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Measuring Inflammatory Foot Disease in Rheumatoid Arthritis: Development and Validation of the Rheumatoid Arthritis Foot Disease Activity Index–5

Omission of foot joints from composite global disease activity indices may lead to underestimation of foot and overall disease in rheumatoid arthritis (RA) and under‐treatment. The aim of this study was to evaluate the measurement properties of the Rheumatoid Arthritis Foot Disease Activity Index–5 (RADAI‐F5), a newly developed patient‐reported outcome measure for capturing foot disease activity in people with RA.


INTRODUCTION
Foot pain and disability are common in people who have rheumatoid arthritis (RA), with up to 90% experiencing diseaserelated foot symptoms during the course of their disease (1)(2)(3)(4). Synovitis in the small joints of the feet is present at the onset of RA in up to 70% of patients (5). With the implementation of pharmacologic management, the prevalence of forefoot disease stabilizes at 40-50% after 2 years, but the prevalence of radiographic joint damage increases from 20% to 50% (5). Approximately half of patients experience hindfoot joint problems (6), and clinically important soft tissue disease such as tibialis posterior tenosynovitis has a reported prevalence ranging from 13% to 64% (3).
The management of RA involves a treat-to-target strategy that comprises regular review, objective assessment of disease activity, and escalation of treatment if there is persistent disease activity. The aim is to achieve clinical remission (or low disease activity) (7,8). Evaluation of inflammatory disease activity in RA | 1291 involves the composite disease activity indices, of which the most widely used are the 28-joint count Disease Activity Score using the erythrocyte sedimentation rate (DAS28-ESR) (9), the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI) (10). These include 28-joint counts for tenderness and swelling that omit the joints and soft tissues of the feet (11). Recent studies have demonstrated that approximately one-third of patients with RA classified by the DAS28, SDAI, and/or CDAI as in remission had clinically determined active foot synovitis (2,11,12). Although the examination of foot joints is recommended (13), patients treated solely according to disease activity indices may be at risk of ongoing foot joint damage (11,14).
Various self-reported measures of RA disease activity have been validated, including 2 versions of the Rheumatoid Arthritis Disease Activity Index (RADAI and modified ) (15,16). While these tools are more likely to capture foot disease activity than composite indices that exclude examination of foot joints, they are not widely used in clinical practice. Several questionnaires have been developed for measuring RA-related foot problems, including the Foot Impact Scale (FIS), the Foot Function Index (FFI), and the Salford Rheumatoid Arthritis Foot Evaluation instrument (17)(18)(19). These largely focus on disability as opposed to disease activity, and so have limited value for informing medical management. In addition, these tools lack feasibility in clinical practice due to a high number of items and associated time burden, as well as the absence of clinically meaningful categories for ease of interpretation.
The current gold standard technique for measuring foot disease activity is magnetic resonance imaging (MRI) (20). The more widely used imaging alternative is musculoskeletal ultrasound, which is less sensitive than MRI and more specific than clinical examination of disease activity in RA (20)(21)(22). However, these methods are not routinely used due to impracticalities such as cost of scans/equipment, time to perform scans, training needs, and the risk of exposure to contrast agents. There is also a lack of consensus concerning how to approach medical management of subclinical disease detected using musculoskeletal ultrasound (23).
Therefore, there is no widely used, validated, and clinically feasible method for the assessment of foot disease activity in RA. We propose that a patient-reported outcome measure designed to measure local foot disease activity may provide an opportunity for a treat-to-target medical approach that does not exclude foot disease activity. Accordingly, the purpose of this study was to develop and validate a new concise measure of foot disease activity for people with RA.

