SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To investigate the frequency and costs associated with ambulatory medical care utilization over an 8-year period in patients prior to the diagnosis of rheumatoid arthritis (RA).

Methods

We used Taiwan's National Health Insurance Research Database to identify 691 newly diagnosed RA cases between 2005 and 2010. We selected 1,382 controls without RA, frequency matched by sex, age, and the catastrophic illness certificate application year of the cases. The frequency and costs of ambulatory medical care utilization between the RA patients and controls were compared using the 2-sample Kolmogorov-Smirnov test.

Results

The median frequency of ambulatory medical care utilization was significantly higher in RA patients compared with controls (29 versus 13; P < 0.001) in the year before diagnosis. The differences remained significant throughout all 8 annual periods before diagnosis. Similarly, the inflation-adjusted costs of ambulatory medical care utilization in RA patients increased annually over the study period, from a median of $212 eight years preceding diagnosis to $798 one year preceding diagnosis. Frequency of ambulatory medical care utilization due to diseases of the musculoskeletal system and connective tissue (P < 0.001), acute respiratory infections (P < 0.001), diseases of the upper respiratory tract (P = 0.01), and diseases of the upper gastrointestinal tract (P = 0.04) were higher among RA patients in the 2-year period preceding diagnosis.

Conclusion

We found increased frequency and costs of ambulatory care utilization among RA patients in Taiwan preceding diagnosis of RA.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Rheumatoid arthritis (RA) is a chronic and disabling disease characterized by persistent synovitis, systemic inflammation, and the presence of autoantibodies such as anti–citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) ([1]). The interaction of heritable genetic factors with environmental factors such as smoking is crucial to the pathogenesis of RA ([2, 3]).

Results of several early cohort studies on arthritis also revealed that 13–54% of patients with undifferentiated arthritis developed RA within 2 years ([4]). Early diagnosis and treatment of RA patients could reduce joint damage, increase remission rate ([5, 6]), and decrease excess mortality associated with RA ([7]). Treatment of undifferentiated arthritis by disease-modifying antirheumatic drugs (DMARDs) could also postpone the time to the diagnosis of RA ([8]). Since the early diagnosis of RA is of importance for its outcome, the classification criteria for diagnosing RA were changed in 2010 in order for RA to be diagnosed earlier ([9]).

It is well documented that immunologic abnormalities appear in the sera many years before a definitive diagnosis of RA, including the presence of ACPAs and RF ([10, 11]). Therefore, it was postulated that there might be a subclinical phase in RA patients before the onset of apparent clinical signs and symptoms ([12]). These findings suggest that there might be a long induction period for the development of RA. We hypothesized that there should be an increase in the frequency and costs of ambulatory medical care utilization in RA patients prior to the diagnosis of RA. Therefore, we used a nationwide population-based insurance data set to compare the frequency and costs of ambulatory medical care utilization between RA patients and controls up to 8 years prior to the diagnosis of RA.

Box 1. Significance & Innovations

  • This was a retrospective comparison study using nationwide population-based cohort data investigating ambulatory medical care utilization in rheumatoid arthritis (RA) patients prior to the diagnosis of RA.
  • The frequency and costs of ambulatory medical care utilization in RA patients gradually increased as time approached the diagnosis.
  • Diseases of the musculoskeletal system and connective tissue, acute respiratory infections, diseases of the upper respiratory tract, and diseases of the esophagus, stomach, and duodenum were the main causes of ambulatory medical care utilization among RA patients preceding the diagnosis of RA.
  • This article showed a significant increase in ambulatory medical care utilization in Taiwanese patients with RA, compared with control subjects, at least 8 years before their diagnosis of RA.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Study design and data sources

This was a retrospective comparison study using nationwide population-based cohort data. Data analyzed in this study were retrieved from the Longitudinal Health Insurance Database 2000 (LHID2000) of the Taiwan National Health Insurance Research Database (NHIRD). The NHIRD consists of deidentified secondary data of inpatient and ambulatory medical care services of all enrollees in the National Health Insurance (NHI) scheme. The NHI is a single-payer compulsory social health insurance program instituted in 1995 and covers more than 99% of Taiwan's population ([13]).

The LHID2000 contains medical claims and enrollment information from 1996–2010 of a random sample of 1 million beneficiaries registered in 2000, which represents approximately 5% of Taiwan's population. This study was approved by the local Institutional Review Board and Ethics Committee of Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan (10004021).

Study subjects

We included patients ages ≥18 years with a definitive diagnosis of RA who sought ambulatory health care services for RA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 714.0) between January 1, 2005 and December 31, 2010.

