Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of periarticular bone loss is associated with clinical remission and ACR70-Response in rheumatoid arthritis

  • Clinical Trials
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

The aim of this study, based on a post hoc analysis of the data set used in the RAPID 1 trial, focuses on the associations between metacarpal bone mineral density, as estimated by digital X-ray radiogrammetry (DXR), and clinical remission as well as ACR70-Response in rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP). The trial evaluates a total of 345 RA patients treated with methotrexate versus CZP 200 mg versus CZP 400 mg. All patients underwent X-rays of the hand at baseline and week 52 as well as computerized calculations of bone mineral density (BMD) by DXR. Clinical remission was defined as DAS28 < 2.6. ACR70-Response was also evaluated. The radiological assessment of disease progression was estimated using the modified total Sharp Score. The mean difference for DAS28 was observed for patients treated with CZP 400 mg (median: − 3.53, minimum: − 6.77; maximum: + 0.48) and CZP 200 mg (median: − 3.13, minimum: − 6.37; maximum: − 0.52) compared to the methotrexate group (median − 2.41, minimum: − 4.76; maximum: + 0.31). The DXR-BMD showed a minor bone loss for the treatment groups undergoing therapy with CZP 200 mg (median: − 0.009 g/cm2, minimum: − 0.059 g/cm2; maximum: + 0.095 g/cm2) and CZP 400 mg (median: − 0.008 g/cm2, minimum: − 0.064 g/cm2; maximum: + 0.080 g/cm2). The methotrexate group presented an advanced periarticular metacarpal bone loss as measured by DXR-BMD (median: − 0.024 g/cm2, minimum: − 0.102 g/cm2; maximum: + 0.057 g/cm2). In the case of clinical remission and ACR70-Response, no significant change of the DXR-BMD was observed for both CZP groups. The study highlights that patients treated with CZP show a less accentuated periarticular bone loss as estimated by DXR in comparison to patients with methotrexate plus placebo. In addition, patients with clinical remission and ACR70-Response revealed no periarticular demineralisation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BMD:

Bone mineral density (g/cm2) estimated by digital X-ray radiogrammetry

CRP:

C-reactive protein

CT:

Cortical thickness (cm) estimated by digital X-ray radiogrammetry

DAS28:

Disease activity score 28

DXR:

Digital X-ray radiogrammetry

MCI:

Metacarpal index estimated by digital X-ray radiogrammetry

MTX:

Methotrexate

n.s.:

Not significant

OPG:

Osteoprotegerin

RA:

Rheumatoid arthritis

RANKL:

Receptor activators of the nuclear κB ligand

TNFα:

Tumor necrosis factorα

W:

Metacarpal bone width (cm) estimated by digital X-ray radiogrammetry

References

  1. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219. https://doi.org/10.1016/S0140-6736(17)31472-1

    Article  PubMed  CAS  Google Scholar 

  2. Guler-Yuksel M, Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Groenendael JH, Mallée C, de Bois MH, Breedveld FC, Dijkmans BA, Lems WF (2009) Changes in hand and generalized bone mineral density in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 68:330–3336. https://doi.org/10.1136/ard.2007.086348

    Article  PubMed  CAS  Google Scholar 

  3. Pfeil A, Haugeberg G, Renz DM, Reinhardt L, Jung C, Franz M, Wolf G, Böttcher J (2017) Digital X-ray radiogrammetry and its sensitivity and specificity for the identification of rheumatoid arthritis-related cortical hand bone loss. J Bone Miner Metab 35:192–198. https://doi.org/10.1007/s00774-016-0741-3

    Article  PubMed  CAS  Google Scholar 

  4. Wevers-de Boer KV, Heimans L, Visser K, Kälvesten J, Goekoop RJ, van Oosterhout M, Harbers JB, Bijkerk C, Steup-Beekman M, de Buck MP, de Sonnaville PB, Huizinga TW, Allaart CF (2015) Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1 year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study. Ann Rheum Dis 74:341–346. https://doi.org/10.1136/annrheumdis-2013-203749

