Sihvonen et al Antibodies and mortality in RA - PDF document

Sihvonen, et al: Antibodies and mortality in RA Personal non-commercial use only. The Journal of Rheumatology Copyright ꤀2005. All rights reserved. The Predictive Value of Rheumatoid Factor Isotypes,Anti-Cyclic Citrullinated Peptide Antibodies, andAntineutrophil Cytoplasmic Antibodies for Mortalityin Patients with Rheumatoid Arthritis SUSANNASIHVONEN, MARKKU KORPELA, ANU MUSTILA, and JUKKAMUSTONEN ABSTRACT.Objective. To evaluate the significance of rheumatoid factor (RF) and its isotypes (IgARF, IgG RF, The study population comprised 604 patients with RAparticipating in a cross-sectionaln = 604n = 206n = 206n = 184n = 184ANCAn = 200n = 200Vital status was assessedin 1999 and multivariate Cox regression analysis used to compare mortality in RApatients with orwithout different antibodies. Of the 604 patients with RA, 55% were positive for RF, 66% for anti-CCP, and 14.5% forperinuclear ANCA. T19%40%40%IgAand IgM RF levels predicted increased mortality, while positive anti-CCPor ANCAdid not. Patients with RAwith positive RF, especially IgAand IgM isotypes, carry a risk of Key Indexing Terms: ANTINEUTROPHILCYTOPLASMIC ANTIBODIES MORTALITYRHEUMATOID FACTOR From the Department of Internal Medicine and Centre for LaboratoryMedicine, Department of Clinical Microbiology, Tampere UniversityHospital, and the University of Tampere Medical School, Tampere,Supported by grants from the Medical Research Fund of TampereS. Sihvonen, MD; M. Korpela, MD, PhD, Department of InternalMedicine, Tampere University Hospital; A. Mustila, MD, PhD, Centre forLaboratory Medicine, Tampere University Hospital; J. Mustonen, MD,PhD, Univers

ity of Tampere.Address reprint requests to Dr. S. Sihvonen, Department of InternalMedicine, Tampere University Hospital, PO Box 2000, Fin-33521,Tampere, Finland. E-mail: susanna.sihvonen@fimnet.fi patients with RARFRF but these antibodies are also present in relatively high per-centages in other autoimmune diseases and infections andeven in healthy persons, particularly elderly individuals many have been either less sensitive or technically incon-venient for routine use. Antibodies against cyclic citrullinat- and werefound to have very high specificity were soon available and after few yearsÕdevelopment of theCCPantigen, test sensitivity rose to a high level. Anti-CCPcan be detected at an early stage, even before onset of clin- Among serological markers, RF has been recognized asan important predictor of more severe disease, includingextraarticular manifestations or bone erosion increased mortality Anti-CCPand antineutrophil This is the first study to evaluate anti-CCPand ANCAwith MATERIALS AND METHODS Study population. ampere (170,511 inhabitants inthat year, 3.5% of the population of Finland) 1051 persons (834 women, criteria of the 1958 American Rheumatism Association renal and urinary tract diseases, treatments, and severity of RA(using forexample the Health Assessment Questionnaire, HAQ) were carefully age of 604 RApatients was 59 ±13 years and the mean duration of RA15Altogether, 103 RApatients had clinical signs or symptoms of renal dis- ity in the univariate model (HR = 1.68, p = 0.034; Table 2).Table 2). If HAQ or subcutaneous nodules were added intothe model, high anti-CCPlevel did not predict mortali

ty. A40%40%antibod-by 1999. Mortality was not significantly different in theseanti-CCPdid not predict mortality in the univariate or mul-tivariate model (Table 2).T41%38%38%the pANCA-negative RApatients had died by 1999 (Figure Our objective was to analyze whether RF, anti-CCP, andand ANCAin but the risk related to positive RF has variedconsiderably (OR 1.93Ð11.9) also been reported to be associated with increasing mortali- 1 However, only IgM RF and not other RF iso- 11-13 RF (WaRo or FS-RF positive) predicted increased mortalitywhen all patients with RAwere included in the statisticalmethods was taken into account. The risk of death var-ied from 1.32 to 1.80 depending on the definition of RF pos- However, in a smaller subgroup (only patients with anti-CCPantibody determination) high FS-WaRo titers but notRF isotypes predicted increased mortality. If the HAQ orRAnodules were added to the multivariate model, positiveRF did not predict increased mortality. This might be due toin fact measuring the same aspect: disease severity. BothIgARF and IgM RF levels predicted increased mortality inthe multivariate model including age, sex, and disease dura-the model, IgARF level still predicted increased mortality.patients with nephropathy and 69% of RApatients withoutThe cutoff level of FS-RF (³30for FS-RF was 대15 IU/ml or ³20 IU/ml, the proportion ofRF positive patients rose to 67% or 64%, respectively. RF has an immune complex pro-cessing capacity to activate the complement cascade con- High RF levels havebeen associated with subcutaneous nodules and extraartic- have themselves been reported to correlate with increase