The NHI specified 30 categories of catastrophic illness for enrollees with major injuries or illnesses (e.g., cancers, hemophilia, autoimmune diseases including RA, chronic renal failure, etc.). Eligible patients can apply for catastrophic illness certificates and if approved, holders of the certificates are exempted from copayment of related medical cost. The issuance of certificates is validated with careful review of medical records, laboratory studies, and imaging studies by at least 2 specialists. A diagnosis of RA was made according to the 1987 American College of Rheumatology (ACR) revised criteria for the classification of RA ([14]). Several studies focusing on the epidemiology of systemic autoimmune diseases, especially RA, have been published using the NHIRD ([15-18]). In this study, the date of application of the catastrophic illness certificate was assigned as the index date for the RA patients. A total of 691 RA patients were included in our analysis.

Controls in this study were selected from the LHID2000. First, individuals diagnosed with RA between 1996 and 2010 were excluded. Second, 2 controls for each RA patient were selected and frequency matched with RA patients with regard to sex, age, and year of the index date. In the controls, the index date was defined as the date of a randomly selected ambulatory visit that occurred during the matched index year.

Study variables

In Taiwan, the costs of medical services for ambulatory services and hospitalization were separately calculated by the NHI. In this study, we investigated the frequency and costs of ambulatory medical care utilization, but not those associated with hospitalization. Costs of ambulatory medical care include physician consultation fees (Western medicine, dentistry, and traditional Chinese medicine), visits to emergency departments, medical procedures, pharmacy expenditure, laboratory diagnosis tests, imaging examination, and rehabilitation therapy. All costs in this study were converted to US dollars based on the annual exchange rate and adjusted to 2010 figures using Taiwan's consumer price index.

All of the study subjects were retrospectively tracked up to 8 years preceding the index date to examine the frequency and costs of ambulatory medical care utilization. The frequency and costs of the ambulatory medical care utilization on the index date itself were excluded from the analysis. The main causes of the ambulatory medical care utilization were defined by the principal diagnosis of the ICD-9-CM coding system ([19]).

Regarding economic status, we divided the subjects' monthly income into low (≤$565), medium ($566–1,390), and high (≥$1,391) categories. We classified the geographic location in which the subjects resided into north, central, south, and east regions. We also applied Deyo adaptation of the Charlson Comorbidity Index (CCI) ([20]) to quantify the comorbidity pattern of the subjects based on the medical records of the RA patients and controls during a 6-month period prior to the beginning of the 8-year study period.

Statistical analysis

We analyzed the data using SAS statistical software, version 9.2. Data were expressed as the mean ± SD or median with interquartile range, as appropriate. Chi-square test and the 2-sample nonparametric Kolmogorov-Smirnov test were used to examine the characteristics between RA patients and control subjects. Analyses of the frequency and costs of ambulatory medical care utilization between the 2 groups were conducted using the 2-sample nonparametric Kolmogorov-Smirnov test.

Trend in the frequency of ambulatory medical care utilization across the 8 annual periods was evaluated using generalized estimating equations (GEEs) with Poisson log-linear link function. GEE was used because it takes into account the statistical dependence of multiple observations over time for each subject. Both the frequency and costs of medical care utilization were adjusted for age, sex, and the CCI in the GEE models. The incident rate ratio was estimated with GEEs using the frequency of 8 years preceding diagnosis as the reference category. Trend in the costs of ambulatory medical care utilization was evaluated using GEEs with log-link function with gamma distribution. The cost ratio was estimated using the cost data of 8 years preceding diagnosis as the reference category. A P value less than 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Demographic data of RA patients and the control group

There were no significant differences in the distributions of sex, age, monthly income, geographic regions, and the CCI between RA patients and controls (Table 1).

Table 1. Characteristics of the patients with RA and controls*
 RA patients (n = 691)Controls (n = 1,382)P
  1. Values are the number (percentage) unless indicated otherwise. Monthly income amount was converted to US dollars based on annual exchange rates and adjusted for Taiwan's consumer price index. RA = rheumatoid arthritis.

