Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort

Harris A Ahmad, Evo Alemao, Zhenchao Guo, Christine K Iannaccone, Michelle L Frits, Michael Weinblatt, Nancy A Shadick, Harris A Ahmad, Evo Alemao, Zhenchao Guo, Christine K Iannaccone, Michelle L Frits, Michael Weinblatt, Nancy A Shadick

Abstract

Introduction: To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA).

Methods: Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR-BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2-immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1-3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] < 2.6) and bone loss was also explored.

Results: A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [-], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2- group. DXR-BMD was lower in the anti-CCP2+ vs. the anti-CCP2- groups (Gp1-3 vs. anti-CCP2-: P < 0.0001 for left and right hands). DXR-BMD decreased with increasing anti-CCP2 titer (P < 0.001 for left and right hands). Patients with low DXR-BMD were less likely to have a DAS28 (CRP) < 2.6 (P = 0.0181).

Conclusion: Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity.

Funding: Bristol-Myers Squibb.

Trial registration: Clinicaltrials.gov identifier, NCT01793103.

Keywords: Anti-cyclic citrullinated antibodies; Bone density; Osteoporosis; Rheumatoid arthritis.

Figures

Fig. 1
Fig. 1
Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) design
Fig. 2
Fig. 2
Association between DXR–BMD and anti-CCP2 antibody status and titer in a left hand and b right hand. Number of patients in each titer group: anti-CCP2–, n = 47; Gp1, n = 34; GP2, n = 34; Gp3, n = 34. Timeframe between DXR–BMD and anti-CCP2 measurements (months [SD]) were 0.6 (1.4) for anti-CCP2–, 1.8 (2.3) for Gp1, 1.1 (1.8) for GP2, and 1.0 (1.7) for Gp3 (P > 0.05 for comparison between the anti-CCP2+ groups and the anti-CCP2– group). Anti-CCP2 anti-cyclic citrullinated peptide-2 antibodies, anti-CCP2– anti-CCP2 antibody negative, anti-CCP2+ anti-CCP2 antibody positive, DXR–BMD digital X-ray radiogrammetry–bone mineral density, Gp group
Fig. 3
Fig. 3
Association between DXR–BMD and DAS28 (CRP)  CRP C-reactive protein, DAS28 Disease Activity in 28 joints, DXR–BMD digital X-ray radiogrammetry–bone mineral density

