Measures of Rheumatoid Arthritis Disease Activity

INTRODUCTION

A treat-to-target management approach remains the standard of care in rheumatoid arthritis (RA) (1). To effectively implement this strategy, regular assessment of RA disease activity is required. Numerous RA disease activity measures have been developed for this purpose, varying widely in their components, calculation, psychometric performance, and feasibility for use. In 2011, Anderson et al. summarized the psychometric performance of RA disease activity measures in a single publication to serve as a reference for providers and to inform American College of Rheumatology (ACR) recommendations on RA disease activity measures (2, 3). Since that time, additional disease activity measures have been developed and further evaluation of existing measures has been completed. For this reason, the ACR recently convened a working group to provide an update on recommendations for RA disease activity measures (4). Following an updated systematic literature review and assessment of psychometric performance using COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) tools, the working group selected RA disease activity measures that met a minimum criteria for regular use as well as the following preferred disease activity measures recommended for regular use: the Clinical Disease Activity Index (CDAI), Disease Activity Score with 28-Joint Counts (DAS28), Patient Activity Scale-II (PAS-II), Routine Assessment of Patient Index Data 3 (RAPID3), and Simplified Disease Activity Index (SDAI).

In this manuscript, we comprehensively summarize in a narrative fashion, to the best of our abilities, the characteristics and performance of RA disease activity measures to serve as an updated guide to clinicians and researchers. We included all disease activity measures that were selected as preferred by the ACR working group or fulfilled minimum criteria for regular use (4). Most currently used RA disease activity measures have been derived from the ACR core measures set that includes swollen and tender joint counts, provider and patient global assessment of disease activity, pain, physical function, and acute phase reactants (5). Because composite indices outperform individual components for the longitudinal assessment of RA disease activity (6, 7), we have not detailed the performance of individual ACR core measures. Furthermore, while there is increased use of advanced imaging modalities such as ultrasound and magnetic resonance imaging, their inclusion was beyond the scope of this review. Included studies were identified by the initial systematic literature review conducted by Anderson et al. (3), the recent systematic literature review informing updated ACR recommendations (4), and focused literature searches.

Critically assessing the performance of RA disease activity measures is inherently challenging as a “gold standard” does not exist. Initial disease activity measures developed based on clinician assessment of disease activity that resulted in treatment changes have subsequently served as the standard for validation of newer measures. Comparing composite measures against each other is further complicated by various cutoffs proposed to define disease activity categories, which may influence the degree of agreement between measures. Additionally, there is significant variability in the number and quality of studies, as well as the specific approach used to assess psychometric performance, for each measure.

The psychometric properties assessed included floor and ceiling effects, reliability, validity, responsiveness, and generalizability. Because studies vary in the reporting of the different types of validity (content, criterion, and construct), we present the definitions used in this review. Content validity included face validity, inclusion of ACR core measures (5), and the degree to which each component of a composite measure contributed to the variance of the measure. We defined criterion validity as how well the scores correlated with other established RA disease activity measures (many studies using the DAS28 as the “gold standard”) and agreed with categorization into disease activity states (concurrent criterion validity) as well as its predictive criterion validity (e.g. predicting radiographic progression or worsening disability). Construct validity (convergent and discordant) was defined by whether a disease activity measure appropriately agrees/disagrees to a related construct (e.g. higher levels of disease activity should correlate with physical function and negatively correlate with health-related quality of life).

CLINICAL DISEASE ACTIVITY INDEX (CDAI)

Description

Purpose.

The CDAI combines individual component measures into a simple, continuous measure of RA disease activity that does not require acute phase reactants and is feasible for use in routine practice.

Content.

The CDAI includes a 28-swollen joint count (28SJC), 28-tender joint count (28TJC), patient global assessment of disease activity (PtGA) and provider global assessment of disease activity (PrGA) scored on a 10-point visual analog scale (VAS).

Number of items.

The CDAI has 4 items.

Recall period for items.

No long-term recall is required for calculation of the CDAI.

Cost to use.

The CDAI is free to use.

How to obtain.

A sample form and calculator for the CDAI can be found at: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments. A calculator can also be found within the ACR Guidelines and Criteria mobile application.

Practical Application

Method of administration.

Patient self-assessment of disease activity on a VAS. Provider assessment of disease activity on a VAS and 28-swollen and tender joint counts. This can be completed by paper or, if available, computerized forms.

Scoring.

The CDAI (range 0–76) is scored from the sum of the 28SJC (0–28), 28TJC (0–28), PtGA (0–10), and PrGA (0–10).

Scoring interpretation.

Disease activity levels are interpreted as follows: remission (≤2.8), low disease activity (>2.8–10), moderate disease activity (>10–22), and high disease activity (>22).

Respondent time to complete.

Less than 10 seconds to provide PtGA.

Administrative burden.

Test can be administered in 2–5 minutes. No equipment or software needed, unless calculator is preferred for calculation of the CDAI.

Translations/adaptations.

Proposed variations of the CDAI include the modified CDAI (8) and patient-derived CDAI (9).

Psychometric information

Floor and ceiling effects.

Though not universally seen, the CDAI has exhibited a floor effect in some observational studies (10–12).

Reliability.

Internal consistency:

The internal consistency of the CDAI is modest with Cronbach’s alpha ranging from 0.21–0.78 (10, 11, 13–15).

Test-retest:

When repeat testing was done in 1-week intervals, the test-retest reliability of the CDAI was high in two independent RA cohorts with a correlation of 0.89–0.90 and intraclass correlation coefficient (ICC) of 0.89 (9, 16). The smallest detectable difference (SDD) for the CDAI is 8.1.

Validity.

Content:

The CDAI contains 4 of the 7 ACR core measures. It was derived from the SDAI by removing acute phase reactants, which were shown to account for only 5% of the variance of the SDAI (17). As the 28SJC and 28TJC do not incorporate examination of the foot, patients in low disease activity or remission may have residual foot synovitis (18, 19).

Criterion:

The CDAI correlates strongly (r = 0.74–0.93) with the DAS28 (12, 20–25). In general, the CDAI and DAS28 demonstrated moderate agreement in disease activity state categorization with kappa ranging from 0.35–0.82 (14, 21, 23–28). Correlation of scores and agreement in disease activity state categorization was strongest with the SDAI (r = 0.98–0.99; kappa = 0.79–0.99) (14, 21, 24, 25, 27, 28). Compared to DAS28 remission, criteria for CDAI remission is more stringent (14, 29). The CDAI has been shown to accurately identify patients with minimal disease activity (area under the receiver operating curve [AUROC] 0.96) and discriminate between ACR response categories (13, 17). Attainment of CDAI remission at 6 months predicted radiographic stability at 5 years in a cohort of 43 patients with RA (positive predictive value [PPV] 83.7%, odds ratio [OR] 3.43) (17, 30–33). In a study of 535 RA patients, 19% those in CDAI remission had radiographic progression, which was similar to the SDAI and fewer than for the DAS28-CRP (34).

Construct:

CDAI correlates with patient-reported pain (r = 0.67) (35), physical function measured by the Health Assessment Questionnaire (HAQ) (r = 0.45) (17), power doppler ultrasound scores (r = 0.6), joint damage on plain radiographs (17, 36), and MRI synovitis (r = 0.18–0.25) (8).

Responsiveness.

The CDAI has moderate to large responsiveness to change in RA disease activity, with standardized response means (SRM) ranging from 0.52–1.24 (10, 12, 37). The minimal clinically important difference (MCID) for change in CDAI is 12 for patients with high disease activity, 6 for patients with moderate disease activity, and 1 for patients with low disease activity (38). The minimal clinically important improvement (MCII) for the CDAI is 12 (16, 37).

