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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Ann Rheum Dis. Author manuscript; available in PMC Jun 24, 2011.
Published in final edited form as:
PMCID: PMC3122886
NIHMSID: NIHMS304329

Anti-CCP antibody and rheumatoid factor concentrations predict greater disease burden in U.S. veterans with rheumatoid arthritis

Abstract

Objective

To examine associations of anti-cyclic citrullinated peptide antibody (aCCP) and rheumatoid factor (RF) concentrations with future disease burden in patients with rheumatoid arthritis (RA).

Methods

Outcome measures were examined in U.S. veterans with RA and included: 1) proportion of observation in remission (Disease Activity Score [DAS]28 ≤ 2.6), 2) remission for ≥ 3 consecutive months, and 3) area under the curve [AUC] for DAS28. Associations of autoantibody concentration (per 100 unit increments) with outcomes were examined using multivariate regression.

Results

Patients (n = 855) were predominantly men (91%) with mean (SD) age of 66 (11) years and 2.3 (1.2) years of follow-up. Most were aCCP (75%) and RF (80%) positive. After multivariate adjustment, aCCP (OR 0.93; 95% CI 0.91-0.96) and RF concentrations (OR 0.92; 95% CI 0.90-0.95) were associated with a lower odds of remission, a lower proportion of observation in remission (p = 0.054 and p = 0.014, respectively), and greater AUC DAS28 (p = 0.05 and p = 0.002, respectively). In aCCP+ / RF- patients, higher aCCP concentrations were associated with an increased likelihood of remission (OR 1.10; 95% CI 1.00-1.20). Among aCCP- / RF+ patients, higher RF concentrations trended towards an inverse association with remission (OR 0.81; 95% CI 0.58-1.13).

Conclusions

aCCP concentrations (particularly in RF positive patients) are associated with poor prognosis in U.S. veterans with RA. Analyses of autoantibody discordant patients suggest that RF concentrations may be a stronger predictor of disease burden than aCCP concentration.

Keywords: rheumatoid arthritis, cyclic citrullinated peptide, rheumatoid factor, disease activity, clinical remission

Rheumatoid factor (RF) has long been a component of the diagnostic criteria for rheumatoid arthritis (RA) [1]. Although the sensitivity of RF is approximately 75-80%, its specificity is modest. RF is found in 3-5% of the general population, and in up to 30% of the elderly [2]. Despite this limitation, RF is well studied and its associations with a more severe disease course have been extensively described. HighRF concentrations, for example, are associated with unremitting disease, in addition to the presence of subcutaneous nodules and other extra-articular disease manifestations [3, 4].

Recently, anti-cyclic citrullinated peptide antibody (aCCP) has been shown to be reasonably sensitive (65-80%) and highly specific for RA (up to 98%) [2, 5, and recently reviewed in 6]. Not only is aCCP useful in diagnosis, its presence has been shown to predate clinical disease, by several years in some instances, and it is useful in identifying those with undifferentiated arthritis who will eventually develop RA [7]. Moreover, aCCP status provides important prognostic information in RA. Numerous studies have shown that aCCP positivity is associated with joint damage and radiographic progression [e.g., 8-10], and Rönnelid et al. showed that aCCP seropositive patients had more active disease during follow-up than seronegative patients [11]. However, only a small number of studies have considered the magnitude of aCCP concentrations, rather than qualitative aCCP status (seropositive or seronegative), and none have examined the prognostic value of aCCP in a predominantly male cohort of RA patients.

While RA is more common in women than men at a ratio of approximately 3:1, there is still a significant proportion of RA patients who are male. The literature is conflicted as to the impact of gender on disease course [e.g, 12-14], and the largest study to date examining these effects included 79% women [14]. There are data suggesting that men with RA have higher rates of autoantibody seropositivity, but no studies examining associations of disease related autoantibodies with disease course in large populations of men.

Given the potential toxicity of disease-modifying anti-rheumatic drugs (DMARDs) and the benefit of early/aggressive treatment, the prompt identification of RA patients at greatest risk for unfavorable outcomes is important in guiding early treatment decisions. The relative paucity of data on the prognostic value of aCCP concentration beyond seropositivity and the potential clinical utility of such information indicate a clear need for inquiry. The aim of this study was to examine the extent to which the magnitude of aCCP and RF concentrations are associated with disease burden and clinical remission in a well-characterized population of U.S. veterans with established RA, a population composed predominantly of older men with longstanding disease.

