This prospective study investigated the utility of baseline CXCL13 levels in predicting methotrexate response and monitoring disease activity in 50 treatment-naive early rheumatoid arthritis (RA) patients (2010 American College of Rheumatology/European League Against Rheumatism criteria) treated with methotrexate. Participants were categorized into methotrexate responders (MTX-R, n = 29) and nonresponders (MTX-NR, n = 21) at 12 weeks. Baseline CXCL13 levels were significantly higher in MTX-R compared with MTX-NR (P = 0.035). Receiver operating characteristic curve analysis identified a baseline CXCL13 cutoff of >100 pg/mL for predicting methotrexate response, with 69% sensitivity, 52% specificity, and 62% accuracy. Posttreatment, CXCL13 levels decreased significantly in MTX-R (P < 0.001) but remained unchanged in MTX-NR. Disease activity parameters (eg, DAS-28) correlated with CXCL13 dynamics, though specific coefficients were not detailed. The study highlights CXCL13 as a potential biomarker for stratifying methotrexate therapy, with higher baseline levels favoring therapeutic response and posttreatment reductions reflecting clinical improvement. While moderate diagnostic accuracy limits standalone use, CXCL13 may complement existing tools to guide early personalized treatment. Further validation in larger cohorts is warranted to confirm its role in optimizing RA management.
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References
1.
AldridgeJ, LundellA-C, AnderssonK, et al.Blood chemokine levels are markers of disease activity but not predictors of remission in early rheumatoid arthritis. Clin Exp Rheumatol, 2022; 40(7):1393–1402; doi: 10.5556/3/clinexprheumatol/idogmj
2.
BakkerMF, JacobsJWG, VerstappenSMM, et al.Tight control in the treatment of rheumatoid arthritis: Efficacy and feasibility. Annals of the Rheumatic Diseases, 2007; 66(Suppl 3):i56–i60; doi: 10.1136/ard.2007.078360
3.
BaoY-Q, WangJ-P, DaiZ-W, et al.Increased circulating CXCL13 Levels in systemic lupus erythematosus and rheumatoid arthritis: A meta-analysis. Clin Rheumatol, 2020; 39(1):281–290; doi: 10.1007/s10067-019-04775-z
4.
BechmanK, DalrympleA, Southey-BassolsC, et al.A systematic review of CXCL13 as a biomarker of disease and treatment response in rheumatoid arthritis. BMC Rheumatol, 2020; 4(1):70; doi: 10.1186/s41927-020-00154-3
5.
BelloAE, PerkinsEL, JayR, et al.Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis. Open Access Rheumatol, 2017; 9:67–79; doi: 10.2147/OARRR.S131668
6.
BugattiS, ManzoA, VitoloB, et al.High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease. Rheumatology (Oxford), 2014; 53(10):1886–1895; doi: 10.1093/rheumatology/keu163
7.
CarlsenHS, BaekkevoldES, MortonHC, et al.Monocyte-like and mature macrophages produce CXCL13 (B Cell-Attracting Chemokine 1) in inflammatory lesions with lymphoid neogenesis. Blood, 2004; 104(10):3021–3027; doi: 10.1182/blood-2004-02-0701
8.
De JongPH, HazesJM, HanHK, et al.Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-Year data of the tREACH trial. Ann Rheum Dis, 2014; 73(7):1331–1339; doi: 10.1136/annrheumdis-2013-204788
9.
De StefanoL, Bozzalla CassioneE, SammaliY, et al.High serum levels of CXCL13 predict lower response to csDMARDs in both ACPA-Positive and ACPA-Negative early rheumatoid arthritis. Rheumatology, 2025; 64(5):keae596–k2468; doi: 10.1093/rheumatology/keae596
10.
Den UylD, Ter WeeM, BoersM, et al.A non-inferiority trial of an attenuated combination strategy (‘COBRA-Light’) compared to the original COBRA strategy: Clinical results after 26 weeks. Annals of the Rheumatic Diseases, 2014; 73(6):1071–1078; doi: 10.1136/annrheumdis-2012-202818
11.
FinckhA, LiangMH, van HerckenrodeCM, et al.Long-Term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum, 2006; 55(6):864–872; doi: 10.1002/art.22353
12.
FraenkelL, BathonJM, EnglandBR, et al.2021 American College of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken), 2021; 73(7):924–939; doi: 10.1002/acr.24596
13.
Goekoop-RuitermanYPM, De Vries-BouwstraJK, AllaartCF, et al.Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the best study): A randomized, controlled trial. Arthritis Rheum, 2005; 52(11):3381–3390; doi: 10.1002/art.21405
14.
GreisenSR, ScheldeKK, RasmussenTK, et al.CXCL13 predicts disease activity in early rheumatoid arthritis and could be an indicator of the therapeutic ‘window of opportunity’. Arthritis Res Ther, 2014; 16(5):434; doi: 10.1186/s13075-014-0434-z
15.
GrigorC, CapellH, StirlingA, et al.Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA Study): A single-blind randomised controlled trial. Lancet, 2004; 364(9430):263–269; doi: 10.1016/S0140-6736(04)16676-2
16.
