The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.
Leflunomide
Polymorphism
Rheumatoid arthritis
Therapy
Journal
Clinical rheumatology
ISSN: 1434-9949
Titre abrégé: Clin Rheumatol
Pays: Germany
ID NLM: 8211469
Informations de publication
Date de publication:
Sep 2023
Sep 2023
Historique:
received:
11
04
2023
accepted:
26
05
2023
revised:
15
05
2023
medline:
10
8
2023
pubmed:
8
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
Rheumatoid arthritis (RA) is a disease affecting around 1% of the population in developed countries and can be treated with leflunomide. The higher prevalence of RA among women and numerous previous studies suggested the crucial role of sex hormones. Cytochrome CYB5A regulates the synthesis of androgens. Therefore, the aim of this study was to determine the association between common CYB5A gene polymorphism and the response to leflunomide in women with RA. This study included 111 patients. All of them received oral leflunomide monotherapy at a dose of 20 mg daily. Women were genotyped for the presence of CYB5A rs1790834 polymorphism and evaluated monthly for 6 months following the initiation of treatment. After 6 months of therapy, patients with the GG genotype had higher DAS28 values and less improvement in DAS28 compared to patients with the GA and AA genotypes (p = 0.04). No statistically significant differences were found in relation to other disease activity parameters. The results of the current study suggest a possible association of the CYB5A rs1790834 polymorphism with some disease activity parameters in RA patients treated with leflunomide during the initial therapy period. However, confirmation of the effect of this polymorphism on the efficacy of leflunomide treatment requires further studies. Key Points • Leflunomide is the synthetic disease-modifying anti-rheumatic drug used in the therapy of rheumatoid arthritis. • CYB5A rs1790834 gene polymorphism may influence the clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.
Identifiants
pubmed: 37289314
doi: 10.1007/s10067-023-06653-1
pii: 10.1007/s10067-023-06653-1
doi:
Substances chimiques
Leflunomide
G162GK9U4W
Isoxazoles
0
Antirheumatic Agents
0
CYB5A protein, human
0
Cytochromes b5
9035-39-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2477-2483Informations de copyright
© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).
Références
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038
pubmed: 27156434
doi: 10.1016/S0140-6736(16)30173-8
Gabriel SE (2001) The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 27(2):269–281
pubmed: 11396092
doi: 10.1016/S0889-857X(05)70201-5
Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE (2010) Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum 62(6):1576–1582
pubmed: 20191579
pmcid: 2929692
doi: 10.1002/art.27425
McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219
pubmed: 22150039
doi: 10.1056/NEJMra1004965
Aletaha D, Smolen JS (2018) Diagnosis and management of rheumatoid arthritis: a review. JAMA 320(13):1360–1372
pubmed: 30285183
doi: 10.1001/jama.2018.13103
Das S, Padhan P (2017) An overview of the extraarticular involvement in rheumatoid arthritis and its management. J Pharmacol Pharmacother 8(3):81–86
pubmed: 29081614
pmcid: 5642136
Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM (2017) Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 31(1):3–18
pubmed: 29221595
pmcid: 5726551
doi: 10.1016/j.berh.2017.08.003
Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH (2002) Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis. Semin Arthritis Rheum 31(6):355–360
pubmed: 12077707
doi: 10.1053/sarh.2002.32552
Liu WX, Jiang Y, Hu QX, You XB (2016) HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: a systemic review and meta-analysis. Clin Invest Med 39(6):E182–E203
pubmed: 27917778
doi: 10.25011/cim.v39i6.27487
Padyukov L (2022) Genetics of rheumatoid arthritis. Semin Immunopathol 44(1):47–62
pubmed: 35088123
pmcid: 8837504
doi: 10.1007/s00281-022-00912-0
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506(7488):376–381
pubmed: 24390342
doi: 10.1038/nature12873
Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514
pubmed: 20453842
pmcid: 4243840
doi: 10.1038/ng.582
Ham S, Bae J-B, Lee S, Kim B-J, Han B-G, Kwok S-K et al (2019) Epigenetic analysis in rheumatoid arthritis synoviocytes. Exp Mol Med 51(2):1–13
pubmed: 30820026
