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Association between air pollutants and initiation of biological therapy in patients with ankylosing spondylitis: a nationwide, population-based, nested case–control study

Arthritis Research & Therapy volume 25, Article number: 75 (2023) Cite this article

Abstract

Background

Outdoor air pollution has been found to trigger systemic inflammatory responses and aggravate the activity of certain rheumatic diseases. However, few studies have explored the influence of air pollution on the activity of ankylosing spondylitis (AS). As patients with active AS in Taiwan can be reimbursed through the National Health Insurance programme for biological therapy, we investigated the association between air pollutants and the initiation of reimbursed biologics for active AS.

Methods

Since 2011, hourly concentrations of ambient air pollutants, including PM2.5, PM10, NO2, CO, SO2, and O3, have been estimated in Taiwan. Using Taiwanese National Health Insurance Research Database, we identified patients with newly diagnosed AS from 2003 to 2013. We selected 584 patients initiating biologics from 2012 to 2013 and 2336 gender-, age at biologic initiation-, year of AS diagnosis- and disease duration-matched controls. We examined the associations of biologics initiation with air pollutants exposure within 1 year prior to biologic use whilst adjusting for potential confounders, including disease duration, urbanisation level, monthly income, Charlson comorbidity index (CCI), uveitis, psoriasis and the use of medications for AS. Results are shown as adjusted odds ratio (aOR) with 95% confidence intervals (CIs).

Results

The initiation of biologics was associated with exposure to CO (per 1 ppm) (aOR, 8.57; 95% CI, 2.02–36.32) and NO2 (per 10 ppb) (aOR, 0.23; 95% CI, 0.11–0.50). Other independent predictors included disease duration (incremental year, aOR, 8.95), CCI (aOR, 1.31), psoriasis (aOR, 25.19), use of non-steroidal anti-inflammatory drugs (aOR, 23.66), methotrexate use (aOR, 4.50; 95% CI, 2.93–7.00), sulfasalazine use (aOR, 12.16; 95% CI, 8.98–15.45) and prednisolone equivalent dosages (mg/day, aOR, 1.12).

Conclusions

This nationwide, population-based study revealed the initiation of reimbursed biologics was positively associated with CO levels, but negatively associated with NO2 levels. Major limitations included lack of information on individual smoking status and multicollinearity amongst air pollutants.

Introduction

Ankylosing spondylitis (AS) is a systemic disease characterised by chronic inflammation of axial and peripheral joint and subsequent ankylosis, resulting in an impairment of productivity and activity of living, as well as an increasing socioeconomic burden [1, 2]. AS in Taiwan features a male predominance, with the standardised prevalence being 0.24% in 2010 and an incidence rate of 0.42–0.50 cases per 1000 person-years [3]. Early intervention is essential in controlling inflammation through first-line pharmacological treatment, using non-steroidal anti-inflammatory drugs (NSAID) for spinal and peripheral involvement and conventional synthetic disease-modifying antirheumatic drugs for peripheral arthritis. For AS patients showing an inadequate response to first-line therapy, the use of biologics, including tumour necrosis factor inhibitors and interleukin-17 inhibitors, is indicated [4]. AS patients in Taiwan can access biologics through reimbursement of NHI programme or through self-funded use. The therapy can be used through NHI reimbursement if they have two records of high disease activity at least 4 weeks apart, defined as the simultaneous presence of serum levels of erythrocyte sedimentation rate > 28 mm/h, C-reactive protein > 1.0 mg/dl, and Bath Ankylosing Spondylitis Disease Activity Index ≥ 6 though having undergone the following treatments: (i) full doses of at least two different NSAID therapies over 4 weeks respectively at the same medical institution for at least 3 months unless intolerance; or (ii) concomitant use of NSAIDs and sulfasalazine at a dose of 2 g per day over 4 months unless intolerance for peripheral arthritis.

