Background
Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disease. The expression and outcomes of the disease vary, ranging from mild, limited disease to severe disease that is associated with progressive joint destruction, significantly compromised health-related quality of life (HRQOL), and reduced survival. Some clinical symptoms of RA, such as morning joint stiffness (MJS), may follow a circadian pattern and the rhythm of pro-inflammatory cytokines, such as interleukin-6 (IL-6). The increase in nocturnal anti-inflammatory cortisol seen in patients with RA is generally insufficient to suppress the ongoing joint inflammation, often resulting in joint stiffness in the morning [
1‐
3].
Prior research illustrates the importance of early morning stiffness or difficulty moving joints for patients with RA. In a study of 916 patients with recent onset of RA (disease duration ≤24 months), Westhoff et al. [
4] reported that for many patients, morning stiffness impacts their HRQOL, functional capability, and ability to continue to work. These findings are supported by recent survey research conducted by Mattila et al. [
5] in patients with RA (duration >6 months) who experience impairment of morning function at least 3 times per week. Of the 534 working respondents, 47% indicated morning stiffness affected their work performance, and 33% indicated it led to a late arrival at work. Of the 224 retired participants, 159 (71%) stopped working earlier than their expected retirement age, with 64% of these participants giving RA-related morning stiffness as a reason for their retirement [
5]. Indeed, MJS is an important and clinically meaningful element of disease activity [
6].
Patient-reported outcome (PRO) measures of symptoms like MJS are important tools to aid clinicians in treating patients with RA, facilitate doctor-patient communication to improve the quality of patient care, and contribute to better patient outcomes [
7]. Despite the importance of MJS to patients with RA [
4,
6], the assessment of MJS is not currently a measured component in several recommended endpoints in clinical trials, such as the American College of Rheumatology (ACR), Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28), Clinical Disease Activity Index (CDAI), or Simplified Disease Activity Index (SDAI).
To address this need, two daily electronic PRO diary items were created to assess both the duration and severity of MJS from the patient’s perspective. The content validity of these two items were supported through a targeted literature review, interviews with health-care providers, and qualitative concept elicitation and cognitive debriefing interviews with patients with RA [
8]. These interviews confirmed the relevance of duration and severity of MJS as symptoms of RA, as well as the appropriateness of terminology used to assess these symptoms.
This study reports the assessment of the psychometric properties (i.e., reliability, validity, and responsiveness) of two PRO items administered daily, the Duration of MJS and Severity of MJS, in patients with moderately to severely active RA who participated in two Phase 3 clinical trials for baricitinib RA-BEAM and RA-BUILD.
Results
Baseline demographics for the total modified intent-to-treat population, patients with Day 1 diary scores, and patients with Week 12 diary scores are provided in Table
1. Baseline and Week 12 scores for Duration of MJS PRO, Severity of MJS PRO, and other assessments are presented in Table
2, while score distributions for Duration of MJS PRO and Severity of MJS PRO are found in Additional file
1: Table S1. As can be seen in Tables
1 and
2, there was a large amount of missing data at the Day 1 assessment period. This missing data was due to multiple reasons as shown in Additional file
1: Table S2, such as the diary device alarm not sounding until the following day or the diary device being given to the patient after Day 1. Sensitivity analyses with the imputation for missing data at Day 1 (
n = 1041 for RA-BEAM and
n = 563 for RA-BUILD, respectively) demonstrated similar comparisons to the results presented in this document.
