Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients
O. Vittecoq1,2,,
S. Pouplin2,
K. Krzanowska2,
F. Jouen-Beades1,
J. F. Ménard3,
A. Gayet4,
A. Daragon1,2,
F. Tron1 and
X. Le Loët1,2
1 Inserm Unité 519 and Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFRMP 23), Faculté de Médecine et de Pharmacie,
2 Service de Rhumatologie, Centre Hospitalier Universitaire de Rouen,
3 Unité de Biométrie, Centre Hospitalier Universitaire de Rouen and
4 Collège des Rhumatologues de Haute-Normandie, Rouen, France
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Abstract
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Objective. To evaluate the predictive value of clinical, biological and radiological parameters for the prognosis of rheumatoid arthritis (RA) in a community-recruited cohort.
Methods. Ninety-one patients (mean age 49 yr, female/male ratio 2.9) with RA of limited duration (median 2 yr), 80% recruited from the community, were prospectively enrolled in 1996 (T1) and followed until 1999 (T2). Data collected at T1 were demographic characteristics, Ritchie articular index (RAI), extra-articular manifestations, Health Assessment Questionnaire (HAQ) score, C-reactive protein (CRP) and autoantibodies (autoAbs) [rheumatoid factors (RF), detected by latex fixation test and ELISA (IgM, IgA and IgG isotypes), anti-filaggrin, detected by immunofluorescence (anti-keratin antibodies, AKA; anti-perinuclear factor antibodies, APF) and ELISA (anti-citrullinated rat filaggrin antibodies, ACRFA), anti-Sa, anti-calpastatin recognizing the 27 C-terminal fragment (ACAST-C27) and domain I (ACAST-DI), anti-cardiolipin (ACL), antineutrophil cytoplasmic antibodies (ANCA), anti-annexin V (aANX V) and anti-Ro]. Hands were radiographed at T1 and T2, and read using the Sharp method as modified by van der Heijde. The main assessment criterion was progression of radiologically detected damage between T1 and T2.
Results. At T1, RA activity was mild (RAI 11/78; mean CRP 14 mg/ml), with minor functional disability (HAQ 0.8/3) and mild X-ray destruction (mean total Sharp score 9.2/280). At T1, 96% of the patients were on treatment (prednisone 72%, DMARDs 95%). The latex test detected autoAb in 46% of patients, RF-IgM was detected in 51%, RF-IgA in 36%, RF-IgG in 32%, AKA in 33%, APF in 45%, ACRFA in 45%, ACAST-C27 in 14%, ACAST-DI in 5%, anti-Sa in 22%, ACL in 3%, ANCA in 28%, aANX V in 9% and anti-Ro in 2%. At T2, the mean total Sharp score was 22.9. According to univariate analysis, T1 parameters associated with the independent variable were RAI, HAQ, CRP, latex test positivity and T1 Sharp scores. Multivariate analysis retained only latex test positivity and, to a lesser degree, joint-space narrowing score as independent predictors of radiological progression.
Conclusion. RF is the main factor that can predict radiological progression in community cases of RA of limited duration.
KEY WORDS: Rheumatoid arthritis, Community-based population, Prognosis, Autoantibodies, Radiological progression, Rheumatoid factor.
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Introduction
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As soon as the diagnosis of rheumatoid arthritis (RA) is made, the question arises as to whether the rheumatism will undergo severe progression. After 10 yr of evolution, RA is responsible for functional disability in almost half of the patients. In addition, some patients develop particularly severe disease, with major joint destruction and the appearance of extra-articular manifestations that can be life-threatening. It is for this reason that the determination of criteria predictive of severity is urgently needed, so that adapted, more aggressive therapy (anti-tumor necrosis factor
, interleukin 1 receptor antagonist, etc.) can be prescribed early for patients with factors associated with a poor prognosis [1].
