Discriminant validity, responsiveness and reliability of the arthritis-specific Work Productivity Survey assessing workplace and household productivity within and outside the home in patients with axial spondyloarthritis, including nonradiographic axial spondyloarthritis and ankylosing spondylitis

Data from the double-blind period of the RAPID-axSpA (efficacy and safety of certolizumab pegol (CZP) in axSpA) trial (double-blind and placebo-controlled to week 24, dose-blind to week 48 and then open-label to week 204) were used to conduct the psychometric validation of WPS [21]. In the first 24 weeks of RAPID-axSpA, CZP 200 mg every 2 weeks (Q2W), 400 mg every 4 weeks (Q4W) or placebo were investigated. The trial was conducted at 83 centers across North America, Latin America, Western Europe and Central/Eastern Europe from March 2010 to October 2011. Institutional review boards or ethics committees approved the protocol at each center (see Additional file 1). All patients gave written consent, and the study was conducted in accordance with the Declaration of Helsinki [21].

Patients were randomly assigned 1:1:1 to receive (1) placebo (saline) Q2W, or subcutaneous CZP 400 mg at Weeks 0, 2 and 4 (loading dose) followed by either (2) 200 mg CZP Q2W or (3) 400 mg CZP Q4W until Week 24. Placebo patients who did not achieve at least Assessment of SpondyloArthritis International Society (ASAS) 20% improvement criteria (ASAS20) response at both week 14 and week 16 remained blinded, but were rerandomized to active treatment at week 16 in a 1:1 ratio (CZP 200 mg Q2W or CZP 400 mg Q4W) and received the loading dose at weeks 16, 18 and 20. CZP patients continued to receive the initially assigned dose [21].

The primary efficacy endpoint was the ASAS20 response at week 12 [22, 23]. Secondary and exploratory endpoints included the ASAS40, ASAS50, ASAS70, Total and Nocturnal Spinal Pain, physical functioning assessed by Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS), health-related quality of life (HRQoL), assessed using the Short Form 36-item health survey (SF-36), EuroQoL 5 dimensions (EQ-5D) and the Ankylosing Spondylitis Quality of Life Scale (ASQoL), and productivity measured using the WPS.

The WPS is a disease-specific questionnaire used to assess the impact of arthritis on workplace and household productivity, as well as daily activities during the preceding month. It is interviewer-administered and self-reported by the patient and has a 1-month recall period [17].

The first item of the WPS addresses current labor market participation (employment outside the home), as well as providing normative and comparative data on employment status. This is a strong indicator of ability to work, because not working implies complete loss of paid productivity. Two items capture self-reported absenteeism (days of work missed) and presenteeism (days with productivity reduced by at least half) due to arthritis, and two items capture the same concepts but apply to nonpaid (household) work. Additional items capture the respondent’s estimate of the extent to which arthritis has interfered with work productivity (paid and nonpaid) on a scale of 0 to 10 (0 = no interference and 10 = complete interference), the number of days in the past month that outside help was hired because of arthritis, and the number of days in the past month family, social or leisure activities were missed because of arthritis [17].

The ASDAS is a composite score derived from a number of assessments, which are scored by the subject and physician and multiplied by a proven formula, with lower scores indicating low disease activity [24]. The BASFI comprises 10 items assessing physical function over the preceding week [25]. The summary score from this scale is the mean of the 10 items and ranges from 0 to 10, with 0 representing the best state (lower disease activity) and 10 the worst state. The minimum clinically important difference (MCID) for BASFI is one point.

The BASDAI is the most commonly used instrument to measure the disease activity of ankylosing spondylitis over the preceding week, and ranges from 0 to 10, with 0 representing the best state and 10 the worst state. The BASDAI50 is defined as an improvement of at least 50% in the BASDAI compared to baseline. A response criterion for the BASDAI is defined by an MCID decrease of at least one [26].

Total and Nocturnal Spinal Pain are assessed by two questions rated on a 0 to 10 numerical rating scale (NRS), where 0 = no pain and 10 = most severe pain. The ASQoL is an 18-item questionnaire, each item of which is used to assess the patient’s current opinion on his or her quality of life [27]. Each item is scored as 1 = yes or 0 = no. The summary score is the total of the yes and no scores, thus ranging from 0 (best HRQoL) to 18 (worst HRQoL).