Table 1
Patient Demographic and Disease Characteristics for Patients with Electronic Diary Assessments at Day 1 and Patients with Week 12 Electronic Diary Assessments (mITT Population) for RA-BEAM and RA-BUILD
Age (years) |
Mean (SD) | 53.3 (12.1) | 53.2 (12.3) | 53.2 (12.0) | 51.8 (12.3) | 51.5 (12.3) | 51.8 (12.3) |
Gender, n (%) |
Female | 1009 (77.3%) | 414 (77.1%) | 989 (77.2%) | 560 (81.9%) | 262 (84.0%) | 546 (82.0%) |
Race, n (%) |
White | 818 (62.7%) | 422 (78.6%) | 801 (62.5%) | 457 (66.8%) | 254 (81.4%) | 444 (66.7%) |
Black or African American | 10 (0.8%) | 5 (0.9%) | 9 (0.7%) | 28 (4.1%) | 16 (5.1%) | 27 (4.1%) |
Asian | 392 (30.0%) | 45 (8.4%) | 388 (30.3%) | 180 (26.3%) | 31 (9.9%) | 176 (26.4%) |
American Indian or Alaska Native | 63 (4.8%) | 49 (9.1%) | 61 (4.8%) | 14 (2.0%) | 8 (2.6%) | 14 (2.1%) |
Native Hawaiian or Other Pacific Islander | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.1%) | 0 (0.0%) | 1 (0.1%) |
Multiple | 21 (1.6%) | 16 (3.0%) | 21 (1.6%) | 3 (0.4%) | 2 (0.6%) | 3 (0.5%) |
Missing | 1 (0.1%) | 0 (0.0%) | 1 (0.1%) | 1 (0.1%) | 1 (0.3%) | 1 (0.2%) |
Years from RA diagnosis |
Mean (SD) [min, max] | 8.7 (8.2) [0–56] | 8.7 (8.0) [0–40] | 8.6 (8.1) [0–56] | 6.3 (7.3) [0–53] | 6.2 (6.5) [0–41] | 6.4 (7.4) [0–53] |
Table 2
Instrument Scores at Day 1 and Week 12 for RA-BEAM and RA-BUILD
Duration of MJS, Mean (SD) | 152.8 (180.8) | 96.7 (144.7) | 160.7 (174.8) | 103.5 (147.5) |
Severity of MJS, Mean (SD) | 5.8 (2.2) | 3.5 (2.4) | 5.7 (2.1) | 3.7 (2.4) |
Severity of Worst Tiredness, Mean (SD) | 5.8 (2.1) | 4.0 (2.3) | 6.0 (2.1) | 4.1 (2.4) |
Severity of Worst Joint Pain, Mean (SD) | 6.1 (2.0) | 4.0 (2.3) | 6.0 (2.1) | 4.2 (2.4) |
Patient’s Assessment of Pain, Mean (SD) | 60.8 (22.3) | 34.9 (24.1) | 58.0 (22.1) | 36.5 (24.9) |
Patient’s Global Assessment of Disease Activity, Mean (SD) | 62.4 (21.8) | 36.3 (23.5) | 60.7 (21.1) | 37.7 (24.0) |
SF-36 |
Role Physical Domain, Mean (SD) | 35.5 (10.4) | 41.8 (10.2) | 35.3 (9.2) | 40.7 (9.6) |
Bodily Pain Domain, Mean (SD) | 34.7 (7.8) | 42.5 (8.7) | 34.9 (7.6) | 41.9 (9.0) |
General Health Domain, Mean (SD) | 36.8 (8.5) | 41.6 (8.9) | 36.8 (8.3) | 42.0 (9.4) |
Social Functioning Domain, Mean (SD) | 40.8 (11.6) | 45.4 (10.5) | 40.2 (11.2) | 44.7 (10.3) |
Vitality Domain, Mean (SD) | 43.7 (10.0) | 49.4 (9.8) | 41.9 (10.1) | 48.4 (10.0) |
Role Emotional Domain, Mean (SD) | 41.1 (12.6) | 45.5 (10.9) | 40.9 (12.3) | 44.8 (11.2) |
Mental Health Domain, Mean (SD) | 43.0 (11.3) | 47.1 (10.7) | 42.9 (11.6) | 47.1 (11.3) |
Physical Functioning Domain, Mean (SD) | 32.2 (10.4) | 38.7 (10.9) | 32.2 (10.2) | 38.2 (10.9) |
Mental Component Score, Mean (SD) | 46.4 (11.8) | 49.8 (10.8) | 45.7 (11.8) | 49.3 (11.1) |
Physical Component Score, Mean (SD) | 32.3 (8.6) | 39.4 (9.3) | 32.3 (8.3) | 38.8 (9.4) |
QIDS-SR16 Total Score, Mean (SD) | 8.0 (5.0) | 5.9 (4.2) | 8.4 (4.9) | 6.2 (4.3) |
HAQ-DI Total Score, Mean (SD) | 1.56 (0.68) | 1.03 (0.70) | 1.52 (0.61) | 1.03 (0.66) |
PhGA, Mean (SD) | 65.0 (16.9) | 31.0 (21.7) | 63.5 (17.4) | 33.9 (22.4) |
CDAI, Mean (SD) | 37.83 (12.55) | 18.68 (13.54) | 36.05 (12.12) | 18.04 (13.15) |
DAS28-ESR, Mean (SD) | 6.43 (0.97) | 4.62 (1.46) | 6.22 (0.97) | 4.50 (1.37) |
DAS28-hsCRP, Mean (SD) | 5.73 (0.94) | 3.93 (1.39) | 5.55 (0.91) | 3.84 (1.35) |
Reliability (test-retest)
For RA-BEAM and RA-BUILD, the ICCs for weekly mean Duration of MJS and Severity of MJS ranged from 0.88 to 0.91 from Week 1 to 2 (RA-BEAM n = 412; RA-BUILD n = 185) and from 0.90 to 0.93 from Week 4 to Week 8 (RA-BEAM n = 417; RA-BUILD n = 215). These values provide evidence for substantial agreement between assessment periods among stable patients.
