J Rheum Dis.  2022 Apr;29(2):98-107. 10.4078/jrd.2022.29.2.98.

Time-integrated Cumulative Parameters Predictive of Radiographic Progression of Rheumatoid Arthritis: Real-world Data From a Prospective Single-center Cohort

• Park Y
• Li ML
• Kim JW
• Koh JH
• Park YJ
• Kim WU

• KMID: 2527549
• DOI: http://doi.org/10.4078/jrd.2022.29.2.98

Abstract

Objective
With many chronic inflammatory diseases, outcomes are determined by assessing both disease activity at presentation and cumulative activity over time. Here, we investigated whether cumulative activity better reflects the radiographic progression (RP) of rheumatoid arthritis (RA) than measurement of activity at a single time point.
Methods
From a prospective cohort of RA patients, most of whom were treated with anti-rheumatic drugs, we selected 117 subjects for whom laboratory, clinical, and radiographic parameters potentially influencing RP were monitored serially for more than 1 year. X-ray images of both hands and both feet were scored using the van der Heijde modified total Sharp score (mTSS). In addition to cross-sectional values at baseline, longitudinal and cumulative values for each parameter were calculated in a timeintegrated and averaged manner.
Results
Among the values measured at baseline, mTSS, but not the baseline erythrocyte sedimentation rate (ESR) or C-reactive protein level, was associated with RP. By contrast, multivariate analyses identified cumulative values such as the cumulative ESR, cumulative tender joint count, cumulative swollen joint count (SJC), and cumulative Disease Activity Score 28-ESR as major determinants of RP. In particular, the cumulative SJC showed the best predictive performance for RP.
Conclusion
This study highlights the importance of cumulative indices for predicting progression of RA. Specifically, dynamic and cumulative values of RA activity-related factors, particularly the cumulative SJC, may be the major determinants of RP in the current practice.

Keyword

Rheumatoid arthritis; Prognosis; Biomarkers

Figure

• 

  Fig. 1 Time-integrated cumulative values of clinical parameters related to rheumatoid arthritis disease activity. (A~G) Cumulative values of RF, ESR, CRP, DAS28-ESR, TJC, SJC, and sCD14. (H) Heatmap showing the p-value represented by –log (p-value). Bars indicate the median and interquartile ranges. All statistical analyses were performed using the Mann–Whitney U-test. RP: radiographic progression, RF rheumatoid factor, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, DAS28: Disease Activity Score 28, TJC: tender joint count, SJC: swollen joint count, sCD14: soluble CD14, mTSS: modified total Sharp score. *p<0.05, ***p<0.001.

• 

  Fig. 2 Diagnostic performance of the baseline mTSS, cumulative SJC, cumulative TJC, and cumulative DAS28-ESR for discriminating radiographic progression (RP). (A) Receiver operating characteristic curves of baseline mTSS, cumulative SJC, cumulative TJC, and cumulative DAS28-ESR. (B) Sensitivity, specificity, and cut-off values for clinical parameters predicting occurrence of RP. mTSS: modified total Sharp score, SJC: swollen joint count, TJC: tender joint count, DAS28: Disease Activity Score 28, ESR: erythrocyte sedimentation rate.

Reference

1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. 2018; Rheumatoid arthritis. Nat Rev Dis Primers. 4:18001. DOI: 10.1038/nrdp.2018.1. PMID: 29417936.

2. van der Heijde D. 2001; Radiographic progression in rheumatoid arthritis: does it reflect outcome? Does it reflect treatment? Ann Rheum Dis. 60 Suppl 3:iii47–50.

3. Aletaha D, Smolen JS. 2018; Diagnosis and management of rheumatoid arthritis: a review. JAMA. 320:1360–72. DOI: 10.1001/jama.2018.13103. PMID: 30285183.

4. Oh YJ, Park B, Moon KW. 2019; Effect of drug adherence on treatment outcome in rheumatoid arthritis. J Rheum Dis. 26:264–72. DOI: 10.4078/jrd.2019.26.4.264.

5. Murray E, Ellis A, Butylkova Y, Skup M, Kalabic J, Garg V. 2018; Systematic review and network meta-analysis: effect of biologics on radiographic progression in rheumatoid arthritis. J Comp Eff Res. 7:959–74. DOI: 10.2217/cer-2017-0106. PMID: 30129776.

6. Park YJ, Gherghe AM, van der Heijde D. 2020; Radiographic progression in clinical trials in rheumatoid arthritis: a systemic literature review of trials performed by industry. RMD Open. 6:e001277. DOI: 10.1136/rmdopen-2020-001277. PMID: 32669455. PMCID: PMC7425197.

7. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. 2012; Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 64:640–7. DOI: 10.1002/acr.21649. PMID: 22473918. PMCID: PMC4028066.