    Article  PubMed  CAS  Google Scholar 

  5. Böttcher J, Pfeil A, Rosholm A, Petrovitch A, Seidl BE, Malich A, Schäfer ML, Kramer A, Mentzel HJ, Lehmann G, Hein G, Kaiser WA (2005) Digital X-ray radiogrammetry combined with semi-automated analysis of joint space distances as a new diagnostic approach in rheumatoid arthritis—a cross-sectional and longitudinal study. Arthritis Rheum 52:3850–3859. https://doi.org/10.1002/art.21606

    Article  PubMed  Google Scholar 

  6. Böttcher J, Pfeil A, Schäfer ML, Petrovitch A, Seidl BE, Mentzel HJ, Lehmann G, Malich A, Heyne JP, Hein G, Wolf G, Kaiser WA (2006) Normative data for digital X-ray radiogrammetry from a female and male German cohort. J Clin Densitom 9:341–350. https://doi.org/10.1016/j.jocd.2006.05.010

    Article  PubMed  Google Scholar 

  7. Hoff M, Haugeberg G, Kvien TK (2007) Hand bone loss as outcome measure in established rheumatoid arthritis: a two-year observational study comparing cortical and total bone loss. Arthritis Res Ther 9:R81. https://doi.org/10.1186/ar2280

    Article  PubMed  PubMed Central  Google Scholar 

  8. Böttcher J, Pfeil A, Rosholm A, Malich A, Petrovitch A, Heinrich B, Lehmann G, Mentzel HJ, Hein G, Linss W, Kaiser WA (2005) Influence of image-capturing parameters on digital X-ray radiogrammetry. J Clin Densitom 8:87–94

    Article  PubMed  Google Scholar 

  9. Böttcher J, Pfeil A, Rosholm A, Sörös P, Petrovitch A, Schaefer ML, Seidl BE, Malich A, Hansch A, Wolf G, Kaiser WA (2006) Computerized quantification of joint space narrowing and periarticular demineralization in patients with rheumatoid arthritis based on digital X-ray radiogrammetry. Investig Radiol 41:36–44. https://doi.org/10.1097/01.rli.0000191594.76235.a0

    Article  Google Scholar 

  10. Pfeil A, Haugeberg G, Hansch A, Renz DM, Lehmann G, Malich A, Wolf G, Böttcher J (2011) The value of digital X-ray radiogrammetry in the assessment of inflammatory bone loss in rheumatoid arthritis. Arthritis Care Res (Hoboken) 63:666–674. https://doi.org/10.1002/acr.20423

    Article  Google Scholar 

  11. Platten M, Kisten Y, Kälvesten J, Arnaud L, Forslind K, van Vollenhoven R (2017) Fully automated joint space width measurement and digital X-ray radiogrammetry in early RA. RMD Open 3:e000369. https://doi.org/10.1136/rmdopen-2016-000369

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ziegelasch M, Forslind K, Skogh T, Riklund K, Kastbom A, Berglin E (2017) Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year. Arthritis Res Ther 19:195. https://doi.org/10.1186/s13075-017-1403-0

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kälvesten J, Lui LY, Brismar T, Cummings S (2016) Digital X-ray radiogrammetry in the study of osteoporotic fractures: comparison to dual energy X-ray absorptiometry and FRAX. Bone 86:30–35. https://doi.org/10.1016/j.bone.2016.02.011

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pfeil A, Lippold J, Eidner T, Lehmann G, Oelzner P, Renz DM, Hansch A, Wolf G, Hein G, Kaiser WA, Böttcher J (2009) Effects of leflunomide and methotrexate in rheumatoid arthritis detected by digital X-ray radiogrammetry and computer-aided joint space analysis. Rheumatol Int 29:287–295. https://doi.org/10.1007/s00296-008-0682-9

    Article  PubMed  CAS  Google Scholar 

  15. Hoff M, Kvien TK, Kalvesten J, Elden A, Haugeberg G (2009) Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study. Ann Rheum Dis 68:1171–1176. https://doi.org/10.1136/ard.2008.091264

    Article  PubMed  CAS  Google Scholar 

  16. Keystone E, Heijde D van der, Landewé MD Jr, Vollenhoven R, Combe RV, Emery B, Strand P, Mease V, Desai P, Pavelka C K (2008) Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 58:3319–3329. https://doi.org/10.1002/art.23964