Convergent and discriminant validity
Results supporting convergent validity of Duration of MJS and Severity of MJS are found in Table
3. For Duration of MJS, small-to-moderate associations were found between Duration of MJS and other assessments of RA symptoms, assessments of function, and clinician-reported assessments at Day 1 and Week 12. At Day 1 and Week 12, respectively, Duration of MJS was most strongly associated with Severity of MJS (RA-BEAM
r = 0.36 and 0.45; RA-BUILD
r = 0.35 and 0.52) and Severity of Worst Joint Pain (RA-BEAM
r = 0.29 and 0.41; RA-BUILD
r = 0.30 and 0.47), followed by the patient’s assessment of pain (RA-BEAM
r = 0.24 and 0.38; RA-BUILD
r = 0.23 and 0.39) and PtGA (RA-BEAM
r = 0.19 and 0.36; RA_BUILD
r = 0.28 and 0.37).
Table 3
Pearson Correlations between Duration of MJS, Severity of MJS, Severity of Worst Tiredness, and Other Instruments in RA-BEAM and RA-BUILD
Day 1 |
Duration of MJS | – | – | – | – | 537 | 0.36*** | 311 | 0.35*** |
Severity of MJS | 537 | 0.36*** | 311 | 0.35*** | – | – | – | – |
Severity of Worst Tiredness | 537 | 0.21*** | 311 | 0.09 | 537 | 0.66*** | 311 | 0.52*** |
Severity of Worst Joint Pain | 537 | 0.29*** | 310 | 0.30*** | 537 | 0.79*** | 310 | 0.75*** |
SF-36 |
Role Physical Domain | 535 | −0.24*** | 311 | −0.23*** | 535 | −0.43*** | 312 | −0.40*** |
Bodily Pain Domain | 535 | −0.30*** | 311 | −0.29*** | 535 | −0.65*** | 312 | −0.51*** |
General Health Domain | 535 | −0.09* | 311 | −0.18** | 535 | −0.30*** | 312 | −0.25*** |
Social Functioning Domain | 535 | −0.16*** | 311 | −0.24*** | 535 | −0.38*** | 312 | −0.41*** |
Vitality Domain | 535 | −0.21*** | 311 | −0.18** | 535 | −0.42*** | 312 | −0.32*** |
Role Emotional Domain | 535 | −0.07 | 311 | −0.12* | 535 | −0.27*** | 312 | −0.25*** |
Mental Health Domain | 535 | −0.10* | 311 | −0.20*** | 535 | −0.31*** | 312 | −0.27*** |
Physical Functioning Domain | 535 | −0.25*** | 311 | −0.28*** | 535 | −0.51*** | 312 | −0.47*** |
Mental Component Score | 535 | −0.07 | 311 | −0.15** | 535 | −0.26*** | 312 | −0.25*** |
Physical Component Score | 535 | −0.29*** | 311 | −0.27*** | 535 | −0.54*** | 312 | −0.44*** |
HAQ-DI Total Score | 535 | 0.22*** | 311 | 0.26*** | 535 | 0.53*** | 312 | 0.46*** |
QIDS-SR16 Total Score | 535 | 0.15*** | 311 | 0.26*** | 535 | 0.34*** | 312 | 0.28*** |
Patient’s Assessment of Pain | 535 | 0.24*** | 311 | 0.23*** | 535 | 0.59*** | 312 | 0.54*** |
PtGA | 535 | 0.19*** | 311 | 0.28*** | 535 | 0.59*** | 312 | 0.53*** |
Tender Joint Count 28 | 537 | 0.09* | 311 | 0.15** | 537 | 0.26*** | 312 | 0.43*** |
Swollen Joint Count 28 | 537 | 0.06 | 311 | 0.13* | 537 | 0.21*** | 312 | 0.24*** |