PATIENTS AND METHODS
Development of the questionnaire. The design and content of the Rheumatoid Arthritis Foot Disease Activity Index-5 (RADAI-F5) was derived from the mRADAI-5, a 5-item patientreported outcome measure for the self-report of global disease activity, developed and evaluated by Leeb et al (16) and Rintelen et al (24). It is completed in a numerical rating scale format from 0 to 10 and scored by an average summary score ranging 0-10. The RADAI-F5 was developed by editing the mRADAI-5 with an opening statement: "Thinking only of your feet," and editing the original questions to subsequently read as follows: "How active was your arthritis in your feet over the last 6 months?" (0 = completely inactive to 10 = extremely active); "How active is your foot arthritis today with respect to joint tenderness and swelling?" (0 = completely inactive to 10 = extremely active); "How severe is your arthritis pain in your feet today?" (0 = no pain to 10 = unbearable pain); "How would you describe your general foot health today?" (0 = very good to 10 = very bad); "Did you experience foot joint stiffness on awakening yesterday morning? If yes, how long was this stiffness in your feet?" (0 = no stiffness to 10 = stiffness the whole day). The RADAI-F5 is scored by an average summary score ranging from 0 to 10.
Study setting and participants. The 2 data sources for this study were 1) a primary RADAI-F5 validation study, conducted at rheumatology outpatient clinics at Glasgow Royal Infirmary, Gartnavel General Hospital, and Stobhill Hospital within the Greater Glasgow and Clyde National Health Service Board, and 2) a larger randomized controlled trial, the details of which have been published previously (25). Briefly, the trial was a multicenter, parallel-group, randomized controlled trial with 6-and 12-month follow-up periods, with participants randomly allocated to either customized or prefabricated foot orthoses. Trial participants were recruited from rheumatology outpatient clinics within NHS Grampian, Fife, and Lanarkshire, Lothian Health Boards, Dorset Healthcare University Trust, and Homerton University Hospital Trust.
Participants were included if they were ages 18-75 years, with a definitive clinical diagnosis of RA. Patients were excluded if they were unable to read, write, and/or understand the English

SIGNIFICANCE & INNOVATIONS
• The Rheumatoid Arthritis Foot Disease Activity Index-5 (RADAI-F5) is the first patient-reported outcome measure designed to measure localized foot disease activity in rheumatoid arthritis. • The RADAI-F5 is valid, reliable, and responsive to change, and is feasible for use in clinical practice to measure foot disease in people with rheumatoid arthritis. • The RADAI-F5 provides a means for measuring foot disease activity that is not captured by composite global disease activity indices such as the 28-joint count Disease Activity Score using the erythrocyte sedimentation rate.
language, or if they were diagnosed with other major medical conditions that could have diminished their ability to distinguish between RA-related foot problems and problems due to alternative disease mechanisms. Ethical approval was obtained from the West of Scotland Research Ethics Committee 5 (13/WS/0106) and the East of England Essex Research Ethics Committee (15/ EE/0410). Participants were recruited consecutively, and written consent was obtained from all participants.

Data collection and measures.
Demographic and clinical information was collected at baseline, including age, sex and disease duration. The newly developed RADAI-F5 was collected at baseline, 1 week from baseline, and 6 months from baseline. All other measurements were recorded at baseline and 6 months. The DAS28-ESR scores were recorded by rheumatologists as part of routine care and made available to researchers. The mRA-DAI-5 was collected as an additional self-reported measure of global disease activity (16). Foot-related impairments and disability were evaluated using the FFI (18), and the FIS (17). The FFI is a widely used and extensively validated 23-item patientreported outcome measure, completed using a 100-mm visual analog scale format, providing a mean summary score from 0 to 100 (higher scores indicating worse disability) (18). The FIS is an extensively validated RA-specific 51-item measure with domains for impairment/footwear (21-items) and activity limitation/participation restriction (30-items). It is completed using a yes/no dichotomous format, and scores for domains are calculated by summating "yes" responses (higher scores indicating worse disability) (17).