The evolution of RA varies widely from one subject to another and is generally considered to be unpredictable. Nevertheless, a poor prognosis is classically associated with certain risk factors: some demographic factors; signs of severe disease activity; elevated levels of C-reactive protein (CRP); the early appearance of bone erosions; being a carrier of disease-susceptibility HLA-DRB1 alleles; and having high titres of the majority of autoantibodies (autoAb) usually associated with RA, such as rheumatoid factor (RF) [215]. However, these findings have often been contradictory, particularly the prognostic value of high-risk HLA alleles, which has recently been questioned because of results from a community-recruited population of patients with early RA [1618]. The discrepancies have usually been attributed to the different methods used [19]. Indeed, most studies attempting to identify these predictive factors have been retrospective, conducted in hospital-recruited populations and, as a consequence, not representative of community cases of RA. In addition, these studies have usually been cross-sectional, which generates confusion between predictive value and the simple association of certain factors with a poor prognosis.
To identify factors that are able to predict the evolution of RA accurately, it is necessary to use an appropriate method, such as that recommended by van der Heijde [19]. The method used must satisfy at least some of the following criteria: a prospective, longitudinal design, including RA patients diagnosed early; a study cohort homogeneous in terms of comparable durations of rheumatism, absence of disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids at inclusion; the use of the same therapeutic strategy for the entire group for the duration of follow-up; community-based recruitment, so that the sample will indeed be representative of the general population; and a duration of observation adapted to the assessment criterion chosen (either 2 or 3 yr for radiological joint damage, because 90% of bone erosions appear during the first 3 yr of the disease) [20]. About 15 studies have met the majority of these criteria [2136]. The most studied biological parameters are the erythrocyte sedimentation rate, CRP, and RF of the IgM isotype. The latter, when detected by agglutination tests, tended to indicate a poor outcome [2127], but few studies have evaluated the prognostic value of RF isotypes and their results have been discordant. Other autoAbs associated with RA have only rarely been assessed with such a method. To the best of our knowledge, with the exception of a recently published multiparameter study [34], no investigation has simultaneously evaluated the prognostic values of the principal autoAbs associated with RA, notably those recognizing calpastatin, and autoAbs usually associated with vascular lesions, i.e. those directed against cardiolipin, lactoferrin, which is the main representative of the family of anti-neutrophil cytoplasmic antibodies (ANCA) in RA [37], and annexin V.
The objective of this study on patients with RA of relatively recent onset (median duration 2 yr), recruited from the community and followed for 3 yr, was to identify factors, especially autoAbs, of prognostic value for RA.
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Materials and methods
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Patients
A cohort of 127 patients with RA with a duration of less than 5 yr and satisfying at least four of the seven ACR 1987 criteria [38], was recruited between 01 February and 01 July 1996. Eighty per cent of the patients were recruited through 29 rheumatologists in private practice belonging to the Upper Normandy College of Rheumatologists and 120 general practitioners of this region, and 20% through the staff rheumatologists of Rouen, Elbeuf and Le Havre hospitals. This community recruitment was made possible by (i) the availability of a health-care network involving rheumatologists in private practice and the Department of Rheumatology of the Rouen teaching hospital, and (ii) the help of the local press in disseminating information about the study. It fell within the framework of the study Therapeutic strategies during rheumatoid arthritis: impact on the quality of life [39]. The initial objectives of this study were to compare RA patients with individuals who did not have a chronic disease, so as to quantify the utilization of health-care that was directly attributable to RA, and to evaluate the effect of certain therapeutic strategies on the quality of life of patients suffering from RA. After verification of the criteria of inclusion and exclusion (a handicap predating RA, presence of another chronic, incapacitating and evolving disease), every evaluation was conducted independently of any medical consultation at the patient's home by two investigators: a clinical research physician and a nurse from the Rheumatology Department of Rouen University Hospital. The first such assessment took place in 1996 (T1) and consisted of the collection of relevant clinical data and a blood sample (serum was frozen at -80°C) for the analysis of biological markers, and making anteroposterior radiographs of the hands and wrists. Almost all patients were already receiving corticosteroids and/or DMARDs at inclusion. Only 102 of the 127 patients who were eligible for the study consented to have blood analyses and hand radiographs at baseline, and thus were included in the present study. During the 3-yr observation period, from 1996 to 1999, rheumatological follow-up was performed by the patient's rheumatologist. In 1999 (T2), the patients did not undergo a physical examination, but the treating physician obtained an HAQ score and hand and wrist radiographs for each patient. Ninety-one patients for whom T1 and T2 blood samples and radiographs were available were retained for the analysis. Two experienced rheumatologists (AD and XLL) read the radiographs randomly, applying the Sharp score as modified by van der Heijde et al. [40], and established three scores: (i) an evaluation of joint narrowing; (ii) an assessment of bone erosions; and (iii) a total score corresponding to the sum of the first two scores. Only the mean value of the scores of the two readers were used for statistical analyses.