Age, years  0.98
Mean ± SD53.8 ± 14.753.7 ± 14.8 
Median (range)54 (18–93)54 (19–93) 
Sex  1.00
Male230 (33.3)460 (33.3) 
Female461 (66.7)922 (66.7) 
Monthly income  0.80
≤$56581 (11.7)170 (12.3) 
$566–1,390315 (45.6)658 (47.6) 
≥$1,391295 (42.7)554 (40.1) 
Geographic region  0.98
North241 (34.9)505 (36.5) 
Central198 (28.7)397 (28.7) 
South202 (29.2)392 (28.4) 
East50 (7.2)88 (6.4) 
Charlson Comorbidity Index  0.99
Mean ± SD0.16 ± 0.630.14 ± 0.54 
Median (range)0 (0–8)0 (0–7) 

Frequency and costs of ambulatory medical visits

We found that RA patients used ambulatory medical services more frequently than controls prior to the diagnosis of RA (Table 2). Even tracking back to 8 years before the diagnosis of RA, patients with RA still had a small but significant increase in the median frequency of ambulatory visits compared to controls (14 versus 12; P < 0.001) prior to the diagnosis of RA. The differences gradually increased as time approached the diagnosis of RA. Indeed, the magnitude of the differences in the median frequency of ambulatory visits became largest (29 versus 13; P < 0.001) in the year prior to the diagnosis of RA.

Table 2. Annual frequency and costs of ambulatory medical care utilization over an 8-year period preceding the diagnosis of RA*
Years preceding RA diagnosisAnnual frequency of ambulatory medical care utilizationAnnual costs of ambulatory medical care utilization
RA patients (n = 691)Controls (n = 1,382)PaRA patients (n = 691)Controls (n = 1,382)Pa
  1. Costs were converted to US dollars based on annual exchange rates and adjusted to 2010 figures based on Taiwan's consumer price index. RA = rheumatoid arthritis; IQR = interquartile range.

  2. a

    P values were obtained using the 2-sample nonparametric Kolmogorov-Smirnov test.

8  < 0.001  0.003
Mean ± SD19.12 ± 17.7116.09 ± 15.45 387 ± 797346 ± 793 
Median (IQR)14 (7–26)12 (5–23) 212 (88–484)181 (66–410) 
7  < 0.001  < 0.001
Mean ± SD19.74 ± 17.7016.49 ± 15.67 430 ± 847382 ± 999 
Median (IQR)15 (6–27)12 (5–23) 239 (92–527)195 (74–416) 
6  < 0.001  < 0.001
Mean ± SD20.96 ± 18.2916.38 ± 15.40 458 ± 840383 ± 989 
Median (IQR)16 (7–29)12 (5–23) 274 (113–579)198 (72–453) 
5  < 0.001  < 0.001
Mean ± SD21.17 ± 19.0316.41 ± 15.68 505 ± 1,330411 ± 997 
Median (IQR)16 (8–30)12 (5–22) 280 (109–591)214 (81–441) 
4  < 0.001  < 0.001
Mean ± SD22.07 ± 19.4516.82 ± 16.35 570 ± 1,697456 ± 1,187 
Median (IQR)17 (8–30)13 (5–23) 321 (126–646)218 (77–495) 
3  < 0.001  < 0.001
Mean ± SD23.24 ± 20.0217.28 ± 17.11 572 ± 1,032505 ± 1,446 
Median (IQR)18 (8–33)13 (5–24) 352 (134–722)230 (76–525) 
2  < 0.001  < 0.001
Mean ± SD25.94 ± 21.8317.50 ± 17.09 666 ± 994504 ± 1,223 
Median (IQR)20 (10–35)13 (5–25) 434 (180–869)238 (76–558) 
1  < 0.001  < 0.001
Mean ± SD33.24 ± 21.8017.23 ± 17.41 1,070 ± 1,440502 ± 1,051 
Median (IQR)29 (17–44)13 (5–24) 798 (465–1,297)245 (77–556) 

Similarly, the inflation-adjusted costs of ambulatory health care utilization were significantly higher in the RA patients compared with the controls prior to the diagnosis of RA. The median cost of annual ambulatory visits was higher in RA patients compared with the controls ($212 versus $181; P = 0.003) 8 years prior to diagnosis. The differences between the 2 groups increased gradually as time approached the diagnosis of RA and became largest in the year before diagnosis ($798 versus $245; P < 0.001) (Table 2).

In addition, we analyzed the trend of the annual frequency of ambulatory visits in RA patients and controls across an 8-year period. Compared to the frequency 8 years prior to the diagnosis of RA, there was a significant trend of increasing the annual frequency of ambulatory care visits in RA patients (β = 0.08, P < 0.001). In contrast, there was no significant trend over the 8-year period in the controls (β = 0.02, P = 0.06) (Table 3). With regard to costs of ambulatory care visits, a significant increasing trend was observed in both groups. The increasing trend was stronger in RA patients than in controls (β = 0.08 versus β = 0.03) (Table 4). Over the 8-year period, the annual costs of ambulatory care visits tripled in RA patients, but increased by only 77% in controls.