doi: 10.1038/s12276-019-0215-5
Giannini D, Antonucci M, Petrelli F, Bilia S, Alunno A, Puxeddu I (2020) One year in review 2020: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 38(3):387–397
pubmed: 32324123
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581
pubmed: 20872595
doi: 10.1002/art.27584
Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A et al (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685–699
Miceli-Richard C, Dougados M (2003) Leflunomide for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 4(6):987–997
pubmed: 12783594
doi: 10.1517/14656566.4.6.987
Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ (2016) Leflunomide use and risk of lung disease in rheumatoid arthritis: a systematic literature review and metaanalysis of randomized controlled trials. J Rheumatol 43(5):855–860
pubmed: 26980577
doi: 10.3899/jrheum.150674
Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V et al (1999) Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 93(3):198–208
pubmed: 10600330
doi: 10.1006/clim.1999.4777
Dziedziejko V, Kurzawski M, Safranow K, Ossowski A, Piatek J, Parafiniuk M et al (2012) Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide. Eur J Clin Pharmacol 68(4):371–377
pubmed: 21997404
doi: 10.1007/s00228-011-1131-3
Dayer JM, Cutolo M (2005) Is there a rationale to using leflunomide in early rheumatoid arthritis? Clin Exp Rheumatol 23(3):404–412
pubmed: 15971434
Saad MN, Mabrouk MS, Eldeib AM, Shaker OG (2016) Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: a systematic review and meta-analysis. J Adv Res 7(1):1–16
pubmed: 26843965
doi: 10.1016/j.jare.2015.01.008
Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F et al (2009) Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther 11(1):R7
pubmed: 19144159
pmcid: 2688237
Kvien TK, Uhlig T, Ødegård S, Heiberg MS (2006) Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci 1069:212–222
pubmed: 16855148
doi: 10.1196/annals.1351.019
Cutolo M, Montagna P, Brizzolara R, Sulli A, Seriolo B, Villaggio B et al (2009) Sex hormones modulate the effects of leflunomide on cytokine production by cultures of differentiated monocyte/macrophages and synovial macrophages from rheumatoid arthritis patients. J Autoimmun 32(3–4):254–260
pubmed: 19324522
doi: 10.1016/j.jaut.2009.02.016
Montagna P, Brizzolara R, Soldano S, Pizzorni C, Sulli A, Cutolo M (2009) Sex hormones and leflunomide treatment of human macrophage cultures: effects on apoptosis. Int J Clin Exp Med 2(3):221–232
pubmed: 19918315
pmcid: 2777270
Karlson EW, Chibnik LB, McGrath M, Chang SC, Keenan BT, Costenbader KH et al (2009) A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis. Arthritis Res Ther 11(3):R97
pubmed: 19555469
pmcid: 2714153
doi: 10.1186/ar2742
Cutolo M (2009) Androgens in rheumatoid arthritis: when are they effectors? Arthritis Res Ther 11(5):126
pubmed: 19804618
pmcid: 2787302
doi: 10.1186/ar2804
Stark K, Straub RH, Rovenský J, Blažičková S, Eiselt G, Schmidt M (2015) CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis Res Ther 17(1):56
pubmed: 25890314
pmcid: 4372052
doi: 10.1186/s13075-015-0574-9
Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F et al (2009) Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther 11(1):1–12
Cutolo M, Capellino S, Montagna P, Villaggio B, Sulli A, Seriolo B et al (2003) New roles for estrogens in rheumatoid arthritis. Clin Exp Rheumatol 21(6):687–690
pubmed: 14740444
Cutolo M (2009) Androgens in rheumatoid arthritis: when are they effectors? Arthritis Res Ther 11(5):1–3
doi: 10.1186/ar2804
Karlson EW, Chibnik LB, McGrath M, Chang S-C, Keenan BT, Costenbader KH et al (2009) A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis. Arthritis Res Ther 11(3):1–12
doi: 10.1186/ar2742
Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M et al (2003) Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol 30(12):2597–2605
pubmed: 14719200
Cutolo M, Montagna P, Brizzolara R, Sulli A, Seriolo B, Villaggio B et al (2009) Sex hormones modulate the effects of leflunomide on cytokine production by cultures of differentiated monocyte/macrophages and synovial macrophages from rheumatoid arthritis patients. J Autoimmun 32(3–4):254–260
pubmed: 19324522
doi: 10.1016/j.jaut.2009.02.016
Montagna P, Brizzolara R, Soldano S, Pizzorni C, Sulli A, Cutolo M (2009) Sex hormones and leflunomide treatment of human macrophage cultures: effects on apoptosis. Int J Clin Exp Med 2(3):221