Outdoor air pollution has been found to trigger systemic inflammatory responses [5], and long-term exposure to air pollution is associated with an increased risk of development or aggravation of certain immune-mediated diseases [6, 7]. Long-term exposure to particulate matter < 2.5 μm in size (PM2.5) has been found strongly correlated with worse AS outcomes [8]. However, whether air pollutants other than PMs, including carbon monoxide (CO), sulphur dioxide (SO2), ozone (O3) and nitrogen dioxide (NO2), are associated with AS disease activity remains uncertain. As the harm of air pollution to rheumatic diseases is becoming an issue of concern for rheumatologists globally, a preliminary large-scale census is imperative. In Taiwan, the National Health Insurance Research Database (NHIRD) has facilitated longitudinal epidemiologic studies. Also, a database of estimated levels of ambient air pollutants is available and can be linked to the NHIRD. Therefore, we investigated the association between levels of air pollutants with the initiation of biologics, a proxy for high activity, in patients with AS using the NHIRD linking to database of ambient air pollutant levels.

Materials and methods

Study design

This was a nationwide, population-based, nested case–control study.

Source of data

The claims data on AS study subjects were obtained from the NHIRD from January 1, 2003, to December 31, 2013. An obligatory, single-payer NHI programme covering more than 99% of Taiwan’s population was implemented on March 1, 1995 [9], and has facilitated population-based longitudinal epidemiologic studies. The NHIRD includes claims data concerning demographics, outpatient and admission services, medical expenditures covered by NHI, diagnoses and procedures with corresponding International Classification of Diseases-Ninth Revision-Clinical Modification (ICD-9-CM) codes, and medication prescriptions with corresponding Anatomical Therapeutic Chemical Classification codes, whilst lacking certain personal data, including weight, alcohol and tobacco use, and AS disease activity, damage and functional measures.

Estimated mean levels of the exposed ambient air pollutants

Since 2011, the concentrations of various ambient air pollutants at 374 residential locations in Taiwan, except for Kinmen and Mazu, have been estimated using a spatio-temporal model built by a deep-learning approach [10]. This model has assessed the concentrations of air pollutants at each location using a graph convolutional neural network, with the levels at each location calculated based on data taken from three air quality censoring stations near the specified location. We used the hourly concentrations of air pollutants across 60 air quality censoring stations to estimate the mean levels of air pollutants, including PM2.5, PM10, NO2, CO, SO2 and O3, within 1 year before index dates [11].

Study subjects

In Taiwan, AS was diagnosed based on either 1984 modified New York criteria [12] or 2009 Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis [13, 14]. In this study, newly diagnosed AS patients aged ≥ 20 years were identified as those having at least three ambulatory visits with an AS diagnosis (ICD-9-CM code 720.0) and a concurrent prescription of NSAIDs, corticosteroids, sulfasalazine or methotrexate from 2003 to 2013. Patients who also had outpatient or inpatient visits with a diagnosis of rheumatoid arthritis (ICD-9-CM code 714.0) and who used biologics, including etanercept, adalimumab and golimumab before the first date of outpatient or inpatient visit with AS diagnosis were excluded. Patients with history of biologics use not within the NHI reimbursement period for active AS (i.e. use of adalimumab before August 1, 2009, etanercept before November 1, 2009, and golimumab before January 1, 2012) or biologics without NHI reimbursement (i.e. use of biologics other than adalimumab, etanercept and golimumab), and those without outpatient visits after 2009 were excluded, in order to ensure all biologics users were prescribed the approved biologics for active AS reimbursed by NHI. Those residing in Kinmen and Mazu were excluded to ensure the estimated air pollutant levels at all subjects’ residential locations could be obtained.

Selection of biologics case group and matched control group

From the abovementioned population, subjects who initiated NHI-reimbursed biologics were identified as the biologics case group, and those who did not as the control group. All subjects were designated specific index dates, which was the date of first NHI-reimbursed biologics initiation for biologics cases and date of first outpatient department visit each year for controls. After matching for the year of index dates between the two groups, we then examine whether exposure to air pollutants within 1 year before first NHI-reimbursed biologics initiation for active AS influenced patients’ disease activity. We matched subjects in both groups at a 1:4 ratio for gender, age at first NHI-reimbursed biologic initiation (± 3 years), year of first AS diagnosis, and AS disease duration (± 0.3 years) to adjust for confounding effects [15].