METHODS

Study subjects

Study subjects included United States (U.S.) veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry [15] with active enrollment sites at VA Medical Centers in Dallas, TX, Denver, CO, Jackson, MS, Omaha, NE, Portland, OR, Salt Lake City, UT, and Washington, D.C. The registry has received Institutional Review Board approval at each site and patients provided informed written consent prior to enrollment. All patients satisfied American College of Rheumatology (ACR) classification criteria for RA [1].

Clinical measures

In addition to collecting serum and DNA at enrollment, VARA includes baseline and longitudinal clinical data, the latter collected as part of routine care. Enrollment variables include: diagnostic criteria (nodules and radiographic erosions—based on medical documentation), comorbidity, smoking status (never, former, or current), sociodemographics (education, race/ethnicity, age, sex), dates of RA diagnosis, and prior DMARD use. aCCP (IgG) was measured on banked serum using a second generation ELISA (Diastat, Axis-Shield Diagnostics Ltd., Dundee, Scotland, UK, positivity ≥ 5 U/ml) . RF was determined by nephelometry (Siemens Healthcare Diagnostics, Munich, Germany, positivity ≥ 15 IU/ml).

Measures collected at enrollment and during follow-up included tender and swollen joint counts (0-28), erythrocyte sedimentation rate (ESR, mm/h), pain (0-10), a 10-item multidimensional Health Assessment Questionnaire score (MD-HAQ, range 0-3) [16], patient global well-being (100 mm visual analog scale) and treatments. RA treatments were classified in three categories: 1) biologic agents, including infliximab, etanecept, adalimumab, rituximab, and abatacept; 2) non-biologic DMARDs, including methotrexate, sulfasalazine, leflunomide, minocycline, doxycycline, and hydroxychloroquine; and 3) prednisone.

Patients were excluded if autoantibody data (both RF and aCCP) were not available. Patients were also excluded ifthey had only a single clinical observation and/or follow-up duration < 6 months. Finally, patients for whom the 4-variable Disease Activity Score based on 28 joint counts (DAS28) [17] could not be calculated after accounting for missing variables were also excluded.

Outcome variables

Three outcomes were examined and included: . 1) achievement of sustained remission, defined as at least 2 consecutive observations, separated by at least 3 months, with DAS28 ≤ 2.6—a level which has been widely used as indicative of remission [18]; 2) proportion of follow-up time spent in remission (a continuous measure, range 0-1) to account for differences in follow-up duration(time in remission credited only when remission was maintained for at least 2 sequential visits; and 3) the area under the DAS28 curve (AUC) per year of follow-up (see AUC example in Figure 1).

Figure 1
Visual representation of the Disease Activity Score (DAS)28 area under the curve (AUC), indicated by the gray hatched area. The horizontal line represents the threshold for clinical remission (DAS28 = 2.6).

Statistical analyses

For missing components of DAS28 (tender and swollen joint counts [3.5% of observations missing], ESR [8.2% of observations missing], and patient global well-being [11.9% of observations missing]), a last observation carried forward approach was used. If there were no preceding observations, the first observation was carried backwards. For educational level (missing in 203 patients), dichotomized as high school graduate or not, multiple imputation techniques (Stata10 command ‘uvis’, StataCorp, College Station, TX), were employed based on age, race/ethnicity, gender, and smoking status. Finally, for smoking status (missing for 11 patients), imputation techniques were used, based on age, race, gender, education level, and comorbidities of chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD).