dmortality in RA Although the difference in prognosis Sihvonen, et al: Antibodies and mortality in RA Personal non-commercial use only. The Journal of Rheumatology Copyright ꤀2005. All rights reserved. Table 1. Characteristics of RApatients with or without different antibodies in the original study in 1988. Results are expressed as medians unless otherwisedefined. Comparison between patients with and without different antibodies was made using StudentÕs t tfor continuous variablesfor continuous variablesfor categorical variablesfor categorical variablesvalues less than 0.05 were considered significant. RF was considered positive if quantitative immunotur-bidic assay was ³30 U/ml or Waaler-Rose-test titers 대64.n = 604n = 604Anti-CCPn = 184n = 184pANCAn = 198n = 198PosNegpPosNegpPosNegp330n = 274n = 122n = 62n = 29n = 169Age, yrs59.757.30.02163.958.70.00559.962.30.301Male, %24200.16126260.91514280.111Disease duration, yrs14.214.70.59415.716.30.71519.315.40.054ESR, mm/h332536.830.270.08346320.002Hb, g/l1281301261300.0651221290.018HAQ, 1Ð30.710.430.880.540.0011.110.680.003Subcutaneous nodules, %463045220.00552390.179Nephropathy, %17.316.70.67352.554.80.94372450.005Positive RF, %72*19*0.00159*56*0.809Positive anti-CCP, %88*40*66*56*0.105Assessment Questionnaire; ESR: erythrocyte sedimentation rate; Hb: hemoglobin. * Percentages were calculated only for patients with both antibody deter- between RF-positive and RF-negative RApatients is quiteobvious, the role of RF is not clear.In our cohort, 66% of patients had anti-CCPantibodies, a Nineteen percent of patients with RF were anti-CCP-nega-tive and 40% without RF

had anti-CCP. The proportion ofRF-negative patients with anti-CCPis similar to that previ- Presence of anti-CCPdid not predictmortality when a cutoff value of 25 U was used. However,ity risk. Patients with RF or anti-CCPantibodies appeared tobe subject to higher mortality than those without these anti- The Journal of Rheumatology 2005; 32:11 Personal non-commercial use only. The Journal of Rheumatology Copyright ꤀2005. All rights reserved. Figure 1. Kaplan-Meier plots for mortality according to the presence or absence of (A) rheumatoid factor (RF); (B) anti-citrullinated peptide antibodies (anti-CCP); (C) RF and/or anti-CCP; and (D) perinuclear antineutrophil cytoplasmic antibodies (pANCA). 8.Kroot EJ, De Jong BA, van Leeuwen MA, et al. The prognosticrecent-onset rheumatoid arthritis. Arthritis Rheum 2000;43:1831-5.9.Vencovsky J, Machacek S, Sedova L, et al. Autoantibodies can bearthritis. Ann Rheum Dis 2003;62:427-30.10.Reilly P, Cosh P, Maddison J, Rasker J, Silman A. Mortality andpatients. Ann Rheum Dis 1990;49:363-9.11.Jacobbson L, Knowler W, Pillemer S, et al. Rheumatoid arthritisand mortality. Alongitudinal study of Pima Indians. Arthritis12.Gabriel S, Crowson C, OÕFallon W. Mortality in rheumatoid 13.Glennas A, Kvien T, Andrup O, Karstensen B, Munthe E. Recentstudy. J Rheumatol 2000;27:101-8.14.Wolfe F, Michaud K, Gefeller O, Choi H. Predicting mortality inpatients with rheumatoid arthritis. Arthritis Rheum 15.Bas S, Genevay S, Meyer O, Gabay C. Anti-cyclic citrullinatedpeptide antibodies, IGM and IgArheumatoid factors in the Forslind K, Ahlmen M, Eberhard K, Halfstršm I, Svensson B.anti-CCPanti-CC

PAnn Rheum Dis 2004;63:1090-5.Mustila A, Paimela L, Leirisalo-Repo M, Huhtala H, Miettinen A.rheumatoid arthritis. An early marker of progressive erosive disease. Arthritis Rheum 2000;43:1371-7.disease with associated nephropathy. Arthritis Rheum Ropes MW, Bennet GA, Cobb S, Jacox R, Jessar RA. Revision of21.Teppo AM, Maury C. Enzyme immunoassay of complement 22.Maury C, Teppo AM, Wafin F, Wegelius O, Friman C, Koskimiesin patients with rheumatoid arthritis. Ann Rheum Dis 23.Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. APMIS 1989;97 Suppl24.Wiik A. Granulocyte-specific antinuclear antibodies. Allergy25.Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A.arthritis: a population based study. Scand J Rheumatol26.Sihvonen S, Korpela M, Mustonen J, Laippala P, Pasternack A.27.Firestein G. Evolving concepts of rheumatoid arthritis. Nature28.Zvaifler N. The immunopathology of joint inflammation in rheumatoid arthritis. Adv Immunol 1973;16:265-336.9.Gordon D, Stein J, Broder I. The extra-articular features of rheumatoid arthritis. Asystemic study of 127 cases. Am J Med30.Scott D, Bacon PA. Rheumatoid vasculitis. Clin Rheumatol1983;2:311-4.Turesson C, OÕFallon W, Crowson C. Occurrence of extra-articularKastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCPrheumatoid arthritis (the Swedish TIRAproject). Ann Rheum Disger F, Siebert U, Hemlkearthritis. Ann Rheum Dis 2004;63:1079-84.de Bandt M, Meyer O, Haim T, Kahn M. Antineutrophil The Journal of Rheumatology 2005; 32:11 Personal non-commercial use only. The Journal of Rheumatology Copyright ꤀2005. All rights rese