Anti-CCP-positive patients with RA have a higher 10-year probability of fracture evaluated by FRAX®: a registry study of RA with osteoporosis/fracture

This interim analysis of RA-related osteoporosis/fracture in an RA registry was conducted at CGMHK. In the registry, consecutive RA patients who had visited the rheumatology clinic at CGMHK since September 1, 2014, and fulfilled the 1987 American College of Rheumatology (ACR) revised criteria [14] or the 2010 ACR/European League Against Rheumatism classification criteria for RA [9] were enrolled. Those who were < 20 years of age, had any malignancy within the past 5 years, had an estimated life expectancy < 3 years, or were unwilling to participate in the study were excluded from the registry program.

Clinical assessments included demographic data (age, height, weight, body mass index [BMI]), presence and/or levels of anti-CCP, and RF. Disease duration was defined as the time that elapsed between the onset of first disease-related symptoms and enrollment. RA activity was quantified by using a health assessment questionnaire and disease activity score was assessed using the Disease Activity Score in 28 joints based on ESR  (DAS28-ESR). Information on current medications at the time of registration, including disease-modifying antirheumatic drugs (DMARDs), antiosteoporosis regimens, glucocorticoids, and biologic disease-modifying antirheumatic drugs (bDMARDs), was collected. In addition, lifestyle, evidence of previous fragility fracture (history or radiographic), and risk factors for fragility fracture based on the FRAX® tool were recorded. The 10-year probability of major and hip fractures, calculated using the FRAX® tool with FN BMD (Taiwan version), of each patient was collected as well. Anti-CCP, ESR, CRP, and BMD were measured at enrollment using a dual-energy X-ray absorptiometry scanner (Delphi A; Hologic Corp., Waltham, MA, USA) for hip (total), FN, and lumbar spine (L1–L4) areas. All procedures were performed by International Society for Clinical Densitometry-certified technicians in accordance with the manufacturer’s standardized procedures. Anteroposterior radiographs of the thoracolumbar spine as well as kidney, ureter, and bladder x-rays were obtained at enrollment for each participant to evaluate any radiographic spinal fractures.

The participants were categorized into two groups according to anti-CCP-positive (anti-CCP+) or anti-CCP− status and into four groups (I–IV) according to anti-CCP level quartiles. The participants provided written informed consent and the Regional Ethical Review Board of CGMHK approved the study (104-3530B), which was performed according to the principles of the Helsinki declaration.

RF and anti-CCP were determined by immunonephelometry using a BN ProSpec System (Siemens Healthcare, Erlangen, Germany) as well as a second-generation Phadia ImmunoCAP 250 EliA CCP assay (Phadia, Freiburg, Germany) according to the manufacturers’ recommendations. A positive result for anti-CCP was above a cutoff value of 7 U/ml, whereas that for RF was a value > 15 IU/ml. CRP and ESR were measured by using nephelometric and Westergren methods, respectively.

Data were checked for normality. Anti-CCP values were used as continuous variables and additionally categorized into quartiles. If the baseline characteristics had a skewed distribution, nonparametric methods were used for analysis. Independent groups were compared using the Mann-Whitney U test for continuous variables and the chi-square test for dichotomous variables. For comparing characteristics between anti-CCP quartiles, we used analysis of variance or the Kruskal-Wallis H test for comparing means or medians, respectively. Normally distributed continuous variables are expressed as mean ± SD, and nonnormally distributed variables are expressed as median (IQR). All analyses were performed using R version 3.1.2 software (R Foundation for Statistical Computing, Vienna, Austria). The level of significance was set at 0.05.

Table 1 shows the demographic and clinical characteristics of the 521 patients. A total of 359 (68.9%) patients were anti-CCP+. The median (IQR) age was 59 (14) years, BMI was 23.1 (5) kg/m², and disease duration was 11 (13) years. The study population consisted mainly of women (n = 447; 85.8%), of whom 80.3% were postmenopausal. The median (IQR) menopause age was 50 (2) years.

Compared with anti-CCP− patients, anti-CCP+ patients had significantly higher levels of anti-CCP (U/ml) (183 [283] vs. 0.9 [1.1], p < 0.0001), RF (IU/ml) (129 [288.9] vs. 10.6 [6.8], p < 0.0001), ESR (mm/h) (19 [24] vs. 13.5 [18.0], p < 0.0001), CRP (mg/L) (3.2 [8.6] vs. 1.7 [5.7], p = 0.0005), DAS28-ESR (3.2 [1.7] vs. 2.8 [1.4], p = 0.0001), and higher RF+ rate (86.2% vs. 25.3%, p < 0.0001). The two groups were comparable in terms of demographics, rate of antiosteoporosis regimens, glucocorticoids and bDMARD, and comorbidities.

The prevalence of osteoporosis (FN; T-score less than or equal to −2.5) and rate of prevalent fracture were comparable between the anti-CCP+ and anti-CCP− groups (31.7% vs. 24.5%, p = 0.0993; and 18.7% vs. 18.5%, p = 0.9687). Compared with anti-CCP− patients, anti-CCP+ patients had a significantly lower FN BMD (g/cm²) level (0.614 [0.144] vs. 0.643 [0.142], p = 0.0196) (Fig. 1a), as well as a significantly higher smoking rate (8.4% vs. 3.1%, p = 0.0261). In terms of 10-year probability of major and hip fractures defined using the FRAX® tool, anti-CCP+ patients demonstrated a significantly higher probability than anti-CCP− patients (15.0 [18.9] vs. 12.0 [15.3, p = 0.0461) and (5.0 [9.2] vs. 3.6 [8.2], p = 0.0118), respectively (Table 1, Fig. 1b).