Due to the available estimated levels of exposed air pollutants gathered from 2011, we included subjects with index dates between 2012 and 2013 only for final analyses. The process for the selection of study subjects for final analysis is depicted in Fig. 1.

Fig. 1
figure 1

Flow diagram of enrollment, categorisation and matching for comparison of study subjects. For AS patients in Taiwan, the start of biologic use under NHI reimbursement was August 1, 2009, for adalimumab; November 1, 2009, for etanercept; and January 1, 2012, for golimumab. Amongst NHI-reimbursed biologics users, 1036 patients initiated with adalimumab, 614 with etanercept, and 118 with golimumab. The index date is the date of the first NHI-reimbursed biologics initiation for biologics cases and the date of first outpatient department visits each year for controls. Age at first NHI-reimbursed biologics initiation, or age at index date, is regarded as the patient’s age in this study. AS disease duration indicates the period between first diagnosis of AS and first NHI-reimbursed biologics initiation (index date). AS, ankylosing spondylitis; NHI, National Health Insurance; NHIRD, National Health Insurance Research Database

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Potential confounders

Potential confounders existing within 1 year before index date to be adjusted included socioeconomic status, represented by monthly income and urbanisation level of residence, comorbidities, extra-articular manifestations, and use of medications for AS. Four clusters of urbanisation levels were categorised according to the density of population (people/km2), population ratio of those aged ≥ 65 years, population ratio of agricultural workers and number of physicians per 100,000 individuals, with level 1 indicating the most urbanised districts and level 4 the least [16]. Four clusters of monthly income were stratified based on quartiles. Charlson Comorbidity Index (CCI) at the year of index date was used to represent patients’ general comorbid condition [17]. The presence of comorbidities used to calculate the CCI was defined as the occurrence of ≥ 3 outpatient visits or ≥ 1 inpatient visit with a corresponding ICD-9-CM code within one year before index date. Extra-articular manifestations, including uveitis, psoriasis and inflammatory bowel disease, were diagnosed by corresponding specialists and recognised by their ICD-9 codes, with those diagnosed more than 1 year before index date being excluded. The medications involved included NSAIDs, methotrexate, sulfasalazine and systemic corticosteroids and were identified by their Anatomical Therapeutic Chemical classification codes. The impact of daily dosage of corticosteroids, shown as prednisolone equivalent dose, on biologics initiation was also adjusted. The summary of included diseases, manifestations, medications and their corresponding codes is given in Supplementary Table 1, Additional file 1.

After adjusting for the above potential confounders through conditional logistic regression analyses, we examined the association between levels of air pollutants and biologics initiation for active AS.

Sensitivity analysis

We also conducted analyses using the time horizon of within 3 months before index date for the sensitivity analysis.

Statistical analyses

Continuous variables are shown as mean ± standard deviation and categorical variables as number (percentage) of patients. Between groups, we compared continuous variables by the independent t-test and categorical variables by chi-square test or Fisher’s exact test.

Because the impact of air pollutants might have multicollinearity and correlation based on their chemical properties, a correlation table including variance inflation factors (VIF) of each air pollutant amongst all pollutants and Pearson correlation coefficients with p-values of all pairs of air pollutants was plotted. VIF ≥ 10 was considered significant multicollinearity necessitating being corrected.

We examined the association between biologics initiation and levels of exposed air pollutants using multivariable conditional logistic regression models for adjustment, shown as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). A probability (p) of < 0.05 was considered statistically significant. Statistical calculations were performed using the Statistical Package for the Social Sciences (SPSS), Windows Version 13.0 (SPSS Inc., Chicago, IL, USA).

