The Burden of Rheumatoid Arthritis in Spain

According to a systematic review of studies in adults, the prevalence of Rheumatoid Arthritis (RA) is 0.2-1.1% in developed countries, is higher in women, and has a large geographical variation [1]. The incidence of the disease varies, depending on country, from 0.1 to 0.5 patients per 1000 inhabitants [1]. RA is associated with frequent comorbid conditions, especially cardiovascular diseases, gastrointestinal disorders, infections, psychiatric disorders and, more infrequently, some malignancies [2]. Importantly, RA is associated with an excess mortality of over 40% compared with the general population [3,4].


Prevalence and incidence
In the three studies reporting the prevalence and/or incidence of RA in Spain [6][7][8], results were similar to those of other comparable countries or regions [1].
The EPISER study evaluated the prevalence of musculoskeletal disorders in Spain and randomly selected 2998 adults from the censuses of 20 cities [8]. Diagnostic assessment using the 1987 American College of Rheumatology (ACR) criteria was possible in 2192 subjects. The authors identified 11 patients (nine women and two men) with RA and reported a prevalence of 0.5% (95% confidence interval [CI]: 0.25 to 0.85); prevalence was higher in women than in men (0.8% [95% CI: 0.4 to 1.1] and 0.2% [95% CI: <0.5], respectively) [9]. Extrapolating the data to a population of around 40 million, they estimated that there were 150,000-200,000 cases of RA in Spain. A population-based study was carried out in Catalonia (Eastern Spain) using a primary care database (SIDIAP [Information System for the Development of Research at Primary Care]) that included data from about 5.4 million people aged 14 years or older and a follow-up period of 4 years for the incidence calculation (see next paragraph) [10]. In the evaluable patients (n=4,895,307), these authors reported an age-and sex-standardized prevalence of RA (International Classification of Diseases  codes M05 and M06) slightly lower (0.42% [95% CI: 0.41 to 0.42]) than the overall prevalence in the EPISER study [8]. The prevalence of RA in the EPISER study and the study conducted in Catalonia is within the range reported for developed countries (0.2-1.1%) in a systematic review of the epidemiology of RA [1]. Results were also consistent with those reported in south European countries (range 0.31-0.50%), which were lower than those reported in north European countries (0.44-0.80%) or the USA (1.07%) [1].
The incidence of RA in Spain has been estimated in two studies [9,10]. Carbonell et al. conducted a study in 20 specialized rheumatology units throughout Spain that, over 1 year, recruited patients with suspected early arthritis attending associated primary care centers (83.4% of the referrals), other specialists (9.3%), and emergency departments (3.4%).9 From 2467 referrals and a reference population of 4,342,378 adults, 362 patients were diagnosed with RA using the 1987 ACR criteria, giving an estimated annual incidence of RA of 0.08 cases per 1000 person-years in those aged >16 years [9]. The incidence was twice as high in females (0.11 cases/1000 inhabitants [95% CI: 0.10 to 0.13]) as in males (0.05 cases/1000 inhabitants [95% CI: 0.04 to 0.06]), and increased with increasing age, showing a peak at 51-60 years in women (0.18 cases/1000 inhabitants [95% CI: 0.14 to 0.24]) and at >70 years in men (0.16 cases/1000 inhabitants [95% CI: 0.12 to 0.22]). A more recent study using the SIDIAP database, mentioned earlier, reported an age-and sex-standardized incidence of RA (according to ICD-10 codes) of 0.20 per 1000 person-years (95% CI: 0.19 to 0.20);10 the age-standardized incidence was again at least twice as high in females (0.28/1000 person-years [95% CI: 0.27 to 0.29]) as in males (0.12/1000 person-years [95% CI: 0.11 to 0.12]), and increased with age, showing a peak at the age range of 65 to <70 years (0.51/1000 and 0.31/1000 person-years in women and men, respectively). These incidence rates are also within the range for other developed countries (0.1-0.5/1000 inhabitants).1 Similarly, the predominance of RA in females is consistent with that reported worldwide [1].

Comorbidity and mortality
The comorbidities present in patients with RA in Spain were described in three studies [21,24,25]. Unfortunately, none of these studies included a general population comparison group, and therefore no robust conclusions can be drawn regarding the type or prevalence of comorbidities in patients with RA. In addition, the information on cancer rates is based on a study with small sample size making the findings inconclusive. However, despite these limitations, the information from these studies is contributory.
The studies reporting mortality data from patients with RA in Spain are summarized in Table 1. One study reporting results for all-cause mortality used data from 182 consecutive patients at a tertiary hospital in central Spain followed for 9 years or until death [23]. Results of this study suggested an 85% excess mortality compared with the general population, which is higher than the values reported in two systematic reviews that included studies enrolling patients from a number of countries [standardized mortality ratios (SMRs) 1.44 and 1.48] [3,4]. SMRs in Spain were higher in males than in females (2.34 and 2.09, respectively; no CIs reported). The most frequent causes of death were cardiovascular disease (21%), infection (21%), and kidney failure (17.3%) [23].
In another study, the cardiovascular mortality SMR was 1.78 (CI not provided) in 182 patients with RA from a center in northwestern Spain who were followed for 9-9.5 years or until death [11]. This excess of cardiovascular mortality is consistent with the comorbidity profile previously mentioned.
Two studies have reported that cancer deaths are not increased in Spanish patients with RA (Table 1) [12,13]. The cancer SMR in both studies was 1.0. However, in the largest study, mortality was increased for lung adenocarcinoma, with an SMR of 4.5 (95% CI: 2.1 to 8.5) and renal carcinoma, with an SMR of 8.7 (95% CI: 1.1 to 31.4) [13].