Baseline aCCP and RF were considered dichotomously (seropositive vs. seronegative), categorically as low, moderate, and high concentration (using tertiles of seropositive patients and referent to seronegative), and continuously. Among aCCP positive patients, the thresholds for low, moderate, and high concentration groups were as follows: ≥ 5 U/ml, ≥ 123.5 U/ml, and ≥ 321.1 U/ml. For RF seropositive patients, the thresholds for the categorical groups were ≥ 15 IU/ml, ≥ 90.4 IU/ml, and ≥ 341 IU/ml. Associations between aCCP, RF, and the three outcomes were examined using linear regression for continuous outcomes and logistic regression for dichotomous outcomes. Given the high concordance of aCCP and RF status (69%), these autoantibodies were modeled separately in primary analyses. All models were adjusted for age and sex. Additional covariates included in multivariate models were race, education, disease duration, follow-up time, smoking status, comorbidity (a count of presence of diabetes mellitus, ischemic heart disease, hypertension, cerebrovascular disease, chronic kidney disease, hyperlipidemia, and chronic obstructive pulmonary disease; range 0-7), DMARD and/or prednisone use, and disease remission status (DAS28 ≤ 2.6 vs. DAS28 > 2.6) at enrollment. In linear regression models examining the proportion of time in remission, the β-coefficients correspond to fractional changes in time spent in remission (e.g., βi = -0.12 corresponds to 12% less time is spent in remission for each increase in the ith covariate). Pharmacologic interventions, based on the three aforementioned categories, were accounted for using two approaches: use of medication at enrollment and the addition of new medications (within classes) during follow-up. Differences based on the enrollment site were accounted for via cluster analysis. In subanalyses, we examined the associations of aCCP and RF with outcomes among patients with recent-onset disease, defined as disease duration of less than 2 years at enrollment. We also examined the associations of autoantibody concentrations with our outcomes in those patients with discordant autoantibody status to more closely examine the importance of the individual autoantibodies.

RESULTS

Patient Selection

Of the total 1,195 patients enrolled as of January 1, 2009, aCCP and RF data were available for 1,103. Excluding patients with fewer than 2 observations, or less than 6 months follow-up, 859 patients were eligible for analysis. Finally, after removing those patients with insufficient data following imputation for calculation of DAS28 scores, 855 patients (7,562 observations) remained.

Baseline characteristics

Patients were predominantly Caucasian men with well-established RA [Table 1] Additional characteristics, including measures of disease burden at enrollment (nodules and DAS28), follow-up duration, medication use, comorbidity score, and autoantibody status are summarized in Table 1. A majority of patients were positive for aCCP (75%) and RF (80%). Discordant autoantibody status was relatively uncommon (18%), while dual autoantibody positivity was far more common (69%).

Table 1
Patient characteristics overall and based on disease activity at enrollment; proportion (%) or mean (SD). Data reflect status at enrollment, with the exception of follow-up duration*.

Sustained remission

An episode of sustained remission (including ≥ 2 consecutive visits more than 3 months apart) was achieved by 309 (36%) patients. After multivariate adjustment, both baseline aCCP (OR 0.70; 95% CI 0.57-0.87) and RF (OR 0.61; 95% CI 0.47-0.79) positivity were associated with a lower odds ofsustained remission [Figure 2]. Likewise, higher concentrations of baseline aCCP and RF (modeled as a continuous variable and in ordered categories) were also associated with lower likelihood of sustained remission. The associations of ordered autoantibody categories with remission were most pronounced at the highest concentrations, recognizing that the association of intermediate aCCP concentrations did not reach statistical significance. Covariates associated with a higher likelihood of sustained remission in models examining continuous aCCP concentration included years of disease duration (OR 1.01; 95% CI 1.00-1.02), male sex (OR 1.71; 95% CI 1.15-2.54), years of follow-up (OR 1.51; 95% CI 1.27-1.80), and clinical remission at enrollment (OR 11.9; 95% CI 8.67-16.4). Covariates independently associated with a lower likelihood of remission included older age (OR 0.97; 95% CI 0.95-0.98), high school education (OR 0.60; 95% CI 0.42-0.87), non-biologic DMARD use at enrollment (OR 0.81; 95% CI 0.69-0.95), and the addition of 2 (OR 0.67; 95% CI 0.53-0.85) or 3 (OR 0.29; 95% CI 0.12-0.67) new pharmacologic agents during follow-up.

Figure 2
Age- and sex-adjusted (■) and multivariate (○) associations of anti-CCP antibody (panel a) and rheumatoid factor (panel b) status and concentration with the achievement of sustained remission (defined as Disease Activity Score [DAS]28 ...