Results

Baseline characteristics of the study population

The flow diagram regarding enrollment, categorisation and matching for comparisons in the study population is shown in Fig. 1. After the process surrounding the selection of study subjects for final analysis, we enrolled 2920 AS patients, consisting of 584 patients who initiated NHI-reimbursed biologics as the cases, including 237 with etanercept, 242 with adalimumab and 105 with golimumab, along with 2336 patients who did not as the controls (Table 1 and Supplementary Table 2, Additional file 1). The study population was predominantly composed of male subjects (n = 2,455, 84.1%). The mean age at first NHI-reimbursed biologic initiation was 40.2 ± 12.8 years in the cases and 40.4 ± 12.5 in the controls (p = 0.77). The disease duration of AS was 6.1 ± 3.5 years for the cases and 6.0 ± 3.5 for the controls (p = 0.44).

Table 1 Baseline characteristics amongst matched study subjects with and without initiation of reimbursed biologics
Full size table

Regarding socioeconomic status, the monthly incomes subjects received were independent of requirements for biologics therapy (p = 0.70). With regard to levels of urbanisation, a lower proportion of biologics cases resided in more urbanised districts (p = 0.01).

The CCIs at the year of index date were 0.4 ± 0.8 in the cases and 0.2 ± 0.7 in the controls (p < 0.01), with a higher proportion of subjects with CCIs ≥ 1 seen in the cases (p < 0.01), indicating that AS patients initiating biologics therapy suffered from more comorbidities. Higher proportions of subjects in the cases presented with extra-articular manifestations, including uveitis (p < 0.01), psoriasis (p < 0.01), and inflammatory bowel disease (p = 0.01) within 1 year before their biologics initiation.

Biologics cases possessed higher proportions of subjects taking NSAIDs (p < 0.01), methotrexate (p < 0.01), sulfasalazine (p < 0.01) and systemic corticosteroids p < 0.01), with higher prednisolone equivalent doses as well (p < 0.01) before biologics initiation.

Subjects in the cases were exposed to lower levels of ambient SO2 (p = 0.01), NO2 (p < 0.01) and CO (p = 0.02), than those in the controls.

Effect of multicollinearity for air pollutant levels

The correlation table showing the levels of multicollinearity for all exposed air pollutant levels and levels of correlation for all pairs of them within 1 year before index date was presented in Table 2. Significant effect of multicollinearity was found for NO2 (VIF = 11). With respect to NO2, a significantly positive correlation was found between CO and NO2 levels (correlation coefficient: 0.904). The other pair bearing high correlation was PM2.5 and PM10, but the VIFs of both were not demonstrated with significant multicollinearity.

Table 2 Correlation table for ambient air pollutant levels within one year before index date
Full size table

A correlation table using the time horizon of within 3 months before index date was demonstrated in Supplementary Table 3, Additional file 1, showing consistent results with those in Table 2.

Association between exposed levels of air pollutants and high AS activity necessitating initiation of NHI-reimbursed biologics

The results from multivariable conditional logistic regression analyses are presented as model 1 in Table 3. Initiation of biologics for active AS was not associated with age at biologics initiation, socioeconomic status or diagnosis of uveitis and inflammatory bowel disease within 1 year before biologics initiation. It was however positively associated with disease duration, CCI at year of index date, diagnosis of psoriasis and use of NSAIDs, methotrexate, sulfasalazine and systemic corticosteroids in a dose-dependent manner within 1 year before biologics initiation.

Table 3 Association between initiation of reimbursed biologics and air pollutants in adjustment for potential confounders
Full size table

As for exposed levels of air pollutants, the initiation of biologics was not associated with PM2.5, PM10 or SO2 levels. It tended to be negatively associated with O3 levels, whilst being positively associated with CO levels and negatively with NO2 levels in a significant manner. However, due to significant multicollinearity for NO2 and correlation between NO2 and CO levels, multivariable regression analyses without adjustment for NO2 and CO exposure were respectively presented as models 2 and 3. In both models, the difference from model 1 was significantly negative impact of higher monthly incomes (≥ 45,801 New Taiwan dollars). In model 2, the differences from model 1 were the negative impact of SO2 exposure and no impact of CO exposure. Otherwise, the results amongst the three models were consistent.