Generalizability.

The CDAI may be influenced by sex, with a study of 557 RA patients showing the median CDAI was significantly higher in females (11.3 vs 7.1) (35). CDAI scores are higher among RA patients with comorbid fibromyalgia (39).

Use in clinical trials.

The CDAI is endorsed for, and has been used in, randomized controlled trials in RA.

Critical Appraisal of Overall Value to the Rheumatology Community

The CDAI was derived from the SDAI to provide a composite RA disease activity measure that is highly feasible for use in routine practice by removing the requirement of acute phase reactants, which has not affected its validity (17). Requirement of formal 28-joint counts may impact feasibility in some practice settings, but the simplicity of scoring makes it attractive for point-of-care use. While sex and fibromyalgia may affect CDAI scores (35, 40), the CDAI is a reliable, valid (content, criterion, and construct), and responsive measure of RA disease activity that has been tested in numerous studies and RA populations. The CDAI is endorsed by the ACR as a preferred measure for the regular assessment of RA disease activity (4).

DISEASE ACTIVITY SCORE (DAS) AND DISEASE ACTIVITY SCORE WITH 28-JOINT COUNTS (DAS28)

Description

Purpose.

The DAS was developed using physician judgement of disease activity based on starting or stopping DMARD therapy (41). Due to the complexity of the DAS, a modified version using 28-joints (DAS28) was developed from the DAS. Both combine single components into a composite continuous measure of RA disease activity.

Content.

The DAS includes the number of painful joints using the Ritchie Articular Index (RAI), 44-swollen joint count (44SJC), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), and PtGA on a VAS. The DAS28 includes a 28SJC, 28TJC, ESR or CRP, and PtGA. The PtGA may be removed to provide a 3-variable DAS or DAS28.

Number of items.

The DAS and DAS28 are composed of 4 items, 3 items if the PtGA is removed.

Recall period for items.

No long-term recall is required for the DAS and DAS28.

Cost to use.

Laboratory cost for measurement of acute phase reactants.

How to obtain.

An online calculator for the DAS and DAS28 can be found at: https://www.das-score.nl and https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments. A calculator can also be found in the ACR Guidelines and Criteria mobile application.

Practical Application

Method of administration.

Patient assessment of disease activity on a VAS. Provider assessment of tender joints on the RAI and 44-swollen joint count for DAS and 28 joint counts for the DAS28. Laboratory assessment of acute phase reactant. These can be completed by paper or, if available, computerized forms.

Scoring.

The DAS is scored on a scale of 0–10, incorporating the RAI (0–78), 44SJC (0–44), PtGA VAS (0–100), and ESR (mm/hr). The following formula is used: DAS = 0.54 × √(RAI) + 0.065 × SJC44 + 0.33 × ln(ESR) + 0.0072 × PtGA. The DAS28 is scored on a scale of 0–9.4, incorporating the PtGA VAS (0–100), 28TJC (0–28), 28SJC (0–28), ESR (mm/hr) or CRP (mg/L). The following formulas are used: DAS28-ESR = 0.56 × √(28TJC) + 0.28 × √(28SJC) + 0.70 × ln(ESR) + 0.014 × PtGA; DAS28-CRP = 0.56 × √(28TJC) + 0.28 × √(28SJC) + 0.36 × ln(CRP + 1) + 0.014 × PtGA + 0.96. The DAS28 can be transformed from the DAS using: DAS28 = (1.072 × DAS) + 0.938.

Scoring interpretation.

Disease activity levels for the DAS are interpreted as follows: remission (<1.6), low disease activity (1.6 to <2.4), moderate disease activity (2.4 to <3.7), and high disease activity (≥3.7). Disease activity levels for the DAS28 are interpreted as: remission (<2.6), low disease activity (2.6 to <3.2), moderate disease activity (3.2 to <5.1), and high disease activity (≥5.1). Alternative cut-offs proposed for the DAS28-CRP include: remission (<2.4), low disease activity (2.4 to <2.9), moderate disease activity (2.9 to ≤4.6), high disease activity (>4.6) (42, 43).

Respondent time to complete.

Less than 10 seconds to provide PtGA.

Administrative burden.

The DAS takes approximately 10 minutes to complete and the DAS28 takes approximately 5 minutes to complete, plus time required for processing of laboratory specimen. A calculator is required.

Translations/adaptations.

The DAS and DAS28 can be scored with a C-reactive protein rather than the ESR and 3-item versions are scored without the PtGA. Other adaptations include modifications of the scoring or categories of the DAS28-CRP to better agree with the DAS28-ESR and the patient derived DAS28 (8). A modified version of the DAS28 without acute phase reactants has also been proposed (10).

Psychometric

Floor and ceiling effects.

Less than 15% of RA patients clustered at the minimum or maximum values of the DAS and DAS28 (12, 44).

Reliability

Internal consistency:

Cronbach’s alpha for the DAS (including the RAI, 44SJC, and PtGA) were within 0.73–0.92 (41), while those for the DAS28 ranged from 0.17–0.72 (10, 11, 13–15).

Test-retest:

Test-rest reliability for the DAS and the 3-variable DAS ranges from 0.8–0.89 (44, 45). With repeated testing one week apart, DAS28 correlations ranged from 0.79–0.87, with an ICC of 0.85 (9, 16). Results were similar when retesting at 24 months in patients on stable therapy (46). The SDD for the DAS28 is 1.3 (16).

Validity

Content:

The DAS and DAS28 contain 4 of the 7 ACR core measures. Measures of physical function were excluded during development of the DAS as they were found to contribute less to the performance of the composite index (41). Variations of the DAS and DAS28 strongly correlate with the original versions (r = 0.79–0.99) (12, 21, 24, 28, 47, 48). Agreement in disease activity state categorization between these versions is more variable (kappa 0.4–0.92) (21, 42, 49–51). The DAS28-CRP tends to classify patients to a lower level of disease activity than the DAS28-ESR (43, 50).

Criterion:

The DAS accurately discriminated between high and low disease activity states during validation (52) and in an independent cohort of 202 RA patients (AUROC = 0.93) (53). Similarly, the DAS28 discriminates between ACR response categories, demonstrates high agreement with EULAR response categories (kappa = 0.82–0.86) (17, 50), and discriminates RA flares from inactive RA (AUROC 0.87) (54). The DAS and DAS28 correlate with other RA disease activity measures, often serving as the “gold standard” when assessing the performance of other measures (16, 20–25, 47, 55). The DAS and DAS28 are predictive of radiographic outcomes (31, 56–59), but patients in clinical remission by DAS28 may still be at risk for radiographic progression. In an observational cohort of RA patients in DAS28-CRP remission, radiographic progression occurred in 30%, which was greater than the rate among those in SDAI or CDAI remission (34). MRI findings of joint inflammation including synovitis and bone marrow edema can also be observed in patients in remission by DAS28-ESR or DAS28-CRP (60, 61).

Construct:

The DAS correlates with measures of physical disability (r = 0.70) (52) and radiographic changes (r = 0.31 and r = 0.26) (52). The DAS28 detects changes in PtGA scores (AUROC 0.81–0.83) and correlates (r = 0.40–0.79) with physical function (HAQ) and quality of life (Short Form 36) (13, 17, 62–65). Achieving DAS28 remission is associated with improvements in physical function and health-related quality of life (66).

Responsiveness.