pubmed: 19918315
pmcid: 2777270
Squires EJ, Gray MA, Lou Y (2019) Effect of mutations in porcine CYB5A and CYP17A1 on the metabolism of pregnenolone. J Steroid Biochem Mol Biol 195:105469
pubmed: 31509771
doi: 10.1016/j.jsbmb.2019.105469
Stark K, Straub RH, Rovenský J, Blažičková S, Eiselt G, Schmidt M (2015) CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis Res Ther 17(1):1–11
doi: 10.1186/s13075-015-0574-9
Stark K, Schmidt M, Rovenský J, Blažičková S, Lowin T, Straub RH (2013) Influence of CYB5A gene variants on risk of rheumatoid arthritis and local endocrine function in the joint. Brain Behav Immun 29:S12–S13
doi: 10.1016/j.bbi.2013.01.039
Łączna M, Malinowski D, Paradowska-Gorycka A, Safranow K, Dziedziejko V, Pawlik A (2021) Lack of association between CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with rheumatoid arthritis. Eur J Clin Pharmacol 77(11):1673–1678
pubmed: 34160668
pmcid: 8528780
doi: 10.1007/s00228-021-03172-3
Van Riel P, Renskers L (2016) The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. Clin Exp Rheumatol 34(5 Suppl 101):S40–S44
pubmed: 27762189
Romão VC, Canhão H, Fonseca JE (2013) Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med 11:17
pubmed: 23343013
pmcid: 3606422
doi: 10.1186/1741-7015-11-17
de Moel EC, Derksen VFAM, Trouw LA, Bang H, Collée G, Lard LR et al (2019) In rheumatoid arthritis, changes in autoantibody levels reflect intensity of immunosuppression, not subsequent treatment response. Arthritis Res Ther 21(1):28
pubmed: 30658699
pmcid: 6339446
doi: 10.1186/s13075-019-1815-0
Lequerré T, Jouen F, Brazier M, Clayssens S, Klemmer N, Ménard JF et al (2007) Autoantibodies, metalloproteinases and bone markers in rheumatoid arthritis patients are unable to predict their responses to infliximab. Rheumatology 46(3):446–453
pubmed: 16899502
doi: 10.1093/rheumatology/kel262
Maillefert JF, Puéchal X, Falgarone G, Lizard G, Ornetti P, Solau E et al (2010) Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. Joint Bone Spine 77(6):558–563
pubmed: 20478729
doi: 10.1016/j.jbspin.2010.02.018
Majorczyk E, Mazurek-Mochol M, Pawlik A, Kuśnierczyk P (2022) Clinical factors and the outcome of treatment with methotrexate in rheumatoid arthritis: role of rheumatoid factor, erosive disease and high level of erythrocyte sedimentation rate. J Clin Med 11(20):6078
Van Roon EN, Hoekstra M, Tobi H, Jansen TL, BernelotMoens HJ, Brouwers JR et al (2005) Leflunomide in the treatment of rheumatoid arthritis. An analysis of predictors for treatment continuation. Br J Clin Pharmacol 60(3):319–25
pubmed: 16120072
pmcid: 1884775
doi: 10.1111/j.1365-2125.2005.02430.x
Van Roon EN, Yska JP, Raemaekers J, Jansen TL, van Wanrooy M, Brouwers JR (2004) A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy. J Pharm Biomed Anal 36(1):17–22
pubmed: 15351043
doi: 10.1016/j.jpba.2004.05.019
Van Roon EN, Jansen TL, van de Laar MA, Janssen M, Yska JP, Keuper R et al (2005) Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64(4):569–574
pubmed: 15345501
doi: 10.1136/ard.2004.025205
Van Roon EN, Jansen TL, Mourad L, Houtman PM, Bruyn GA, Griep EN et al (2004) Leflunomide in active rheumatoid arthritis: a prospective study in daily practice. Br J Clin Pharmacol 57(6):790–797
pubmed: 15151525
pmcid: 1884519
doi: 10.1111/j.1365-2125.2004.02075.x
Van Roon EN, Jansen TL, Mourad L, Houtman PM, Bruyn GA, Griep EN et al (2004) Leflunomide in active rheumatoid arthritis: a prospective study in daily practice. Br J Clin Pharmacol 58(2):201–208
pubmed: 15255803
pmcid: 1884578
doi: 10.1111/j.1365-2125.2004.02131.x
Smolen JS, Emery P, Kalden JR, Riel PLCMV, Dougados M, Strand CV et al (2004) The efficacy of leflunomide monotherapy in rheumatoid arthritis: towards the goals of disease modifying antirheumatic drug therapy. J Rheumatol 71:13–20
Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J et al (1995) Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum. 38(11):1595–603
pubmed: 7488280
doi: 10.1002/art.1780381111
Poór G, Strand V, Group LMS (2004) Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial. Rheumatology 43(6):744–749
doi: 10.1093/rheumatology/keh168
Van Roon EN, Jansen TL, Houtman NM, Spoelstra P, Brouwers JR (2004) Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity. Drug Saf 27(5):345–352
pubmed: 15061688
doi: 10.2165/00002018-200427050-00006