Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis

BMC Musculoskeletal Disorders

Ronald Anderson²  Mohammed Tikly³  Gregory R. Tintinger²  Eustasius Musenge¹  Pieter W. A. Meyer²  Bridget Hodkinson³  Mahmood M. T. M. Ally² 

[1] Biostatistics and Epidemiology Division, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, York Road, Johannesburg 2193, South Africa;Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria 0001, South Africa;Division of Rheumatology, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Chris Hani Road, Johannesburg 2013, South Africa

关键词: Rheumatoid arthritis;    Disease modifying antirheumatic drugs;    Shared epitope;    Cytokines;    Anticyclic citrullinated peptide antibodies;   

Others  :  1227765
DOI  :  10.1186/s12891-015-0587-1

 received in 2015-03-02, accepted in 2015-05-18,  发布年份 2015

【 摘 要 】

Background

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.

Patients and methods

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).

Results

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.

Conclusions

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.

【 授权许可】

   
2015 Ally et al.; licensee BioMed Central.

【 参考文献 】

• [1]Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 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.
• [2]Modi S, Soejima M, Levesque MC. The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses. Clin Exp Immunol. 2013; 173:8-17.
• [3]Morozzi G, Fabbroni M, Bellisai F, Cucini S, Simpatico A, Galeazzi M. Low serum level of COMP, a cartilage turnover marker, predicts rapid and high ACR70 response to adalimumab therapy in rheumatoid arthritis. Clin Rheumatol. 2007; 26:1335-8.
• [4]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.
• [5]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.
• [6]Bobbio-Pallavicini F, Alpini C, Caporali R, Avalle S, Bugatti S, Montecucco C. Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res Ther. 2004; 6:R264-72.
• [7]Caramaschi P, Biasi D, Tonolli E, Pieropan S, Martinelli N, Carletto A et al.. Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment. Rheumatol Int. 2005; 26:58-62.
• [8]Chen HA, Lin KC, Chen CH, Liao HT, Wang HP, Chang HN et al.. The effect of etanercept on anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann Rheum Dis. 2006; 65:35-9.
• [9]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.
• [10]Atzeni F, Sarzi-Puttini P, Dell’ Acqua D, de Portu S, Cecchini G, Cruini C et al.. Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study. Arthritis Res Ther. 2006; 8:R3.
• [11]Braun J, Rau R. An update on methotrexate. Curr Opin Rheumatol. 2009; 21:216-23.
• [12]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.
• [13]De Rycke L, Verhelst X, Kruithof E, Van den Bosch F, Hoffman IE, Veys EM et al.. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis. 2005; 64:299-302.
• [14]Visser K, Verpoort KN, van Dongen H, van der Kooij SM, Allaart CF, Toes RE et al.. Pretreatment serum levels of anti-cyclic citrullinated peptide antibodies are associated with the response to methotrexate in recent-onset arthritis. Ann Rheum Dis. 2008; 67:1194-5.
• [15]Lal P, Su Z, Holweg CT, Silverman GJ, Schwartzman S, Kelman A et al.. Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituzimab treatment. Arthritis Rheum. 2011; 63:3681-91.
• [16]Kasama T, Isojima S, Umemura M, Tsukamoto H, Tokunaga T, Furuya H et al.. Serum macrophage migration inhibitory factor levels are correlated with response to tocilizumab therapy in patients with rheumatoid arthritis. Rheumatol Int. 2014; 34:429-33.
• [17]van Roon JA, Jacobs K, Verstappen S, Bijlsma J, Lafeber F. Reduction of serum interleukin 7 levels upon methotrexate therapy in early rheumatoid arthritis correlates with disease suppression. Ann Rheum Dis. 2008; 67:1054-5.
• [18]Maillefert JF, Puéchal X, Falgarone G, Lizard G, Ornetti P, Solau E et al.. Réseau Rhumato Study Group: Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. Joint Bone Spine. 2010; 77:558-63.
• [19]Nishina N, Kaneko Y, Kameda H, Kuwana M, Takeuchi T. Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. Clin Rheumatol. 2013; 32:1661-6.
• [20]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.
• [21]Kilic T, Ural D, Ural E, Yumuk Z, Agacdiken A, Sahin T et al.. Relation between proinflammatory to anti-inflammatory cytokine ratios and long-term prognosis in patients with non-ST elevation acute coronary syndrome. Heart. 2006; 92:1041-6.
• [22]Niewold TB, Harrison MJ, Paget SA. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. QJM. 2007; 100:193-201.
• [23]Haroon N, Misra R, Aggarwal A. Tailor-made therapy in rheumathoid arthritis: fact or fiction? Isr Med Assoc J. 2008; 10:139-41.
