A Benchmarking Study Evaluating Axial Spondyloarthritis Burden in Spain and Other European Countries. Results from the Spanish Atlas and the European Map of Axial Spondyloarthritis (EMAS) Studies

To compare the burden of disease in Spanish patients with axial spondyloarthritis (axSpA) vs other European countries (OEC).


| INTRODUC TI ON
Axial spondyloarthritis (axSpA) is a disease associated with a high degree of disease burden and disability, 1 and consequently with a high cost per patient to European national health systems. [2][3][4] This disease has been the focus of extensive research in recent decades.
From this growing interest in axSpA, different research registries and cohorts have emerged at national levels in Europe. Some examples are the DANBIO, 5 DESIR, 6 GESPIC, 7 OASIS, 8 SPACE, 9 SWISS,10 or REGISPONSER, 11 the objectives of which are to study the characteristics of axSpA and understand the clinical aspects to improve patient management and treatment. However, despite the relevant clinical value of these studies, which allowed researchers to reach a better understanding of the functioning of axSpA and related conditions, these records have some limitations in providing answers to further research questions. On the one hand, there is a trend in these studies to leave aside life spheres that are of key importance from the patient's perspective, such as work experience or mental health. On the other hand, most of these registries and cohorts have been carried out on a national level and it is therefore not possible to compare data between different countries.
The systematic study of other life spheres, also affected by the disease either in a direct or indirect way, escapes clinical studies almost entirely. To give an example, only the DESIR cohort study collects some data on the impact of axSpA on working life for the total study population, based on indirect measures such as absenteeism through sick leave or level of disability. 6 There is a wide research gap not only on the disease's impact on working life, but also in the association of the condition with poorer psychological health or the patient's perspective with respect to their own disease.
Additionally, despite the rigor of the studies presented, they utilize different methodologies in terms of sample inclusion criteria, sampling method and variables collected, so a comparison of the disease characteristics and status of patients with axSpA between European countries is not possible. Some studies are international, like the OASIS. However, its scope covers only 3 countries of similar geographical and socio-economic conditions (France, Belgium, and the Netherlands). 8 Even if great efforts are being made in order to carry out joint studies of different registries that allow for greater generalizability of results, this research is still subject to problems due to the different methodologies used by said registries, leading to sample bias 12 or lack of comparability of the relevant indicators for axSpA patients' health. 13 All of these reasons made it necessary to conduct a study on axSpA from the patient's perspective, collecting representative country samples under 1 common methodology, thereby allowing comparisons of national data in relation to a European framework.
That is one of the main objectives of the European Map of Axial Spondyloarthritis (EMAS), upon which data for this study is based.
Benchmarking studies in axSpA may provide evidence of disparities, making it necessary to improve the healthcare and management of these patients. The aim of this study is to analyze the burden of the disease in axSpA patients in Spain compared with that of patients from other European countries (OEC) in terms of sociodemographic characteristics, diagnostic journey, disease activity, function, and psychosocial wellbeing.

| The Atlas and EMAS working groups
The Atlas of Axial Spondyloarthritis in Spain is an initiative of the

| Design and survey development
The Atlas of Axial Spondyloarthritis in Spain is a cross-sectional study gathering data through an online survey of 680 unselected patients with self-reported axSpA diagnosis. 14 This Spanish survey was adapted into the EMAS survey, which recruited an additional 2166 axSpA patients from 12 different European countries other than Spain: Austria, possible causal factors, highlighting the need to increase the number of rheumatologists, the training of healthcare professionals, and improving axSpA patients' working conditions.

K E Y W O R D S
ankylosing spondylitis, axial spondyloarthritis, diagnostic delay, employment status, patientreported outcomes, psychological distress Belgium, France, Germany, Italy, the Netherlands, Norway, Russia, Slovenia, Sweden, Switzerland, the United Kingdom. To develop the EMAS questionnaire, the steering committee and participating countries were asked to assess and modify questions for local relevance, with guidance to only make essential changes in order to maintain consistency between the Atlas and EMAS studies, on a pan-European level.
The EMAS questionnaire was developed in English and subsequently translated into the languages of the other European countries involved (Dutch, French, German, Italian, Russian, Swedish, and Slovenian). The final EMAS patient questionnaire included 108 items of the original 116 of the Atlas, related to 12 different areas: socio-demographic and anthropometric characteristics, disability and performance, work life, daily life, lifestyle habits, diagnostic process, healthcare resource use, treatment, other disorders/diseases, psychological health, disease outcomes, and patient experience of living with the disease. All indicators collected for the EMAS survey were patient-reported outcomes.
In addition, a range of supplementary indices were collected in the questionnaire to assess specific areas. The cut-off point of 3 implied those with a score of 3 or more may be experiencing psychological distress. 17

