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 of AS, corresponding CCI, incidental psoriasis and use of NSAIDs, methotrexate, sulfasalazine and systemic corticosteroids in a dose-dependent manner within one year before biologics initiation. The main finding was that it was positively associated with exposed CO levels and negatively with NO2 levels, whilst no significant influence was found in the remaining pollutants, which hadn’t yet been reported in the available English literature.
We still found disease duration to be associated with the activity of AS after matching by duration within a range of 0.3 years. Longer disease or symptom duration has been linked to poorer treatment response and outcomes(17, 18). The prolonged disease duration largely stems from a delayed diagnosis, which remains the major challenge in current practice and would tthen incur refractory disease activity, more radiographic damage, worse physical and psychological impairment, and a greater healthcare burden(19). This issue warrants additional campaigns and strategies to promote early referral and management initiation. We also reported disease activity 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(20), and that those with active disease would confront higher medication and healthcare costs(21). 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(22), we revealed that only incidental psoriasis within one year before biologics initiation had a \strong association with high disease activity. According to an unadjusted comparison performed by Fitzgerald et al.(23), axial spondyloarthritis patients with comorbidities tended to have extra-articular manifestations, particularly psoriasis, compared with those having an isolated disease, although this wasn’t the case in a study performed by Zhao et al.(24) This probably also reflected the differences in geographical and methodological backgrounds.
Levels of various gaseous substances, including both CO and NO2, rise with increased traffic activities and biomass burning, which constitute the main sources of air pollution(25, 26). Some studies reported a positive correlation between the ambient CO and NO2 levels due to influence of CO on the oxidation of NO to NO2, whilst they were found negatively correlated with ambient O3 levels as a result of photochemical reactions(27, 28). These findings were similar to ours.
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(29), 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.
Air pollution was found immunologically to induce inflammatory immune responses, involving innate and adaptive immunity, from pulmonary to systemic sites(30, 31), thus resulting in the development and progression of autoimmune diseases(32). Nevertheless, the influence of air pollution on the pathogenesis 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(33–35), which are the main components of immunopathological mechanisms in AS. Ambient PMs containing ligands of aryl hydrocarbon receptor, a cytosolic toxicant-responding transcription factor, enhances Th17 differentiation and may therefore potentiate underlying autoinflammation of AS(36, 37). The relationship between air pollution and the response of pulmonary type 3 innate lymphoid cells hasn’t yet been clearly investigated(38). 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.
The novel finding in our study was that exposure to ambient CO can be an aggravating factor, and exposure to ambient NO2 a protecting factor, regarding AS disease activity. There are currently few available studies directly exploring the immunopathological impact of specific air pollutants on the evolvement of AS. Previous studies have abundantly elucidated the significantly positive association between systemic inflammation, mostly represented by serum C-reactive protein levels, and exposure to various air pollutant categories(39, 40), yet a negative association with long-term exposure to ambient O3 from recent studies(41, 42). The above influences proved to be modest however. Adequate use of ozone therapy has been introduced for patients with active AS despite insufficient explanations surrounding its immunological mechanism(43), although 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(44), conflicting results were found regarding repeated daily exposure to 2 ppm of NO2 in small-sample human studies(45, 46). Our results suggest a protective effect with outdoor NO2, which is similar to that of a study investigating the influence of household NO2(47). Lacking available data presenting the impact of NO2 and O3 on AS, the abovementioned epidemiological and immunological gap deserves future research to clarify.
Knowing that air pollution acts as an inducer of inflammation, our study was the first to explore the connection between the severity of air pollution and the evolvement of AS activity. The novelty we also presented was the respective impact of the six air pollutant categories had on AS. This population-based study was conducted to collectively elucidate the connection having rarely been researched before. 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 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 limitations. First, use of an administrative database hindered us from information on known aggravating factors, including tobacco and alcohol use(48), dietary and exercise habits(8, 49), and stressful events(50). Additionally, real adherence to medications and outpatient follow-up and concomitant alternative medication use remained indefinite, which could be confounders. Second, although we only considered patients having at least three ambulatory visits with AS diagnosis and concurrent AS-related medications to be AS patients, the accuracy of AS diagnosis may still be of concern. Third, the estimated mean levels of exposed air pollutants at residential locations were unable to properly represent the exact amount of exposure in each subject. Fourth, as a population-based study in Taiwan, generalizability may be limited. Facing the above limitations, we minimised the bias by matching gender, age at first biologics initiation, year of AS diagnosis and disease duration, as well as adjusting for potential confounders. Matching the year of index dates allowed us to define the temporal relationship between exposure to ambient air pollutants before biologics initiation and the subsequent active AS. Future studies involving designs bearing higher potency evidence and longer follow-up periods, studies using an individualised recording of exposed pollutant amounts, and immunological research targeting the pathogenesis of AS remain warranted to confirm our findings.