To evaluate the content validity and practical burden of the RADAI-F5, 3 additional items were evaluated: a 5-point Likert scale regarding questionnaire relevance to participants (ranging from extremely irrelevant to extremely relevant), a 5-point Likert scale regarding participants' opinions on the readability/understanding of the new questionnaire (ranging from very difficult to very easy), and the time taken to complete the questionnaire (in minutes).
Statistical analysis. Data were analyzed using SPSS 25 and Excel 2016. Descriptive statistics for age (median [interquartile range (IQR)]) in years, sex (female:male ratio), and disease duration (median [IQR]) in months were generated for all participants at baseline. The RADAI-F5 was examined using factor analysis by principal component analysis to reveal the structure and item loading. The Kaiser-Meyer-Olkin test and Bartlett's test of sphericity were undertaken to determine data suitability for factor analysis. The number of factors extracted was decided by a combination of Kaiser's rule (eigenvalues >1), examination of the scree plot, and interpretation of items' contribution to the factor. To test internal consistency, we evaluated the inter-item correlation matrix and calculated Cronbach's alpha, a measure of consistency between items in a scale. A Cronbach's α = 0.7-0.9 was considered acceptable (26,27).
Hypotheses were generated a priori to examine the extent to which baseline scores (construct validity) and 0-6-month change scores (longitudinal validity) on the RADAI-F5 were associated with baseline and 0-6-month change scores from other measures in a manner that was theoretically consistent (28). Hypotheses for construct validity, which focused on baseline scores, were specified as follows: moderate positive correlations between the RADAI-F5 score and mRADAI-5, FFI, and FIS domains, and a positive weak correlation between the RADAI-F5 score and the DAS28 score. Hypotheses for longitudinal validity, which focused on 0-6-month change scores, were identical except for the FIS subscales, where a weak positive correlation was anticipated, because the FIS is less responsive to change (29). Spearman's rank (r s ) correlation and 95% confidence intervals (95% CIs) were used to test these hypotheses, and coefficients were interpreted as follows: 0-0.09 = negligible, 0.1-0.39 = weak, 0.4-0.69 = moderate, 0.7-0.89 = strong, and 0.9-1.0 = very strong (30).
The 1-week (test-retest) reliability was examined using a 2-way mixed intraclass correlation coefficient (ICC) with corresponding 95% CIs for baseline and 1-week scores. Once preliminary foot disease categories were established (see below), Cohen's quadratic weighted kappa and corresponding 95% CI for foot disease categories (remission, low, moderate, high) were calculated, with values >0.61 indicating substantial reliability (31).
Absolute measurement error was evaluated using the standard error of measurement (SEm), derived by dividing the SD of the mean change between the 2 measurements (SD change /  (32)(33)(34). Responsiveness was evaluated using 4 different effect size statistics: Wilcoxon's signed ranks test, Cohen's d, the standardized response mean, and Guyatt's Index (35). In the absence of an anchor question to calculate the minimum important difference (MID), the MID was calculated using a value of 0.5 × SD change scores between baseline and 6 months. Guyatt's Index, representing the magnitude and variability in change scores relative to its MID, was calculated as MID/ √ (2 × SD change ) (36). Effect sizes were interpreted as follows: <0.15 = negligible, ≥0.15 to <0.40 = small, ≥0.40 to <0.75 = medium, ≥0.75 to <1.10 = large, ≥1.10 to <1.45 = very large, and ≥1.45 = huge (35).
Participants were classified according to mRADAI-5 thresholds for remission, mild, moderate, or high disease activity. With participants assigned to the mRADAI-5 reference categories, the third quartile of corresponding RADAI-F5 scores was calculated to establish the thresholds for respective RADAI-F5 categories (24). Cohen's quadratic weighted kappa and 95% CI were used to evaluate agreement between disease activity categories between the mRADAI-5 and the RADAI-F5.