Criteria evaluated at inclusion
Different clinical, biological and radiographic data were collected at T1 to determine their ability to predict RA progression. The clinical parameters studied were: demographic information (age, sex); the number of painful joints, defined by the Ritchie articular index; the presence or absence of subcutaneous nodules; and the HAQ score [41]. The radiographic findings corresponded to the T1 Sharp scores. The biological markers were CRP and, especially, the following: RFs detected with the latex-fixation test (LFT), and their IgM, IgA and IgG isotypes [42], determined by enzyme-linked immunosorbent assay (ELISA), as were those reacting with recombinant citrullinated rat filaggrin (ACRFA) [43], lactoferrin, cardiolipin, annexin V, Ro, C-terminal peptide (ACAST-C27) and domain I (ACAST-DI) of calpastatin [37, 44]; and those detected by indirect immunofluorescence recognizing keratin [anti-keratin antibodies (AKA)], perinuclear factor [anti-perinuclear factor (APF)] [42] and neutrophil cytoplasmic antigens (ANCA) [37]. Anti-Sa were identified by immunoblotting [42]. HLA phenotyping was not included because the high-risk alleles were not sought. Only the HLA-DR haplotype (DR1, DR4, ...) was determined.
Main assessment criterion
Because of the heterogeneity of the durations (0.255 yr) of disease at the time of inclusion, the principal assessment criterion was the radiologically detected progression of hand joint damage, as assessed by the difference between the T1 and T2 Sharp scores.
Statistical analyses
Differences between the T1 and T2 Sharp scores were evaluated using a non-parametric Wilcoxon test.
The dependent variable was the progression of the total Sharp score between T1 and T2. We decided to compare the third of the patients (n=25) with the highest scores with the remained two-thirds (n=66). The cut-off value was a difference of 14 units in the delta Sharp score. This distinction seemed justified by the fact that approximately 2030% of RA patients undergo progression to severe forms.
Univariate analyses to search for possible associations among the initial parameters, which included dichotomous (presence or absence of autoAb) and continuous (CRP, Sharp and HAQ scores, autoAb titres) variables, and the dependent variable used Fisher's exact test and the MannWhitney U-test. An association was considered significant when P was <0.05.
To determine factors predictive of severe progression, logistic regression multivariate analysis was conducted and the results were expressed as odds ratios and 95% confidence intervals (CI). Independent variables with P < 0.15 in the univariate analyses were included in the multivariate analysis. On the basis of the results of this analysis, we established a composite index and determined the percentage of patients classified correctly.
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Results
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Clinical characteristics of the patients at inclusion
These data are summarized in Table 1
. At T1, 91 patients had mildly active RA, as indicated by the mean Ritchie articular index and mean CRP concentration, and slightly disabling disease, as shown by the mean HAQ score. Disease was not yet very severe, as indicated by the rarity of extra-articular manifestations, essentially represented by subcutaneous nodules and/or a sicca syndrome (suspected from information collected during history-taking) and minor joint destruction. Almost all patients (95%) were taking a DMARD, especially methotrexate (53%). Almost three-quarters of the patients were on corticotherapy at a mean dose of 7.2±6.2 mg/day (range 040 mg/day).