The SF-36 is a widely used generic HRQoL instrument used to evaluate eight health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health [28]. The eight domains are summarized in two component summaries: the Physical Component Summary (PCS) and the Mental Component Summary (MCS) [26]. Scores on the SF-36 range between 0 and 100, with higher scores indicating a better HRQoL.

The EQ-5D questionnaire is comprised of a five-item health status measure and a Visual Analogue Scale (VAS). Each of the five dimensions is divided into three levels: no problem, some or moderate problems and extreme problems, scored as 1, 2, and 3, respectively. The EQ-5D VAS records the respondent’s self-rated health status on a vertical 20-cm scale, 0 to 100 graduated (0 = worst imaginable health status and 100 = best imaginable health status).

The ASAS20 response is defined as an improvement of at least 20% and absolute improvement of at least one unit on a 0 to 10 NRS in at least three of four domains: patient’s global assessment of disease Activity, total spinal pain NRS score, BASFI and mean of BASDAI questions 5 and 6 concerning morning stiffness intensity and duration and the absence of deterioration in the potential remaining domain, with deterioration defined as a relative worsening of at least 20% and an absolute worsening of at least one unit [29].

The ASAS criteria for 40%, 50% or 70% improvement are defined as relative improvements of at least 40%, 50% or 70% and absolute improvement of at least two units on a 0 to 10 NRS in at least three of the four domains and no worsening at all in the remaining domain.

Further details of the questionnaires assessed are included in Additional file 2.

The assessment of the psychometric properties (discriminant validity, responsiveness and reliability) of the WPS was performed on the overall axSpA randomized set (RS) population, regardless of the randomization group. Analyses were also performed on the nr-axSpA and AS subpopulations separately.

The known-groups validity method was used to compare the productivity scores between patients with a worse health state versus patients with a better health state. A patient with a worse health state was considered to be a patient with a higher disease activity, a worse HRQoL level or a lower physical functioning level, whereas a patient with a better health state was defined as having either a lower disease activity, a better HRQoL or a higher physical functioning level, respectively. The assumption tested through the known-groups validity method was that patients with a worse health state were expected a priori to have higher losses in paid and household work productivity (that is, higher WPS scores to Q2 to Q9) due to their disease, compared with patients in a better health state. For this purpose, known groups were formed using the first- and third-quartile scores for each outcome as cutoff points in order to avoid comparison of unbalanced groups [17]. Patients with baseline SF-36 scores at or above the third quartile, or ASQoL or fatigue NRS (from BASDAI) scores at or below the first quartile, were considered to have a “better” HRQoL, and those with SF-36 scores at or below the first quartile or ASQoL or fatigue NRS scores at or above the third quartile were defined as having “worse” HRQoL. Similarly, “better” and “worse” physical function were defined as BASFI scores at or below the first quartile and at or above the third quartile, or SF-36 physical function or SF-36 PCS scores at or above the third quartile and at or below the first quartile, respectively. Patients with ASDAS, BASDAI, or total/nocturnal spine pain score at or below the first quartile were considered to have “low” disease activity/severity, whereas ASDAS, BASDAI, or total/nocturnal spine pain score at or above the third quartile indicated “high” disease activity/severity.

The discriminant validity of the WPS was assessed using baseline observed data. To test the validity of productivity at paid work (WPS Q2-Q4), cutoff points were computed only on the patients employed outside the home, whereas the thresholds were computed on all patients for productivity within the home (Q5-Q9). Sensitivity analyses were performed using a median cutoff threshold.

A nonparametric bootstrap-t method was used to compare the mean WPS question responses between the known groups [30]. This method was favored because of the highly skewed distribution of the WPS scores. Bootstrap analyses were performed with 10,000 replications. A variance stabilizing transformation was used in order to adjust for dependence between the bootstrap values and the corresponding standard error.