• [24]Halilova KI, Brown EE, Morgan SL, Bridges SL, Hwang MH, Arnett DK et al.. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int J Rheumatol. 2012; 2012:978396.
• [25]Romão VC, Canhão H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med. 2013; 11:17.
• [26]Meyer PW, Hodkinson B, Ally M, Musenge E, Waddee AA, Fickl H et al.. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediators Inflamm. 2010; 2010:158514.
• [27]Hodkinson B, Musenge E, Ally M, Meyer PW, Anderson R, Tikly M. Response to traditional disease-modifying anti-rheumatic drugs in indigent South Africans with early rheumatoid arthritis. Clin Rheumatol. 2012; 31:613-9.
• [28]Aletaha D, Martinez-Avila J, Kvien TK, Smolen JS. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Ann Rheum Dis. 2012; 71:1190-6.
• [29]du Montcel ST, Michou L, Petit-Teixeira E, Osorio J, Lemaire I, Lasbleiz S et al.. New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum. 2005; 52:1063-8.
• [30]Michou L, Croiseau P, Petit-Teixeira E, du Montcel ST, Lemaire I, Pierlot C et al.. Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. Arthritis Res Ther. 2006; 8:R79.
• [31]Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis. 2004; 63:1085-9.
• [32]Kurkó J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z. Genetics of rheumatoid arthritis — a comprehensive review. Clin Rev Allergy Immunol. 2013; 45:170-9.
• [33]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.
• [34]Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F et al.. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 2005; 52:3813-8.
• [35]Lee DM, Phillips R, Hagan EM, Chibnik LB, Costenbader KH, Schur PH. Quantifying anti-cyclic citrullinated peptide titres: clinical utility and association with tobacco exposure in patients with rheumatoid arthritis. Ann Rheum Dis. 2009; 68:201-8.
• [36]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.
• [37]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.
• [38]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.
• [39]Hyrich KL, Watson KD, Silman AJ, Symmons DP. 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.
• [40]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.
• [41]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.
• [42]Fabre S, Guisset C, Tatem L, Dossat N, Dupuy AM, Cohen JD et al.. Protein biochip array technology to monitor rituximab in rheumatoid arthritis. Clin Exp Immunol. 2009; 155:395-402.
• [43]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.
• [44]Davis JM, Matteson E. Cytokine biomarkers and the promise of personalized therapy in rheumatoid arthritis. Reumatol Clin. 2009; 5:143-6.
• [45]Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G et al.. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis. 2006; 65:453-8.
• [46]Burr ML, Viatte S, Bukhari M, Plant D, Symmonsen DP, Thomson W et al.. Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis. Arthritis Res Ther. 2012; 14:R109.
• [47]Taylor P, Gartemann J, Hsieh J, Creeden J. A systemic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factors as tests for rheumatoid arthritis. Autoimmune Dis. 2011; 2011:815038.
• [48]Miriovsky BJ, Michaud K, Thiele GM, O’Dell JR, Cannon GW, Kerr G et al.. Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis. Ann Rheum Dis. 2010; 69:1292-7.
• [49]McGeough CM, Bjourson AJ. Diagnostic, prognostic and theranostic genetic biomarkers for rheumatoid arthritis. J Clin Cell Immunol. 2012; S6:002.
• [50]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.
• [51]Giles JT, Malayeri AA, Fernandes V, Post W, Blumethal RS, Bluemke D et al.. Left ventricular structure and function in patients with rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging. Arthritis Rheum. 2010; 62:940-51.
• [52]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.
• [53]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.
• [54]Emery P, Dörner T. Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response. Ann Rheum Dis. 2011; 70:2063-70.
• [55]Shimamoto K, Ito T, Ozaki Y, Amuro H, Tanaka A, Nishizawa T et al.. Serum interleukin 6 before and after therapy with tocilizumab Is a principal biomarker in patients with rheumatoid arthritis. J Rheumatol. 2013; 40:1074-81.
• [56]Fabre S, Dupuy AM, Dossat N, Guisset C, Cohen JD, Cristol JP et al.. Protein biochip array technology for cytokine profiling predicts etanercept responsiveness in rheumatoid arthritis. Clin Exp Immunol. 2008; 153:188-95.
• [57]Hueber W, Tomooka BH, Batliwalla F, Li W, Monach PA, Tibshirani RJ et al.. Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Res Ther. 2009; 11:R76.
• [58]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.