| Sample selection and recruitment
Sample selection inclusion criteria for both the Atlas and EMAS studies were the same: to be aged ≥18 years, resident in any of the 13 participating European countries, have a diagnosis of axSpA, including ankylosing spondylitis (also known as radiographic axSpA) and non-radiographic axSpA, and to have paid an axSpA-related visit to a healthcare professional in the 12 months prior to participation.
Participants from the Atlas were recruited from January to March 2016. Survey dissemination of the Atlas was made through press releases, e-mails and website and social media announcements. EMAS participants were recruited between July 2017 and March 2018 by Ipsos SA (formerly GfK) through its online panel of respondents. This firm ensures that patients are fully validated through their connected healthcare professionals around the world who refer patients for research. In Austria, Norway, Slovenia, Sweden, the Netherlands, Italy, Russia, and Spain, patient organizations supported recruitment by distributing the survey link to their members. The questionnaire was completed via an online platform for survey data collection. In addition, the database from the Atlas 18 was adapted to fit the EMAS database in order to allow comparisons between Spanish and the OEC axSpA patients.

| Statistical analysis
Socio-demographic characteristics, life habits, and patient-reported outcomes (BASDAI, spinal stiffness, functional limitation and psychological distress through GHQ-12) were compared between Spanish and OEC axSpA patients. Chi-square test was used for qualitative variables and Mann-Whitney test for quantitative variables. All analyses were carried out using the Statistics Package for Social Sciences (SPSS) v. 25.0.

| RE SULTS
The Spanish sample was characterized by a slightly higher age and lower presence of women than in the OEC sample. The number of people with university studies and the overall income level was lower than the European average. Regarding harmful lifestyle habits, compared to the OEC, a higher percentage of Spanish axSpA patients declared that they smoke. However, although both groups followed a similar trend regarding regular alcohol consumption (more than twice a week), the Spanish sample less frequently reported moderate consumption (between 1 and 2 times a week) and more participants reported occasional drinking or abstinence compared to their European counterparts ( Table 1).
The average mean age of onset of first symptoms of Spanish axSpA participants was more than 3 years lower than in the OEC, overall disease duration was reported to be around 4 years longer, and diagnostic delay more than 1 year greater. As for patientreported outcomes, the Spanish sample also reported a higher rate of human leukocyte antigen (HLA)-B27 positivity. Moreover, the Spanish sample had a slightly higher BASDAI score. However, BASDAI differences were not clinically relevant according to rheumatologic standards. Additionally, Spanish axSpA patients declared a much greater functional limitation than the OEC. They also reported half the rate of inflammatory bowel disease than the OEC (Table 2).
A total of 21.7% of the Spanish sample in the active population was unemployed, while for OEC this figure drops to 9.2%. Moreover, unemployed patients were asked whether they considered that they had to leave or lost their job due to axSpA, to which 62.8% of Spanish and 65.3% of OEC respondents answered "yes". Furthermore, 95.5% of Spanish axSpA patients stated that their disease made it or would make it difficult to find a job compared to 70.3% of the OEC.
However, in the case of Spanish patients who had a job, they reported fewer work-related issues, and less need for workplace adaptation than their European counterparts. Although the reported prevalence of mental disorders (anxiety, depression, and sleep disorders) was significantly lower in the Spanish sample compared to the OEC, the average GHQ-12 score was higher in Spanish axSpA patients. Finally, 95.6% of the Spanish sample reported benefiting from public health insurance while for OEC this figure fell to 77.7% (P < .001; Table 3).
With respect to EMAS data, Spanish patients show a systematically longer diagnostic delay than their European counterparts over the last 2 decades (Table 4).

| D ISCUSS I ON
The results of the EMAS survey allow us to verify a series of unmet needs at the European level as well as particular needs of Spanish patients, such as long diagnostic delay and psychosocial consequences including the deterioration of mental health and high impact of axSpA on working life.

| Country profiles
Despite the organizational heterogeneity of European health systems, some peculiarities of the Spanish health system can be highlighted. Spain has more physicians than the European average (381 vs 353 per 100 000 inhabitants). 19 In fact, this figure places Spain

| Diagnostic delay
The Spanish sample shows an average diagnostic delay of 8.5 years and a median of 6 years, a figure higher than that reported by the

| Burden of the disease
The burden of disease reported by both samples was significant, declaring high levels of disease activity, spinal stiffness and functional limitation overall. However, Spanish axSpA patients reported an even higher BASDAI score than the EMAS OEC average, even higher than the values recorded by other Spain-based axSpA registries like the REGISPONSER. 11 However, mean differences, although statistically significant, were not clinically relevant. Spanish patients also reported greater functional limitation. However, we cannot be sure whether this is due to longer disease duration or whether it is actually associated with the longer diagnostic delay of these patients.