Proportion of time in remission

The mean (SD) proportion of follow-up time spent in remission was 0.14 (0.28). After multivariate adjustments, both aCCP (β = -0.062; p = 0.025) and RF (β = -0.068; p = 0.012) positivity were associated with less time in remission [Table 2]. As with sustained remission, higher levels of aCCP and RF (modeled as concentrations and in ordered categories) were associated with less follow-up time in remission, although aCCP concentration only trended towards significance [Table 2]. Covariates significantly associated with a lower proportion of follow-up in remission in multivariate models examining aCCP concentration included biologic DMARD use at enrollment (β = -0.043; p = 0.036) and the addition of 1 (β = -0.049, p = 0.013), 2 (β = -0.066, p = 0.006), or 3 (β = -0.087, p = 0.008) new pharmacologic agents during follow-up. Covariates independently associated with an increased time in remission included male sex (β = 0.065; p = 0.012) and clinical remission at enrollment (β = 0.341; p = 0.001).

Table 2
Age- and sex-adjusted and multivariate associations of autoantibodies with proportion of time in remission*.

Area under the curve (AUC)

Analyses of AUC DAS28 revealed similar associations as those observed with sustained remission and proportion of time in remission. Following multivariate adjustment, both aCCP (β = 0.17; p = 0.011) and RF (β = 0.23; p = 0.003) positivity were associated with larger AUC [Table 3]. Referent to seronegative patients, those with moderate and high titer aCCP and RF were associated with greater AUC, and autoantibody concentrations were directly associated with AUC [Table 3]. Covariates significantly associated with a greater DAS28 AUC in multivariate models examining aCCP concentrations included the addition of 1 (β = 0.031, p = 0.001), 2 (β = 0.66, p = 0.002), 3 (β = 0.99, p = 0.001), or 4 (β = 0.81, p = 0.001) new pharmacologic agents during follow-up. Covariates independently associated with a decrease in DAS28 AUC included years of follow-up (β = -0.14; p = 0.015), clinical remission at enrollment (β = -1.22; p = 0.001), and the presence of 2 (β = -0.16, p = 0.034) or 3 (β = -0.15, p = 0.038) comorbid conditions.

Table 3
Age- and sex-adjusted and multivariate associations of autoantibodies with DAS28 area under the curve (AUC), standardized per year of follow-up*.

Subanalyses

In age- and sex-adjusted subanalysis of RA patients with recent-onset disease (disease duration < 2 years; n = 153), aCCP (OR 0.56; 95% CI 0.39-0.80) and RF (OR 0.32; 95% CI 0.13-0.79) positivity were inversely associated with sustained remission. Associations of aCCP and RF seropositivity with DAS28 AUC (β = 0.31; p = 0.100 and β = 0.62; p = 0.097, respectively) and proportion of follow-up in remission (β = -0.06; p = 0.328 and β = -0.15; p = 0.087, respectively) were not significant. Results were not changed after multivariate adjustment (data not shown). The inverse associations of aCCP and RF concentrations with sustained remission in patients with recent-onset disease were greatest in those with higher serum concentrations, although not reaching the threshold of statistical significance.

Among aCCP positive / RF negative patients, aCCP concentration was positively associated with the likelihood of achieving sustained clinical remission (OR 1.10; 95% CI 1.00-1.20, per 100 U/ml increase) after multivariate adjustment. Among aCCP negative / RF positive patients, RF concentration trended towards a non-significant inverse association with sustained clinical remission (OR 0.81; 95% CI 0.58-1.13, per 100 IU/ml increase).

DISCUSSION

We have shown that higher absolute concentrations of aCCP and RF in a cohort of U.S. veterans with RA are associated with poorer clinical outcomes including greater disease burden and less sustained remission. These associations appear to be explained primarily by those patients with the highest autoantibody concentrations. As opposed to other investigations showing that aCCP is a stronger predictor than RF in outcomes such as radiographic changes [19, 20], we found that the strength of associations of aCCP and RF with our outcomes were similar. Indeed, results of subanalyses in antibody discordant patients suggest that RF may be more closely associated with increased disease activity over follow-up than aCCP.