The responsiveness of the WPS to clinical changes in a patient’s condition over time was evaluated by comparing the changes from baseline in productivity scores between clinical responders versus nonresponders at week 12 (as measured by ASAS20 criteria). The assumption tested was that clinical responders would have higher improvements in productivity at work outside the home and within the household versus nonresponders, reflected by higher negative changes (in absolute value) in WPS scores.

According to the primary analysis, patients were considered a “responder” if they met the criteria of ASAS20 improvement from baseline at week 12. Any patient who did not meet the criteria for ASAS20 was considered a “nonresponder”.

The reliability of the WPS was tested in conjunction with the responsiveness to the ASAS20 clinical response by comparing the changes in WPS scores in patients achieving ASAS40, ASAS50, BASDAI50, ASDAS major improvement (MI), ASDAS clinically important improvement (CII), total/nocturnal back pain MCID and BASFI MCID responses at week 12 versus nonresponders.

WPS score changes from baseline at week 12 were compared between week 12 clinical responders versus nonresponders using a nonparametric bootstrap-t method. A variance stabilizing transformation was used in order to adjust for dependence observed between bootstrap values and the corresponding standard error. Bootstrap analyses were performed with 10,000 replications.

In addition to the comparison of the changes in WPS scores between the clinical responders and nonresponders, the standardized response mean (SRM) was calculated. The SRM is one of the most widely used measures of the effect size of the response, indicating whether the change was large relative to the variability of the measurements. The SRM is estimated as the mean change in scores between two visits divided by the standard deviation of that change in scores. Thresholds for the SRM (absolute values) were proposed by Cohen [31] to interpret the size of the effects: “small” from 0.2 to 0.5, “moderate” from 0.5 to 0.8 and “large” greater than 0.8.

The responsiveness and reliability of the WPS was assessed at week 12 on all RS patients, regardless of the randomization group.

A total of 325 patients were randomized, and 298 (91.7%) patients completed the 24-week phase. In the overall axSpA population, RS patients had a mean age of approximately 39.6 years, with 78.8% of patients between ages 25 and 54 years. Over half (61.5%) of the patients were male, and most (90.2%) were white (Table 1). In the AS subpopulation, the mean age (41.5 years) was higher compared to the nr-axSpA subpopulation (37.4 years), and AS patients were also more likely to be male compared to nr-axSpA patients (72.5% versus 48.3%, respectively) (Table 1).

Patients in the overall axSpA population reported a median time since disease diagnosis of 3.9 years. In the AS subpopulation, the median time since diagnosis was 5.5 years, and for the nr-axSpA subpopulation it was 2.5 years (Table 1). The majority (78.5%) of patients in the overall axSpA population tested positive for human leukocyte antigen (HLA) B27; this was also true for the AS and nr-axSpA subpopulations (81.5% and 74.8%, respectively). In general, BASDAI scores were similar, whereas BASMI and BASFI scores were lower, in the nr-axSpA subpopulation relative to the AS subpopulation, indicating comparable disease burden but less limitation in function and mobility in patients with nr-axSpA (Table 1).

Whereas the largest percentage of patients in the overall axSpA population and AS subpopulation were from the Eastern Europe (43.4% and 55.1%, respectively), patients in the nr-axSpA subpopulation were more evenly distributed among North Americans (27.2%), Western Europeans (34.7%), and Eastern Europeans (29.3%).

At baseline, 69.2% of patients in the overall axSpA population were employed outside the home, 12.3% were unable to work due to axSpA, 5.8% were students and 5.5% were retired. The rest were homemakers (3.1%), unable to work due to non-axSpA health problems (1.9%) or had other nonemployment status (2.2%) (Table 2). Generally similar employment rates were noted in the nr-axSpA and AS subpopulation, although in the nr-axSpA subpopulation there were slightly more patients employed outside the home, homemakers or students, as well as fewer patients who were unable to work due to arthritis or were retired compared to the AS subpopulation (Table 2).

The burden of axSpA at study baseline was high, impacting workplace absenteeism and presenteeism as well as household productivity and participation in daily activities (Table 3).