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Median (IQR) values were obtained for readability and relevant Likert scores and completion time. For evaluation of floor and ceiling effects for the RADAI-F5 in the RA population, we adopted the conventional 15% threshold for patients achieving the highest and lowest scores to define ceiling and floor effect, respectively (32,37). To evaluate structural validity via factor analysis, a minimum sample size of n ≥100 at baseline was targeted a priori to achieve a participant-to-item ratio of 20 (38). For hypotheses testing for construct and longitudinal validity, between 61 and 123 participants were required to detect at least weak correlation coefficients from 0.25 to 0.35 at 80% power and 0.05 significance level (G*Power 3.1.9.2).

RESULTS
A total of 142 participants (72.5% female) with a median age of 55.5 years (IQR 50-62 years) and median disease duration of 10 months (IQR 3.6-20.8 months) took part, including 37 from the primary RADAI-F5 study and 105 from the randomized controlled trial. A total of 84 participants completed the RADAI-F5 at 1 week for reproducibility analyses, and 64 completed 6-month followups for responsiveness analyses. Median (IQR) DAS28-ESR and mRADAI-5 scores indicated that participants were typically in a moderate disease activity state at study baseline (Table 1). For DAS28-ESR disease categories, 21.5% were in remission, 8.4% had low disease activity, 47.7% had moderate disease activity, and 22.4% had high disease activity. Median (IQR) FFI, FIS impairment/footwear, and FIS activity limitation/participation restriction subscale scores suggested that participants typically presented with moderate foot-related disability at baseline (Table 1).
Dimensionality. The Kaiser-Meyer-Olkin value of 0.83 and highly significant Bartlett's test (P < 0.001) indicated sampling adequacy and suitability for structure detection and factor analysis. Both Kaiser's "eignenvalue >1" rule and scree plot examination suggested a 1-factor solution, and this solution explained 73.18% of the common variance. Item loadings on the factor were uniformly >0.4, indicating that all items contributed significantly to the aggregate score.  (Figure 1). Sixty percent of associations for construct validity were in line with a priori hypotheses and therefore largely theoretically consistent. Construct and longitudinal validity analyses are shown in Table 2.   Reliability. Mean ± SD RADAI-F5 scores for baseline and 1 week were 4.8 ± 2.58 and 4.91 ± 2.74, respectively. The mean ± SD difference between baseline and 1 week for the RADAI-F5 was 0.11 ± 1.37. The ICC for 1-week reproducibility was 0.87 (95% CI 0.80, 0.91; P ≤ 0.001), indicating very good reproducibility.
Absolute measurement error. The SEm value calculated for the RADAI-F5 from baseline and 1-week data was 0.97. This value can be interpreted as follows: if a patient scores 3 on the RADAI-F5, we can be 68% confident that their true score lies between 2.03 and 3.97, and 95% confident that their true score lies between 1.1 and 4.9. The limits of agreement were -2.57 and 2.80. From the Bland-Altman plot (Figure 2), we can conclude that 97.6% of the differences between the 2 time points were within the 95% limits. Exploration of the plot suggests that there may be a minor funnel effect, with spread increasing slightly with increasing mean concentration (higher foot disease activity). The 95% smallest detectable change value was estimated as 2.69, representing 26.9% of the RADAI-F5 scale maximum range, meaning that we can be 95% confident that a change score of 2.69 or more is a true change.
Responsiveness. The RADAI-F5 exhibited high responsiveness to change over 6 months, as evidenced by highly significant Wilcoxon's signed rank tests (P < 0.001) with a very large effect size (0.91), Cohen's d = 0.64 (medium effect size), and a standardized response mean of 0.97 (very large effect size). The MID value obtained from the distribution method (0.5 × SD change ) was 1.16, and the subsequent Guyatt Index value calculated was 0.70 (medium effect size). These values can be interpreted as a consistent pattern of medium-to-high responsiveness for the RADAI-F5.
