The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study

The data used in this nationwide, population-based study were obtained from the Swedish national healthcare registers.

Healthcare provision in Sweden is largely funded by the taxpayer and is independent of individual financial or insurance considerations. There is an upper limit to an individual’s yearly costs for medical consultations and prescription medications. Patients with an inflammatory rheumatic disease such as AS are usually diagnosed at public or (less commonly) private rheumatology clinics. Such cases are rarely definitively diagnosed in a primary care setting [25].

Ethical approval for the study was granted by the Regional Ethics Committee, Karolinska Institute, Stockholm, Sweden. Patient consent was waived, as data were derived either from administrative registers that do not require informed consent or quality registers where the consent is already given at the time point of first registration.

The NPR comprises the Inpatient Register (IPR) and the Outpatient Register (OPR). The IPR was launched in 1964, and complete national coverage (almost 100%) was achieved in 1987. The IPR contains data (medical and administrative) derived from all patients discharged from hospitals in Sweden [21]. The OPR for public specialized care was started in 2001. The national coverage of the OPR is lower (approximately 73% in 2008 and 87% in 2011) [26,27] than that of the IPR, mainly due to missing data from private caregivers. Visits to primary care facilities are not covered by the NPR. Diagnoses are registered using the Swedish version of the ICD codes [22]. The present study used the NPR to identify AS cases and AS-related clinical manifestations between 1967 and 2009. An additional table shows the ICD codes used in the present study (Additional file 1: Table S1).

The Swedish Prescribed Drug Register [28] contains information about all prescribed drugs dispensed by Swedish pharmacies since July 2005. This register was used to determine the exposure of patients with a registered diagnosis of AS to NSAIDs, oral corticosteroids, and sDMARDs during 2009. Exposure to TNFi during 2009 was based on data retrieved from the Swedish Biologics Register (the Anti-Rheumatic Therapy in Sweden Register; ARTIS) [29], which was initiated in 1999 and includes over 85% of subcutaneous and intravenous TNFi prescribed for AS [30]. An individual was considered to be “exposed” in 2009 if they had at least one prescription dispensed or, in the case of TNFi, were listed in ARTIS as receiving medication during 2009.

Demographic data were obtained from Statistics Sweden [31], which holds data on immigration, emigration, and residency, as well as data on socio-economic factors (for example, marital status and level of formal education) for all those residing in Sweden.

Vital status on 31 December 2009 was determined via the cause-of-death register [32], which provides information on the date and cause(s) of death for all residents since 1961.

All data in the Swedish national healthcare registers are accessed via a personal identification number, which provides the link between all of the registers used in the present analyses [33].

All individuals with an ICD diagnosis registration of AS between 1967 and 2009 were identified from the NPR (Figure 1). The base case definition required at least one AS diagnosis to be registered in the NPR (IPR 1967 to 2009 and/or OPR 2001 to 2009) by any department at a specialized care center. The strict case definition required at least one AS diagnosis to be registered by a department of rheumatology or internal medicine (Figure 1), a definition that we have previously found to have a high validity [23].

The case definitions used herein included individuals who had received their AS diagnosis for the first time before the age of 16, and also individuals diagnosed with juvenile idiopathic arthritis who had a subsequent diagnosis of AS. This is because these conditions were considered to be part of the same adult AS phenotype.

Results were obtained for individuals aged 16 to 64 years in 2009. The upper age limit was chosen to ensure a high case identification and at the same time minimize the flawing of the results which could be possibly caused by the inclusion of older individuals. Although >95% of patients with AS experience disease onset before the age of 45, there is a considerable delay (8 to 15 years) in obtaining a definitive diagnosis from a specialist in Sweden [23,15], meaning that a high age limit was required in order to maximize the number of cases enrolled. Moreover, since the major source used to identify AS cases, the OPR, did not start until 2001, the ability to accurately identify AS cases in older age groups with earlier disease onset, and who were exclusively diagnosed in a specialized outpatient care setting, was limited. Estimates of disease prevalence in older age groups may also be flawed due to the high mortality among AS patients [34]. Also, it may be that few AS diagnoses are made in older age groups due to either the limited impact of the disease on older people [35] or the influence of other major age-related co-morbidities on diagnosis registration patterns.

There are six healthcare regions in Sweden: one northern, one southern, and four in between (the southeastern and western regions, and the Uppsala-Örebro and Stockholm regions). These regions were used to calculate the regional prevalence of clinically diagnosed AS and are presented in Additional file 2: Figure S1.

The level of formal education was classified into three categories (≤9 years, 10 to 12 years, and >12 years of schooling). The prevalence of clinically diagnosed AS in relation to the level of education is presented for those aged ≥30 years, the age by which the majority of the population is expected to have completed their studies.

The total point prevalence of clinically diagnosed AS was estimated on 31 December 2009 according to both the base case and strict case definitions, and after stratification according to sex and age. Despite the cumulative ascertainment of AS cases, the term “point prevalence” is used. Considering that AS is a chronic disease, individuals with a previous registered AS diagnosis, alive and living in Sweden in 2009, are assumed having an AS diagnosis on 31 December 2009 as well. The point prevalence of AS was thus calculated by taking the number of AS individuals according to each definition and dividing it by the Swedish population on 31 December 2009 with similar age. Furthermore, the prevalence was estimated for subgroups based on AS-related clinical manifestations and pharmacological treatment, by taking the number of AS individuals (according to the base case definition) having dispensed prescriptions for each pharmacological treatment during any part of 2009, or those with a registered diagnosis of AS-related disease manifestations between 1967 and 2009, and dividing it by the Swedish population on 31 December 2009 with similar age. Crude and age-/sex-standardized point prevalence estimates according to healthcare region and level of formal education were also calculated. Standardization was performed to the Swedish population aged 16 to 64 years in 2009. For comparisons between the sexes, the Chi-squared test was used for categorical variables, and the Student’s t-test was used for normally distributed continuous variables. P-values <0.05 were considered statistically significant. For comparisons between geographical location and socio-economic factors, statistical significance was based on the absence of overlap between the estimated 95% confidence interval (CI). Logistic regression models adjusted for age and AS-related clinical manifestations (psoriasis, inflammatory bowel disease, anterior uveitis, and peripheral arthritis) were used to examine sex-related differences in treatment patterns. All analyses were performed using IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp and Microsoft Excel 2010, Microsoft Corporation, One Microsoft Way, Redmond, WA, USA.