The online version of this article (doi:10.1186/s12891-015-0587-1) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
MA was responsible for the study design, clinical assessment, analysis, communication of data and drafting the manuscript. PWAM was responsible for the study design and the generation, analysis, communication of data and critical revision of important intellectual content. BH was responsible for the study design, clinical assessment, analysis, communication of data and critical revision of important intellectual content. EM was responsible for the statistical design, data analysis and critical revision of important intellectual content. GT was responsible for study design, analysis of data and critical revision of important intellectual content. MT was responsible for the study design, served as the clinical coordinator, and performed data analysis, critical revision of important intellectual content. RA was responsible for the study design, analysis, critical revision of important intellectual content and coordinator. All authors read and approved the final manuscript.
To measure circulating anti-citrullinated peptide antibodies (ACPA) and cytokines pre- and 6 months post-therapy as a strategy to predict and optimize responses to traditional disease-modifying antirheumatic drugs (DMARDs) in early RA, which is an unmet need in developing countries.
A cohort of 140 predominantly (88.5 %) black female South African patients with early RA was treated with synthetic DMARDs, mostly methotrexate (MTX) alone, or in combination with low-dose oral corticosteroids (CS). Circulating ACPA and a panel of circulating cytokines/chemokines/growth factors were measured at baseline and after 6 months of therapy in relation to disease activity and Shared Epitope (SE).
Following 6 months of therapy, the median simplified disease activity index (SDAI) declined from a baseline of 41.4 to 16.0 (p = 0.0001) for the entire cohort, which was paralleled by significant falls in median serum ACPA levels (516.6 vs. 255.7 units/ml, p = <0.0001) and several of the circulating cytokines (IL-4, IL-7, IL-8, G-CSF, VEGF; p < 0.0010 – p < 0.0001) which were most evident in the subgroup of patients treated with a combination of MTX and CS. Although biomarker concentrations decreased most notably in the low-disease activity group post-therapy, no significant correlations between these biomarkers and disease activity were observed, Baseline ACPA levels, but not SDAI or cytokines, were significantly higher in the subgroup of risk allele-positive patients (561.1 vs. 331.9 units/ml, p < 0.05), while no associations with ACPA and a smoking history were evident.
The use of DMARDs in RA is associated with significant decreases in ACPA and cytokines which did not correlate with changes in SDAI, precluding the utility of serial measurement of these biomarkers to monitor early responses to therapy, but may have prognostic value.
Additional file 1: Table S1. SDAI (Simplified disease activity index) base line disease activity. Table S2. changes in SDAI and circulating biomarker concentrations following 6 months of synthetic DMARD therapy. Table S3. SDAI (Simplified disease activity index) response at 6 months. Table S4. SDAI (Simplified disease activity index) response at 6 months treatment sub-groups. Table S5. SDAI (Simplified disease activity index) response at 6 months risk allele sub-groups.12891_2015_587_MOESM1_ESM.pdf
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 3rd CO, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;2010(62):2569–81. CrossRef
Alex P, Szodoray P, Knowlton N, Dozmorov IM, Turner M, Frank MB, et al. Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis. Clin Exp Rheumatol. 2007;25:584–92. PubMed
Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis. 2004;63:1218–21. CrossRefPubMedPubMedCentral
Mikuls TR, O”Dell JR, Stoner JA, Parrish LA, Arend WP, Norris JM, et al. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody. Arthritis Rheum. 2004;50:3776–82. CrossRefPubMed
Bobbio-Pallavicini F, Caporali R, Bugatti S, Montecucco C. What can we learn from treatment-induced changes in rheumatoid factor and anti-citrullinated Peptide antibodies? J Rheumatol. 2008;35:1903–5. PubMed
Simsek I. Predictors of response to TNF inhibitors in rheumatoid arthritis – do we have new tools for personalized medicine? Bull NYU Hosp Jt Dis. 2012;70:187–90. PubMed
Haroon N, Misra R, Aggarwal A. Tailor-made therapy in rheumathoid arthritis: fact or fiction? Isr Med Assoc J. 2008;10:139–41. PubMed
Kapitány A, Szabó Z, Lakos G, Aleksza M, Végvári A, Soós L, et al. Associations between serum anti-CCP antibody, rheumatoid factor levels and HLA-DR4 expression in Hungarian patients with rheumatoid arthritis. Isr Med Assoc J. 2008;10:32–6. PubMed
da Mota LM, dos Santos Neto LL, Pereira IA, Burlingame R, Ménard HA, Laurindo IM. Autoantibodies as predictors of biological therapy for early rheumatoid arthritis. Acta Reumatol Port. 2010;35:156–66. PubMed
Braun-Moscovici Y, Markovits D, Zinder O, Schapira D, Rozin A, Ehrenburg M, et al. Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis. J Rheumatol. 2006;33:497–500. PubMed
Katchamart W, Johnson S, Lin HJ, Phumethum V, Salliot C, Bombardier C. Predictors for remission in rheumatoid arthritis patients: A systemic review. Arthritis Care Res (Hoboken). 2010;62:1128–43. CrossRef
Hyrich KL, Watson KD, Silman AJ, Symmons DP, British Society for Rheumatology Biologics Register. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2006;45:1558–65. CrossRef
Bizzaro N, Bartoloni E, Morozzi G, Manganelli S, Riccieri V, Sabatini P, et al. Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2 year prospective study. Arthritis Res Ther. 2013;15:R16. CrossRefPubMedPubMedCentral
Meyer O, Nicaise-Roland P, Santos MD, Labarre C, Dougados M, Goupille P, et al. Serial determination of cyclic citrullinated peptide autoantibodies predicted 5 year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis. Arthritis Res Ther. 2006;8:R40. CrossRefPubMedPubMedCentral
Cuchacovich M, Catalan D, Wainstein E, Gatica H, Soto L, Aravena O, et al. Basal anti-cyclic citrullinated peptide (anti-CCP) antibody levels and a decrease in anti-CCP titres are associated with clinical response to adalimumab in rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:1067–73. PubMed
McGeough CM, Bjourson AJ. Diagnostic, prognostic and theranostic genetic biomarkers for rheumatoid arthritis. J Clin Cell Immunol. 2012;S6:002. doi:10.4172/2155-9899.S6-002.
Marasovic-Krstulovic D, Martinovic-Kaliterna D, Fabijanic D, Morovic-Vergles J. Are the anti-cyclic citrullinated peptide antibodies independent predictors of myocardial involvement in patients with active rheumatoid arthritis? Rheumatology (Oxford). 2011;50:1505–12. CrossRef
Nowak D, Lewandowicz J, Dbkowska B, Marczak J. Combination of methotrexate and prednizone decreases circulating concentrations of interleukin 1 beta and Interleukin 6 in patients with rheumatoid arthritis. Poor correlation of cytokine suppression with clinical improvement. Int J Immunopathol Pharmacol. 1999;12:13–21. PubMed
Visvanathan S, Marini JC, Smolen JS, Clair EW, Pritchard C, Shergy W, et al. Changes in biomarkers of inflammation and bone turnover and associations with clinical efficacy following infliximab plus methotrexate therapy in patients with early rheumatoid arthritis. J Rheumatol. 2007;34:1465–74. PubMed
Potter C, Hyrich KL, Tracey A, Lunt M, Plant D, Symmons DP, et al. Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of share epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis. 2009;68:69–74. CrossRefPubMed
- Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis
Mahmood M. T. M. Ally
Pieter W. A. Meyer
Gregory R. Tintinger
- BioMed Central
Neu im Fachgebiet Orthopädie und Unfallchirurgie
Mail Icon II