In patients treated with methotrexate and sulfasalazine, the DAS was highly responsive with a SRM of 1.9 (67). The DAS28 is highly responsive to changes in RA disease activity with SRMs reported between 0.87–1.94 and similar performance among the DAS28-ESR, DAS28-CRP, and 3-variable DAS28 (12, 37, 68–70). The minimum important difference (MID) for the DAS and DAS28 is 1.2; EULAR considers this a good response and changes between 0.6 to 1.2 a moderate response (44, 71). The MCII of the DAS28-ESR is 1.2 and 1.0 for the DAS28-CRP (37).

Generalizability.

The DAS and DAS28 have been extensively utilized in multiple RA populations and are considered widely generalizable. Acute phase reactant measurement may be influenced by age, sex, and adiposity (72, 73). The DAS and DAS28 may overestimate disease activity in the setting of chronic pain syndromes (e.g. fibromyalgia) (39, 74).

Use in clinical trials.

The DAS and DAS28 are regularly used in clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The DAS was one of the first composite measures of RA disease activity and has been extensively validated. The DAS28 was derived from the DAS and is more widely used, owing to similar psychometric performance and better feasibility. These measures are reliable and have excellent validity (content, criterion, and construct) and responsiveness, serving as the primary disease activity measures in most RA clinical trials. The DAS and DAS28 may overestimate disease activity chronic pain disorders are present, and acute phase reactants may be influenced by age, sex, and adiposity (72, 73). Patients in DAS28 remission may be at risk for subclinical synovitis and radiographic progression, though imaging-guided treatment has not yet been shown to improve outcomes (75). While the scores are highly correlated, the DAS28-CRP tends to underestimate disease activity compared to the DAS28-ESR and alternative disease activity state categories have been proposed for the DAS28-CRP (43, 50). Measurement of the DAS or DAS28 may not be feasible in some settings owing to the need for formal joints counts, acute phase reactants, and requirement of calculators for scoring. Utilizing the most recent ESR may be a reasonable option when repeat laboratory measurement is not feasible (76), but providers must consider whether significant clinical and/or treatment changes have occurred since the time of the last acute phase reactant. Based on its psychometric performance and feasibility, the DAS28 is endorsed by the ACR as a preferred RA disease activity measure (4).

HOSPITAL UNIVERSITARIO LA PRINCESA INDEX (HUPI)

Description

Purpose.

The HUPI combines single measures into a continuous measure of RA disease activity. It contains similar components of other ACR-endorsed disease activity measures, though offers a simpler scoring scheme and flexibility to incorporate either the ESR, CRP, or both, making it potentially more feasible for routine use.

Content.

The HUPI includes a 28SJC, 28TJC, PtGA scored on a VAS, and an acute phase reactant (ESR, CRP, or both).

Number of items.

The HUPI contains 4 items, or 5 items if both an ESR and CRP are used.

Recall period for items.

No long-term recall is required to complete the HUPI.

Cost to use.

Laboratory costs for acute phase reactant measurement.

How to obtain.

A table detailing how variables are scored can be found at: https://journals.plos.org/plosone/article/figures?id=10.1371/journal.pone.0161727.

Practical Application

Method of administration.

Provider assessment of joint counts. Patient assessment of global health. Laboratory measure of acute phase reactant. The HUPI can be completed using paper or, if available, electronic form.

Scoring.

The HUPI is scored on a scale of 0–12 as a simple sum of its 4 components. Components are each given a score (0, 1, 2, or 3) based on cutoff values for the 28SJC (0, 1–2, 3–4, or >4 joints), 28TJC (0, 1, 2–3, >3 for males; 0, 1–2, 3–6, >6 for females), PtGA (0–15, 16–30, 31–50, >50), CRP (≤0.10, 0.11–0.80, 0.81–1.50, or >1.50 mg/L), and/or ESR (0–10, 11–15, 16–20, or >20 mm/hr for males; 0–15, 16–20, 21–30, or >30 mm/hr for females). If both a CRP and ESR are used, then the average of those two component scores is used in the formula.

Scoring interpretation.

Disease activity cutoffs for the HUPI are determined as follows: remission (≤2), low disease activity (>2–≤5), moderate disease activity (>5–≤9), and high disease activity (>9) (77).

Respondent time to complete.

Less than 10 seconds to provide PtGA.

Administrative burden.

The HUPI takes approximately 5 minutes to complete, plus time required for processing laboratory specimen. A reference table and calculator may be required.

Translations/adaptations.

No adaptations or translations are readily available.

Psychometric

Floor and ceiling effects.

The HUPI may exhibit a ceiling effect in RA populations with high levels of disease activity. In an international clinical trial of tocilizumab in active RA (ACT-RAY), more than 40% of RA patients had the maximum HUPI score (78).

Reliability

Internal Consistency:

Internal consistency of the HUPI (Cronbach’s alpha of 0.63) was modestly higher than the DAS28-ESR, DAS28-CRP, SDAI, and CDAI (Cronbach’s alpha of 0.46–0.52) (13).

Test-retest:

Test-retest reliability of the HUPI has not been evaluated.

Validity

Content:

The HUPI contains 4 of the 7 ACR core set of measures for assessment of RA disease activity.

Criterion:

The HUPI strongly to very strongly correlates with the DAS28-ESR (r = 0.89), DAS28-CRP (r = 0.91), SDAI (r = 0.71), and CDAI (r = 0.82) (13). The HUPI is also able to discriminate patients with minimal disease activity (AUROC 0.96), low vs. moderate activity (AUROC 0.91), moderate vs. high activity (AUROC 0.89), and remission accurately (AUROC 0.89–0.98), comparable to the DAS28 and better than the SDAI and CDAI (77). The predictive validity of the HUPI has not been established.

Construct:

The HUPI correlates with physical function measured by the HAQ (r = 0.69) (78).

Responsiveness.

Responsiveness of the HUPI was assessed in three independent RA cohorts. Change in the HUPI correlated with changes in DAS28, CDAI, and SDAI (r = 0.48–0.91). Standardized effect size (SES) for the HUPI (ranging from 1.55–3.69 in two cohorts where improvement occurred) were similar to or better than the aforementioned other disease activity measures (78). Serving as the MID, a change in the HUPI of 4 units corresponds to a DAS28 change of 1.2 (77).

Generalizability.

The HUPI was derived in early arthritis cohorts and has been tested in other RA cohorts and post hoc analyses from clinical trials. The HUPI considers the influence of sex on both the PtGA and ESR.

Use in clinical trials.

The HUPI has not been used in clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The HUPI was developed using the same ACR core measures as the DAS28, with the intent to reduce the influence of sex and choice of acute phase reactant on its validity. In the few studies evaluating the HUPI, it has demonstrated good validity, comparing favorably to other commonly used RA disease activity measures (13, 77). Despite a ceiling effect, the HUPI is responsive to change and the MID has been established (13, 77, 78). Lacking is assessment of the HUPI in diverse RA populations (such as those with chronic pain disorders), determination of its reliability and predictive criterion validity, and experience with its use in clinical settings. The flexibility to score with or without acute phase reactants contributes to the feasibility of the HUPI, though formal joint counts and a scoring table are required. Strengths of the HUPI are the reduced influence of sex and choice of acute phase reactant on its score, but its use is not widespread and additional psychometric testing is needed. The HUPI met the minimum criteria for regular use by the ACR (4).

MULTI-BIOMARKER DISEASE ACTIVITY SCORE (MBDA, Vectra ^®)

Description

Purpose.

The MBDA score is a RA disease activity measure composed of 12 serum biomarkers developed to predict DAS28-CRP score.

Content.

The MBDA score incorporates serum concentrations of interleukin-6 (IL-6), tumor necrosis factor receptor type I (TNFRI), vascular cell adhesion molecule 1 (VCAM-1), epidermal growth factor (EGF), vascular endothelial growth factor A (VEGF-A), YKL-40, matrix metalloproteinase 1 (MMP-1), MMP-3, CRP, serum amyloid A (SAA), leptin, and resistin.