Interpretability. For remission according to the mRA-DAI-5, the RADAI-F5 median and third quartile were 0.73 and 1.0 (n = 11). Therefore, the remission state was defined as a RADAI-F5 score ranging from 0 to 1.0. The same procedure applied to define the disease categories for mild, moderate, and high disease activity, resulting in the following ranges: >1 to 3.6 for mild disease activity (n = 15), >3.6 to 5.7 for moderate disease activity (n = 42), and >5.7 to 10 for high disease activity (n = 65) ( Table 3). Agreement between the RADAI-F5 and mRADAI-5 categories was good, as expressed by 72.5% exact agreement and Cohen's quadratic weighted κ = 0.71 (95% CI 0.56, 0.85). For the newly derived RADAI-F5 disease categories, agreement between baseline and 1 week was good, as expressed by 70.0% exact agreement and Cohen's quadratic weighted κ = 0.81 (95% CI 0.75, 0.88). Characteristics of disease and foot-related disability status within newly developed RADAI-F5 disease categories are shown in Table 3.

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Content validity and practical burden. Participants largely considered the RADAI-F5 to be relevant for measuring foot disease activity in RA, with 53% and 29% indicating that it was relevant and extremely relevant, respectively ( Figure 3A). Participants largely considered the RADAI-F5 to be easy to read and understand, with 45.8% and 40% indicating that it was easy and very easy to read/understand, respectively ( Figure 3B). The median time to complete the questionnaire was 5 minutes (IQR 2-15). Overall the RADAI-F5 appears to have good content validity and low completion burden.
Floor/ceiling effects. A total of 6 participants (4.33%) achieved the lowest possible RADAI-F5 score (0), and 0 participants achieved the highest possible score (10). Based on the 15% threshold levels, the RADAI-F5 does not exhibit a ceiling or floor effect.

DISCUSSION
We have developed and validated a 5-item patient-reported outcome measure, named the Rheumatoid Arthritis Foot Disease Figure 2. Bland-Altman plot for the Rheumatoid Arthritis Foot Disease Activity Index-5 (RADAI-F5) summary score, with data points illustrating average scores from 2 time points separated by 1 week (n = 84) against the difference between the corresponding baseline and 1-week scores, bias (solid line represents the average SD for baseline to 1-week scores for all participants), bias upper and lower 95% confidence interval limits (inner broken lines), and upper and lower limits of agreement (outer broken lines). Activity Index (RADAI-F5) to allow for the monitoring of inflammatory foot disease activity in people with established and early RA. The psychometric properties meet the recommended standards set by the International Society for Quality of Life Research (39) and the Consensus Based Standards for the Selection of Health Measurement Instruments (40), demonstrating good construct validity, reliability, content validity, internal consistency, responsiveness, and interpretability. The new patient-reported outcome measure is designed to be quick and simple for patients to complete and clinicians to score and interpret, so that it can be used alongside composite disease activity indices in clinical practice. We anticipate that future use of the RADAI-F5 as an adjunct to composite disease activity indices will improve local disease monitoring and may facilitate better medical management of foot disease activity. The RADAI-F5 may also be used alongside existing disease-specific foot disability patient-reported outcome measures such as the FIS in rehabilitation settings to distinguish between inflammatory and mechanical/functional foot impairments, which may help to inform new and extended paradigms of foot care in early RA (41). Moreover, the RADAI-F5 could possibly negate the need for composite disease activity scores to be recorded for RA foot research purposes (often collected to account for confounding).