There were 130, 127, 132, and 132 patients in groups I–IV, respectively (Table 2). Age, sex, rate of menopause, age at menopause, BMI, time from symptoms to diagnosis, disease duration, rate of antiosteoporosis regimens/glucocorticoids/bDMARDs, and comorbidities were balanced between the groups, whereas the smoking rate (p = 0.0075) was significantly different among groups (Table 2).

Regarding variables related to RA disease activity, the rate of RF+ (p < 0.0001) and levels of RF (p < 0.0001), ESR (p < 0.0001), CRP (p = 0.0012), and DAS28-ESR (p = 0.0001) were significantly different among the groups and correlated with anti-CCP levels. BMD at the spine (L1–L4) (p = 0.0394), hip (total) (p = 0.0041), and FN (p = 0.0033) differed significantly among the groups (Table 2), whereas the prevalence of osteoporosis, rate of previous fracture, and number of falls in the previous year were comparable. The 10-year probabilities of major fracture (p = 0.0067) and hip fracture (p = 0.0013) among the groups were significantly different (Table 2).

A subgroup analysis revealed that the BMD values at the spine (L1–L4) (p = 0.026), hip (total) (p = 0.002), and FN (p = 0.002) in group II, but not in group III or IV, were significantly lower than those in group I (Fig. 2a–c). In addition, there was a significantly higher 10-year probability of major fracture (p = 0.005) (Fig. 3a) in group II than in group I. The 10-year probabilities of hip fracture in group II (p = 0.001), III (p = 0.034), and IV (p = 0.035) (Fig. 3b) were significantly higher than that of group I.

Although there are many fracture risk assessment tools available worldwide, the most widely used in Taiwan is the FRAX® tool (Taiwan version). Its use can help in estimation of the 10-year absolute risk of major and hip fractures among individuals ≥ 40 years old. The FRAX® tool includes parameters such as sex, age, BMI, previous fracture, smoking, glucocorticoid use, diagnosis of RA, and BMD. However, shortcomings exist for rheumatologists using the FRAX® tool to evaluate the risk of fracture specifically for RA patients, because the tool does not include other well-known risk factors of fracture for patients with RA, such as disease activity or duration. Despite its shortcomings, this tool has been validated in several countries, except in the United Kingdom [28], for RA patients [29, 30].

Using the FRAX® tool, we found that anti-CCP+ RA patients had a higher risk of 10-year probability of major or hip fracture than anti-CCP− RA patients (Table 1, Fig. 1b). In addition, anti-CCP+ RA patients had a higher 10-year probability of hip fracture than anti-CCP− RA patients at all anti-CCP levels (Table 2, Fig. 3b). The reason why anti-CCP+ is associated with an elevated 10-year probability of fracture in our cohort is twofold. First, in terms of risk factors in the FRAX® tool, we found the rates of smokers and FN BMD in anti-CCP+ patients were significantly higher than those of anti-CCP− patients. Second, other risk factors, including age, previous fracture, and glucocorticoid use, in anti-CCP+ patients were numerically, albeit not significantly, higher than in anti-CCP− patients (Table 1). In addition, we found that if the factors of FN BMD and smoking were excluded from the calculation of FRAX® score, anti-CCP+ RA patients still had significantly higher FRAX® scores (hip) (data not shown) than their anti-CCP− counterparts. This suggests that the summation effect of other risk factors can explain the differences in the FRAX® score (hip) between the two groups as well.

Regarding the relationship between anti-CCP level and fracture risk, only the risk of major fracture was higher in group II than in group I (p = 0.005) (Fig. 3a), whereas the risks of hip fracture were significantly higher in groups II–IV than in group I. The smoking rate was proportional to the anti-CCP levels (Table 2). However, BMD was not proportional to the anti-CCP levels. The elevated risk of major fracture in group II and the rates of hip fracture in groups II–IV can also been explained by the summation effect of other risk factors in the FRAX® tool. These findings suggest that, in the future, those using the FRAX® tool to evaluate the fracture risk for patients with RA should consider the positivity/titer of anti-CCP, because it has been suggested for adjustment of FRAX® score by doses of glucocorticoid [31].

The disease activity markers of ESR, CRP, and DAS28-ESR were significantly different between patients with anti-CCP+ and anti-CCP− status and among groups I–IV. The marker levels were proportional to the anti-CCP levels in our cohort. Whether anti-CCP-associated higher disease activity in patients with RA is related to the long-term risk of fracture requires further validation studies.

The present study has limitations. This investigation is a cross-sectional study of patients with established RA. Although reversion from anti-CCP+ to anti-CCP− status was not observed in a 2-year observational study [32], the anti-CCP levels are subject to treatment changes in patients with RA [33, 34]. Whether the positivity or levels of anti-CCP after long-term treatment (10 years) in our cohort were changed is unknown. However, because the anti-CCP+ rate (68.9%) of our cohort was compatible with that of a previous study [35], it seems that long-term treatment in our cohort would not change the positivity of anti-CCP. Hence, the application of anti-CCP in the prediction of 10-year probability of fracture in established RA appears reliable. In addition, the application of the FRAX® tool for estimating fracture risk is limited to populations aged ≥ 40 years. In addition, anti-CCP positivity, disease activity, and disease duration were not included in the FRAX® tool in the evaluation of 10-year probability of fracture for RA patients. Whether the application of anti-CCP positivity could be used to estimate the 10-year probability of fracture by using the FRAX® tool with younger patients with RA warrants further investigation. Finally, the heterogeneity of our cohort fulfilled the 1987 or 2010 ACR classification criteria, which could be considered another drawback of our study. Whether the sensitivity of using anti-CCP for estimating the 10-year probability of fracture for RA patients would be the same under different criteria is unknown.