Number of items.

The MBDA score contains 12 items.

Recall period for items.

As it is a laboratory measure, no recall period is required.

Cost to use.

There is a fee for obtaining the MBDA score.

How to obtain.

The MBDA score is obtained by blood draw and sent for processing in a dedicated laboratory.

Practical Application

Method of administration.

The MBDA score is a laboratory measure requiring a peripheral blood draw.

Scoring.

The MBDA score ranges from 1–100, with the scores being provided by the company. No scoring of individual components is required on the part of the provider. Biomarker concentrations, aside from the CRP, are transformed to the power 1/10 to normally distribute, then used to create predicted scores for each component of the DAS28: predicted 28TJC, predicted 28SJC, and predicted PtGA. The following formula is then used: MBDA score = 0.56 × √ (28PTJC) + 0.28 × √ (28PSJC) + 0.14x (PPtGA) + 0.36log[CRP +1] + 0.96) × 10.53 + 1) (79).

Scoring interpretation.

The results of the MBDA can be interpreted as follows: low disease activity (1–29), moderate disease activity (30–44), high disease activity (>44) (79).

Respondent time to complete.

No response time is required, but patients are required to have a peripheral blood draw.

Administrative burden.

The MBDA score requires sample collection, processing, and shipping for measurement. Results are typically provided in 5–7 days.

Translations/adaptations.

An adjusted MBDA score corrects for adiposity via leptin or body mass index.

Psychometric

Floor and ceiling effects.

Floor and ceiling effects have not been observed (80).

Reliability.

The internal consistency and test-retest reliability of the MBDA have not been specifically assessed. Precision of individual biomarkers as well as the MBDA score were defined across 4 different serum pools. Individual biomarkers demonstrated acceptable (coefficient of variation <20%) intra-assay (5.3–18.8%) and inter-assay (6.5–17.6%) variability. The MBDA score was found to be highly precise, with a mean intra-assay variation of 1.1% and median inter-assay variation of 1.6% (81).

Validity

Content:

The MBDA score includes the ACR core measure of acute phase reactant. While not including other core measures, it is scored by predicting the 28SJC, 28TJC, and PtGA (79). After excluding CRP, the MBDA score was still associated with SJC28 (r = 0.35), TJC28 (r = 0.81), and PrGA (r = 0.68) (82).

Criterion:

In a recent meta-analysis pooling 8 studies, the MBDA score moderately correlated with the DAS28-CRP (r = 0.41) and DAS28-ESR (r = 0.48), while weaker correlations were seen with the SDAI (r = 0.35), CDAI (r = 0.26), and RAPID-3 (r = 0.23) (83). Disease activity categories were concordant between the MBDA score and the DAS28-CRP in 77.1% of patients and the CDAI in 72.3% of patients (84). In a separate cohort, 120 serum samples of RA patients treated with methotrexate were assessed and demonstrated only fair agreement with the DAS28-CRP (kappa = 0.20–0.41) (82). Regarding its predictive validity, several studies have shown the MBDA score to predict radiographic progression, although cutoffs to define radiographic progression and effect sizes were highly variable and not universally predictive (82, 85–90). In a recent study that pooled five independent cohorts of RA patients, a low or moderate MBDA score was more predictive of radiographic stability in 1 year compared to the DAS28-CRP, with negative predictive values between 93–97% (56).

Construct:

The MBDA exhibits moderate correlation with physical function assessed by the HAQ cross sectionally (r = 0.5) and longitudinally (r = 0.48) (91).

Responsiveness.

SRM of the MBDA have not yet been assessed. In pooled cohorts, changes in MBDA correlated modestly with changes in DAS28-CRP (r = 0.42), SDAI (r = 0.33), CDAI (r = 0.26), and RAPID-3 (r = 0.31) (83). In 22 RA patients with moderate or high disease activity, the MID of the MBDA was determined to be 8 (92).

Generalizability.

The MBDA score has been evaluated in typical, U.S. and international cohorts. Because IL-6 is included in the MBDA score algorithm and increases with tocilizumab treatment, the MBDA score should be used cautiously in the context of tocilizumab therapy (84). Additionally, age and obesity may influence MBDA score results, thus recently proposed scoring modifications incorporating leptin or body mass index should be considered (93, 94). The MBDA score is not affected by fibromyalgia (39).

Use in clinical trials.

The MBDA score has not been used as the outcome measure for clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The MBDA score is a laboratory test that compiles 12 serum biomarkers into an RA disease activity score of 0–100 based on predicting components of the DAS28-CRP. The MBDA score is precise, has a defined MID, and has good criterion and construct validity, correlating with other RA disease activity measures and physical function as well as predicting radiographic progression. Without patient or provider components, face and content validity may be questioned. As an entirely objective measure of RA disease activity, the MBDA score may be of use in the setting of chronic pain syndromes, such fibromyalgia (39). Other factors, such as age, obesity, and use of tocilizumab may impact its validity (84, 93, 94). Routine use of the MBDA score is limited by its feasibility (requiring 5–7 days for score availability) and costs. The MBDA score met the minimum criteria for regular use by the ACR (4).

PATIENT ACTIVITY SCORE (PAS) AND PATIENT ACTIVITY SCORE-II (PAS-II)

Description

Purpose.

The PAS and PAS-II are patient-reported questionnaires that combine single measures into a continuous, composite measure of disease activity. The PAS-II includes fewer questions, which may improve feasibility for routine use.

Content.

Both measures include patient assessment of pain on a VAS and PtGA. The PAS evaluates physical function using the HAQ while the PAS-II uses the HAQ-II.

Number of items.

Both the PAS and PAS-II have 3 items.

Recall period for items.

No long-term recall is required.

Cost to use.

The PAS and PAS-II are free to use.

How to obtain.

A sample form and calculator for the PAS-II can be found at: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments. A calculator can also be found within the ACR Guidelines and Criteria mobile application.

Practical Application

Method of administration.

Patient completion by paper or, if available, electronic form.

Scoring.

Both the PAS and PAS-II are scored on a 0–10 scale. Pain is assessed on a VAS (0–10). PtGA is assessed on a VAS (0–10). The HAQ and HAQ-II are scored from 0–3. The following formula can be used: PAS = (3.3 × HAQ + PtGA + pain) / 3; PAS-II = (3.3 × HAQ-II + PtGA + pain) / 3.

Scoring interpretation.

Disease activity levels for both the PAS and PAS-II can be interpreted as follows: remission (≤0.25), low disease activity (>0.26 to 3.70), moderate disease activity (3.71 to <8.0), high disease activity (≥8.0).

Respondent time to complete.

Both indices take <5 minutes for patients to complete. Since the HAQ-II has fewer questions than the HAQ, PAS-II can be completed more quickly.

Administrative burden.

In total, the PAS and PAS-II take <5 minutes to complete and score. A calculator is required.

Translations/adaptations.

While the cross-cultural validity of the PAS and PAS-II has not been specifically assessed, translations and cultural adaptations of the HAQ and HAQ-II are available in several languages (95).

Psychometric

Floor and ceiling effects.

The PAS and PAS-II appear to have a modest floor effect (12, 96).

Reliability.

The internal consistency and test-retest reliability of the PAS and PAS-II have not been assessed.

Validity

Content:

The PAS and PAS-II contain 3 of the ACR core measures for assessment of RA disease activity.