A key finding of this study is that evidence of convergent validity was observed between the RADAI-F5 and the mRADAI-5, and divergent validity between the RADAI-F5 and the DAS28-ESR. This finding was anticipated a priori and is theoretically consistent with existing evidence demonstrating that composite disease activity indices that omit foot joints do not adequately capture foot synovitis (11). Indeed, the majority of our a priori  specified hypotheses were confirmed for strength of associations between disease activity/foot disability measures with the RADAI-F5. The correlation between RADAI-F5 and mRADAI-5 was slightly stronger than anticipated, but perhaps unsurprising given the similarities of these instruments. Another explanation is that relative to the DAS28-ESR, the mRADAI-5 has the ability to capture foot disease activity because it includes questions that cover all joints as a whole (16). Importantly, RADAI-F5 and mRA-DAI-5 scores were not perfectly correlated, and 72.5% agreement was observed between respective disease activity categories for each instrument, suggesting they capture local and global disease, respectively. The RADAI-F5 demonstrated very good reliability characteristics in terms of 1-week reproducibility of summary scores and agreement between baseline and 1-week disease categories. However, the 95% smallest detectable change (2.69) derived from the SEm (0.97) was larger than anticipated and exceeded the preliminary MID value (1.16) that was obtained via the distribution method. This means that if an individual patient has a change score as large as the preliminary MID, we cannot be 95% confident that this change is not due to measurement error (33). This finding may be explained by the presence of outliers rather than systematically large change scores ( Figure 3, Supplementary Figures 1-5 Inspection of outliers suggested a tendency for larger change scores in those patients with shorter disease durations. Moreover, the RADAI-F5 summary change scores appeared to be predominantly driven by larger change scores for individual items 4 (general foot health) and 5 (morning stiffness in the feet), which may be more unstable over shorter periods of time. This possibility suggests that the instrument stability period of 1 week adopted here may be too long to evaluate the instrument in those whose disease may be unstable. Moreover, changes in therapy such as administration of intramuscular steroids could possibly have affected 1-week scores. Anchor-based derivations of RADAI-F5 MID are now planned because these are recommended and should be assigned the most weight when estimating the MID (38,42). We recommend that population-specific RADAI-F5 MID values be derived for future longitudinal studies seeking to measure changes in foot disease over time.
A strength of the RADAI-F5 is that it appears to demonstrate a consistent pattern of good responsiveness and theoretical consistency for longitudinal measurement, as has been reported for other global disease activity patient-reported outcome measures (16,43). We evaluated responsiveness using data from a pragmatic trial comparing customized versus prefabricated foot orthoses plus routine medical care in early RA (25). While the responsiveness results over a 6-month period are promising, medical care was not standardized, and so drugs and dosages varied between participants. Nevertheless, theoretically consistent associations for change scores between the RADAI-F5 and alternative instruments were observed, suggesting that it could be used longitudinally to measure changes in foot disease activity in early RA.
Preliminary foot disease category thresholds are proposed here to enhance applicability in routine clinical care in line with conventional categories adopted in other global disease activity patient-reported outcome measures and composite indices (24). While there is a relatively broad spectrum of RADAI-F5 scores in the study sample, we observed a negatively skewed distribution, indicative of predominant moderate-to-high foot disease activity within the sample. As a result, there were proportionally fewer participants allocated to remission and mild categories than the moderate and high categories. We also acknowledge that in the absence of a gold standard outcome measure for quantifying foot disease activity, the mRADAI-5 (a global index of disease activity) was the best available reference score for establishing foot disease activity categories. While threshold cutoffs appear to have good face validity, further evaluation using alternative approaches such as receiver operating characteristic curves may be appropriate. Our future work will seek to confirm preliminary foot disease activity category thresholds reported here with greater focus on those with more established disease who are in remission or low global disease activity states. We will also seek to determine whether treatment regimens would frequently be changed due to detection of persistent moderate foot disease in patients who are in low disease activity or remission states according to DAS28-ESR.
We have confirmed that the RADAI-F5 is valid, reliable, responsive, acceptable to patients, and potentially feasible for use in clinical practice in terms of ease of completion, quick scoring, and interpretability. The RADAI-F5 is freely available for use from www.gcu.ac.uk/centr eforl iving/ radai -f5 and is recommended for use by rheumatologists and/or rheumatology nurse specialists alongside composite global disease activity indices, and by Allied Health Professionals such as podiatrists and physiotherapists involved in delivering nonmedical foot care in RA.