| Working impact
Unemployment rates differ greatly from the Spanish general population (17.2%) to that estimated for the EU-28 (6.8%). 36 When employment status is examined for axSpA patients, an increase in unemployment rates is appreciated in both Spain and Europe despite both samples reporting a higher level of education than the general population. 37 However, Spanish axSpA patients' unemployment rates show a steeper increase than that of their European counterparts, and the unemployment gap becomes larger between both groups.
When examining employed patients, the Spanish were less likely to report interference of the disease in their work performance compared to the OEC. Spanish participants declared fewer work-related issues overall, fewer workplace adaptations, and a smaller influence of axSpA on work choice. This is striking, as research points to a strong relationship between problems and needs in working life and burden of disease. 38 If burden of disease is equivalent between Spain and OEC, interference of the condition at work should also be similar.
Therefore, it is more likely that work outcomes reported by the Spanish sample are due to a more precarious labor scenario (characterized by high unemployment rates, short-term duration jobs, low salaries, and gender inequalities), compared to the European Union context. 39 Thus, Spanish axSpA patients would not report an influence of axSpA on work choice in an already constrained market,

| Mental burden
The impact of axSpA on mental health is well documented. 41,42 The EMAS sample showed a high prevalence of mental health issues among axSpA patients, higher than those collected by the

| Strengths and limitations
The EMAS project represents the largest axSpA patient survey to date, including 2846 respondents from 13 European countries. Its main objective was to understand the patient's perspective through a holistic approach using a questionnaire developed for patients by patients. As such, EMAS collected not only clinical characteristics of the disease but also the patient-reported impact on psychological health, daily activities, work, and lifestyle, all of which are considered relevant aspects by axSpA patients. The focus of its design added to its international scope, enables a head-to-head comparison of patient-reported outcomes at the pan-European level in areas that are often overlooked by research.
We acknowledge that EMAS has some limitations. First, the survey was based on self-reported data and did not attempt to confirm participant diagnosis, nor did it seek to support participant responses with clinician-reported assessments. Nevertheless, the characteristics of the sample matched those of previous cohorts including patients with confirmed axSpA, and as the aim of the survey was to better understand the patient perspective, direct feedback was preferred. Second, as 1 of the inclusion criteria was to have had at least 1 visit to a rheumatologist in the last 12 months, the sample could be biased in excluding patients not requiring a follow-up appointment and thus, with controlled disease activity. In this way, this study could have overestimated the severity of some disease outcomes, especially those related to disease activity.
Additionally, non-validated indices were used for assessing functional limitations in daily activities and spinal stiffness. This was due to patients expressing their concern during the preliminary phase of the survey development about not being able to report relevant aspects of their disease not included in other scales or indices considered. In any case, Cronbach alpha values obtained for the indices employed in EMAS showed good reliability of these instruments in this sample. 14 Lastly, the 2 recruitment methods employed (GfK patient panel and patient organizations) resulted in differences in sample sizes between countries, naturally skewing the aggregated European data toward the experiences of patients in countries with a greater sample weight.
Despite these limitations, EMAS adopts a multidisciplinary approach, including the medical and patient community within the research team aiming to understand the patient experience from a holistic perspective. Additionally, workers with axSpA with a similar burden of disease, as their European counterparts, receive less support in the workplace.

| CON CLUS IONS
All this could be affecting patients' levels of psychological distress.
Managing axSpA from a holistic approach, including the perspective of health psychologists, rehabilitation therapists, social workers, and related professions, should be key for clinical improvement and quality of life in these patients in Spain, as well as in Europe.

ACK N OWLED G EM ENTS
We would like to thank all patients and patient organizations who participated in the EMAS study. This study was funded by Novartis Pharma AG.

AUTH O R S' CO NTR I B UTI O N S
Marco Garrido-Cumbrera, Laura Christen, Sergio Sanz-Gómez, José Correa-Fernández and Victoria Navarro-Compán designed the study, José Correa-Fernández carried out data analysis. All authors contributed to interpretation of the data, helped to draft the manuscript and approved its final version to be submitted; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

E TH I C S A PPROVA L
The manuscript does not contain clinical studies.

CO N S E NT TO PA RTI CI PATE
All participants were asked to provide explicit opt-in consent prior to participating in the survey.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data are available via the corresponding author upon reasonable request.