Criterion:

The PAS has not been validated against the DAS or DAS28, though strongly correlated with the RAPID3 (r = 0.89) and RADAI (r = 0.79) in cross section (12). The PAS-II accurately discriminates active from inactive disease (AUROC 0.55–0.82) (97, 98). Additionally, the PAS-II showed fair agreement in disease activity categorization with the DAS28-ESR (kappa = 0.29–0.54) and DAS28-CRP (kappa = 0.36), and slightly higher agreement with SDAI (kappa = 0.60) and CDAI (kappa = 0.40–0.60) (97, 99). The predictive validity of the PAS and PAS-II has not been assessed.

Construct:

The PAS and PAS-II exhibit moderate agreement with quality of life as assessed by the EuroQOL (Tau = 0.59) (96). The PAS accurately discriminated improvements in overall health assessed by the SF-36 (AUROC 0.79) (12). The PAS-II correlates with patient-reported fatigue (r = 0.84) as well as provider assessed swollen (r = 0.47) and tender (r = 0.48) joint counts (97).

Responsiveness.

The PAS demonstrated similar responsiveness as the DAS28-ESR, DAS28-CRP, SDAI, CDAI, MOI-RA, RAPID-3, and RADAI (SES = 1.57) (12). Changes in PAS also correlated with changes in RAPID3 (r = 0.89) (12). The MCID of the PAS-II was determined to be 0.5 (100).

Generalizability.

The PAS and PAS-II have been assessed in typical, female-predominant RA populations. As the PAS and PASII contain patient-reported measures of pain, they may be influenced by non-RA related pain and should be interpreted carefully in that context (40).

Use in clinical trials.

The PAS and PAS-II have not been used in clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The PAS and PAS-II are composite measures of RA disease activity that include individual patient-reported ACR core measures. The PAS and PAS-II differ from each other and the RAPID3 only by the HAQ version used. The PAS-II contains the shorter HAQ-II, which performs as well as the more extensive HAQ and has less of a floor effect (101). While not extensively assessed, the PAS and PAS-II have reasonable content, criterion, and construct validity. Despite a modest floor effect, they possess good responsiveness. Implementation of both measures is highly feasible given the limited time it takes patients to complete its components and the simplicity to score. The PAS and PAS-II are not specific to RA and their scores may be influenced by chronic pain disorders. The PAS-II was endorsed by the ACR as a preferred RA disease activity measure for regular use (4).

RHEUMATOID ARTHRITIS DISEASE ACTIVITY INDEX and RHEUMATOID ARTHRITIS DISEASE ACTIVITY INDEX 5 (RADAI and RADAI-5)

Description

Purpose.

The RADAI and RADAI-5 are patient-reported composite RA disease activity measures. The RADAI was derived from the Rapid Assessment of Disease Activity in Rheumatology (RADAR) questionnaire while the RADAI-5 aimed to assess similar constructs, but improve the feasibility of its assessment and calculation.

Content.

The RADAI contains a PtGA, patient assessed degree of joint pain and swelling on a VAS, patient reported pain on a VAS, duration of morning stiffness, and a 16-joint PtTJC. The RADAI-5 contains 5 patient-reported items on a VAS scale: PtGA, joint pain and swelling, overall pain, general health, and joint stiffness.

Number of items.

The RADAI and RADAI-5 both contain 5 items.

Recall period for items.

The RADAI and RADAI-5 require a recall period of 6 months.

Cost to use.

The RADAI and RADAI-5 are free to use.

How to obtain.

A sample RADAI form can be found within the following link: https://www.rheumatology.org/Portals/0/Files/A%20Self-Administered%20Rheumatoid%20Arthritis%20Disease%20Activity%20Index%20(RADAI)%20for%20Epidemiologic%20Research.pdf. A sample RADAI-5 can be found within the following article: https://www.clinexprheumatol.org/article.asp?a=8604.

Practical Application

Method of administration.

Both the RADAI and RADAI-5 are patient-reported assessments.

Scoring.

Components of the RADAI are standardized to range from 0–10. The PtGA, assessment of joint pain and swelling, and overall pain are scored on a VAS (0–10). Morning stiffness (0–6) is transformed by dividing by 6, then multiplied by 10. The PtTJC scores 16 joints (0=no pain to 3=severe pain for each) and is then transformed similarly to a 0–10 scale. The RADAI is then calculated as the mean of its five components. The RADAI-5 (range 0–10) is calculated as the mean of its five component scores, which are all reported on a VAS with a range of 0–10.

Scoring interpretation.

The RADAI can be interpreted as follows: low disease activity (<2.2), moderate disease activity (≥2.2 to ≤4.9), and high disease activity (>4.9). The RADAI-5 can be interpreted as follows: remission (≤1.4), low disease activity (1.6–3.0), moderate disease activity (3.2–5.4), and high disease activity (≥5.6).

Respondent time to complete.

The RADAI takes 5–10 minutes and RADAI-5 approximately 5 minutes for respondents to complete.

Administrative burden.

As mentioned above, these indices take approximately 5 minutes to complete. They can be administered by paper or, if available, electronic form.

Translations/adaptations.

A Thai version of the RADAI has been developed and validated (102). The RADAI-5 has been validated in Turkish and German language (103, 104).

Psychometric

Floor and ceiling effects.

The RADAI and RADAI-5 have a mild floor effect (11, 105).

Reliability.

Internal consistency:

The internal consistency of the RADAI was excellent with a Cronbach’s alpha of 0.91 (106). The RADAI-5 demonstrates similar internal consistency (alpha = 0.91–0.92) (11, 107).

Test-retest:

When repeat testing was performed one week apart, the reliability of the RADAI was excellent (r = 0.89 and ICC = 0.92) (16). The SDD of the RADAI is 1.5 (16).

Validity

Content:

The RADAI and RADAI-5 both contain 3 of the 7 ACR core measures. Factor analysis of the RADAI and RADAI-5 demonstrated that all items loaded to a single factor, meaning the measures are unidimensional (11, 106). Joint assessments in the RADAI are patient-derived which variably correlates with provider assessment (108–112).

Criterion:

In its development, the RADAI demonstrated moderate correlation with the DAS (r = 0.53) (106). Moderate to strong correlations have also been observed with the DAS28-ESR (r = 0.53–0.72), DAS28-CRP (r = 0.48–0.56), SDAI (r = 0.65–0.80), CDAI (r = 0.67–0.84), and RAPID3 (r = 0.81–0.89) (16, 105, 113, 114). Correlations are similar between the RADAI-5 and DAS28-ESR (r = 0.64), DAS28-CRP (r = 0.72), SDAI (r = 0.74), and CDAI (r = 0.74) (103). Using a cutoff of <2.2, the RADAI discriminated moderate-high vs. low DAS28 disease activity with a sensitivity of 63% and specificity of 71% (115). RADAI-5 remission criteria identified RA patients meeting the Boolean definition of remission with a sensitivity of 78% and specificity of 86% (116). The predictive validity of the RADAI and RADAI-5 has not been assessed.

Construct:

During its development, the RADAI demonstrated moderate correlation with PrGA (r = 0.54), HAQ (r = 0.57), and CRP (r = 0.43) (106). The RADAI-5 demonstrated moderate agreement with physical function as assessed by the multidimensional HAQ (MDHAQ) (Tau = 0.47) (11).

Responsiveness.

The RADAI was responsive to changes in disease activity, with a SES of 1.36–1.58, similar to that of the DAS28-ESR and DAS28-CRP (12, 54). Changes in RADAI over time correlated with changes in DAS28-CRP (r = 0.51), CDAI (r = 0.63), and RAPID-5 (r = 0.66) (114). Changes in the RADAI-5 demonstrated similar correlations with change in the DAS28-ESR and CDAI (103). The MCID of the RADAI is between 1–1.4 (3, 117).

Generalizability.