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TABLE 1. Demographic, clinical and biological characteristics at inclusion (T1) of the 91 RA patients forming the study cohort
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Serological profiles of RA patients at inclusion
The frequencies of the different autoAb populations studied are reported in Table 1
. Around half of the patients had RF of the IgM isotype. ELISA seemed better able to detect RF than LFT. At least one of the autoAbs reputed to be more specific to RA, i.e. the association of at least two RF isotypes [45], AKA, APF, ACRFA, anti-Sa or ACAST-C27 [44], was found in 82% of the RA patients studied and, notably, in 69% of the RA patients whose LFT had been negative.
Factors predicting radiological progression
The means of the three radiological scores at T1 and T2 are given in Table 2
. Although the T1T2 differences were statistically significant, disease progression appeared to be moderate. The assessment criterion retained for this study was radiological progression as defined by the T1T2 difference in Sharp score.
Univariate analysis
As shown in Table 3
, several clinical factors (Ritchie articular index, HAQ score), biological markers (CRP, LFT) and radiological findings (Sharp joint-narrowing, erosion and total scores) considered individually were associated with the dependent variable. The positivity of the different autoAbs belonging to the same family of autoAb, i.e. RF (LFT, RF-IgM, RF-IgA, RF-IgG), anti-filaggrin (AKA, APF, ACRFA), ACALP (ACALP-C27, ACALP-DI) and those considered to be associated with vascular lesions (recognizing lactoferrin, cardiolipin, annexin V, ACALP-DI) [46], were not predictive of radiological progression, regardless of whether we evaluated the simultaneous presence of these autoAbs or the presence of at least two of them.
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TABLE 3. Univariate analysis of a potential association between baseline parameters taken individually and radiological progression of hand-joint damage over the 3-yr follow-up period
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Multivariate analysis
Our logistic regression multivariate analysis identified two independent factors able to predict radiological progression: the presence (but not the titre) of RF-IgM detected by LFT and the initial Sharp joint-narrowing score. According to the results of this analysis, LFT positivity represents the main factor predictive of more severe progression of hand-joint destruction (Table 4
). No other autoAb population or clinical factor was able to predict radiological progression. This model, which was able to classify 80% of the patients correctly, has the following characteristics: sensitivity 52%, specificity 91%, positive-predictive value 69%, and negative-predictive value 83%.
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TABLE 4. Factors predictive of the progression of hand-joint damage according to a multivariate analysis of the parameters selected by univariate analysis for a cohort of 91 community-recruited patients with RA of semi-recent duration, followed for 3 yr
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Discussion
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We attempted to identify factors predictive of the progression of the joint destruction in RA by conducting a prospective longitudinal study that included 102 patients with RA that had been evolving for less than 5 yr (mean 2.2 yr) and followed for 3 yr. We analysed the results obtained for the 91 patients for whom T1 and T2 blood samples and radiographs were available. This cohort differs from most of those studied previously and reported in the literature (Table 5
), particularly in terms of recruitment, which was predominantly from the community. Moreover, the fact that the initial evaluation was carried out at the patient's home and not instigated at the patient's request for any symptom related to RA or treatment meant that cohort was more representative. Other studies have also evaluated populations of mixed recruitment [26, 29, 30, 32, 35, 36], but sometimes not clearly described. To the best of our knowledge, this is the second multiparametric evaluation of different autoAbs associated with RA. We decided not to include the genetic factors linked to the HLA system because of the controversial influence of the HLA-DR on the prognosis of RA and the cost of such analyses.
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TABLE 5. Abilities of different autoAb populations to predict radiological progression as assessed in cohorts of patients with RA of relatively short duration and followed for several years
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Despite its predominantly community recruitment, our cohort has its weaknesses, as all the patients did not satisfy all the criteria listed in the Introduction. Some of the omissions were minor, such as the absence of multi-annual evaluations during the observation period and the number of patients lost to follow-up (10.8%), which can be explained in part by the relative youth of our population, which was thus active and mobile, and also their refusal to undergo paraclinical examinations. Others merit more attention. For example, the patients we recruited usually had RA that had been evolving for more than 1 yr (80%; median duration 2 yr), and they were thus not a population with RA of very recent onset. This group was also heterogeneous because the duration of symptoms at inclusion varied from 3 months to 5 yr. Finally, the overwhelming majority of patients (95%) were already receiving a DMARD or corticosteroid therapy at inclusion.