Table 3. Trend of annual frequency of ambulatory medical care utilization over an 8-year period preceding the diagnosis of RA*
Years preceding RA diagnosisRA patientsaControlsb
βIRR95% CIPβIRR95% CIP
  1. Estimates were adjusted for age, sex, and the Charlson Comorbidity Index using generalized estimating equations with a Poisson log-linear function. RA = rheumatoid arthritis; IRR = incident rate ratio; 95% CI = 95% confidence interval.

  2. a

    β = 0.08, P < 0.001 for trend test.

  3. b

    β = 0.02, P = 0.06 for trend test.

8 (ref.)        
70.031.030.99–1.070.190.021.020.99–1.060.20
60.091.091.05–1.160.0010.021.020.98–1.060.37
50.091.101.04–1.150.0010.021.020.97–1.060.41
40.141.151.08–1.22< 0.0010.051.051.00–1.110.03
30.181.201.13–1.27< 0.0010.081.071.02–1.130.02
20.291.341.26–1.43< 0.0010.091.101.05–1.160.01
10.541.701.60–1.81< 0.0010.101.111.05–1.170.01
Table 4. Trend of annual costs of ambulatory medical care utilization over an 8-year period preceding the diagnosis of RA*
Years preceding RA diagnosisRA patientsaControlsb
βIRR95% CIPβIRR95% CIP
  1. Costs were converted to US dollars based on annual exchange rates and adjusted to 2010 figures based on Taiwan's consumer price index. Estimates were adjusted for age, sex, and the Charlson Comorbidity Index using generalized estimating equations with log-link function and gamma distribution. RA = rheumatoid arthritis; IRR = incident rate ratio; 95% CI = 95% confidence interval.

  2. a

    β = 0.08, P < 0.001 for trend test.

  3. b

    β = 0.03, P = 0.001 for trend test.

8 (ref.)        
70.121.211.09–1.350.0010.101.101.02–1.180.01
60.161.381.21–1.500.0010.121.131.04–1.280.001
50.361.691.37–1.95< 0.0010.151.161.05–1.27< 0.001
40.491.811.51–2.19< 0.0010.271.321.20–1.44< 0.001
30.661.961.73–2.34< 0.0010.381.461.32–1.63< 0.001
20.732.402.10–2.75< 0.0010.511.661.45–1.90< 0.001
10.943.062.73–3.50< 0.0010.571.771.57–1.98< 0.001

Principal causes of ambulatory visits prior to the diagnosis of RA

Since RA patients had a significantly higher annual frequency of ambulatory medical care utilization than controls prior to diagnosis, especially 2 years preceding diagnosis, we further compared the top 3 principal diagnoses for the ambulatory visits during that time period. The top 3 principal diagnoses were diseases of the musculoskeletal system, respiratory system, and digestive system (Table 5). The ambulatory medical care utilization of these diseases was significantly greater in RA patients compared with controls.

Table 5. Causes of ambulatory medical care utilization in patients with RA in a 2-year period preceding the diagnosis of RA*
Diagnosis (ICD-9-CM code)RA patients (n = 691)Controls (n = 1,382)Pa
  1. Values are the mean ± SD. RA = rheumatoid arthritis; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.

  2. a

    P values were obtained using the 2-sample nonparametric Kolmogorov-Smirnov test.

Diseases of the musculoskeletal system and connective tissue (710–739)17.30 ± 15.483.79 ± 8.12< 0.001
Diseases of the respiratory system (460–519)8.28 ± 10.826.33 ± 9.53< 0.001
Acute respiratory infections (460–466)6.95 ± 8.935.45 ± 8.13< 0.001
Other diseases of the upper respiratory tract (470–478)0.65 ± 1.790.56 ± 2.530.01
Pneumonia and influenza (480–488)0.04 ± 1.030.00 ± 0.000.71
Chronic obstructive pulmonary disease and allied conditions (490–496)0.65 ± 3.510.44 ± 2.250.53
Pneumoconioses and other lung diseases due to external agents (500–508)0.04 ± 1.030.00 ± 0.000.98
Other diseases of the respiratory system (510–519)0.09 ± 1.400.03 ± 0.390.99
Diseases of the digestive system (520–579)6.20 ± 7.994.89 ± 6.95< 0.001
Diseases of the oral cavity, salivary glands, and jaws (520–529)3.25 ± 4.552.88 ± 4.290.23
Diseases of the esophagus, stomach, and duodenum (530–537)1.78 ± 4.281.30 ± 3.910.04
Appendicitis (540–543)0.00 ± 0.080.00 ± 0.110.99
Hernia of the abdominal cavity (550–553)0.01 ± 0.120.01 ± 1.420.99
Noninfectious enteritis and colitis (555–558)0.53 ± 2.660.33 ± 1.140.41
Other diseases of the intestines and peritoneum (560–569)0.44 ± 2.200.36 ± 1.870.98
Diseases of the liver (570–573)0.33 ± 1.630.20 ± 1.320.51
Diseases of the gallbladder and biliary tract (574–576)0.02 ± 1.360.05 ± 0.840.99
Other (577–579)0.09 ± 1.410.03 ± 0.390.99

