Background
Axial spondyloarthritis (SpA) include diseases with predominantly axial involvement, such as ankylosing spondylitis (AS), psoriatic arthritis (PsA) and non-radiographic axial SpA which have as key symptoms both inflammatory back pain and stiffness [
1]–[
4].
Over the last decade, significant advances have been achieved in the development and validation of new tools for the evaluation of disease activity in axial SpA [
5]. Most of them are based on self-reported questionnaires that include evaluation of pain and stiffness, patient’s or physician’s global assessment (PtGA or PhGA, respectively), acute phase reactants evaluation or on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [
6] which is most frequently used in clinical trials. Although BASDAI has been endorsed by ASAS for the treatment monitoring and measurement of disease activity in axial SpA [
7], it demonstrated to have a limited face and construct validity. Moreover it is not sensitive to change (lack of responsivity) [
8] and does not include any objective measures of activity [
9]. Recently, AS Disease Activity Score (ASDAS) has been proposed by ASAS working Group for the evaluation of disease activity in patients with AS [
10],[
11]. ASDAS is the first validated disease activity system which combines both patient-reported outcome measures and acute-phase reactants levels. However, the equation used to calculate the ASDAS score is relatively complex (since requires a calculator) to be quickly assessed in the busy daily clinical practice. In this way Sommerfleck et al. [
12] developed a simplified version of the ASDAS, named Simplified AS Disease Activity Score (SASDAS) which, keeping the sensitive characteristics of the ASDAS, can be considered an intuitive and easy way to assess the disease activity in patients with axial SpA. SASDAS is based on the recently developed disease activity indices for rheumatoid arthritis (RA) such as the Simplified Disease Activity Index (SDAI) [
13] and disease activity index for the assessment of reactive arthritis (DAREA) [
14] which demonstrated to be valid and reliable in daily clinical practice in AS patients.
Taking into account these information we addressed the aims of our study in the following points: 1) to test the construct validity of the SASDAS to define disease activity in patients with axial SpA and 2) to compare its internal and external responsiveness with ASDAS CRP/ESR and the BASDAI, in an observational cohort of patients with axial SpA.
Discussion
Several recent studies have been performed to identify and measure the outcomes of treatment of axial SpA in both research and clinical practice. The development of valid, reproducible and objective tool for the evaluation of disease activity in axial SpA is difficult, although valuable instruments have been recommended by several researchers [
37]. Among the proposed composite indices, BASDAI has acceptable properties as a measure of disease activity in axial SpA. Nevertheless, there are few issues with regard the items content and appropriateness of response formats of BASDAI [
38]. Further, it has been shown that the BASDAI is an ambiguous measure of disease activity in patients with peripheral or axial disease activity and that reflects only patient’s perspectives and not necessarily captures the entire spectrum of disease activity [
39]. For that reason ASAS group has tried to go a step further in the evaluation of disease activity in AS by developing the ASAS-endorsed disease activity score (termed ASDAS) [
10]. The ASDAS is an index that tries to reflect several aspects of disease activity and correlates well with both physician’s and patient’s perception of disease activity, with respect to BASDAI. Furthermore, ASDAS has been shown to well correlate with biomarkers of cartilage [e.g. matrix metalloproteinase 3 (MMP-3) and osteocalcin] and bone turnover (e.g. C-terminal crosslinking telopeptide of type II collagen) [
40]. This indicates that ASDAS may better reflect the inflammatory disease processes in SpA with comparison to BASDAI.
Even the final decision to define the most appropriate set of domains of ASDAS has not yet been taken, ASDAS-CRP is the one widely recommended [
11]. ASDAS was found to be applicable also in subgroups without elevated CRP and/or peripheral swelling joints [
41].
Despite the excellent psychometric properties of ASDAS for the evaluation of disease activity in axial SpA, this index is not easy to use in the everyday clinical practice. This relevant aspect has recently led to a major revision of ASDAS, in order to simplify the index [
12]. Undoubtedly, the SASDAS index improves the evaluation of disease activity in daily practice and real-life conditions and, moreover, complies the recommendations of the OMERACT group [
42].
In our study we have investigated the construct validity of the SASDAS in evaluating the disease activity and we have compared the internal and external responsiveness of SADSAS and ASDAS ESR/CRP and traditional BASDAI in a cohort of patients with axial SpA. Compared with conventional clinical measures of disease activity, functional and general health status, SASDAS have demonstrated adequate construct validity and was equally or more responsive to changes in disease activity than conventional composite measures.
Similarly to the original study [
12], we have found a very high degree of correlation between these composite indices. The highest correlations were seen between SASDAS and ASDAS-ESR and between SASDAS and BASDAI score. Strong correlations were also found between SASDAS and ASDAS-CRP, SASDAS and BASFI and SASDAS and EQ-5D. Further, the categorization of cut-off of SASDAS versus those of both the ASDAS CRP/ESR have confirmed a significant high overall agreement.