Because of these methodological lapses, we retained the progression over 3 yr of radiologically detected joint damage, as assessed by the T1T2 difference in total Sharp score, as the assessment criterion, and we limited our analysis to hand radiographs. We do not think this choice introduced a methodological bias into the interpretation of our findings. First of all, the kinetics of joint destruction vary widely from one patient to another, as indicated by the different profiles (at least five) of radiological progression that have been described for RA patients followed prospectively for 30 yr [47]. As a result, evaluating radiological progression in patients whose RA had been evolving for 2 yr does not represent a limiting factor. This seems particularly true in community-recruited patients, for whom the kinetics of joint destruction have not been well documented. In addition, it has been shown to be more pertinent to quantify radiological damage in the hands, for which the progression of joint lesions was significantly associated with more severe functional disability and thus with a greater negative impact on the quality of life [26].
Despite these methodological weaknesses, our results are in accordance with those reported in the literature, notably the studies by van der Heide et al. [26] and Uhlig et al. [31], for whom the presence of RF and the degree of radiological damage at inclusion were the factors most predictive of radiological progression in the hands and feet. While the extent of disease activity has often been reported to have informative value in terms of prognosis [2426, 29], neither of the criteria of disease activity evaluated in this study (Ritchie articular index, CRP) was predictive of radiological progression. This observation is not surprising, in that the patients were initially evaluated independently of any request for treatment and, consequently, their disease activity was relatively well controlled by therapy. In addition, with the exception of LFT-detected RF, no other autoAb seems to be able to predict radiological progression.
Several explanations are possible. First of all, it is important to specify that most of the assays used to detect these autoAbs are not standardized. Also, we cannot exclude the possibility that the medications prescribed before inclusion affected the titres of these autoAbs and thus the overall test results. Nonetheless, the frequency of each of the autoAbs evaluated is in agreement with values reported previously for rheumatisms of comparable duration [48], with the exception of RF-IgM, which was usually close to 60%. These findings are in accordance with the fact that RFs are the autoAbs most sensitive to the different therapies prescribed [49]. It is probable that the DMARD and/or corticosteroid therapies modified the RF titres regardless of whether they were detected by LFT or ELISA. This sensitivity to treatment might explain why (i) only LFT positivity, considered as a dichotomous variable (present or absent), and not the high titres of this autoAb, as observed in several other studies [22, 27, 35], was predictive of radiological progression; and (ii) RF isotypes, notably IgA, had no prognostic value, in contrast to what was shown in another study that had used an appropriate method [25]. The autoAbs usually associated with vascular diseases are not informative in the context of RA. This holds true for ANCA, whose potential contribution had been suggested by the results of a prospective longitudinal study of 82 untreated RA patients with less than 1 yr of disease duration who were followed for 7 yr [33]. However, in that study, pANCA (perinuclear labelling pattern) and their titres had a significant association with radiological progression only after 7 yr of follow-up; at 3 yr only RF positivity had a predictive value. Furthermore, the authors of the study were unable to demonstrate any prognostic value for autoAbs recognizing pANCA antigenic specificities (lactoferrin, myeloperoxidase, cathepsin G, lysozyme, elastase); this is probably more pertinent because of the difficulty in interpreting patterns of indirect immunofluorescence labelling on neutrophils. We too found that anti-lactoferrin autoAb had no predictive value for radiological progression. In addition, ACALP-DI and anti-annexin V autoAbs, which had never been studied previously with such an approach, had no predictive value. Hence, according to our multivariate analysis of autoAbs with a logistic regression model, only LFT-detected RF-IgM were predictive of the prognosis, defined as the progression of joint destruction, assessed using the difference between total Sharp scores at T1 and T2, i.e. over 3 yr. The same result was obtained in a prospective longitudinal study set in a therapeutic trial comparing methotrexate and sulphasalazine in 191 patients with RA of recent onset (<1 yr), followed for 3 yr [34]. That multiparametric analysis also examined the prognostic value of different autoAbs associated with RA, some of which were also investigated in the present study (RF isotypes, AKA, APF, ACALP-C27, anti-Sa) and others not (anti-RA33, anti-Hsp70/93, anti-RA1).