Among the disorders of the respiratory system, frequency of ambulatory visits for acute respiratory infections (ICD-9-CM codes 460–466, including acute nasopharyngitis, acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis, acute upper respiratory tract infection of multiple sites, and acute bronchitis) and other diseases of the upper respiratory tract (ICD-9-CM codes 470–478, including deviated nasal septum, nasal polyp, chronic pharyngitis and nasopharyngitis, chronic sinusitis, chronic disease of the tonsils and adenoids, peritonsillar abscess, chronic laryngitis and laryngotracheitis, and allergic rhinitis) were significantly higher in RA patients compared with controls. Among the disorders of the digestive system, the frequency of ambulatory visits for diseases of the esophagus, stomach, and duodenum (ICD-9-CM codes 520–529, including diseases of the esophagus, gastric ulcer, duodenal ulcer, peptic ulcer, gastrojejunal ulcer, gastritis, duodenitis, and dysfunction of the stomach) was significantly higher in RA patients compared with controls.

Increased ambulatory medical care utilization due to diseases of the musculoskeletal system over an 8-year period prior to the diagnosis of RA

Since the main cause for an increase in the frequency of ambulatory visits among RA patients prior to diagnosis of RA was diseases of the musculoskeletal system, we analyzed the frequency of ambulatory visits due to diseases of the musculoskeletal system over an 8-year period prior to diagnosis to estimate the potential induction period of RA. Surprisingly, even 8 years prior to diagnosis, a significantly higher frequency of ambulatory visits for the musculoskeletal system disorders could still be observed in RA patients compared with controls (mean ± SD 1.6 ± 4.1 versus 1.1 ± 3.1; P < 0.001), and the difference became greater as time approached the diagnosis of RA (Table 6).

Table 6. Frequency of ambulatory medical care utilization for diseases of the musculoskeletal system over an 8-year period preceding the diagnosis of RA*
Years preceding RA diagnosisRA patientsControlsPa
  1. Values are the mean ± SD. RA = rheumatoid arthritis.

  2. a

    P values were obtained using the 2-sample nonparametric Kolmogorov-Smirnov test.

81.61 ± 4.121.05 ± 3.05< 0.001
72.25 ± 5.211.30 ± 3.370.002
63.00 ± 5.701.51 ± 3.63< 0.001
52.93 ± 5.611.66 ± 4.12< 0.001
43.38 ± 5.911.69 ± 4.14< 0.001
34.08 ± 6.601.97 ± 4.52< 0.001
25.40 ± 7.741.96 ± 4.44< 0.001
111.90 ± 9.651.82 ± 4.43< 0.001

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Few studies have addressed common medical disorders in the period prior to the diagnosis of RA. Maradit-Kremers et al ([21]) and Kerola et al ([22]) demonstrated an increased risk of coronary heart disease, whereas Chen et al ([16]) showed a slightly elevated risk for periodontitis. However, our study provided a more comprehensive view of the medical disorders in RA patients before diagnosis. Overall, we observed that the annual frequency and costs of ambulatory medical care utilization were higher in RA patients compared with controls and showed a gradual increase over a period of 8 years prior to the diagnosis of RA.

An increase in the annual frequency and costs of ambulatory medical care utilization over the period of several years was expected. A definite diagnosis of RA depends on the diagnosis criteria used. In our study, the diagnosis of RA was based on the 1987 ACR revised criteria ([14]). It has been shown that there was a 5-year time lag for patients to be diagnosed as having RA when using the 1987 ACR revised criteria compared with the 2010 criteria ([23]). Therefore, we speculated that using the 1987 ACR revised criteria could lead to a longer pre-RA period.