For the high correlation between PM10 and PM2.5 levels, multivariable regression models with adjustment for PM10 or PM2.5 exposure were presented in Supplementary Table 4, Additional file 1, showing consistent results regarding the adjustments. Models adjusting for PM10 or PM2.5 exposure using within 3 months before index date as the time horizon was demonstrated in Supplementary Table 5, Additional file 1, also showing consistent results amongst the models.

Discussion

For adult patients with AS requiring medical therapy, the present study exhibited the positive association of active AS necessitating initiation of first NHI-reimbursed biologics with the disease duration, corresponding CCI, incidental psoriasis and use of NSAIDs, methotrexate, sulfasalazine and systemic corticosteroids in a dose-dependent manner within 1 year before biologics initiation. The main finding was that it was positively associated with exposed CO levels and negatively with NO2 levels, which had not yet been reported in the available English literature.

The novel finding was that exposure to ambient CO can be an aggravating factor, but exposure to ambient NO2 a protecting factor, regarding use of biologics indicated for high AS activity. Nevertheless, the impact of multicollinearity for NO2 and correlation between NO2 and CO levels might cause the variation of aORs for CO exposure amongst the models. Some studies reported a positive correlation between ambient CO and NO2 levels due to the influence of CO on the oxidation of NO to NO2, whilst both levels were found negatively correlated with O3 level as a result of photochemical reactions [18, 19]. These findings might explain the high correlation between CO and NO2 levels. Previous studies have abundantly elucidated the significant association between systemic inflammation and exposure to air pollutants [20, 21], yet a negative association with long-term O3 exposure from recent studies [22, 23]. Adequate use of ozone therapy has been introduced for patients with active AS despite insufficient explanations surrounding its immunological mechanism [24], but this may not be applicable to our finding of a potential protective effect seen in ambient O3. Although NO2 is a definite activator of airway inflammation [25], conflicting results were found regarding repeated daily exposure to 2 ppm of NO2 in small-sample human studies [26, 27]. Our results suggest a protective effect with outdoor NO2, which is conflicting with results of many studies but similar to that of a study investigating the influence of household NO2 [28]. Lacking available data presenting the impact of NO2 and O3 on AS, the abovementioned epidemiological and immunological gap deserves future research to clarify.

Air pollution was found to induce inflammatory immune responses, involving innate and adaptive immunity, from pulmonary to systemic sites [29, 30], and thus resulting in the development and progression of autoimmune diseases [31]. Nevertheless, the influence of air pollution on the pathogenesis and evolvement of AS has been insufficiently illustrated. Recent research has revealed the involvement of tumour necrosis factor and T helper 17 cells (Th17) in proinflammatory responses [32,33,34], which are the main components of immunopathological mechanisms in AS. Ambient PMs containing ligands of aryl hydrocarbon receptor, a cytosolic toxicant-responding transcription factor, enhance Th17 differentiation and may therefore potentiate underlying autoinflammation of AS [35, 36]. The relationship between air pollution and the response of pulmonary type 3 innate lymphoid cells has not yet been clearly investigated [37]. The immunological results were predominantly derived from cell-based studies, and whether these results can be translated into clinically significant immunopathology warrants additional in vivo studies to confirm.