Our results regarding aCCP magnitude are consistent with recent reports. Berglin et al. found that aCCP concentration, beyond aCCP positivity, was indicative of more aggressive radiographic progression and worse disease severity [8]. In the study by Rönnelid et al., higher aCCP concentrations at baseline were associated with greater disease activity during follow-up [11]. Turesson et al. showed in a small case-control study that patients with extra-articular disease tended to have higher aCCP concentrations, though the association did not reach significance [4]. While each of these studies showed relationships between aCCP concentration and disease burden, our study is unique in its simultaneous consideration of both aCCP and RF concentrations, its larger sample size, and its predominantly male cohort.

The results of this investigation may have limited generalizability, particularly since this study population was composed primarily of older men. However, men with RA are historically underrepresented in epidemiological studies, though they comprise up to one-third of all affected cases. Furthermore, men with RA have been shown to have more aggressive disease course than women, one characterized by increased radiographic progression, a higher prevalence of extra-articular manifestations, and greater disease-related mortality [12, 13]. The VA represents the largest integrated health care system in the U.S. and as such provides a unique opportunity to study a diverse and arguably vulnerable RA population where socioeconomic barriers to healthcare access are limited.

Another possible limitation is the length of disease duration at enrollment with a mean of approximately 12 years and the corresponding receipt of previous RA-related therapies. This is potentially important since other investigations have shown that aCCP and RF concentrations can be influenced by DMARD treatment, although the magnitude of this effect appears to be modest (approximately 10% change in serum concentrations associated with biological therapy) [22]. Furthermore, changes in aCCP related to RA treatments only rarely result in a change in aCCP status (e.g. seroconversion from positive to negative) and are generally insufficient to cause changes in the aCCP categories examined in this study [23]. Our subanalyses limited to a select number of patients with recent-onset disease, showed risk estimates that were similar to those from analyses of entire study population, suggesting that the associations of aCCP and RF concentrations with disease burden are independent of disease duration. Although we examined DMARD (biologic and non-biologic) and glucocorticoid use as potential confounders (both at baseline and initiations during follow-up), we did not examine the associations of autoantibody concentrations with treatment responses to specific therapeutic agents given the heterogeneity in treatments received. This may be relevant since the associations of autoantibody concentrations with disease burden could be operative through specific effects on treatment response. We also recognize that the definition of sustained clinical remission in RA is not universally established. However, by considering disease burden in three different outcome variables, which showed consistent relationships with aCCP magnitude, the limitations of these definitions appear to be less relevant.

In summary, our results show that higher baseline aCCP concentrations are associated with greater disease burden over time in U.S. veterans with established RA, a prognostic attribute that extends beyond that of the qualitative (seropositive vs. seronegative) status. Although limited in power, our subanalyses of patients with discordant RF/aCCP status suggests that RF positivity may actually drive the observed associations of aCCP with increased disease burden. While displaying less favorable diagnostic metrics than aCCP, higher RF concentrations may be more closely associated with increased disease activity over follow-up. These results emphasize the importance of further investigations in larger, more diverse RA populations including individuals with discordant antibody status.

ACKNOWLEDGEMENTS

The authors wish to thank Ms. Debra Bergman and Mr. Bart Hamilton with their assistance in this work and the many U.S. veterans who have generously participated in this research.

Acknowledgements / Funding: Dr. Miriovsky's effort was supported by the Ephraim P. Engleman Endowed Resident Reseach Preceptorship from the American College of Rheumatology (ACR) Research and Education Foundation. This work was funded by a grant from NIH / NIAMS (R03 AR054539, PI Mikuls). The VARA Registry has received research support from the Health Services Research & Development (HSR&D) Program of the Veterans Health Administration (VHA) in addition to unrestricted research funds from Abbott Laboratories and Bristol-Myers Squibb. Dr. Mikuls receives research support from NIAMS (K23 AR050004) and the VHA (VA Merit). Dr. Caplan is supported by a VA HSR&D Career Development Award.

Footnotes

DISCLAIMER

The views expressed in this article are those of the authors and do not necessarily reflect the position of policy of the Department of Veteran Affairs.

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