The RADAI and RADAI-5 have been tested in typical, female-predominant RA populations. Sex does not appear to influence the RADAI-5 (11). The RADAI appears to be less reliable than the DAS28-CRP during pregnancy (118).

Use in clinical trials.

The RADAI has not been widely used in clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The RADAI was developed from the more extensive RADAR questionnaire to provide a feasible, patient-assessed measure of RA disease activity. The RADAI-5 was designed to further simplify assessment and scoring. Both measures appear to have a mild floor effect and they are unidimensional. However, they are highly reliable, have good validity (content, criterion and construct), and are responsive to change, with thresholds for meaningful change having been proposed. These patient-reported measures are feasible for use, particularly the RADAI-5 which does not require an extensive patient TJC. The RADAI and RADAI-5 are generalizable, having been tested in several different cohorts, settings, and countries. However, factors such as poor health literacy, chronic pain syndromes, or pregnancy may influence the validity of these measures (40, 118, 119). Both the RADAI and RADAI-5 fulfilled minimum criteria for regular use by the ACR (4).

ROUTINE ASSESSMENT OF PATIENT ACTIVITY INDEX (RAPID3, RAPID4, RAPID5)

Description

Purpose.

The RAPID3 and RAPID4 are patient-derived questionnaires that combines individual measures into a continuous measure of RA disease activity. The RAPID5 additionally adds a PrGA.

Content.

The RAPID3 contains a patient assessment of pain on a VAS, PtGA, and a subset of core variables from the MDHAQ. The RAPID4 contains the items included in the RAPID3 plus a patient assessed TJC. The RAPID5 contains the items included in the RAPID4, plus a PrGA.

Number of items.

The RAPID indices contain 3, 4, or 5 items, corresponding to the number included in each name.

Recall period for items.

A recall period of 1 week is required for completion of the MDHAQ contained in each measure.

Cost to use.

The RAPID indices are available to academic researchers free of cost. Use of the MDHAQ-RAPID3 in an electronic medical record or by pharmaceutical companies are subject to fees.

How to obtain.

A request for use of the MDHAQ-RAPID3 can be submitted at the following link: https://www.corptransinc.com/sites/mdhaq-rapid3/instrument-information/instrument-scoring-(1). A sample form and calculator for the RAPID3 can be found at: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments. A calculator can also be found within the ACR Guidelines and Criteria mobile application.

Practical Application

Method of administration.

The RAPID3 and RAPID4 are composed solely of patient items. The RAPID5 requires completion of patient items as well as provider assessment.

Scoring.

The RAPID3 (range 0–30) is calculated by the sum of the patient assessment of pain on a VAS (0–10), PtGA (0–10), and MDHAQ (0–10). The RAPID4 (0–40) is calculated the same, plus addition of a 16-joint PtTJC (0=no pain to 3=severe pain for each joint) transformed to a 0–10 scale. The RAPID5 (0–50) is calculated as is the RAPID4, plus addition of a PrGA (0–10).

Scoring interpretation.

Disease activity categories for the RAPID3 are interpreted as follows: near remission (≤3), low disease activity (4–6), moderate disease activity (7–12), and high disease activity (≥13). The RAPID4 is interpreted as: near remission (≤4), low disease activity (5–8), moderate disease activity (9–16), and high disease activity (≥17). The RAPID5 is interpreted as: near remission (≤5), low disease activity (6–10), moderate disease activity (11–20), and high disease activity (≥21) (120).

Respondent time to complete.

Less than 2 minutes to complete the RAPID3; 5–10 minutes to complete the RAPID4 and RAPID5.

Administrative burden.

The RAPID indices are scored in <1 minute, for a total completion time between 5–10 minutes. These can be administered by paper or, if available, electronic form. A calculator or scoring conversion is required. Training may be necessary for PtTJC scoring.

Translations/adaptations.

A Japanese version of the RAPID3 has been previously validated (121). Several additional translations are available from RWS Life Sciences (https://www.corptransinc.com/sites/mdhaq-rapid3/). A RAPID2 consisting of PtGA and PrGA as well as a RAPID4 with a provider joint count are also available.

Psychometric

Floor and ceiling effects.

Similar to the PAS and PAS-II, the RAPID3 may have a modest floor effect (120).

Reliability

Internal consistency:

The RAPID3 demonstrated excellent internal consistency with a Cronbach’s alpha of 0.87 (11).

Test-retest:

When repeat testing was performed one week apart, the RAPID3 demonstrated excellent reliability with a correlation of r = 0.88 and ICC = 0.90 (16). The SDD for the RAPID3 was found to be 1.5 (16).

Validity

Content:

All RAPID indices are composed of ACR core measures, although the TJC in the RAPID4 is patient-derived. Contributions of each component of the RAPID3 to its variance was assessed, with pain and PtGA contributing equally (37% and 36%), with the MDHAQ contributing slightly less (27%) (122). Addition of a PtTJC in the RAPID4 was found to provide little additional information (122).

Criterion:

Across several studies, the RAPID3 has correlated moderately to strongly with the DAS28-ESR/CRP (r = 0.43–0.73), SDAI (r = 0.66–0.71), and CDAI (r = 0.61–0.76) (16, 20, 22, 55, 113, 123–126). The RAPID4 performed similarly, while the RAPID5 may demonstrate slightly stronger correlations with these measures (113, 114). Though effect sizes are variable across studies, RAPID3 categories generally demonstrate fair agreement with other validated composite disease activity measures as well as EULAR response categories (11, 55, 124, 127, 128). Sustained RAPID3 remission has been associated with significantly reduced radiographic progression (129). In a RCT comparing management based on RAPID3 vs. CDAI, fewer responders were identified by RAPID3 at week 12, but management by both measures led to a similar number achieving DAS28-ESR low disease activity at 52 weeks (130). In a RCT of tocilizumab use in methotrexate non-responders, achieving RAPID3 remission at year 1 predicted the absence of radiographic progression and functional status decline (HAQ) at year 2 (OR 4.6, AUC 0.80) (131).

Construct:

The RAPID measures include a measure of physical function. The RAPID3 correlates moderately with worsening hand function including the signal of functional impairment (r = 0.57) and pulp-to-palm distance (r = 0.44), a measure of total finger flexion (126). Higher RAPID3 scores are associated with poorer quality of life as assessed by the EuroQOL (r = −0.73) (132).

Responsiveness.

In an observational setting, the responsiveness of the RAPID3 (SRM=1.26) was similar to the DAS28-ESR/CRP, CDAI, and SDAI (SRM 1.24–1.46) (12). In a RCT setting, the RAPID3 was less responsive to change than the CDAI after 12 weeks of certolizumab treatment, with the average DAS28-ESR change among RAPID3 nonresponders exceeding the DAS28-ESR MID (130). Response criteria for the RAPID3 (good: decrease >3.6 and end score <6) had fair to moderate agreement with EULAR DAS28-ESR response criteria in post-hoc analyses from two clinical trials (128).

Generalizability.

The RAPID3 has been validated in several RA populations in the US and internationally. RAPID3 scores are higher in osteoarthritis than RA (133) and has been tested in several other rheumatic conditions besides RA (134–136).

Use in clinical trials.