In conclusion, on the basis of data from a cohort of 91 patients with RA of median duration 2 yr, who had already been treated and were recruited predominantly from the community and followed for 3 yr, we were able to identify two factors predictive of radiological progression of RA: positivity for LFT-detected RF-IgM and, to a much lesser degree, the extent of initial cartilage damage (assessed by the Sharp score for joint-narrowing). Our findings, in accordance with data reported in the literature, particularly those from the Norfolk Arthritis Register Study [35], showed that RF is the parameter that is identified most frequently and is the one with the highest prognostic value. Nonetheless, regardless of the composite index derived from logistic regression analysis, correct classification of patients rarely exceeds 80%, meaning that the selected criteria are not applicable at the individual level.
It would clearly be more pragmatic to use a methodological approach in which patients with early inflammatory rheumatisms are recruited from all sources and in which their outcomes are monitored, rather than trying first to identify those patients with RA, which is not always easy to diagnose.
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Acknowledgments
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The authors thank the Polyarthrite rhumatoïde et consommation de soins (Rheumatoid Arthritis and Use of Health Care) group for its contribution, and Janet Jacobson for correcting the manuscript. This study was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM) and grants from the Société Française de Rhumatologie (SFR).
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Notes
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Correspondence to: O. Vittecoq, Service de Rhumatologie, Centre Hospitalier Universitaire de Rouen, 76031 Cedex, France. E-mail: vittecoq.olivier{at}wanadoo.fr 
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References
|
---|
- Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis 1995;54:9447.[ISI][Medline]
- van der Heijde DMFM, van Riel PLCM, van Rijswijk MH, van de Putte LB. Influence of prognostic features on the final outcome in rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum 1988;17:28492.[CrossRef][ISI][Medline]
- Jönsson T, Thorsteinsson J, Kolbeinsson A, Jönasdöttir E, Sigfüsson N, Valdimarsson H. Population study of the importance of rheumatoid factor isotypes in adults. Ann Rheum Dis 1992;51:8638.[Abstract]
- Jönsson T, Arinbjarnarson S, Thorsteinsson J et al. Raised IgA rheumatoid factor (RF) but not IgM RF or IgG RF is associated with extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 1995;24:3725.[ISI][Medline]
- Houssien DA, Jonsson T, Davies E, Scott DL. Rheumatoid factor isotypes, disease activity and the outcome of rheumatoid arthritis: comparative effects of different antigens. Scand J Rheumatol 1998;27:4653.[CrossRef][ISI][Medline]
- Caruso I, Santandrea S, Puttini P et al. Clinical, laboratory and radiographic features in early rheumatoid arthritis. J Rheumatol 1990;17:12637.[ISI][Medline]
- van Schaardenburg D, Hazes JMW, de Boer A, Zwinderman AH, Meijers KAE, Breedveld FC. Outcome of rheumatoid arthritis in relation to age and rheumatoid factor at diagnosis. J Rheumatol 1993;20:4552.[ISI][Medline]
- Naka T, Kondo M, Mashima T. Clinical significance of IgG rheumatoid factor in patients with rheumatoid arthritis. Ryumachi 1995;35:5307.[Medline]
- Aho K, Palosuo T, Matti L et al. Antifilaggrin antibodies in recent-onset arthritis. Scand J Rheumatol 1999;28:1136.[CrossRef][ISI][Medline]
- Paimela L, Gripenberg M, Kurki P, Leirisalo-Repo M. Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis. Ann Rheum Dis 1992;51:7436.[Abstract]