The high frequency of ambulatory medical care utilization in both RA patients and controls observed in this study was in line with previous reports conducted on Taiwanese patients ([19]). Under the Taiwan NHI scheme, the out-of-pocket expenses paid by patients for a single ambulatory visit range from just $1.67 in local clinics to $18.60 in medical centers. Therefore, costs are generally not a barrier for patients to seek medical services. In addition, patients in Taiwan can approach specialists directly without the requirement for a general practitioner referral. Despite the high frequency of ambulatory medical care utilization in the general population of Taiwan, our results still showed a significantly higher utilization in RA patients prior to diagnosis. Another point of interest is the 59% increase in cost ratios in controls comparing the figure 1 year prior to diagnosis relative to that 8 years prior to diagnosis. Since the costs were adjusted for inflation using Taiwan's consumer price index, the possible reasons for the increment could be the effects of aging ([24]) and the appearance of new high-priced drugs in the market over time ([25]).

Compared with control subjects, we also found a significantly higher frequency of ambulatory visits for acute respiratory infections (ICD-9-CM codes 460–466) and other diseases of the upper respiratory tract (ICD-9-CM codes 470–478) in our RA patients. In Taiwan, patients with influenza were frequently classified as having acute respiratory infections, which might explain our results. In addition, Blumentals et al ([26]) reported an increased risk of influenza and its complications in patients with RA, and the incidence of influenza and its complications did not appear to be significantly affected by the concomitant use of DMARDs or biologic agents. Since our pre-RA patients were unlikely to receive any potent immunosuppressive drug, we speculated that an increased risk of respiratory viral infections was the result of their immunologic dysfunction. Regarding the higher frequency of other diseases of the upper respiratory tract in RA patients, we speculated that it might be related to the increased complications associated with acute respiratory tract infections such as chronic pharyngitis, nasopharyngitis, chronic sinusitis, chronic disease of the tonsils and adenoids, peritonsillar abscess, and chronic laryngitis and laryngotracheitis. However, further studies will be required to clarify this finding.

Furthermore, we found that RA patients had a significantly higher frequency of ambulatory visits for diseases of the esophagus, stomach, and duodenum (ICD-9-CM codes 530–537) prior to the diagnosis of RA. This group of disorders includes diseases of the esophagus, gastric ulcers, duodenal ulcers, peptic ulcers, gastrojejunal ulcers, gastritis, duodenitis, and dysfunction of the stomach. Since these are common side effects of nonsteroidal antiinflammatory drugs, it is possible that the high frequency of diseases of the esophagus, stomach, and duodenum in RA patients was related to the increased use of these medications.

Joint erosion as a consequence of inflammatory arthritis occurs early in the clinical course of RA. The Canadian Early Arthritis Cohort reported that 28% of patients with early arthritis already had radiographic evidence of erosions ([27]). Early treatment of RA and undifferentiated arthritis with DMARDs and steroids could lead to a higher percentage of remission ([28]) and less joint damage ([29]). Currently, there is no consensus regarding the treatment of undifferentiated arthritis. The use of steroids does not seem able to alter the disease course of undifferentiated arthritis ([30, 31]), but the use of DMARDs ([8]) and biologic agents ([32, 33]) appeared to postpone or even prevent the development of RA. Therefore, it is crucial to identify patients early through the use of tools such as a questionnaire ([34]) in order to provide timely treatment for those at elevated risk of developing RA ([35]).

Several limitations of this study merit attention. First, a time lag could exist between the diagnosis of RA and the application of the catastrophic illness certificate. However, rheumatologists in Taiwan typically apply for the catastrophic illness certificate for their patients soon after a definite diagnosis of RA. Because of the limitation of the information available in the database, the date of a definite diagnosis of RA could only be estimated. We took the date of the last of 3 consecutive visits with a diagnosis of RA issued by rheumatologists in a given patient as the date of his or her definite diagnosis of RA. Based on this estimation of the date of a definite diagnosis of RA, we observed a mean ± SD interval of only 8.1 ± 13.3 days between the diagnosis of RA and the application of the catastrophic illness certificate. Therefore, this relatively short time lag should not affect our results.

Second, because of the limitations of our data source, no radiographic reports, serologic data (including the inflammatory markers ACPAs and RF), or personal habits such as smoking are available. Smoking is an important risk factor for seropositive RA and is associated with disorders such as cancers, chronic obstructive pulmonary diseases, and cardiovascular diseases ([36]). Nevertheless, the effect of smoking on the development of RA is moderate ([37]). In addition, there were no significant differences in the frequency of ambulatory visits for chronic obstructive pulmonary disease between the RA patients and controls in our study (Table 5). Since chronic obstructive pulmonary disease is a critical comorbidity for smoking, the smoking habits between the 2 groups should be similar and therefore should not affect our conclusions.