PhGA | 535 | 0.19*** | 304 | 0.19*** | 535 | 0.32*** | 305 | 0.33*** |
hsCRP | 535 | 0.20*** | 311 | 0.27*** | 535 | 0.48*** | 312 | 0.53*** |
Week 12a
|
Duration of MJS | – | – | – | – | 1281 | 0.45*** | 666 | 0.52*** |
Severity of MJS | 1281 | 0.45*** | 666 | 0.52*** | – | – | – | – |
Severity of Worst Tiredness | 1281 | 0.32*** | 666 | 0.38*** | 1281 | 0.79*** | 666 | 0.77*** |
Severity of Worst Joint Pain | 1281 | 0.41*** | 666 | 0.47*** | 1281 | 0.89*** | 666 | 0.89*** |
SF-36 |
Role Physical Domain | 1233 | −0.23*** | 632 | −0.29*** | 1233 | −0.47*** | 632 | −0.45*** |
Bodily Pain Domain | 1233 | −0.31*** | 632 | −0.36*** | 1233 | −0.59*** | 632 | −0.55*** |
General Health Domain | 1233 | −0.15*** | 632 | −0.19*** | 1233 | −0.36*** | 632 | −0.30*** |
Social Functioning Domain | 1233 | −0.18*** | 632 | −0.30*** | 1233 | −0.43*** | 632 | −0.46*** |
Vitality Domain | 1233 | −0.19*** | 632 | −0.29*** | 1233 | −0.41*** | 632 | −0.39*** |
Role Emotional Domain | 1233 | −0.18*** | 632 | −0.23*** | 1233 | −0.39*** | 632 | −0.33*** |
Mental Health Domain | 1233 | −0.16*** | 632 | −0.21*** | 1233 | −0.33*** | 632 | −0.30*** |
Physical Functioning Domain | 1233 | −0.22*** | 632 | −0.32*** | 1233 | −0.49*** | 632 | −0.46*** |
Mental Component Score | 1233 | −0.14*** | 632 | −0.21*** | 1233 | −0.31*** | 632 | −0.29*** |
Physical Component Score | 1233 | −0.25*** | 632 | −0.31*** | 1233 | −0.52*** | 632 | −0.48*** |
HAQ-DI Total Score | 1233 | 0.23*** | 632 | 0.31*** | 1233 | 0.55*** | 632 | 0.51*** |
QIDS-SR16 Total Score | 1231 | 0.20*** | 632 | 0.24*** | 1231 | 0.34*** | 632 | 0.31*** |
Patient’s Assessment of Pain | 1233 | 0.38*** | 632 | 0.39*** | 1233 | 0.78*** | 632 | 0.72*** |
PtGA | 1233 | 0.36*** | 632 | 0.37*** | 1233 | 0.74*** | 632 | 0.67*** |
Tender Joint Count 28 | 1231 | 0.16*** | 630 | 0.31*** | 1231 | 0.39*** | 630 | 0.44*** |
Swollen Joint Count 28 | 1231 | 0.16*** | 630 | 0.22*** | 1231 | 0.28*** | 630 | 0.31*** |
PhGA | 1224 | 0.21*** | 627 | 0.29*** | 1224 | 0.41*** | 627 | 0.44*** |
hsCRP | 1220 | 0.26*** | 623 | 0.37*** | 1220 | 0.57*** | 623 | 0.57*** |
For Severity of MJS, moderate-to-large associations were found between Severity of MJS and other assessments of RA symptoms, assessments of function, and clinician-reported assessments at Day 1 and Week 12. At Day 1 and Week 12, respectively, Severity of MJS was most strongly associated with Severity of Worst Joint Pain (RA-BEAM r = 0.79 and 0.89; RA-BUILD r = 0.75 and 0.89), patient’s assessment of pain (RA-BEAM r = 0.59 and 0.78; RA-BUILD r = 0.54 and 0.72), and Severity of Worst Tiredness (RA-BEAM r = 0.66 and 0.79; RA-BUILD r = 0.52 and 0.77).