8. Lillegraven S, Prince FH, Shadick NA, Bykerk VP, Lu B, Frits ML, et al. 2012; Remission and radiographic outcome in rheumatoid arthritis: application of the 2011 ACR/EULAR remission criteria in an observational cohort. Ann Rheum Dis. 71:681–6. DOI: 10.1136/ard.2011.154625. PMID: 21994234.

9. Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. 2008; An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum. 58:2958–67. DOI: 10.1002/art.23945. PMID: 18821687.

10. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. 2011; Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 13:R141. DOI: 10.1186/ar3455. PMID: 21884601. PMCID: PMC3308069.

11. Landewé R, van der Heijde D, Klareskog L, van Vollenhoven R, Fatenejad S. 2006; Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes. Arthritis Rheum. 54:3119–25. DOI: 10.1002/art.22143. PMID: 17009230.

12. Ten Klooster PM, Versteeg LGA, Oude Voshaar MAH, de la Torre I, De Leonardis F, Fakhouri W, et al. 2019; Radiographic progression can still occur in individual patients with low or moderate disease activity in the current treat-to-target paradigm: real-world data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Arthritis Res Ther. 21:237. DOI: 10.1186/s13075-019-2030-8. PMID: 31718678. PMCID: PMC6852758.

13. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B. 2004; Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 63:1090–5. DOI: 10.1136/ard.2003.014233. PMID: 15308518. PMCID: PMC1755129.

14. Navarro-Compán V, Gherghe AM, Smolen JS, Aletaha D, Landewé R, van der Heijde D. 2015; Relationship between disease activity indices and their individual components and radiographic progression in RA: a systematic literature review. Rheumatology (Oxford). 54:994–1007. DOI: 10.1093/rheumatology/keu413. PMID: 25416711.

15. Landewé RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, et al. 2002; COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum. 46:347–56. DOI: 10.1002/art.10083. PMID: 11840436.

16. 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. 62:2569–81. DOI: 10.1002/art.27584. PMID: 20872595.

17. van der Heijde D. 2000; How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol. 27:261–3. DOI: 10.1097/00002281-200007000-00005. PMID: 10910177.

18. Matthews JN, Altman DG, Campbell MJ, Royston P. 1990; Analysis of serial measurements in medical research. BMJ. 300:230–5. DOI: 10.1136/bmj.300.6719.230. PMID: 2106931. PMCID: PMC1662068.

19. Park YJ, Yoo SA, Hwang D, Cho CS, Kim WU. 2016; Identification of novel urinary biomarkers for assessing disease activity and prognosis of rheumatoid arthritis. Exp Mol Med. 48:e211. DOI: 10.1038/emm.2015.120. PMID: 26915672. PMCID: PMC4892870.

20. Mikuls TR, LeVan TD, Sayles H, Yu F, Caplan L, Cannon GW, et al. 2011; Soluble CD14 and CD14 polymorphisms in rheumatoid arthritis. J Rheumatol. 38:2509–16. DOI: 10.3899/jrheum.110378. PMID: 21921097.

21. Listing J, Rau R, Müller B, Alten R, Gromnica-Ihle E, Hagemann D, et al. 2000; HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of radiographic progression in early rheumatoid arthritis. Berlin Collaborating Rheumatological Study Group. J Rheumatol. 27:2100–9.

22. Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. 2007; Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 146:797–808. DOI: 10.7326/0003-4819-146-11-200706050-00008. PMID: 17548411.

23. Kim H, Sung YK. 2021; Epidemiology of rheumatoid arthritis in Korea. J Rheum Dis. 28:60–7. DOI: 10.4078/jrd.2021.28.2.60.

24. Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2016; 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 68:1–26. DOI: 10.1002/art.39480. PMID: 26545940.

25. Smolen JS, Landewé 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. 79:685–99. DOI: 10.1136/annrheumdis-2019-216655. PMID: 31969328.

26. Gossec L, Dougados M, Goupille P, Cantagrel A, Sibilia J, Meyer O, et al. 2004; Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study. Ann Rheum Dis. 63:675–80. DOI: 10.1136/ard.2003.010611. PMID: 15140774. PMCID: PMC1755028.

27. Welsing PM, Landewé RB, van Riel PL, Boers M, van Gestel AM, van der Linden S, et al. 2004; The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis. Arthritis Rheum. 50:2082–93. DOI: 10.1002/art.20350. PMID: 15248205.

28. Wick MC, Lindblad S, Klareskog L, Van Vollenhoven RF. 2004; Relationship between inflammation and joint destruction in early rheumatoid arthritis: a mathematical description. Ann Rheum Dis. 63:848–52. DOI: 10.1136/ard.2003.015172. PMID: 15194582. PMCID: PMC1755049.