Chinese Registry of rheumatoid arthritis (CREDIT): II. prevalence and risk factors of major comorbidities in Chinese patients with rheumatoid arthritis
Jin et al. Arthritis Research & Therapy
Chinese Registry of rheumatoid arthritis (CREDIT): II. prevalence and risk factors of major comorbidities in Chinese patients with rheumatoid arthritis
Shangyi Jin 0 1
Mengtao Li 0 1
Yongfei Fang 0 3
Qin Li 2
Ju Liu 8
Xinwang Duan 7
Yi Liu 6
Rui Wu 5
Xiaofei Shi 10
Yongfu Wang 9
Zhenyu Jiang 4
Yanhong Wang 11
Chen Yu 1
Qian Wang 1
Xinping Tian 1
Yan Zhao 1
Xiaofeng Zeng 1
0 Equal contributors
1 Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education , No. 1 Shuaifuyuan, Wangfujing Ave, 100730 Beijing , China
2 Department of Rheumatology, The First People's Hospital of Yunnan Province , Kunming, Yunnan , China
3 Department of Rheumatology, Southwest Hospital, Third Military Medical University , Chongqing , China
4 Department of Rheumatology, The First Hospital of Jilin University , Changchun, Jilin , China
5 Department of Rheumatology, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China
6 Department of Rheumatology, West China Hospital, Sichuan University , Chengdu, Sichuan , China
7 Department of Rheumatology, The Second Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China
8 Department of Rheumatology, Jiujiang No.1 People's Hospital , Jiujiang, Jiangxi , China
9 Department of Rheumatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology , Baotou, Inner Mongolia , China
10 Department of Rheumatology, The First Affiliated Hospital of Henan University of Science and Technology , Luoyang, Henan , China
11 Department of Epidemiology and Bio-statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College , Beijing , China
Background: Rheumatoid arthritis patients are at higher risk of developing comorbidities. The main objective of this study was to evaluate the prevalence of major comorbidities in Chinese rheumatoid arthritis patients. We also aimed to identify factors associated with these comorbidities. Methods: Baseline demographic, clinical characteristics and comorbidity data from RA patients enrolled in the Chinese Registry of rhEumatoiD arthrITis (CREDIT) from Nov 2016 to August 2017 were presented and compared with those from five other registries across the world. Possible factors related to three major comorbidities (cardiovascular disease, fragility fracture and malignancy) were identified using multivariate logistic regression analyses. Results: A total of 13,210 RA patients were included (80.6% female, mean age 52.9 years and median RA duration 4.0 years). Baseline prevalence rates of major comorbidities were calculated: CVD, 2.2% (95% CI 2.0-2.5%); fragility fracture, 1.7% (95% CI 1.5-1.9%); malignancy, 0.6% (95% CI 0.5-0.7%); overall major comorbidities, 4.2% (95% CI 3.9-4.6%). Advanced age was associated with all comorbidities. Male gender and disease duration were positively related to CVD. Female sex and longer disease duration were potential risk factors for fragility fractures. Ever use of methotrexate (MTX) was negatively related to baseline comorbidities. Conclusions: Patients with rheumatoid arthritis in China have similar prevalence of comorbidities with other Asian countries. Advanced age and long disease duration are possible risk factors for comorbidities. On the contrary, MTX may protect RA patients from several major comorbidities, supporting its central role in the management of rheumatoid arthritis.
Rheumatoid arthritis; Comorbidity; Cardiovascular disease; Fragility fracture; Malignancy; Risk factor; Methotrexate
Rheumatoid arthritis (RA) is a common systemic
autoimmune disease characterized by synovial hyperplasia,
chronic joint inflammation, and extra-articular
manifestations. In addition to joint deformity and disability that
are directly related to joint inflammation, patients with
RA are also reported to have higher prevalence of
comorbidities such as cardiovascular disease, osteoporotic
fracture and malignancy [
]. The presence of
comorbidities may increase the mortality of RA patients and
affect their treatment strategies, resulting in worse
]. According to this, the prediction and
management of comorbidities have been increasingly
important in the long-term management of RA .
To better understand the presence and development
of comorbidities in RA patients, several registries and
cohorts all over the world have included related
information in their data collection. Baseline data for prior
and current comorbidities are collected at enrollment,
and during follow-up visits incident conditions are
]. These data provide information about the
prevalence, incidence, risk factors and other
characteristics of selected comorbidities, which may further be
referred by rheumatologists to improve comorbidity
detection and management strategies.