In contrast, smaller correlations between Duration and Severity of MJS with SF-36 MCS, SF-36 Role Emotional, and the QIDS-SR16 at Day 1 (r = −0.07 to 0.34) and Week 12 (r = −0.39 to 0.34) were observed, indicating that the SF-36 and QIDS-SR16 assessments measure more distally related constructs.
These findings demonstrate adequate convergent and discriminant validity, as well as the uniqueness of Duration of MJS and Severity of MJS compared to other PROs and clinical measures of RA in patients with moderately to severely active RA.
Known-groups validity
Due to small sample sizes in the lower DAS28-ESR subgroups at Day 1 (i.e., <5% of the sample in each score category) in RA-BEAM and RA-BUILD, patients were categorized into only 2 subgroups: ≤5.1 and >5.1 (Table
4). At Day 1 in both studies, patients with higher DAS28-ESR scores reported a significantly longer Duration of MJS measured in minutes (RA-BEAM:
p = 0.028; RA-BUILD:
p = 0.033) and significantly greater Severity of MJS (RA-BEAM:
p = 0.001; RA-BUILD:
p = 0.001) than those patients with lower DAS28-ESR scores. Similar findings were evident for both studies at Week 4.
Table 4
Known-Groups Validity of Duration of MJS and Severity of MJS Using DAS28-ESR Subgroups at Day 1 and Week 4, and CDAI Subgroups at Day 1
PRO/Study | DAS28-ESR Category |
p-value, ES |
≤5.1 N, Mean (SD), Median | >5.1 N, Mean (SD), Median |
Duration of MJS Day 1 |
RA-BEAM | 39, 120.5 (190.8), 60.0 | 496, 155.3 (180.1), 90.0 | 0.028a, 0.19 |
RA-BUILD | 36, 132.8 (191.5), 60.0 | 273, 164.9 (173.1), 120 | 0.033a, 0.18 |
Duration of MJS Week 4 |
RA-BEAM | 619, 76.1 (108.6), 37.3 | 587, 133.6 (153.5), 73.6 | 0.001a, 0.43 |
RA-BUILD | 327, 77.6 (112.0), 40.0 | 286, 151.1 (158.3), 94.6 | 0.001a, 0.54 |
Severity of MJS at Day 1 |
RA-BEAM | 39, 4.4 (2.7) | 496, 5.9 (2.1) | 0.001b, 0.70 |
RA-BUILD | 36, 4.0, (1.7) | 274, 5.9 (2.0) | 0.001b, 0.97 |
Severity of MJS at Week 4 |
RA-BEAM | 619, 3.0 (1.9) | 587, 5.1 (2.1) | 0.001b, 1.05 |
RA-BUILD | 327, 3.1 (1.9) | 286, 5.3 (2.0) | 0.001b, 1.13 |
| CDAI Category |
p-value, ES |
0.0 to ≤22.0 N, Mean (SD), Median | >22.0 to ≤76.0 N, Mean (SD), Median |
Duration of MJS Day 1 |
RA-BEAM | 36, 144.1 (198.3), 90.0 | 497, 153.9 (180.0), 90.0 | 0.305a, 0.05 |
RA-BUILD | 26, 111.9 (162.7), 60.0 | 278, 162.3 (170.6), 120 | 0.016a, 0.30 |
Severity of MJS at Day 1 |
RA-BEAM | 36, 4.7 (2.4) | 497, 5.9 (2.1) | 0.001b, 0.57 |
RA-BUILD | 26, 3.7 (1.6) | 278, 5.9 (2.1) | 0.001b, 1.07 |
Similar to the approach taken for the DAS28-ESR analyses, due to small sample sizes in the lower CDAI subgroups, patients were categorized into 2 subgroups based on the CDAI at Day 1 (0.0 to ≤22.0 and >22.0 to ≤76.0) and 3 subgroups at Week 4 (0.0 to ≤10.0, >10.0 to ≤22.0, and >22.0 to ≤76.0). At Day 1, patients with higher CDAI scores experienced a significantly longer Duration of MJS in RA-BUILD (median = 60.0 vs. 120.0,
p = 0.016) and greater Severity of MJS in both RA-BEAM and RA-BUILD (RA-BEAM: mean = 4.7 vs. 5.9,
p = 0.001; RA-BUILD: 3.7 vs. 5.9,
p = 0.001) than those patients with a lower CDAI score (Table
4). However, at Week 4, the Duration of MJS was significantly longer and the Severity of MJS was significantly greater in patients with higher CDAI scores than in patients with low CDAI scores in both studies (all
p = 0.001) (Table
5). All values increased linearly with higher CDAI scores, where all post-hoc comparisons using Scheffé adjustment were statistically significant (
p = 0.001), except for the comparison of median Duration of MJS values between CDAI categories of 0.0 to ≤10.0 versus >10.0 to ≤22.0 in RA-BUILD. These findings indicate that the Duration of MJS and Severity of MJS PROs are able to distinguish between known groups based on disease severity.