- Westgeest AAA, Boerbooms AMT, Jongmans M, Vandenbroucke JP, Vierwinden G, van de Putte LBA. Antiperinuclear factor: indication of more severe disease in seronegative rheumatoid arthritis. J Rheumatol 1987;14:8937.[ISI][Medline]
- Hayem G, Chazerain P, Combe B et al. Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis. J Rheumatol 1999;26:713.[ISI][Medline]
- Boire G, Ménard HA. Clinical significance of anti-Ro/SSA antibody in rheumatoid arthritis. J Rheumatol 1988;15:3914.[ISI][Medline]
- Coremans IEM, Hagen EC, Daha MR et al. Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum 1992;35:146675.[ISI][Medline]
- Hayem G, De Bandt M, Palazzo E et al. Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis. Ann Rheum Dis 1999;58:2916.[Abstract/Free Full Text]
- Harrison B, Thomson W, Symmons D et al. The influence of HLA-DRB1 alleles and rheumatoid factor on disease outcome in an inception cohort of patients with early inflammatory arthritis. Arthritis Rheum 1999;42:217483.[CrossRef][ISI][Medline]
- Gough A, Faint A, Salmon M et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 1994;37:116670.[ISI][Medline]
- Valenzuela-Castano A, Garcia-Lopez A, Perez-Vilches D, Rodriguez-Perez R, Gonzalez-Escribano MF, Nunez-Roldan A. The predictive value of the HLA shared epitope for severity of radiological joint damage in patients with rheumatoid arthritis. A 10 year observational prospective study. J Rheumatol 2000;27:5714.[ISI][Medline]
- van der Heijde DMFM. The continuing challenge of predictive factors in rheumatoid arthritis: prediction or association? J Rheumatol 1997;24:68.[ISI][Medline]
- Brook A, Corbett M. Radiographic change in early rheumatoid disease. Ann Rheum Dis 1977;36:713.[Abstract]
- Mottönen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis 1988;47:64853.[Abstract]
- Paimela L, Palosuo T, Leirisalo-Repo M et al. Prognostic value of quantitative measurement of rheumatoid factor in early rheumatoid arthritis. Br J Rheumatol 1995;34:114650.[ISI][Medline]
- Fex E, Jonsson K, Johnson U, Eberhardt K. Development of radiographic damage during the first 56 yr of rheumatoid arthritis. A prospective follow-up study of a Swedish cohort. Br J Rheumatol 1996;35:110615.[CrossRef][ISI][Medline]
- van der Heijde DMFM, van Riel PLCM, van Leeuwen MA, van Thof MA, van Rijswijk MH, van de Putte LBAI. Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. A prospective follow-up of 147 patients. Br J Rheumatol 1992;31:51925.[ISI][Medline]
- van Zeben D, Hazes JMW, Zwinderman AH, Vandenbroucke JP, Breedveld D. Factors predicting outcome of rheumatoid arthritis: results of a follow-up study. J Rheumatol 1993;20:128896.[ISI][Medline]
- van der Heide A, Remme CA, Hofman DM, Jacobs JWG, Bijcsma JWJ. Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis. Arthritis Rheum 1995;38:146674.[Medline]
- van Leeuwen MA, Westra J, van Riel PLCM, Limburg PC, van Rijswijk MH. IgM, IgA and IgG rheumatoid factors in early rheumatoid arthritis predictive of radiological progression? Scand J Rheumatol 1995;24:14653.[ISI][Medline]
- Eberhardt KB, Svensson B, Truedsson L, Wollheim A. The occurrence of rheumatoid factor isotypes in early definite rheumatoid arthritisno relationship with erosions or disease activity. J Rheumatol 1988;15:10704.[ISI][Medline]
- Mottönen TT, Paimela L, Leirisalo-Repo M, Kautiainen H, Llonen J, Hannonen P. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with sawtooth strategy. Ann Rheum Dis 1998;57:5339.[Abstract/Free Full Text]
- Pease CT, Bhakta BB, Devlin J, Emery P. Does the age of onset of rheumatoid arthritis influence phenotype? A prospective study of outcome and prognostic factors. Rheumatology 1999;38:22843.[Abstract]
- Uhlig T, Smedstad LM, Vaglum P, Moum T, Gerard N, Kvien TK. The course of rheumatoid arthritis and predictors of psychological, physical and radiographic outcome after 5 years of follow-up. Rheumatology 2000;39:73241.[Abstract/Free Full Text]
