, Wu YY, Huang C, et al. . The role of CCL3 in the pathogenesis of rheumatoid arthritis. Rheumatol Ther. (2023) 10:793–808. doi: 10.1007/s40744-023-00554-0 PubMed DOI PMC

Bakheet SA, Ansari MA, Nadeem A, Attia SM, Alhoshani AR, Gul G, et al. . CXCR3 antagonist AMG487 suppresses rheumatoid arthritis pathogenesis and progression by shifting the Th17/Treg cell balance. Cell Signal. (2019) 64:109395. doi: 10.1016/j.cellsig.2019.109395 PubMed DOI

Taams LS. Interleukin-17 in rheumatoid arthritis: Trials and tribulations. J Exp Med. (2020) 217:e20192048. doi: 10.1084/jem.20192048 PubMed DOI PMC

Choy EH, Bendit M, McAleer D, Liu F, Feeney M, Brett S, et al. . Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials. Arthritis Res Ther. (2013) 15:R132. doi: 10.1186/ar4312 PubMed DOI PMC

Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J. Prednisone–induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis. Am J Med. (1981) 71:773–8. doi: 10.1016/0002-9343(81)90363-6 PubMed DOI

Du J, Chen S, Shi J, Zhu X, Ying H, Zhang Y, et al. . The association between the lymphocyte–monocyte ratio and disease activity in rheumatoid arthritis. Clin Rheumatol. (2017) 36:2689–95. doi: 10.1007/s10067-017-3815-2 PubMed DOI

Li M, Xie L. Correlation between NLR, PLR, and LMR and disease activity, efficacy assessment in rheumatoid arthritis. Evid Based Complement Alternat Med. (2021) 2021:4433141. doi: 10.1155/2021/4433141 PubMed DOI PMC

Macfarlane E, Seibel MJ, Zhou H. Arthritis and the role of endogenous glucocorticoids. Bone Res. (2020) 8:33. doi: 10.1038/s41413-020-00112-2 PubMed DOI PMC

Carriere J, Dorfleutner A, Stehlik C. NLRP7: From inflammasome regulation to human disease. Immunology. (2021) 163:363–76. doi: 10.1111/imm.v163.4 PubMed DOI PMC

Bednash JS, Weathington N, Londino J, Rojas M, Gulick DL, Fort R, et al. . Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity. Nat Commun. (2017) 8:15203. doi: 10.1038/ncomms15203 PubMed DOI PMC

Marto N, Morello J, Monteiro EC, Pereira SA. Implications of sulfotransferase activity in interindividual variability in drug response: clinical perspective on current knowledge. Drug Metab Rev. (2017) 49:357–71. doi: 10.1080/03602532.2017.1335749 PubMed DOI

Qu H, Sundberg E, Aulin C, Neog M, Palmblad K, Horne AC, et al. . Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single–center study. Pediatr Rheumatol Online J. (2021) 19:173. doi: 10.1186/s12969-021-00660-9 PubMed DOI PMC

Moraes L, Magnusson MK, Mavroudis G, Polster A, Jonefjäll B, Törnblom H, et al. . Systemic inflammatory protein profiles distinguish irritable bowel syndrome (IBS) and ulcerative colitis, irrespective of inflammation or IBS–like symptoms. Inflammation Bowel Dis. (2020) 26:874–84. doi: 10.1093/ibd/izz322 PubMed DOI PMC

Lai Y, Wang H, Xia X, Wang Z, Fan C, Wang H, et al. . Serum fibroblast growth factor 19 is decreased in patients with overt hypothyroidism and subclinical hypothyroidism. Med (Baltimore). (2016) 95:e5001. doi: 10.1097/MD.0000000000005001 PubMed DOI PMC

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...