We still found disease duration to be associated with AS activity after matching for duration within a range of 0.3 years, but we found low multicollinearity and correlation in terms of age at first NHI-reimbursed biologics initiation and disease duration (Supplementary Table 6, Additional file 1). As most of AS patients experience a disease course featuring intermittent flares [38], it is likely that AS patients exhibit evidence of high disease activity during follow-up visits coinciding with periods of disease flares. In Taiwan, many patients with low adherence to medications or ambulatory visits particularly seek medical attention only during disease flares and thus meet the NHI payment guidelines. This can lead to a bias towards a strong association. Disease activity was reported to be positively associated with corresponding comorbidities and medication use. Our results coincide with those in the majority of previous studies demonstrating that AS patients with comorbidities suffered from higher disease activity [39] and that those with active disease would confront higher medication and healthcare costs [40]. Patients with active AS in Taiwan would indeed have received regimens at a higher intensity to fulfil NHI payment guidelines for biologics administration. Although some studies perceived extra-articular manifestations as signs of uncontrolled systemic inflammation [41], we revealed that only incidental psoriasis within 1 year before biologics initiation had a strong association with high disease activity. According to an unadjusted comparison performed by Fitzgerald et al. [42], patients with comorbidities tended to have extra-articular manifestations, particularly psoriasis, compared with those having an isolated disease, whilst Zhao et al. did not report so [43]. This probably also reflected the differences in geographical and methodological backgrounds.

The available studies exploring the relationship between air pollution and spondyloarthritis are scarce. A case–control study reported a strong correlation between long-term PM2.5 exposure and worse AS outcomes [8]. Air pollution may also exacerbate joint symptoms in AS patients [7]. These findings, together with ours, indicate a negative impact of air pollution on AS evolvement. Park et al. revealed no association between long-term exposure to ambient PMs and incidence of AS in their cohort study [44], showing the limited pathogenetic role PMs play on AS. Facing these results, the impact of different study designs, recording or estimating methods of air pollutant levels, geographical, ethnic, cultural, political and economic issues should be considered for interpretation.

Knowing that air pollutants may modify inflammation, our study was the first to assess the respective association of the six ambient air pollutants with AS disease activity. As air pollution has become an issue attracting more concern worldwide, our study identified it as an urgency worthy of measures towards its prevention, monitoring and abatement for the benefit of public health. Our results may also provide a reference for environmental medicine specialists and administrative authorities to aid in the implementation of prompt policies. For rheumatologists and AS patients, such environmental risk factors surrounding disease deterioration deserve more attention to instructions on modifications to decrease exposure.

Our study has some strengths. First, use of a population-based database can minimise selection bias. Second, besides matching for gender, age at first NHI-reimbursed biologics initiation (± 3 years), year of AS diagnosis and disease duration (± 0.3 years), we adjusted many potential confounders, including socioeconomic status, comorbidities, extra-articular manifestations and use of medications for AS. Third, we conducted sensitivity analyses using different time horizons of air pollutants exposure. However, there are some limitations. First, the NHIRD lacked information on some potential confounding factors, including tobacco and alcohol use [45], dietary and exercise habits [8, 46] and stressful events [47]. Additionally, concomitant alternative medication use and real adherence to medications and outpatient follow-up remain indefinite, so chances are that subjects in the control group have high activity but biologics use. These are unmeasured potential confounders. Second, because of available claims data from 2003 to 2013 and estimated air pollutant levels from 2011, the time horizon of within 1 year before index date cannot speculate the influence from the longer-term exposure. However, we also conducted sensitivity analyses using the time horizon of 3 months and obtained consistent results. Third, although only patients having at least three ambulatory visits with AS diagnosis and concurrent AS-related medications are considered AS patients, the accuracy of AS diagnosis may still be of concern. Fourth, the estimated mean levels of exposed air pollutants at residential locations are unable to properly represent the exact amount of exposure in each subject. Fifth, the impact of the abovementioned multicollinearity is shown. Finally, the results of our study cannot be generalised to non-Tainanese populations. Future studies involving designs bearing higher potency evidence and longer follow-up periods, analysis models presenting the least influence of multicollinearity of air pollutants, studies using an individualised recording of exposed pollutant amounts and immunological research targeting the pathogenesis of AS remain warranted to confirm our findings.