HanBK, KuzinI, GaughanJP, et al.Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: A pilot, prospective study. Arthritis Res Ther, 2016; 18(1):93; doi: 10.1186/s13075-016-0995-0
17.
HazlewoodGS, BarnabeC, TomlinsonG, et al.Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis. Cochrane Database of Systematic Reviews, 2016; 2016(8):CD010227–C14; doi: 10.1002/14651858.CD010227.pub2
18.
HumbyF, BombardieriM, ManzoA, et al.Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med, 2009; 6(1):e1; doi: 10.1371/journal.pmed.0060001
19.
JonesJ, HamiltonBJ, ChallenerG, et al.CXCL13 Is Elevated in Early and in Established Seropositive Rheumatoid Arthritis and Correlates with Rheumatoid Factor Levels. Arthritis and Rheumatism, 2013; 65:S589–S590; doi: 10.1002/art.38216
KobayashiS, MurataK, ShibuyaH, et al.A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid Synovium. Arthritis Rheum, 2013; 65(12):3063–3072; doi: 10.1002/art.38173
22.
KorpelaM, LaasonenL, HannonenP, et al.; FIN-RACo Trial Group. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: Five-Year experience from the FIN-RACo study. Arthritis Rheum, 2004; 50(7):2072–2081; doi: 10.1002/art.20351
23.
LiZ, ChenY, ZulipikaerM, et al.Identification of PSMB9 and CXCL13 as immune-related diagnostic markers for rheumatoid arthritis by machine learning. Curr Pharm Des, 2022; 28(34):2842–2854; doi: 10.2174/1381612828666220831085608
24.
ManzoA, BugattiS, BenaglioF, et al.Baseline serum levels of CXCL13 are associated with ultrasonographic synovitis and predict power doppler persistency in early rheumatoid arthritis. Arthritis and Rheumatism, 2011; 63(10):1–9.
25.
MeeuwisseCM, van der LindenMP, RullmannTA, et al.Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint. Arthritis Rheum, 2011; 63(5):1265–1273; doi: 10.1002/art.30273
26.
MorelandLW, O’DellJR, PaulusHE, et al.; TEAR Investigators. 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, 2012; 64(9):2824–2835; doi: 10.1002/art.34498
27.
MöttönenT, HannonenP, Leirisalo-RepoM, et al.Comparison of Combination Therapy with Single-Drug Therapy in e a Rly Rheumatoid Arthritis: A Randomised Trial. Lancet, 1999; 353(9164):1568–1573.
28.
O’DellJR, LeffR, PaulsenG, et al.Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: Results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum, 2002; 46(5):1164–1170; doi: 10.1002/art.10228
29.
PavyS, ConstantinA, PhamT, et al.Methotrexate therapy for rheumatoid arthritis: Clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine, 2006; 73(4):388–395; doi: 10.1016/j.jbspin.2006.01.007
30.
RiojaI, HughesFJ, SharpCH, et al.Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis Rheum, 2008; 58(8):2257–2267; doi: 10.1002/art.23667
31.
RosengrenS, WeiN, KalunianKC, et al.CXCL13: A novel biomarker of B-Cell return following rituximab treatment and synovitis in patients with rheumatoid arthritis. Rheumatology (Oxford), 2011; 50(3):603–610; doi: 10.1093/rheumatology/keq337
32.
SaundersSA, CapellHA, StirlingA, et al.Triple therapy in early active rheumatoid arthritis: A randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum, 2008; 58(5):1310–1317; doi: 10.1002/art.23449
33.
SheaB, SwindenMV, Tanjong GhogomuE, et al.Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev, 2013; 2013(5):CD000951; doi: 10.1002/14651858.CD000951.pub2
34.
ShiK, HayashidaK, KanekoM, et al.Lymphoid chemokine B cell-attracting Chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol, 2001; 166(1):650–655; doi: 10.4049/jimmunol.166.1.650
35.
SinghJA, SaagKG, Bridges JrSL, et al.2015 American College of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol, 2016; 68(1):1–26; doi: 10.1002/art.39480
36.
SmolenJS, LandewéR, BijlsmaJ, et al.EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis, 2017; 76(6):960–977; doi: 10.1136/annrheumdis-2016-210715
37.
SteunebrinkLMM, VersteegLGA, VonkemanHE, et al.Radiographic progression in early rheumatoid arthritis patients following initial combination versus step-up treat-to- Target Therapy in Daily Clinical Practice : Results from the DREAM Registry. BMC Rheumatol, 2018; 2:1–10; doi: 10.1186/s41927-018-0009-8
38.
van GestelAM, PrevooMLL, Van’t HofMA, et al.Development and validation of the European League against rheumatism response criteria for rheumatoid arthritis: Comparison with the preliminary American College of rheumatology and the World Health Organization/International league against rheumatism criteria. Arthritis & Rheumatism, 1996; 39(1):34–40; doi: 10.1002/art.1780390105