    Article  PubMed  CAS  Google Scholar 

  17. Rosholm A, Hyldstrup L, Baeksgaard L, Grunkin M, Thodberg HH (2001) Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing. Osteoporos Int 12:961–969

    Article  PubMed  CAS  Google Scholar 

  18. Forsblad-d’Elia H, Carlsten H (2011) Hormone replacement therapy in postmenopausal women with rheumatoid arthritis stabilises bone mineral density by digital X-ray radiogrammetry in a randomised controlled trial. Ann Rheum Dis 70:1167–1168. https://doi.org/10.1136/ard.2010.137133

    Article  PubMed  Google Scholar 

  19. Krieckaert CLM, Nurmohamed MT, Wolbink G, Lems WF (2013) Changes in bone mineral density during long-term treatment with adalimumab in patients with rheumatoid arthritis: a cohort study. Rheumatology 52:547–553. https://doi.org/10.1093/rheumatology/kes320

    Article  PubMed  CAS  Google Scholar 

  20. van der Heijde DM, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S, TEMPO Study Investigators (2006) Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomised trial. Arthritis Rheum 54:1063–1074. https://doi.org/10.1002/art.21655

    Article  PubMed  CAS  Google Scholar 

  21. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT (2006) The PREMIER study: a multicenter, randomised, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54:26–37. https://doi.org/10.1002/art.21519

    Article  PubMed  CAS  Google Scholar 

  22. Zerbini CAF, Clark P, Mendez-Sanchez L, Pereira RMR, Messina OD, Uña CR, Adachi JD, Lems WF, Cooper C, Lane NE (2017) Biologic therapies and bone loss in rheumatoid arthritis. Osteoporos Int 28:429–446. https://doi.org/10.1007/s00198-016-3769-2

    Article  PubMed  CAS  Google Scholar 

  23. Haugeberg G, Strand A, Kvien TK, Kirwan JR (2005) Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial. Arch Intern Med 165:1293–1297. https://doi.org/10.1001/archinte.165.11.1293

    Article  PubMed  Google Scholar 

  24. Schett G, Saag KG, Bijlsma JWJ (2010) From bone biology to clinical outcome: state of the art and future perspectives. Ann Rheum Dis 69:1415–1419. https://doi.org/10.1136/ard.2010.135061

    Article  PubMed  CAS  Google Scholar 

  25. Hofbauer LC, Heufelder AE (2001) Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology. J Mol Med 79:243–253

    Article  PubMed  CAS  Google Scholar 

  26. Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y (2004) IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 15:49–60

    Article  PubMed  CAS  Google Scholar 

  27. Schett G (2009) Osteoimmunology in rheumatic disease. Arthritis Res Ther 11:210. https://doi.org/10.1186/ar2571

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Bøyesen P, Hoff M, Ødegård S, Haugeberg G, Syversen SW, Gaarder PI, Okkenhaug C, Kvien TK (2009) Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study. Arthritis Res Ther 11:R103. https://doi.org/10.1186/ar2749

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Böttcher J, Pfeil A, Mentzel HJ, Kramer A, Schäfer ML, Lehmann G, Eidner T, Petrovitch A, Malich A, Hein G, Kaiser WA (2006) Peripheral bone status in rheumatoid arthritis evaluated by digital X-ray radiogrammetry (DXR) and compared with multi-site quantitative ultrasound (QUS). Calcif Tissue Int 78:25–34. https://doi.org/10.1007/s00223-005-0175-8

    Article  PubMed  CAS  Google Scholar 

  30. Hoff M, Bøyesen P, Haugeberg G, Vis M, Woolf AD, Havaardsholm EA, Dijkmans BA, Kvien TK, Uhlig T, Lems WF (2010) High disease activity is a predictor of cortical hand bone loss in post-menopausal patients with established rheumatoid arthritis: a 5-year multicentre longitudinal study. Rheumatology 49:1676–1682. https://doi.org/10.1093/rheumatology/keq125