Patients in jobs with some manual component had a higher number of workplace days missed per month than those in exclusively nonmanual jobs (mean 2.5 versus 1.4 days). Additionally, these patients reported more days per month with patient workplace productivity reduced by at least half compared to those with exclusively nonmanual jobs (mean 6.1 versus 4.3 days, respectively). In terms of household work, employed patients reported a high impact of axSpA symptoms, but the impact was lower compared to nonemployed patients and to patients unable to work due to arthritis (mean household work days missed per month: 4.6 versus 8.4 versus 14.6; mean days per month with household productivity reduced by ≥50%: 6.6 versus 9.4 versus 11.2, respectively).

At baseline, all patients in the axSpA RS population answered at least one of the WPS questions. The completion rates of each of the WPS questions at baseline in the RS population were very high, indicating that the instrument was clear, acceptable and representative of the study population, and therefore that the results can be generalized to a larger axSpA population. There was only one (0.3%) missing answer to WPS Q5 to Q9 at baseline. Among all employed axSpA RS patients who were required to answer WPS Q2 through Q4, the completion rates at baseline were also high, with only two (0.9%) missing answers for Q2 and three (1.3%) missing answers for Q3 and Q4.

Similarly high completion rates of WPS questions were noted in the nr-axSpA and AS subpopulations. At baseline, there was no presence of a ceiling effect, as shown by the very small number of patients with a maximal answer. In the overall axSpA population, two (0.9%) to four (1.8%) of the RS employed patients had an answer ≥30 days to WPS Q2 and Q3, respectively, and ten (4.5%) had a maximum answer of 10 to Q4. Out of all RS patients, 5 (1.5%) to 21 (6.5%) had an answer ≥30 days to WPS Q5 to Q8 or a maximal score of 10 to Q9. Similarly, no ceiling effects were noted in the nr-axSpA and AS subpopulations.

As expected, in terms of floor effect, the percentage of patients with a minimal response varied between the WPS questions, with a higher number of patients answering 0 to Q2 (work days missed in the past month, 69.5% of the employed RS population in the overall axSpA population) and to Q8 (days with outside help hired, 78.1% of the entire RS population), and ranging from 11.3% to 50.5% for the other questions. Similar results were observed in the nr-axSpA and AS subpopulations.

The association coefficients between all WPS questions and different continuous measures assessing the disease activity, physical functioning and HRQoL, were low (<0.3) to moderate (≥0.3 to 0.5), as expected, indicating divergent validity between the individual WPS questions and the other measures considered (Figure 1).The level and the sign (positive or negative) of the Kendall association coefficients indicated that better productivity at work and within the home (as assessed by lower scores to WPS Q2 to Q9) was associated with better HRQoL, less fatigue, better physical functioning or less pain (Figure 1). The range of the association coefficients between the individual WPS questions and the clinical and HRQoL assessments was similar in the overall axSpA, nr-axSpA and AS populations. Nevertheless, higher correlation coefficients were observed in nr-axSpA compared to AS between WPS Q4 (arthritis interference with work productivity (outside home)) and all clinical and HRQoL measures, as well as between Q8 (days with outside help hired) and certain HRQoL measures (SF-36 and ASQoL) (Figure 1).

The known-groups validity analysis indicated that there was a higher burden of arthritis on productivity at both paid work and within the home in patients with a worse health state compared to patients with a better health state (Tables 4 and 5). Among employed patients in the overall axSpA population, patients with a worse health state had higher workplace productivity losses, with significantly more work days lost and more work days with productivity reduced by half, and a statistically higher interference of arthritis on work productivity compared to patients with a better health state (Table 4). In the overall axSpA population, compared with patients with a better health state, patients with a worse health state had larger productivity losses within the household, with, on average, significantly more days of household work lost; more days with household productivity reduced by at least half; more days missed of family, social or leisure activities; more days with outside help hired; and a significantly higher interference of arthritis (all per month) (Table 5).

Similar findings were observed in the nr-axSpA and AS subpopulations, where patients with a worse health state had a higher burden of arthritis on productivity, at both paid work and within home, compared to patients with a better health state (Tables 4 and 5).