Except from the aforementioned RCT comparing RA management by RAPID3 vs. CDAI with certolizumab (130), the RAPID3 is not typically used in clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The RAPID measures of RA disease activity were designed to construct composite patient-reported measures of RA disease activity from the ACR core measures in a feasible manner. The RAPID3 is the most widely used and extensively validated of these indices, with incremental value from the addition of the PtTJC in the RAPID4. While less extensively studied, the RAPID5 may correlate better with other RA disease activity measures (113, 114). The RAPID3 has good reliability, validity (content, criterion, and construct), and reasonable responsiveness. Response criteria have been proposed and compared to EULAR criteria. With extensive testing in observational and clinical trial settings, the measure has good generalizability. However, the measure is not specific to RA with osteoarthritis and other conditions also affecting RAPID3 scores (40, 119). The RAPID measures, particularly the RAPID3, are highly feasible for measurement and scoring of RA disease activity, though it is uncertain whether fees for use have impacted its adoption in electronic medical record systems. Both the RAPID3 and RAPID5 fulfilled the minimal criteria for regular by the ACR, and the RAPID3 was selected as a preferred RA disease activity measure (4).

SIMPLIFIED DISEASE ACTIVITY INDEX (SDAI)

Description

Purpose.

The SDAI combines individual measures into a composite continuous measure of RA disease activity.

Content.

The SDAI includes a 28-joint SJC, 28-joint TJC, PtGA scored on a 10-point VAS, PrGA scored on a VAS, and a CRP.

Number of items.

The SDAI contains 5 items.

Recall period for items.

No long-term recall is required for completion of the SDAI.

Cost to use.

Cost associated with laboratory assessment of CRP.

How to obtain.

A sample form and calculator for the SDAI can be found at: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments. A calculator can also be found within the ACR Guidelines and Criteria mobile application.

Practical Application

Method of administration.

Patient self-assessment of disease activity on a VAS. Provider assessment of disease activity on a VAS, 28SJC, and 28TJC. Laboratory assessment of CRP. This can be completed by paper or, if available, computerized forms.

Scoring.

The SDAI (range 0–86) is calculated by the sum of the 28SJC (0–28), 28TJC (0–28), PtGA (0–10), PrGA (0–10), and CRP (0–10 mg/L).

Scoring interpretation.

SDAI disease activity categories can be interpreted as follows: remission (≤3.3), low disease activity (>3.3 to ≤11.0), moderate disease activity (>11.0 to ≤26), and high disease activity (>26).

Respondent time to complete.

Less than 10 seconds for completion of PtGA.

Administrative burden.

The SDAI takes approximately 5 minutes, plus the time required for laboratory processing and measurement of CRP. It can be completed using paper or, if available, electronic form. No equipment or software needed.

Translations/adaptations.

A modified SDAI that better correlates with MRI evidence of synovitis (8) and both patient-derived (9, 137) and ultrasound-derived SDAI (70) have been proposed.

Psychometric

Floor and ceiling effects.

Evaluation of SDAI scores in observational studies have demonstrated a rightward skew in the distributions of scores, with patients clustering at low disease activity levels and indicating a possible floor effect (10, 138, 139).

Reliability

Internal consistency:

The internal consistency of the SDAI varies between studies, with Cronbach’s alpha ranging from 0.48–0.75 (10, 13, 14).

Test-retest:

The test-retest reliability of the SDAI is excellent. With repeated testing at 1–6 week intervals, the SDAI demonstrated a correlation coefficient of 0.87–0.91 and ICC of 0.77–0.88 (9, 16, 70). The SDD for SDAI is 8.3 (16).

Validity

Content:

The SDAI contains 5 of the 7 ACR core measures and includes patient, provider, and objective laboratory data. The CRP accounts for only 5% of the variance of the SDAI (17), so the SDAI and CDAI are very strongly correlated (16, 20, 21, 24, 25, 28). As the 28SJC and 28TJC do not include examination of the feet, the SDAI may underestimate disease activity in those with foot involvement (18).

Criterion:

Across several studies, the SDAI has demonstrated strong linear correlation with the DAS28-ESR and DAS28-CRP (12, 16, 20–22, 24, 25, 28). Categorization into disease activity states by the SDAI generally demonstrates moderate to strong agreement with DAS28-ESR (kappa = 0.46–0.87) and DAS28-CRP (kappa = 0.38–0.89) categories (14, 21, 23, 25, 27, 28). Remission criteria by SDAI are more stringent than DAS28 (14, 29), demonstrate good agreement with Boolean criteria (kappa = 0.79) (127), and are more closely associated with absence of synovitis on ultrasound than the DAS28 (140). The SDAI is highly predictive of radiographic progression (17, 30, 33, 141, 142), and patients in SDAI remission are at low risk of radiographic progression (143–146). SDAI remission may better predict radiographic stability than DAS28 remission (144).

Construct:

SDAI remission is associated with improved physical function as assessed by the mHAQ, and increasing disease activity levels are associated with poorer function in a dose-dependent manner (66). Improved SDAI scores are associated with improved quality of life as assessed by the EuroQOL-5 domain as well as reduced needs for durable medical equipment (66).

Responsiveness.

The SDAI is highly responsive, with most studies reporting SRMs of 0.97–1.33, similar to that of other composite disease activity measures (12, 37, 70). The MCII for the SDAI is 13 (37).

Generalizability.

The SDAI has been tested in numerous RA populations within the US and internationally. The SDAI may be influenced by sex, with a study of 557 RA patients showing the median SDAI was significantly higher in females (12.2 vs 8.0 in males) (35) and the CRP may be influenced by adiposity (72).

Use in clinical trials.

The SDAI is routinely used in RA clinical trials.

Critical Appraisal of Overall Value to the Rheumatology Community

The SDAI was designed as a composite RA disease activity measure that encompasses the same ACR core measures (5 of 7) as the DAS28 but can be scored easily at the point-of-care. It has been extensively tested, demonstrating good reliability, validity (content, criterion, and construct), and responsiveness. Clinically meaningful changes in its scores have been determined. The simplicity of scoring makes it more feasible for use than the DAS28, though it does still require formal joint counts and a CRP. Many providers may consider using the CDAI in its place since the CRP contributes little to the measures performance (17). Its generalizability is supported by performance assessment in multiple settings and clinical trials. However, sex and adiposity may influence the SDAI (35, 72). The SDAI is recommended by the ACR as a preferred measure for the assessment of RA disease activity (4).

CONCLUSION

Current RA treatment guidelines endorse a treat-to-target approach for the management of RA (1). This approach necessitates regular measurement of RA disease activity with a valid instrument. With a variety of measures available as well as adaptions existing for many of these measures, critical appraisal of their psychometrics and feasibility is crucial to guiding measure selection. In a standardized fashion, we have summarized the contents, psychometric properties, and feasibility of RA disease activity measures to serve as a reference for providers and researchers. While the ACR-endorsed preferred RA disease activity measures (CDAI, DAS28-ESR/CRP, PAS-II, RAPID3, SDAI) stand out for their psychometric performance and feasibility, there are caveats and considerations for the use of all existing RA disease activity measures. This stresses the importance of considering the clinical scenario (e.g. sex, comorbid conditions, and social determinants of health) and understanding each measure’s limitations when making clinical decisions regarding the selection and interpretation of RA disease activity measures. For example, when considering the choice of RA disease activity measure, the setting will heavily influence measure selection. Composite measures with formal joint counts such as DAS28, CDAI, and SDAI will likely remain the measures of choice in clinical trials with their excellent responsiveness and extensive validation. But with increasing interest in self-monitoring of disease activity, alternative care delivery models such as tele-rheumatology, and pragmatic clinical trials, patient-reported measures of RA disease activity are immensely important. Finally, we encourage ongoing psychometric testing of the identified measures and derivation of novel measures of RA disease activity.