Table 5
Known-Groups Validity of Duration of MJS and Severity of MJS Using CDAI Subgroups at Week 4
Duration of MJS Week at Week 4 |
RA-BEAM | 220, 58.3 (95.0), 20.4 | 426, 90.1 (121.8), 47.1 | 567, 133.0 (152.8), 75.7 | 0.001a
| a: 0.001, 0.28; b: 0.001, 0.54; c: 0.001, 0.31 |
RA-BUILD | 134, 70.5 (107.1), 31.4 | 209, 88.1 (123.3), 45.7 | 275, 152.9 (158.9), 95.0 | 0.001a
| a: 0.146, 0.15; b: 0.001, 0.57; c: 0.001, 0.45 |
Severity of MJS at Week 4 |
RA-BEAM | 220, 2.3 (1.7) | 426, 3.6 (2.0) | 567, 5.0 (2.1) | 0.001b
| a: 0.001, 0.68; b: 0.001, 1.35; c: 0.001, 0.68 |
RA-BUILD | 134, 2.5 (1.8) | 209, 3.6 (1.8) | 275, 5.4 (2.0) | 0.001b
| a: 0.001, 0.61; b: 0.001, 1.50; c: 0.001, 0.94 |
Responsiveness
As hypothesized, the responsiveness of the Duration of MJS and Severity of MJS PROs was supported by large and statistically significant differences in median and mean change in Duration of MJS and Severity of MJS, respectively, from Day 1 to Week 12 between patients defined as responders or nonresponders on the basis of the ACR20 at Week 12 (Table
6). For example, for Duration of MJS in RA-BEAM, median change from Day 1 to Week 12 was −35.1 for responders in comparison to −7.0 for nonresponders (
p = 0.001). Similarly, for Severity of MJS in RA-BEAM, mean change was −3.2 compared to −1.1 for responders and nonresponders, respectively (
p = 0.001).
Table 6
Change from Day 1 to Week 12 among ACR20 and DAS28-hsCRP Groups
Duration of MJS |
RA-BEAM |
N, Mean (SD) | 326, −84.2 (167.5) | 211, −17.2 (166.4) | | 88, −92.4 (185.0) | 79, −84.0 (170.1) | 368, −44.2 (165.4) | |
Median d
| −35.1 | −7.0 | 0.001, −0.40 | −55.0 | −30.0 | −12.6 | a: 0.809, −0.05 |
b: 0.001, −0.28 |
c: 0.001, −0.24 |
RA-BUILD |
N, Mean (SD) | 174, −70.1 (139.3) | 137, −19.6 (196.8) | | 61, −87.9 (133.7) | 33, −65.7 (96.7) | 214, −34.1 (185.0) | |
Median d
| −42.9 | −9.1 | 0.001, −0.30 | −50.7 | −40.0 | −26.9 | a: 0.221, −0.18 |
b: 0.001, −0.31 |
c: 0.022, −0.18 |
Severity of MJS |
RA-BEAM |
N, Mean (SD) | 326, −3.2 (2.3) | 211, −1.1 (2.2) | 0.001, −0.90 | 88, −3.7 (2.3) | 79, −3.1 (2.3) | 368, −1.9 (2.4) | a: 0.083, −0.25 |
b: 0.001, −0.76 |
c: 0.001, −0.52 |
RA-BUILD |
N, Mean (SD) | 175, −2.9 (2.3) | 137, −1.0 (2.1) | 0.001, −0.85 | 61, −3.1 (2.5) | 33, −2.6 (2.6) | 215, −1.8 (2.2) | a: 0.264, −0.21 |
b: 0.001, −0.59 |
c: 0.002, −0.35 |
Comparable findings were seen when using DAS28-hsCRP as an anchor, as pairwise comparisons assessing significant differences in median and mean change between DAS28-hsCRP groups of <2.6 versus ≥3.2 (
p = 0.001 for all comparisons), and ≥2.6 and <3.2 versus ≥3.2 were statistically significant (
p < 0.01 for all comparisons) (Table
6). However, the change scores comparisons between <2.6 versus ≥2.6 and <3.2 were not statistically significant for Duration of MJS (RA-BEAM
p = 0.809; RA-BUILD
p = 0.221) or Severity of MJS (RA-BEAM
p = 0.083; RA-BUILD
p = 0.264).