Third, the presence of other systemic connective tissue diseases is possible in patients prior to the diagnosis of RA, which could lead to a higher frequency of ambulatory medical care visits. However, none of the RA patients in our study had a diagnosis of primary Sjögren's syndrome or systemic lupus erythematosus prior to the diagnosis of RA. Therefore, the increased frequency in ambulatory visits observed in RA patients was unlikely to be the result of preexisting systemic connective tissue diseases other than RA.

Finally, the results of our study might not be generalizable to other countries. According to a report comparing the 33 member countries of the Organisation for Economic Co-operation and Development, in 2009, the number of doctor consultations per capita per year ranked highest in Japan (13.2), followed by Korea (13.0) ([38]). These figures were similar to the reported figure of 13.4 consultations per capita in Taiwan ([19]). Conversely, the figures were 3.9 for the US, 5.0 for the UK, 5.5 for Canada, and 8.2 for Germany. Overall, the mean number of annual consultations for the 33 countries was 6.5 per capita ([38]).

In conclusion, in this national population-based study, we found significantly increased frequency and costs of annual ambulatory medical care utilization in RA patients over a period of at least 8 years prior to their clinical diagnosis of RA. Over an 8-year period preceding the diagnosis of RA, the frequency of medical visits related to diseases of the musculoskeletal system and connective tissue gradually increased over time. In addition, there were significant increases in the frequency of medical visits related to diseases of the respiratory tract, esophagus, stomach, and duodenum. Health care professionals should be aware of this comorbidity pattern at the time of the initial diagnosis of RA and provide evaluation of the presence of these diseases in patients with RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Lu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Lu.

Acquisition of data. Tsai.