In China, rheumatoid arthritis has an estimated
prevalence of 0.42%, affecting more than 5 million patients by
]. However, little is known about the
comorbidities of RA in this large RA population. Previous studies
are restricted to relatively small sample size and local
data sources [
]. The Chinese Registry of
rhEumatoiD arthrITis (CREDIT) is the first nationwide
multicenter prospective RA cohort in China. In this study,
based on the preliminary results from CREDIT, we
evaluated the nationwide prevalence of major comorbidities
in Chinese RA patients, as well as the differences
between patients with or without these comorbidities.
By conducting this study, we hope to provide a little
supplement to the relatively limited data in Asia,
especially in China.
The Chinese Registry of rhEumatoiD arthrITis (CREDIT)
established in Nov 2016 is the first nationwide,
multicenter prospective registry of rheumatoid arthritis patients in
China. Its goal is to provide “real-world” data regarding
clinical characteristics and long-term treatment outcomes
of RA in China. Consecutive patients visiting the
participating centers were invited to enroll in the registry if they
fulfilled the 2010 American College of Rheumatology
classification criteria for RA and were able to understand and
complete the questionnaires that were administered [
By the time of this writing in August 2017, more than
13,000 RA patients have been recruited into this cohort by
rheumatologists from 173 centers (departments of
rheumatology in 157 academic and 16 local hospitals),
covering 31 provinces all over the country (see the map of
participating centers in Additional file 1). Data are
collected by rheumatologists by interviewing the patients
using predefined standard online questionnaires, which
include demographic data (age, gender), disease
characteristics, past and present treatment for RA (types of
medication, dosage and treatment course, adverse effects, etc.), as
well as the presence of selected major comorbidities.
Disease characteristics collected include initial fulfillment
of RA diagnostic criteria, disease duration, erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP),
seropositivity for rheumatoid factor (RF) or anti-citrullinated
protein antibodies (anti-CCP), morning stiffness, tender
joint count (TJC, 28 joint count), swollen joint count (SJC,
28 joint count), patient and physician global assessment
(PGA and PhGA) and disease activity measured by disease
activity score 28 (DAS28), SDAI, and CDAI. In the present
study we aimed to analyze the occurrence of three major
comorbidities in adult RA patients, so we only included
patients who were aged 18 years or older and had
complete data for baseline comorbidities.
Informed consent was obtained from all patients at
enrollment. Ethics approval for the registry was obtained
from the Medical Ethics Committee of Peking Union
Medical College Hospital (PUMCH), which was
accepted by all participating centers as the central
institutional review board (IRB).
In the CREDIT registry, the following three
comorbidities are recorded as major comorbidities of RA:
cardiovascular disease (CVD), fragility fracture (osteoporotic
fractures at any sites, such as vertebrae, hip and distal
radius) and malignancy. Cardiovascular diseases include
both coronary artery disease (CAD, consisting of angina
pectoris and myocardial infarction) and stroke (ischemic
or hemorrhagic). For malignancies, data on their sites
and types are also recorded. Presence of these
comorbidities is evaluated and recorded by rheumatologists at
enrollment and each follow-up visit. Baseline comorbidity
information is collected at enrollment. Rheumatologists
ask their patients whether they have been diagnosed
with any of the three major comorbidities by other
physicians. These data are mainly based on patients’ reports,
and corresponding medical records will be checked
when a diagnosis of comorbidity is ambiguous.
We analyzed the baseline characteristics of all patients
included in this study using descriptive statistics (means,
median, and range). Continuous variables were analyzed
according to their distribution. Normally distributed
continuous variables were presented as mean and
standard variation, and non-normally distributed
variables were presented as median and interquartile
range. Categorical variables were presented as rates.
Baseline overall and separate prevalence rates of the
major comorbidities were calculated. In order to
identify possible factors related to the presence of CVD,
fracture and malignancy, we compared the patients
with only one of the three major comorbidities with
those without any comorbidity. Baseline variables
including demographic features, clinical characteristics
and medications were evaluated using univariate and
multivariate logistic regression analyses. For each
variable, the odds ratios (OR) and associated 95%
confidence intervals (CI) were calculated.
Statistical significance was defined as p < 0.05. All
statistical analyses were performed using SPSS software
(version 23.0, IBM SPSS Inc., Armonk, NY, USA).
Baseline characteristics and prevalence of comorbidities
A total of 13,210 patients with complete comorbidity
data were included in this study (see Additional file 2).
Their baseline characteristics are presented in Table 1.