- Kroot EJA, de Jong BAW, van Leeuwen MA et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000;43:18315.[CrossRef][ISI][Medline]
- Mustila A, Paimela L, Leirisalo-Repo M, Huhtala H, Miettinen A. Antineutrophil cytoplasmic antibodies in patients with early rheumatoid arthritis. An early marker of progressive erosive disease. Arthritis Rheum 2000;43:13717.[CrossRef][ISI][Medline]
- Combe B, Dougados M, Goupille P et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study. Arthritis Rheum 2001;44:173643.[CrossRef][ISI][Medline]
- Bukhari M, Lunt M, Harrisson BJ, Scott DG, Symmons DP, Silman AJ. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum 2002;46:90612.[CrossRef][ISI][Medline]
- Jansen LM, van der Horst-Bruinsma IE, van Schaardenburg D, Bezemer PD, Dijkmans BA. Predictors of radiographic joint damage in patients with early rheumatoid arthritis. Ann Rheum Dis 2001;60:9247.[Abstract/Free Full Text]
- Vittecoq O, Jouen-Beades F, Krzanowska K et al. Prospective evaluation of the frequency and clinical significance of anti-neutrophil cytoplasmic and anti-cardiolipin antibodies in community cases of patients with rheumatoid arthritis. Rheumatology 2000;39:4819.[Abstract/Free Full Text]
- Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:31524.[ISI][Medline]
- Girard F, Guillemin F, Novella JL et al. Health-care use by rheumatoid arthritis patients compared with non-arthritic subjects. Rheumatology 2002;41:16775.[Abstract/Free Full Text]
- van der Heijde DMFM, van Riel PLCM, Nuver-Zwart IH, Gribnau FW, van de Putte LBA. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989;13:10368.
- Pouchot J, Guillemin F, Coste J. Mesures de qualité de vie en rhumatologie. Presse Med 1994;23:132830.[ISI][Medline]
- Vittecoq O, Jouen-Beades F, Krzanowska K et al. Rheumatoid factors, anti-filaggrin antibodies, and low in vitro interleukin 2 and interferon
production are useful immunological markers for early diagnosis of community cases of rheumatoid arthritis. Preliminary study. Joint Bone Spine 2001;68:14453.[CrossRef][ISI][Medline]
- Vittecoq O, Inçaurgarat B, Legoedec J et al. High diagnostic value of anti-filaggrin autoantibodies (AFA) detected by a new ELISA using citrullinated and non-citrullinated recombinant proteins as antigens in a cohort of 152 community cases of very early arthritis [abstract]. Ann Rheum Dis 2001;60:S128.[CrossRef]
- Vittecoq O, Salle V, Jouen-Beades F et al. Autoantibodies to the 27 C-terminal amino-acids of calpastatin are detected in a restricted set of connective tissue diseases and may be useful for diagnosis of rheumatoid arthritis in community cases of very early arthritis. Rheumatology 2001;40:112634.[Abstract/Free Full Text]
- Jonsson T, Steisson K, Jonsson H, Geirsson AJ, Thorsteinsson J, Valdimarsson H. Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int 1998;18:11922.[CrossRef][ISI][Medline]
- Salle V, Vittecoq O, Jouen-Beades F et al. High levels of autoantibodies directed against the domain I of calpastatin are related to vasculitis in systemic lupus erythematosus [abstract]. Arthritis Rheum 2000;43:S254.
- Graudal NA, Jurik AG, de Carvalho A, Graudal HK. Radiographic progression in rheumatoid arthritis. A long term prospective study of 109 patients. Arthritis Rheum 1998;41:147080.[CrossRef][ISI][Medline]
- Vittecoq O, Jouen-Beades F, Delpech A, Gilbert D, Tron F, Le Loët X. Autoantibodies in rheumatoid arthritis. Rev Rhum Fr Ed 1995;62:195S200S.
- Hanly JG, Hassan J, Whelan A, Feighery C, Bresnihan B. Effects of gold therapy on the synthesis and quantity of serum and synovial fluid IgM, IgG, and IgA rheumatoid factors in rheumatoid arthritis patients. Arthritis Rheum 1986;29:4807.[ISI][Medline]
Submitted 8 July 2002;
Accepted 20 December 2002