Clinical utility of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica
M. Lopez-Hoyos,
C. Ruiz de Alegria,
R. Blanco,
J. Crespo,
M. Peña,
V. Rodriguez-Valverde and
V. M. Martinez-Taboada
Immunology and Rheumatology Services, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
Correspondence to: V. M. Martinez-Taboada, Rheumatology Service, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain. E-mail: vmartinezt{at}medynet.com
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Abstract
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Background. In a significant number of patients the differential diagnosis between elderly-onset rheumatoid arthritis (EORA) and polymyalgia rheumatica (PMR) is very difficult because of the lack of specific serum markers. Anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) have recently been shown to be highly specific for rheumatoid arthritis (RA). This is the first study addressing the utility of these antibodies in the differential diagnosis between EORA and PMR.
Methods. Serum samples from 57 EORA patients and 49 PMR patients were studied for the presence of anti-CCP Abs and rheumatoid factor (RF). As controls, samples from 41 RA patients (age at onset <60 yr) and 24 aged healthy subjects were analysed.
Results. Sixty-five per cent of EORA patients had anti-CCP Abs, whereas none of the PMR patients or the aged healthy subjects was positive for those antibodies. Ten of the EORA patients started with polymyalgic symptoms and two of them were positive for anti-CCP Abs. Interestingly, there was a significant correlation between anti-CCP Abs and RF in EORA but not in young RA patients.
Conclusions. The presence of anti-CCP Abs in a patient with clinical symptoms of PMR must be interpreted as highly suggestive of EORA.
KEY WORDS: Polymyalgia rheumatica, Rheumatoid arthritis, Elderly, Anti-CCP antibodies.
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Introduction
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The presentation, severity and prognosis of rheumatoid arthritis (RA) differ depending on the age of disease onset [1]. Elderly-onset rheumatoid arthritis (EORA) presents a more frequent acute onset, more frequent constitutional symptoms and often has a polymyalgic onset, with a higher frequency of shoulder involvement, compared with young onset RA (YORA) [2]. The differences in disease phenotype between EORA and YORA are of special importance because they have clinical and therapeutic implications.
Polymyalgia rheumatica (PMR) is a clinical syndrome characterized by pain and stiffness in proximal areas that affects almost exclusively people older than 50 yr [3]. The characteristic clinical picture is usually accompanied by an increase in acute-phase reactants and a dramatic response to low doses of steroids [3]. PMR may occur as an isolated syndrome or accompany other diseases, mainly giant cell arteritis [4]. Among the disorders that may present with a polymyalgic syndrome, EORA is one of the more difficult to distinguish.
Although there are several sets of diagnostic criteria for PMR [5, 6], all of them are mainly clinical and none includes any specific feature. In patients with a polymyalgic syndrome, the presence of peripheral arthritis (hands and feet) strongly suggests the diagnosis of RA. However, at the present time there are no clinical or routine laboratory features allowing early differentiation between PMR and RA with a PMR-like onset [7]. False-positive RF results in aged individuals with PMR make the differential diagnosis of RA difficult. Furthermore, a small percentage of patients with PMR will develop during the follow-up of classic RA [8].
Recently, a new specific assay for RA has been developed, consisting of the detection of anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) [9]. These antibodies were first reported to be of utility in the diagnosis of RA patients 5 yr ago. They are characterized by very high specificity but poor sensitivity [10]. However, modifications of the first ELISA assay for them and the introduction of CCP-1 into the test clearly improved the sensitivity of the assay, which has reached 80% while retaining excellent specificity (98100%) [11]. In recent years, several studies have emphasized the clinical utility of this test in RA patients. Most of its utility comes from the fact that the antibodies can be detected very early, even before clinical symptoms arise [12]. However, there is no previous work specifically addressing the use of anti-CCP Abs in the diagnosis of EORA.
The aim of the present study was to determine the prevalence of anti-CCP Abs in EORA patients and to investigate whether these antibodies may be of help in the differential diagnosis with PMR.