The mean age of these patients was 52.9 years and
80.6% of them were female. The median disease duration
of RA was 4.0 years. Over 83% of the patients were
seropositive for either RF or anti-CCP antibody, and the
mean DAS28 was 4.5. 40.6% of the patients had been
treated with glucocorticoid (GC), and approximately
55.9%, 45.9%, 30.4%, 4.4%, and 8.3% of them had
received methotrexate (MTX), leflunomide (LEF),
hydroxychloroquine (HCQ), sulfasalazine (SSZ) and biologic
disease-modifying antirheumatic drugs (bDMARDs)
therapies, respectively. The baseline characteristics of
patients with or without comorbidities are also
presented separately in Table 1.
Table 2 shows the detailed prevalence of major
comorbidities at baseline. In all, 4.2% of RA patients reported
that they had been diagnosed with at least one of the
three comorbidities. CVD was present in 293 (2.2%)
patients in total, remarkably more prevalent in male
patients (3.6% vs. 1.9%). Among all patients with CVD, 204
reported to have CAD and 108 had a history of stroke.
Prior fragility fractures were reported by 222 (1.7%) at
enrollment, and the prevalence rate was higher for
female patients (1.9% vs. 1.0). Malignancy was the least
common comorbidity among RA patients (n = 78, 0.6%)
in this study, with no difference between genders. The
most frequently involved organs were breast (n = 17),
lung (n = 10), thyroid (n = 7), colorectum (n = 5) and
stomach (n = 4) (see Additional file 3). Compared with
younger subjects, patients over 60 years old had higher
prevalence for all comorbidities. Overlaps between
comorbidities were not prevalent in the study population,
and the most common overlap was between CVD and
fragility fracture (28 patients).
CVD cardiovascular disease, RA rheumatoid arthritis, RF rheumatoid factor, CCP anti-citrullinated protein antibody, DAS28 disease activity score 28, ESR erythrocyte
sedimentation rate, CRP C-reactive protein, GC glucocorticoid, MTX methotrexate, bDMARDs biological disease-modifying antirheumatic drugs
aData are presented as mean ± SD (standard deviation)
bData are presented as median (IQR, interquartile range)
CVD cardiovascular disease
aData on detailed type of CAD were missing from 22 patients
bData on organ of malignancy were missing from three RA patients with malignancies
Factors associated with the presence of major comorbidities
As shown in Table 3, the multivariate analyses of
cardiovascular disease revealed that female gender (OR 0.70,
95% CI 0.53–0.92) ever use of MTX (OR 0.77, 95% CI
0.60–1.00) were negatively related to the presence of
CVD. On the contrary, patients of advanced age (OR
1.09, 95% CI 1.07–1.10) and disease duration longer
than 5 years (OR 1.33, 95% CI 1.03–1.72) were more
likely to have these comorbid conditions. Based on the
multivariate analysis, female sex (OR 2.58, 95% CI 1.59–
4.18), advanced age (OR 1.05, 95% CI 1.04–1.06), RA
duration (OR 1.95, 95% CI 1.44–2.63) and bDMARDs (OR
1.79, 95% CI 1.16–2.76) were associated with history of
fragility fractures. The association between MTX and
decreased risk of fracture was only significant in the
univariate analysis (not shown). As for malignancies, fewer
factors were identified in our analyses. Only advanced age
(OR 1.05, 95% CI 1.03–1.07) and MTX treatment (OR
0.57, 95% CI 0.35–-0.91) were significant associated factors
in the multivariate analysis.
Patients with rheumatoid arthritis tend to have a higher
risk for a number of comorbidities [
]. The presence
bDMARDs 1.04 (0.64–1.69) 0.86 1.79 (1.16–2.76) <0.01* 0.15 (0.02–1.07) 0.06
CVD cardiovascular disease, OR odds ratio, CI confidence interval, RA rheumatoid arthritis, NA not applicable, RF rheumatoid factor, CCP anti-citrullinated protein
antibody, DAS28 disease activity score 28, GC glucocorticoid, MTX methotrexate
*P < 0.05
Age ≥ 60 y
(n = 4319)
of these comorbid conditions was reported to harm their
long-term prognosis, and even result in shortening of
life expectancy [
]. A population-based cohort
study by Gabriel et al. reported that comorbidities
increased risk of death in RA patients, with hazard ratios
(HR) of 1.6 (95% CI 1.2–2.1) for cardiovascular disease
and 1.9 (95% CI 1.4–2.6) for malignancy . Another
cohort study showed the association of hip fracture and
higher mortality in RA patients (1-year mortality
rates18.47% vs. 6.16%) [
]. According to these findings,
how to prevent, detect and manage comorbidities
properly has become a vital issue in the long-term
management of RA patients. In China, CREDIT is the first RA
registry to provide nationwide, multicenter data for
comorbidities as well as related clinical characteristics.