Conclusion

This nationwide, population-based study showed the initiation of NHI-reimbursed biologics, a proxy for high activity, in AS patients was positively associated with exposed ambient CO levels, but negatively associated with NO2 levels. The major limitations include the lack of information on individual smoking status and multicollinearity amongst levels of various air pollutants. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms for the potential influence of ambient CO and NO2 on AS disease activity.

Availability of data and materials

The datasets used and/or analysed in the current study are available from the corresponding author upon reasonable request.

Abbreviations

aOR:

Adjusted odds ratio

AS:

Ankylosing spondylitis

CCI:

Charlson Comorbidity Index

CI:

Confidence interval

CO:

Carbon monoxide

ICD-9-CM:

International Classification of Diseases-Ninth Revision-Clinical Modification

NHI:

National Health Insurance

NHIRD:

National Health Insurance Research Database

NO2 :

Nitrogen dioxide

NSAID:

Non-steroidal anti-inflammatory drug

O3 :

Ozone

PM:

Particulate matter

SO2 :

Sulphur dioxide

SPSS:

Statistical Package for the Social Sciences

Th17:

T helper 17 cells

VIF:

Variance inflation factor

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Authors and Affiliations

  1. Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, No.1650, Sec.4, Taiwan Boulevard, Taichung, 40705, Taiwan

    Chung-Mao Kao, Yi-Ming Chen, Wen-Nan Huang, Yi-Hsing Chen & Hsin-Hua Chen

  2. Division of Translational Medicine, Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Chung-Mao Kao & Yi-Ming Chen

  3. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yi-Ming Chen, Wen-Nan Huang, Yi-Hsing Chen & Hsin-Hua Chen

  4. Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan

    Yi-Ming Chen, Wen-Nan Huang, Yi-Hsing Chen & Hsin-Hua Chen

  5. Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

    Yi-Ming Chen & Hsin-Hua Chen

  6. Department of Business Administration, Ling-Tung University, Taichung, Taiwan

    Wen-Nan Huang

  7. Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan

    Hsin-Hua Chen

  8. Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Hsin-Hua Chen

  9. Big Data Center, National Chung Hsing University, Taichung, Taiwan

    Hsin-Hua Chen

  10. Division of General Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    Hsin-Hua Chen

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  1. Chung-Mao Kao
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  2. Yi-Ming Chen
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Contributions

CMK drafted the manuscript. CMK, YMC, WNH, YHC, and HHC collected the data and interpreted the data. HHC conceived the study, designed the study, performed the statistical analysis, and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Hsin-Hua Chen.

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Ethics approval and consent to participate

The Institutional Review Board of Taichung Veterans General Hospital (IRB number: CE17100B) has approved the present study. Given that claims data were deidentified prior to analyses, informed consent was waived. The National Health Research Institute had released the database for research purposes and therefore had encrypted all personal information.

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Not applicable.

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The authors declare no competing interests.

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Supplementary Information

Additional file 1: Supplementary Table 1.

International Codes of Diseases–Ninth Revision Clinical Modification codes of diseases and manifestations, and Anatomical Therapeutic Chemical classification codes of medications. Supplementary Table 2. Baseline characteristics amongst matched study subjects with use of approved biologics through reimbursement and without the use. Supplementary Table 3. Correlation table for ambient air pollutant levels within three months before index date. Supplementary Table 4. Association between initiation of reimbursed biologics and air pollutants exposed within one year before index date in adjustment for potential confounders other than NO2 or CO exposure. Supplementary Table 5. Association between initiation of reimbursed biologics and air pollutants exposed within three months before index date in adjustment for potential confounders other than NO2 or CO exposure. Supplementary Table 6. Correlation table for age at first reimbursed biologic initiation and disease duration.

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Kao, CM., Chen, YM., Huang, WN. et al. Association between air pollutants and initiation of biological therapy in patients with ankylosing spondylitis: a nationwide, population-based, nested case–control study. Arthritis Res Ther 25, 75 (2023). https://doi.org/10.1186/s13075-023-03060-4

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Keywords

Arthritis Research & Therapy

ISSN: 1478-6362

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