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Methods
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Serum samples were taken for routine tests from 57 EORA patients (disease onset after 60 yr of age) and 49 PMR patients (Table 1). Forty-one patients with classical RA (<60 yr) and 24 healthy subjects were used as control groups. Consent was obtained before the samples were collected and studied. All the RA patients fulfilled the American College of Rheumatology 1987 classification criteria [13]. Patients with PMR were diagnosed according to the criteria proposed by Chuang et al. [6]. The possibility of giant cell arteritis was excluded by cure with low-dose steroids and/or a negative temporal artery biopsy. Levels of serum immunoglobulin G anti-CCP Abs were measured by commercial enzyme-linked immunoassays (ELISAs) (Eurodiagnostica, Arnhem, The Netherlands). A serum was considered positive for anti-CCP Abs if the titre was above 50 IU/ml. Titres of serum RF were also measured by nephelometry (Dade Behring, Marburg, Germany) and sera were considered positive when they showed concentrations above 22 IU/ml. This study was approved by the Hospital Universitario Marqués Valdecillas Local Clinical Research Ethics Committee. Differences between groups of patients were considered significant when P values obtained with Fishers exact test and the MannWhitney test were <0.05. Correlation coefficients were calculated using the Spearman rank test.
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Results and discussion
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Thirty-five (65%) EORA patients showed increased titres of anti-CCP Abs (Table 1). Healthy subjects and PMR patients both had negative serum titres of these autoantibodies. As a control, our assay to measure anti-CCP Abs had a sensitivity of 93% in the diagnosis of classical RA. The titres of anti-CCP Abs in classical RA patients were slightly higher than in EORA patients, although the difference did not reach statistical significance. Using the PMR patients as a negative control group (the initial symptoms of this disorder can mimic those of RA), anti-CCP Abs showed a sensitivity and specificity of 61.4 and 100% respectively for the diagnosis of EORA. The negative and positive predictive values were 69 and 100% respectively.
In comparison with the measurement of anti-CCP Abs, the measurement of RF in EORA sera showed poor results. Thus, the sensitivity and specificity of RF in EORA patients were 54.4 and 83.7% respectively. Negative and positive predictive values were 61.2 and 79.5% respectively.
Ten of the 57 (17.5%) EORA patients presented with a polymyalgic syndrome. Two of these 10 patients showed positive titres of anti-CCP Abs with negative RF, another two patients were positive for both anti-CCP Abs and RF, and the remaining six patients were negative for both Abs.
In EORA patients the serum level of anti-CCP Abs showed a very good correlation with the RF titre (r = 0.601; P<0.001). We did not find a significant correlation in classical RA patients. Anti-CCP Abs are considered of special interest in the diagnosis of seronegative RA. Of the EORA patients without RF, 30.8% were positive for anti-CCP Abs. After a mean follow-up of 47.3 ± 20.8 months, only one PMR patient developed RA; this patient was seronegative for both RF and anti-CCP Abs.
A recent study from Finland [14] showed only one positive case of anti-CCP Abs out of 300 aged healthy subjects. However, 8 and 17% of elderly subjects were positive for anti-filaggrin Abs and RF respectively, indicating the high specificity of anti-CCP Abs in the diagnosis of RA [14]. Likewise, in the present study we did not find any aged healthy subject positive for anti-CCP Abs, and neither did we find any healthy subjects who were positive for RF.
One of the most remarkable findings from our study is that no PMR patient showed a positive titre of anti-CCP Abs. Furthermore, 20% of EORA patients with a polymyalgic onset of the disease had anti-CCP Abs but not RF. This indicates that anti-CCP Abs may be a helpful tool in the differential diagnosis of EORA from PMR. Furthermore, the 100% positive predictive value of anti-CCP Abs confers a remarkable advantage on this serum marker in comparison with RF. Thus, the presence of anti-CCP Abs must be interpreted as highly suggestive of a diagnosis of EORA.
The authors have declared no conflicts of interest.
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Submitted 18 November 2003;
revised version accepted 8 January 2004.