In this study, we assessed the prevalence of three
major comorbidities in Chinese RA patients. Among
cardiovascular disease, fragility fracture, and malignancy,
CVD and fragility fracture were relatively prevalent. To
find the differences between RA patients and normal
population, we compared our results with national
governmental epidemiologic data [
]. The prevalence
rates of CAD, stroke, and malignancy in general adult
population were 1.02%, 1.23%, and 0.29%, compared
with 1.5%, 0.8%, and 0.6% in our study. It suggests that
CAD and malignancy are more common, and stroke is
less common in RA patients. However, our study
population was composed of more women and older
patients than the general population. Due to the lack
of age, gender and region-specific data, we were
unable to calculate the standardized rates of
comorbidities for further comparison. Future studies comparing
RA patients in CREDIT and general population from
community/population-based cohorts will help us to
get a better understanding of this problem.
In comparison with six other large registries across the
world (Table 4) [
14, 17, 25–37
], patients in CREDIT
were younger and had shorter disease duration at
baseline than those in other registries, except for ERAS and
ERAN, which are two inception cohorts for patients
with early RA [
]. Although baseline distributions of
demographic characteristics were broadly comparable
across all registries, high inter-country variability was
observed in the prevalence of comorbidities. Asian RA
patients in IORRA and CREDIT presented lower
prevalence rates of comorbidities compared to those from
USA and European cohorts, which may demonstrate the
effect of geographic and ethnical factors. More studies
are needed to investigate potential reasons for these
observations. As for history of prior fractures, the
prevalence in CREDIT and ERAS was remarkably lower than
those in CORRONA, IORRA and KORONA, which
might be attributed to the focus on fragility fractures in
CREDIT and ERAS as well as a low diagnosis rate of
subclinical fractures. Other possible sources for the
variability in prevalence included disease duration, disease
activity, detection of comorbidities (from self-reports
or medical databases), and treatment strategies in
different countries [
]. Previous studies have indicated
the difficulty to do comparative work across registries
]. The differences between Chinese patients
and those from other countries also suggest that it is
necessary to develop special RA managing strategies
Several possible associated factors were identified by
comparing baseline data between RA patients with and
NR not reported, CAD coronary artery disease, CORRONA Consortium of Rheumatology Researchers of North America Registry, ERAS Early Rheumatoid Arthritis
Study, ERAN Early Rheumatoid Arthritis Network, SRR Swedish Rheumatology Quality of Care Register, NOAR Norfolk Arthritis Register, IORRA Institute of
Rheumatology Rheumatoid Arthritis Cohort, KORONA KORean Observational study Network for Arthritis, CREDIT Chinese Registry of rheumatoid arthritis
aOnly fragility fractures were collected in CREDIT, and all types of prior fractures in other cohorts bData from 12,656 patients, and standard deviation was
cThe prevalence of cardiovascular disease was 4.0%, but no data on CAD or stroke separately
dData derived from 6143 RA patients with ≥1 year follow-up
eData from 3557 patients with ≥1 year follow-up
without the major comorbidities. Advanced age was
associated with all comorbidities, consistent with the
consensus that aging is a traditional risk factor for CVD,
osteoporotic fracture, and malignancy. Male gender, a
typical risk factor for cardiovascular diseases, was
associated with the presence of CVD. Previous studies have
suggested that females have higher risk of osteoporosis
and osteoporotic fractures especially after menopause
], and it was also confirmed by our finding. According
to our analyses, duration of RA is the most important
clinical factor related to the presence of comorbidities. As
indicated by several studies, chronic inflammation
resulted from long-standing autoimmune diseases might be
the major reason for the increased risk of comorbidities in
these diseases [
]. As for medications, GC is widely
believed to cause higher risk of osteoporosis and fracture
, however, it was not related to any comorbidity in our
study. We assumed that it was because we only assessed
ever use of GC without considering the effect of dose,
duration, cumulative exposure, and the sequence between GC
use and the onset of comorbidities. In future follow-up
studies, we will take these factors into consideration and
investigate the relationship between GC and the risk of
incidence comorbidities. In China, use of bDMARDs is
generally in accordance with international guidelines [
However, since these drugs are not covered by the
national health insurance, their high cost is also an
important concern in the treatment decision-making process. In
clinical practice, bDMARDs are given to patients with
moderate to high disease activity, severe joint damage, and
poor responses to conventional medications. Therefore,
the association between bDMARDs and fractures in our
results may only represent an impact of disease severity
on the risk of fractures.