References

    1. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumatol. 1988;31:315–324. doi: 10.1002/art.1780310302.
    1. van der Heijde DM. Radiographic imaging: the ‘gold standard’ for assessment of disease progression in rheumatoid arthritis. Rheumatology (Oxford) 2000;39(Suppl 1):9–16. doi: 10.1093/oxfordjournals.rheumatology.a031496.
    1. Rossini M, Bagnato G, Frediani B, et al. Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis. J Rheumatol. 2011;38:997–1002. doi: 10.3899/jrheum.100829.
    1. Hoff M, Kvien TK, Kalvesten J, et al. Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: subanalysis of the PREMIER study. BMC Musculoskelet Disord. 2011;12:54. doi: 10.1186/1471-2474-12-54.
    1. Orsolini G, Caimmi C, Viapiana O, et al. Titer-dependent effect of anti-citrullinated protein antibodies on systemic bone mass in rheumatoid arthritis patients. Calcif Tissue Int. 2017;101:17–23. doi: 10.1007/s00223-017-0253-8.
    1. Bouxsein ML, Palermo L, Yeung C, et al. Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures. Osteoporos Int. 2002;13:358–365. doi: 10.1007/s001980200040.
    1. Haugeberg G, Lodder MC, Lems WF, et al. Hand cortical bone mass and its associations with radiographic joint damage and fractures in 50–70 year old female patients with rheumatoid arthritis: cross sectional Oslo–Truro–Amsterdam (OSTRA) collaborative study. Ann Rheum Dis. 2004;63:1331–1334. doi: 10.1136/ard.2003.015065.
    1. Book C, Algulin J, Nilsson JA, et al. Bone mineral density in the hand as a predictor for mortality in patients with rheumatoid arthritis. Rheumatology (Oxford) 2009;48:1088–1091. doi: 10.1093/rheumatology/kep169.
    1. Jensen T, Hansen M, Jensen KE, et al. Comparison of dual X-ray absorptiometry (DXA), digital X-ray radiogrammetry (DXR), and conventional radiographs in the evaluation of osteoporosis and bone erosions in patients with rheumatoid arthritis. Scand J Rheumatol. 2005;34:27–33. doi: 10.1080/03009740510017986.
    1. Kapetanovic MC, Lindqvist E, Algulin J, et al. Early changes in bone mineral density measured by digital X-ray radiogrammetry predict up to 20 years radiological outcome in rheumatoid arthritis. Arthritis Res Ther. 2011;13:R31. doi: 10.1186/ar3259.
    1. Hoff M, Haugeberg G, Odegard S, et al. Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up. Ann Rheum Dis. 2009;68:324–329. doi: 10.1136/ard.2007.085985.
    1. Rezaei H, Saevarsdottir S, Geborek P, et al. Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial. BMC Musculoskelet Disord. 2013;14:79. doi: 10.1186/1471-2474-14-79.
    1. Guler-Yuksel M, Allaart CF, Goekoop-Ruiterman YP, et al. Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68:330–336. doi: 10.1136/ard.2007.086348.
    1. Hoff M, Kvien TK, Kalvesten J, et al. Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study. Ann Rheum Dis. 2009;68:1171–1176. doi: 10.1136/ard.2008.091264.
    1. Krieckaert CL, Nurmohamed MT, Wolbink G, et al. Changes in bone mineral density during long-term treatment with adalimumab in patients with rheumatoid arthritis: a cohort study. Rheumatology (Oxford) 2013;52:547–553. doi: 10.1093/rheumatology/kes320.
    1. Vis M, Havaardsholm EA, Haugeberg G, et al. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1495–1499. doi: 10.1136/ard.2005.044198.
    1. Eekman DA, Vis M, Bultink IE, et al. Stable bone mineral density in lumbar spine and hip in contrast to bone loss in the hands during long-term treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:389–390. doi: 10.1136/ard.2009.127787.
    1. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005;7:R949–R958. doi: 10.1186/ar1767.
    1. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569–2581. doi: 10.1002/art.27584.
    1. Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122:1791–1802. doi: 10.1172/JCI60975.
    1. Krishnamurthy A, Joshua V, Haj HA, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis. 2016;75:721–729. doi: 10.1136/annrheumdis-2015-208093.
    1. Kleyer A, Finzel S, Rech J, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis. 2014;73:854–860. doi: 10.1136/annrheumdis-2012-202958.
    1. Boyesen P, Hoff M, Odegard S, et al. 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. 2009;11:R103. doi: 10.1186/ar2749.
    1. Bugatti S, Bogliolo L, Vitolo B, et al. Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis. Arthritis Res Ther. 2016;18:226. doi: 10.1186/s13075-016-1116-9.
    1. Bykerk VP, Shadick N, Frits M, et al. Flares in rheumatoid arthritis: frequency and management. A report from the BRASS registry. J Rheumatol. 2014;41:227–234. doi: 10.3899/jrheum.121521.
    1. Iannaccone CK, Lee YC, Cui J, et al. Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: data from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study. Rheumatology (Oxford) 2011;50:40–46. doi: 10.1093/rheumatology/keq263.
    1. Iannaccone CK, Fossel A, Tsao H, et al. Factors associated with attrition in a longitudinal rheumatoid arthritis registry. Arthritis Care Res (Hoboken) 2013;65:1183–1189. doi: 10.1002/acr.21940.
    1. Desai SP, Gravallese EM, Shadick NA, et al. Hand bone mineral density is associated with both total hip and lumbar spine bone mineral density in post-menopausal women with RA. Rheumatology (Oxford) 2010;49:513–519. doi: 10.1093/rheumatology/kep385.
    1. Hochberg Y. A sharper Bonferroni procedure for multiple significance testing. Biometrika. 1988;75:800–803. doi: 10.1093/biomet/75.4.800.
    1. Forslind K, Kalvesten J, Hafstrom I, et al. Does digital X-ray radiogrammetry have a role in identifying patients at increased risk for joint destruction in early rheumatoid arthritis? Arthritis Res Ther. 2012;14:R219. doi: 10.1186/ar4058.
    1. Black RJ, Spargo L, Schultz C, et al. Decline in hand bone mineral density indicates increased risk of erosive change in early rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014;66:515–522. doi: 10.1002/acr.22199.
    1. Bejarano V, Hensor E, Green M, et al. Relationship between early bone mineral density changes and long-term function and radiographic progression in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:66–70. doi: 10.1002/acr.20553.
    1. Koh JH, Jung SM, Lee JJ, et al. Radiographic structural damage is worse in the dominant than the non-dominant hand in individuals with early rheumatoid arthritis. PLoS One. 2015;10:e0135409. doi: 10.1371/journal.pone.0135409.
    1. Walsh NC, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev. 2010;233:301–312. doi: 10.1111/j.0105-2896.2009.00857.x.
    1. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8:656–664. doi: 10.1038/nrrheum.2012.153.
    1. Bugatti S, Manzo A, Caporali R, et al. Assessment of synovitis to predict bone erosions in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2012;4:235–244. doi: 10.1177/1759720X12453092.

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