Impact on quality of life and perception of quality of life
The five studies reporting results on the Quality of Life (QoL) of patients with RA in Spain are summarized in Table 2. The two studies reporting the impact of RA on quality of life using the SF-36/SF-12 showed an important negative effect on the physical component of    quality of life but inconsistent effects on the mental component [17,19]. Using data from EPISER described above, Loza et al. [17] reported that, after adjusting for several confounders in a multiple linear regression analysis, there was a β coefficient of -10.5 points [95% CI: -17.7 to -3.29] for the physical component score of the SF-12. Surprisingly, the mental component showed a slight but not significant positive effect (a β coefficient of 2.22 points [95% CI: -6.15 to 10.59] for the mental component score of the SF-12) [17]. However, Navarro Sarabia et al., in a random sample of 301 patients selected from 2488 patients from ten participating hospitals throughout Spain, found that all dimensions of QoL, including the mental component, as measured by the SF-36, were significantly reduced in patients with RA compared with the general population, the impact being greater on the physical dimensions and pain [19]. A systematic review of 31 studies from several countries evaluating the impact of RA on QoL using the SF-36 also found a greater negative impact on the physical component than on the mental component [5], supporting the findings from the Spanish studies. A similar deterioration in QoL using the EuroQol 5 Dimensions (EQ-5D) was also reported in an observational study of 247 consecutive patients with RA recruited by 14 rheumatologists at outpatient clinics. The mean EuroQol Visual Analog Scale (EQ-VAS) score was 63.1 and the mean utility value was 0.65; using the Health Utility Index Mark 3, the mean utility score was 0.75.14 In two qualitative studies carried out using similar methodologies, patients with RA perceived HRQoL as their ability to do things, and their perception of HRQoL was influenced by sociodemographic variables such as age, education, and economic level [15,16].

Cost of rheumatoid arthritis in spain
Two studies have analyzed the direct and indirect cost of RA in Spain, and one study evaluated the cost of pharmacologic treatment ( Table 3). The two studies analyzing the cost of RA were 12-month observational studies; one was retrospective [18] and the other was prospective [19]. Direct costs included medical (e.g., medical visits, diagnostic tests, drugs, hospital admissions) and nonmedical (e.g., help, transportation) costs; indirect costs were related to work disability. In both studies, direct costs associated with the disease represented the larger economic burden (70% and 75% of total costs) [18,19]. This is similar to findings from an Italian cost-of-illness study, wherein direct costs represented 69% of the annual costs of RA in 2012 [27]. However, the distribution of direct costs differed: in the retrospective study [18], the greatest contribution was 'nonmedical costs' (60.7% of direct costs), while in the prospective study [19], these costs represented 19.6% of direct costs. Total cost per patient per year also differs between the two Spanish studies: this was estimated at $US10, 419 (2001 values), equivalent to €11,707, and €3600 (2002 values), for the retrospective [18] and prospective [19] cohort studies, respectively. In the Italian study, the annual cost per patient was higher, at €13,595 (2012 values). Unlike the Spanish studies, this Italian study included the cost of productivity of the caregiver (i.e., an annual cost per patient of €1,424) [27].
Although the two Spanish studies may provide useful historical information, they were undertaken more than 10 years ago and do not reflect the current cost of illness in Spain as regards hospitalization rates, type of care, work disability compensation, and drug costs. Importantly, uptake of biologics is now greater than it was 10 years ago, and these treatments contribute considerably to the cost of the disease. For instance, in a study carried out as early as 2001 in 150 consecutive patients recruited from a Spanish hospital, including the cost of etanercept and infliximab treatments increased the annual cost per patient almost six-fold, from €342 to €2019 (2001 values) [22]. Therefore, there is a clear need for further investigation of the cost of RA in Spain.

Conclusion
This review shows that in Spain, RA is associated with deterioration in QoL, increased disability and costs, and, ultimately, an excess mortality. Epidemiologic data on RA in Spain indicate a disease frequency similar to that of other developed countries. Since most studies were carried out several years ago, further research is needed to assess the current situation in Spain, especially with respect to the medical and nonmedical costs associated with the disease.