Analysis and interpretation of data. Lai, Tsai, Li, Koo, Yu, Lu.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Scott DL, Wolfe F, Huizinga TW.Rheumatoid arthritis.Lancet2010;376:1094108.
  • 2
    Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L.Immunity to citrullinated proteins in rheumatoid arthritis.Annu Rev Immunol2008;26:65175.
  • 3
    Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA, Kloppenburg M, de Vries RR, le Cessie S, et al.Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles.Ann Rheum Dis2006;65:36671.
  • 4
    Hazes JM, Luime JJ.The epidemiology of early inflammatory arthritis.Nat Rev Rheumatol2011;7:38190.
  • 5
    Van der Horst-Bruinsma IE, Speyer I, Visser H, Breedveld FC, Hazes JM.Diagnosis and course of early-onset arthritis: results of a special early arthritis clinic compared to routine patient care.Br J Rheumatol1998;37:10848.
  • 6
    Mottonen T, Hannonen P, Korpela M, Nissila M, Kautiainen H, Ilonen J, et al, for the FIN-RACo Trial Group.Delay to institution of therapy and induction of remission using single-drug or combination–disease-modifying antirheumatic drug therapy in early rheumatoid arthritis.Arthritis Rheum2002;46:8948.
  • 7
    Van Nies JA, de Jong Z, van der Helm-van Mil AH, Knevel R, Le Cessie S, Huizinga TW.Improved treatment strategies reduce the increased mortality risk in early RA patients.Rheumatology (Oxford)2010;49:22106.
  • 8
    Van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, Hulsmans HM, et al.Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial.Arthritis Rheum2007;56:142432.
  • 9
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al.2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.Arthritis Rheum2010;62:256981.
  • 10
    Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al.Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors.Arthritis Rheum2004;50:3806.
  • 11
    Arend WP, Firestein GS.Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis.Nat Rev Rheumatol2012;8:57386.
  • 12
    Van de Sande MG, de Hair MJ, van der Leji C, Klarenbeek PL, Bos WH, Smith MD, et al.Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase.Ann Rheum Dis2011;70:7727.
  • 13
    Cheng SH, Chiang TL.The effect of universal health insurance on health care utilization in Taiwan: results from a natural experiment.JAMA1997;278:8993.
  • 14
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al.The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.Arthritis Rheum1988;31:31524.
  • 15
    Chen YJ, Chang YT, Wang CB, Wu CY.The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan.Arthritis Rheum2011;63:3528.
  • 16
    Chen HH, Huang N, Chen YM, Chen TJ, Chou P, Lee YL, et al.Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study.Ann Rheum Dis2013;72:120611.
  • 17
    Yu KH, See LC, Kuo CF, Chou IJ, Chou MJ.Prevalence and incidence in patients with autoimmune rheumatic diseases: a nationwide population-based study in Taiwan.Arthritis Care Res (Hoboken)2013;65:24450.
  • 18
    Lai CH, Lai MS, Lai KL, Chen HH, Chiu YM.Nationwide population-based epidemiologic study of rheumatoid arthritis in Taiwan.Clin Exp Rheumatol2012;30:35863.
  • 19
    Chen TJ, Chou LF, Hwang SJ.Patterns of ambulatory care utilization in Taiwan.BMC Health Serv Res2006;6:54.
  • 20
    Deyo RA, Cherkin DC, Ciol MA.Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.J Clin Epidemiol1992;45:6139.
  • 21
    Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, et al.Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study.Arthritis Rheum2005;52:40211.
  • 22
    Kerola AM, Kerola T, Kauppi MJ, Kautiainen H, Virta LJ, Puolakka K, et al.Cardiovascular comorbidities antedating the diagnosis of rheumatoid arthritis.Ann Rheum Dis2013;72:18269.
  • 23
    Humphreys JH, Verstappen SM, Hyrich KL, Chipping JR, Marshall T, Symmons DP.The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register.Ann Rheum Dis2013;72:131520.
  • 24
    Hsu SW, Lin JD, Chiang PH, Chang YC, Tung HJ.Comparison of outpatient services between elderly people with intellectual disabilities and the general elderly population in Taiwan.Res Dev Disabil2012;33:142936.
  • 25
    Hsiao FY, Tsai YW, Huang WF.Price regulation, new entry, and information shock on pharmaceutical market in Taiwan: a nationwide data-based study from 2001 to 2004.BMC Health Serv Res2010;10:218.
  • 26
    Blumentals WA, Arreglado A, Napalkov P, Toovey S.Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study.BMC Musculoskelet Disord2012;13:158.
  • 27
    Bykerk VP, Jamal S, Boire G, Hitchon CA, Haraoui B, Pope JE, et al.The Canadian Early Arthritis Cohort (CATCH): patients with new-onset synovitis meeting the 2010 ACR/EULAR classification criteria but not the 1987 ACR classification criteria present with less severe disease activity.J Rheumatol2012;39:207180.
  • 28
    Wevers-de Boer K, Visser K, Heimans L, Ronday HK, Molenaar E, Groenendael JH, et al.Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study).Ann Rheum Dis2012;71:14727.
  • 29
    Lukas C, Combe B, Ravaud P, Sibilia J, Landew R, van der Heijde D.Favorable effect of very early disease-modifying antirheumatic drug treatment on radiographic progression in early inflammatory arthritis: data from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (Study and Followup of Early Undifferentiated Polyarthritis).Arthritis Rheum2011;63:180411.
  • 30
    Verstappen SM, McCoy MJ, Roberts C, Dale NE, Hassell AB, Symmons DP.Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial.Ann Rheum Dis2010;69:5039.
  • 31
    Machold KP, Landewe R, Smolen JS, Stamm TA, van der Heijde DM, Verpoort KN, et al.The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis.Ann Rheum Dis2010;69:495502.
  • 32
    Emery P, Durez P, Dougados M, Legerton CW, Becker JC, Vratsanos G, et al.Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial).Ann Rheum Dis2010;69:5106.
  • 33
    Saleem B, Mackie S, Quinn M, Nizam S, Hensor E, Jarrett S, et al.Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?Ann Rheum Dis2008;67:117880.
  • 34
    Bell MJ, Tavares R, Guillemin F, Bykerk VP, Tugwell P, Wells GA.Development of a self-administered early inflammatory arthritis detection tool.BMC Musculoskelet Disord2010;11:50.
  • 35
    De Rooy DP, van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH.Predicting arthritis outcomes: what can be learned from the Leiden Early Arthritis Clinic?Rheumatology (Oxford)2011;50:93100.
  • 36
    Centers for Disease Control and Prevention.Smoking-attributable mortality, years of potential life lost, and productivity losses: United States, 2000-2004.MMWR Morb Mortal Wkly Rep2008;57:12268.
  • 37
    Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, et al.Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases.Ann Rheum Dis2003;62:83541.
  • 38
    Organisation for Economic Co-operation and Development. Health at a glance 2011: OECD indicators.2011. URL: http://www.oecd.org/health/healthataglance.