Discussion
The psychometric properties, including reliability, validity, and responsiveness, of Duration of MJS and Severity of MJS PROs were supported by the results from RA-BEAM and RA-BUILD. Specifically, test-retest reliability analyses revealed high levels of agreement in Duration of MJS and Severity of MJS values among patients considered stable across two assessment periods. In support of construct validity, a priori hypotheses of the relationships between Duration of MJS and Severity of MJS with other related PROs and clinical outcome measures were supported at Day 1 and Week 12 assessment periods. Known-groups validity was similarly supported as median and mean values of Duration of MJS and Severity of MJS were significantly different based on known-groups using the DAS28-ESR and CDAI. Finally, both measures were responsive to change from Day 1 to Week 12 when defining responders using the ACR20. Sensitivity to change was also supported when using the DAS28-hsCRP as an anchor, except for comparisons between the lowest disease activity groups.
However, although these symptoms have been demonstrated to be important to patients with RA, an assessment of these symptoms was excluded from the the core set of disease activity measures. Specifically, rheumatologists have frequently used morning stiffness as an indicator that patient medication changes are needed [
25]. However, in 1993, the core set of disease activity measures for use in RA clinical trials was revised. Studies with therapies available at the time (e.g., csDMARDs, auranofin, nonsteroidal anti-inflammatory drugs [NSAIDs]) suggested that MJS was not sensitive to change with treatment compared to control, and this lack of ability to discriminate treatment from control contributed to this symptom’s exclusion from the core set of measures [
26].
Subsequent to its removal from the ACR core set in 1993, morning stiffness has been found to be an important determining clinical status indicator driving changes to DMARD therapy [
27]. Additional work by Boers et al. [
28] further demonstrated that both duration and severity of morning stiffness are related to other measures of disease activity. The findings from the present study provide support that both the Duration of MJS and Severity of MJS PROs are not only associated with other measures of disease activity in RA but rather are measures that assess distinct symptom experiences by patients. Furthermore, these measures are sensitive to detect change over time in adults with moderately to severely active RA. However, future research is needed in order to determine the relationship of these instruments to patient outcomes over a long term period, and the usability of such instruments in a clinical setting. Given the advent of electronic PRO diaries, these instruments could be used in a clinical setting and collected daily, thus enhancing the dialogue between patients and care providers. Further, using applications on mobile phones, these instruments can be easily completed by patients to track and collect their daily symptoms.
Despite the strong findings related to the reliability, validity, and responsiveness of the Duration of MJS and Severity of MJS PROs, a key limitation to this investigation is the missing data at the Day 1 assessment. As noted above, the missing data were due to a variety of reasons (e.g., device alarm not sounding until the following day). However, sensitivity analyses were conducted after imputing missing Day 1 Duration of MJS and Severity of MJS PRO scores, and results for the evaluations of reliability, validity, and responsiveness of these two PROs remained the same. In addition, the evaluation of responsiveness was limited as the studies’ baseline assessment period consisted of only data at Day 1 rather than a full 7 days of data as was available at Week 12. Finally, all analyses were pooled across countries due to small sample sizes (<5 participants) within certain participating countries. Thus, future research is needed to assess the psychometric properties of both instruments within each country.
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