In our study, MTX was indicated to be a potential
protective factor for comorbidities in RA patients. As
suggested in previous studies [
], treatment with MTX
was associated with a reduced risk of cardiovascular events
[relative risk (RR) 0.72, 95% CI 0.57–0.91] and related
deaths (HR 0.3, 95% CI 0.2–0.7). Possible mechanisms may
include an improvement in the mobility of patients as well
as a decrease in their systemic inflammation. The effect of
MTX on fragility fractures is still controversial. Though
some studies have indicated that MTX has a positive
impact on bone metabolism and bone mineral density (BMD)
stabilization in RA patients, additional studies are required
to determine whether this effect is sufficient to reduce their
risk of fractures [
]. As for the risk of malignancies,
existing evidence is insufficient to make a full assessment
]. Due to its efficacy, safety, low costs and the possibility
to individualized dose and method of administration, MTX
continues to be the anchor drug for RA patients even after
the development of numerous bDMARDs [
]. Our study
suggests that MTX might also benefit RA patients by
reducing the risk of several life-threatening comorbidities,
supporting its central role in the management of RA.
Our study has several limitations. First, in CREDIT,
data on three major comorbidities were collected, since
they were reported to have vital influence on prognosis
and mortality. However, comorbidities missed in this
study, such as infection and interstitial lung diseases,
may also affect long-term outcomes to some extent [
Second, the information on comorbidities and
medications in CREDIT was collected by interviewing patients
and mainly based on their self-reports. Though the three
selected comorbidities are well known and
understandable to patients, and we attempted to minimize potential
bias by further verifying the ambiguous diagnoses of
comorbidities, there still might be a certain degree of
inaccuracy. Third, since all data in this cross-sectional study
were collected at baseline, we were unable to determine
possible cause-effect relationships between rheumatoid
arthritis, comorbidities, and potential risk factors.
In summary, CREDIT is the first nationwide,
multicenter, prospective registry of rheumatoid arthritis in China.
This study presents the preliminary baseline data in
terms of major comorbidities from 13,210 enrolled
patients, and for the first time evaluates the prevalence of
three vital comorbidities in a large, nationwide sample of
Chinese RA patients. Based on our findings, RA patients
with advanced age, longer disease duration, and
traditional factors should be more carefully monitored for
comorbidities. Methotrexate, as the anchor drug in the
treatment of rheumatoid arthritis, may also protect
patients against several comorbidities. On the basis of this
preliminary cross-sectional study, future follow-up studies
are needed for further investigating the characteristics of
Chinese RA patients, as well as the incidence and
predictors of major comorbidities.
Additional file 1: Figure S1. Map of the CREDIT registry participating
centers. (DOC 3195 kb)
Additional file 2: Figure S2. Flow chart of patient selection in the
present study. (DOC 51 kb)
Additional file 3: Table S1. Prevalence of malignancies in CREDIT at
baseline. (DOC 39 kb)
bDMARDs: biologic disease-modifying antirheumatic drugs; CAD: coronary
artery disease; CCP: Anti-citrullinated protein antibody; CI: confidence interval;
CORRONA: Consortium of Rheumatology Researchers of North America
Registry; CRP: C-reactive protein; CVD: cardiovascular disease; DAS28: disease
activity score 28; ERAN: Early Rheumatoid Arthritis Network; ERAS: Early
Rheumatoid Arthritis Study; ESR: erythrocyte sedimentation rate;
GC: glucocorticoid; IORRA: Institute of Rheumatology Rheumatoid Arthritis
Cohort; KORONA: KORean Observational study Network for Arthritis;
MTX: methotrexate; NOAR: Norfolk Arthritis Register; NR: not reported;
OR: odds ratio; RA: rheumatoid arthritis; RF: rheumatoid factor; RR: relative
risk; SRR: Swedish Rheumatology Quality of Care Register
We acknowledged the contributions from CREDIT team all over China and
the HealthCloud Co., Ltd as the system provider.
This study was supported by the Chinese National Key Technology R&D
Program (2017YFC0907601, 2017YFC0907604).
Availability of data and materials
The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
MTL, YFF, QW, XPT, YZ and XFZ participated in the conception and design of
the study. YFF, QL, JL, XWD, YL, RW, XFS, YFW, ZYJ and other CREDIT co-authors
contributed to data acquisition. SYJ, MTL, YHW, and CY participated in data
analysis and interpretation. SYJ and CY drafted the manuscript, and MTL, YHW,
QW and XPT revised the manuscript critically. MTL, YZ and XFZ supervised the
study. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Informed consent was obtained from all patients at enrollment. Ethics approval
for the registry was obtained from the Medical Ethics Committee of Peking Union
Medical College Hospital (PUMCH), which was accepted by all participating
centers as the central institutional review board (IRB).
Consent for publication
The authors declare that they have no competing interests.
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