    Article  PubMed  Google Scholar 

  31. Pfeil A, Oelzner P, Renz DM, Hansch A, Wolf G, Böttcher J (2015) Is there a role for digital X-ray radiogrammetry as surrogate marker for radiological progression and imaging of structural integrity in rheumatoid arthritis? BMC Musculoskelet Disord 16:155. https://doi.org/10.1186/s12891-015-0577-3

    Article  PubMed  PubMed Central  Google Scholar 

  32. Landewé R, Strand V, van der Heijde D (2013) From inhibition of radiographic progression to maintaining structural integrity: a methodological framework for radiographic progression in rheumatoid arthritis and psoriatic arthritis clinical trials. Ann Rheum Dis 72:1113–1117. https://doi.org/10.1136/annrheumdis-2012-203159

    Article  PubMed  Google Scholar 

  33. Pfeil A, Oelzner P, Renz DM, Lehmann G, Wolf G, Böttcher J (2014) Visualisation of structural damage as a surrogate marker of radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis 73:e24. https://doi.org/10.1136/annrheumdis-2013-204786

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Monika Arens (Managing Director, Arewus GmbH) and Jacob Algulin (Managing Director, Sectra, Sweden) for the use of the Digital X-ray Radiogrammetry technique. Further thanks to Thomas Lehmann (PhD) for the statistical advice. Also many thanks to Dr. Natalia de Peyrecave (UCB Pharma, Brussels, Belgium), Dr. Anja Schwarz (UCB Pharma GmbH, Monheim, Germany), Dr. Udo Lendl (UCB Pharma GmbH, Monheim, Germany), Dr. Hans-Joachim Kreutzenbeck (UCB Pharma GmbH, Monheim, Germany), and Dr. Robert Reinhold (UCB Pharma GmbH, Monheim, Germany) for the support in performing the Investigator Initiated Study performed in Jena and for the helpful critical discussion of the data.

Funding

This study is a part of the Investigator Initiated Study “The quantification of inflammatory related periarticular bone loss in certolizumab pegol treated patients with rheumatoid arthritis” which is funded and supported by UCB Pharma GmbH, Monheim, Germany (number: IIS-2014-101458).

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany

    Alexander Pfeil, Anica Nussbaum, Peter Oelzner & Gunter Wolf

  2. Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany

    Diane M. Renz

  3. Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, University Hospital Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany

    Christian Jung

  4. Institute of Diagnostic Radiology, Suedharz-Hospital Nordhausen, Dr.-Robert-Koch-Straße 38, 99734, Nordhausen, Germany

    Ansgar Malich

  5. Institute of Diagnostic and Interventional Radiology, SRH Wald-Klinikum Gera, Straße des Friedens 122, 07548, Gera, Germany

    Joachim Böttcher

Authors
  1. Alexander Pfeil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anica Nussbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diane M. Renz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Oelzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ansgar Malich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gunter Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joachim Böttcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AP designed the study, analyzed the radiographs, performed the statistical analysis, wrote the manuscript, and revised the manuscript. AN performed the BX-measurements and participated on the statistical analysis as well as on the study design. DR analyzed the radiographs, interpreted the radiograph data, and helped to draft the manuscript. CJ performed the statistical analysis and interpreted the data. LR performed the data collection and participated on the statistical analysis. PO edited the manuscript. AM printed the radiographs and evaluated the radiographs. GW interpreted the data and edited the manuscript. JB participated on the study design, read the hand X-ray, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Alexander Pfeil.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical approval was obtained at each site as described previously [15]. The study protocol including the prespecified analysis of X-rays was registered in clinical trials.gov (trial identifier: NCT00152386). In addition, all examinations were performed in accordance with the rules and regulations of the local Human Research and Ethics Committee of the Friedrich-Schiller-University Jena. The study is a retrospective post hoc analysis of data sets which are considered in the RAPID 1 trial [15]. Based on the regulations of the ethics committee of the Friedrich-Schiller-University Jena, a registration and a separate consent from any patient were not necessary.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pfeil, A., Nussbaum, A., Renz, D.M. et al. Inhibition of periarticular bone loss is associated with clinical remission and ACR70-Response in rheumatoid arthritis. Rheumatol Int 39, 637–645 (2019). https://doi.org/10.1007/s00296-018-4226-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-018-4226-7

Keywords

Search

Navigation