It was recently shown that ASDAS performs better than BASDAI in evaluating disease activity in patients with AS. In particular, Lukas et al. [
10] and van der Heijde et al. [
11] have documented a better discriminatory capacity of ASDAS sets compared to BASDAI. Vastesaeger et al. [
43], in concordance with validation of the ASDAS [
11], have demonstrated that ASDAS discriminate better than BASDAI in patients with elevated CRP and was equal to BASDAI in patients with normal CRP. The ASDAS is also a highly effective measure in assessing disease activity and a great discriminatory measurement to assess the efficacy of TNF-a inhibitor in AS and undifferentiated SpA [
44]. However, three other studies that have assessed the validity of BASDAI and ASDAS sets in patients with axial PsA showed conflicting results. Taylor and Harrison [
39] have concluded that BASDAI correlated well with patient perception of disease activity but, was unable to discriminate well between high and low disease activity. Fernández-Sueiro et al. [
45] have shown that BASDAI performed well in differentiating between patients with axial-PsA and those without axial involvement. Eder et al. [
46] have demonstrated that in patients with axial-PsA, ASDAS and BASDAI scores show similar discriminative ability (from moderate to good) and correlation with different constructs of disease activity. ASDAS was not superior to BASDAI in its ability to discriminate between high and low disease activity states in axial-PsA. A confounding factor in these studies that may account for the discrepancy between the results obtained in the axial-PsA could be due to the presence of peripheral arthritis. In fact the peripheral arthritis, in these cases, may have an impact on disease activity level when it is assessed using BASDAI. This may be an advantage of ASDAS with respect to BASDAI, which is affected by peripheral involvement to various degrees, even in subjects with predominantly axial involvement [
47],[
48].
Up-to-date, in clinical practice the decision to start or continue DMARDs or TNF-a blocking therapy in patients with axial SpA is mainly based on BASDAI response, which is solely based on the opinion of the patient. Our results showed that the simplified version of the ASDAS (SASDAS) was sensitive to improvement in patients with axial SpA receiving TNF-inhibitors, with an ES of 1.62 and a SRM of 0.88, and was more responsive than BASDAI (ES 0.93, SRM 0.52). The most efficient composite measure in detecting changes of disease activity was the ASDAS-CRP (ES 1.95; SRM 0.97), whereas the ASDAS-ESR showed an intermediate behaviour (ES 1.33; SRM 0.71).
Our results are consistent with the literature data and further support the good psychometric properties of the ASDAS. In particular, in a 46 weeks prospective, longitudinal multi-center study, Pedersen et al. [
49] have investigated the construct validity and responsiveness of the ASDAS-CRP in patients with SpA treated with anti-TNF drugs. The authors demonstrated that ASDAS had higher responsiveness compared to BASDAI and CRP and thresholds for BASDAI at 20 mm or 50% improvement corresponding to an ASDAS of 1.38 and 1.95, respectively. ASDAS-CRP has demonstrated the highest responsiveness with an effect size of 2.04 and a standardized response mean of 1.45, whereas BASDAI (1.86; 1.36) and CRP (0.63; 0.70) were less responsive. Similarly, in a post hoc analysis of the randomized controller ASCEND trial, van der Heijde et al. found that ASDAS is a validated and highly discriminatory tool for the detection of significant differences between treatments for AS as well as for detecting a significant improvement from baseline with etanercept and SSZ [
50].
Although comparable responses in the ASAS 20, ASAS 40 and ASAS 5/6 and the BASDAI 50 have been achieved by adalimumab, etanercept and infliximab [
51]–[
53], low to moderate levels of responsiveness were reported for the BASDAI in placebo-controlled trials and longitudinal evaluation of active drugs [
54],[
55], in longitudinal evaluation of in-patient rehabilitation [
56] or in combined spa and exercise therapy [
57]–[
61]. Mean score change for the BASDAI did not exceed 1.9 and 1.3 respectively following all physical therapy interventions within a 2 to 40-week follow-up period.
Our study was designed to test the performance of the SASDAS versus ASDAS ESR/CRP and BASDAI in the clinical routine setting, so, we aware that it presents some limitations. First, we have not correlated the composite indices with structural damage and to ensure criterion validity of the composite indices. However, this is the subject of an ongoing study. Second, our study was performed in a single centre within a relatively small catchment area. Third, our work was concentrated only to the simplified version of ASDAS-ESR. We aware tha it would be of great interest to test also the ASDAS-CRP which is currently preferred for the assessment of axial SpA. Our research agenda is currently addressed to this topic in order to improve the scientific interest. Further, it remains to be seen in future long-term analyses whether the presented SASDAS cut-offs for different stages of disease activity will show similar results.
In conclusion, in patients with axial SpA the ASDAS scoring system and SASDAS scores show similar good discriminative ability and correlation with different constructs of disease activity and health status. The SASDAS score did not improve its discriminative ability and responsiveness compared with ASDAS scoring systems. Therefore, since SASDAS is easier to calculate, it may be more practical for clinical use in patients with axial SpA.
Competing interests
The authors would like to make the following statements with regard to their conflicts of interest/financial disclosures: FS has attended advisory board meetings for Bristol-Myers Squibb, AbbVie, Roche, Wyeth Lederle, and Pfizer, and has received research support from Bristol-Myers Squibb. MG has attended advisory board meetings, scientific consultancies and has obtained speaking fees for Abbott Immunology, AbbVie, UCB Pharma, Esaote S.p.a, Bristol-Myers Squibb and Merck Sharp & Dohme. The other authors declare that they have no competing interests.
Authors’ contributions
FS participated in the design of the study and the acquisition and interpretation of data, and performed the statistical analysis and the drafting of the manuscript. AC, SG participated in data acquisition, performed the clinical examinations. MG, GC, MC made substantial contributions to the conception and design of the study, participated in the acquisition of data, was involved in revising the manuscript for important intellectual content and gave final approval of the version of the paper to be published. All authors read and approved the final manuscript.