Table 1:

Practical applications of rheumatoid arthritis disease activity measures

Measure	Number of items	Content/Domains	Method of administration	Recall period	Response format	Range of scores	Score interpretation	Availability of normative data	Cross-cultural validation*
CDAI	4	28TJC 28SJC PtGA PrGA	Patient item, Provider assessment	None	VAS Joint count	0–76	Rem ≤2.8 LDA >2.8 – 10 MDA >10 – 22 HDA >22	Yes	N/A
DAS	3 or 4	RAI 44SJC PtGA ESR	Patient item, Provider assessment, Blood sample	None	VAS Joint count Lab measure	0–10	Rem <1.6 LDA 1.6 – <2.4 MDA 2.5 – <3.7 HDA ≥3.7	Yes	N/A
DAS28-ESR/CRP	3 or 4	28SJC 28TJC PtGA ESR or CRP	Patient item, Provider assessment, Blood sample	None	VAS Joint count Lab measure	0–9.4	Rem <2.6** LDA 2.6 – <3.2** MDA 3.2 – ≤5.1** HDA >5.1**	Yes	N/A
HUPI	4 or 5	28SJC 28TJC PtGA ESR CRP	Patient item, Provider assessment, Blood sample	None	VAS Joint count Lab measure	0–12	Rem ≤2 LDA >2 – ≤5 MDA >5 – ≤9 HAD >9	Yes	N/A
MBDA score	12	IL-6, TNFRI, VCAM-1, EGF, VEGF-A, YKL-40, MMP-1, MMP-3, SAA, leptin, resistin	Blood sample	None	Lab measure	0–100	Rem ≤25 LDA 26 – 29 MDA 30 – 44 HDA >44	Yes	N/A
PAS	3	Pain PtGA HAQ	Patient item	1 week	VAS	0–10	Rem ≤0.25 LDA >0.26 – 3.70 MDA 3.71 – <8.0 HDA ≥8.0	Yes	Yes, for HAQ
PAS-II	3	Pain PtGA HAQ II	Patient item	1 week	VAS	0–10	Rem ≤0.25 LDA >0.26 – 3.70 MDA 3.71 – <8.0 HDA ≥8.0	Yes	Yes, for HAQ-II
RADAI	5	PtGA Pain Swollen and tender joints (on VAS) AM stiffness Pt-TJC	Patient item	6 months	VAS Joint count	0–10	LDA <2.2 MDA ≥2.2 to ≤4.9 HAD >4.9	Yes	Yes
RADAI-5	5	PtGA Pain Swollen and tender joints (on VAS) General health AM Stiffness	Patient item	6 months	VAS	0–10	Rem ≤1.4 LDA 1.6–3.0 MDA 3.2–5.4 HDA ≥5.6	Yes	Yes
RAPID3	3	Pain PtGA MDHAQ*	Patient item	1 week	VAS	0–30	Rem ≤3 LDA 4–6 MDA 7–12 HDA ≥13	Yes	Yes
RAPID4	4	Pain PtGA MDHAQ* Pt-TJC	Patient item	1 week	VAS Joint count	0–40	Rem ≤4 LDA 5–8 MDA 9–16 HDA ≥17	Yes	No
RAPID5	5	Pain PtGA MDHAQ* Pt-TJC PrGA	Patient item, Provider assessment	1 week	VAS Joint count	0–50	Rem ≤5 LDA 6–10 MDA 11–20 HDA ≥21	Yes	No
SDAI	5	28SJC 28TJC PtGA PrGA CRP	Patient item, Provider assessment, Blood draw	None	VAS Joint count Lab measure	0–86	Rem ≤3 LDA >3.3 – ≤11 MDA >11 – ≤26 HDA >26	Yes	N/A

^*Cross-cultural validation in measures not including a patient questionnaire was considered not applicable (N/A).

^**Alternative cutoffs for the DAS28-CRP have been proposed: remission (<2.4), low disease activity (2.4 to <2.9), moderate disease activity (2.9 to ≤4.6), and high disease activity (>4.6).

Abbreviations: CRP, C-reactive protein; EGF, epidermal growth factor; EMS, early morning stiffness; ESR, erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; HDA, high disease activity; IL-6, interleukin 6; LDA, low disease activity; MDA, moderate disease activity; MDHAQ, Multidimensional Health Assessment Questionnaire; mHAQ, modified Health Assessment Questionnaire; MMP, matrix metalloproteinase; PrGA, provider global assessment; PtGA, patient global assessment; Pt-SJC, patient-derived swollen joint count; Pt-TJC, patient-derived tender joint count; RAI, Ritchie articular index; Rem, remission; ROAD, Recent Onset Arthritis Disability questionnaire; SAA, serum amyloid A; SJC, swollen joint count; TJC, tender joint count; TNFRI, tumor necrosis factor receptor type I; VAS, visual analog scale; VCAM-1, vascular cell adhesion molecule 1; VEGF-A, vascular endothelial growth factor A;

Table 2:

Psychometric properties of rheumatoid arthritis disease activity measures

Measure	Floor, ceiling effects	Reliability	Validity	Responsiveness	Minimally important differences	Generalizability	Used in RCTs
CDAI	Possible floor effect	Poor to moderate internal consistency. Strong test-retest reliability.	Content: Contains 4 ACR core measures. Criterion: Moderate to strong correlation and agreement with other RA disease activity measures. Predicts radiographic progression. Construct: Correlates with pain, physical function, and imaging modalities.	Moderate to large responsiveness (SRM 0.54–1.24). Moderate to strong correlation with changes in other RA disease activity measures.	MCID:  1 (LDA)  6 (MDA)  12 (HDA) MCII: 12	May be higher in females and chronic pain.	Yes
DAS	No	Good internal consistency. Strong test-retest reliability.	Content: Contains 4 ACR core measures. Criterion: Discriminates high vs low disease activity. Predicts radiographic progression. Construct: Correlates with physical disability.	Large responsiveness (SRM 1.9).	MID: 1.2 MCII:  DAS28-ESR (1.2)  DAS28-CRP (1.0)	Age, sex, and adiposity may affect acute phase reactants. May be higher in chronic pain.	Yes
DAS28-ESR/CRP	No	Poor to moderate internal consistency. Strong test-retest reliability.	Content: Contains 4 ACR core measures. Criterion: Discriminates ACR response and strong agreement with EULAR response. May underestimate risk of radiographic progression. Construct: Correlates with physical function and quality of life.	Large responsiveness (SRM 0.87–1.94)	1.2	Age, sex, and adiposity may affect acute phase reactants. May be higher in chronic pain.	Yes
HUPI	Possible ceiling effect.	Moderate internal consistency. Test-retest reliability not assessed.	Content: Contains 4 ACR core measures. Criterion: Strong to very strong correlation with other RA disease activity measures. Discriminates disease activity categories. Construct: Correlates with the HAQ.	Large responsiveness (SES 1.55–3.69). Correlates with changes in other RA disease activity measures.	MID: 4	Limited study. Considers the influence of sex on acute phase reactants.	No
MBDA score	No	MBDA score and component biomarker assays are highly precise.	Content: Contains 1 ACR core measure. Biomarkers predict components of DAS28-CRP. Criterion: Moderate correlation with the DAS28-ESR and DAS28-CRP. Predicts radiographic progression. Construct: Moderate correlation with the HAQ.	SRM not assessed. Correlates modestly with changes in other disease activity measures.	MID: 8	Tocilizumab increases IL-6 levels. Age and obesity influence the MBDA (modified score available). Not affected by chronic pain.	No
PAS	Modest floor effect	Not assessed	Content: Contains 3 ACR core measures. Criteria: Strong correlation with RAPID3, RADAI. Construct: Moderate agreement with EuroQOL. Discriminates improvements in SF-36.	Large responsiveness (SES = 1.57). Very strong correlation with changes in RAPID3.	MCID: 0.5 MCII: 1.1 MCIW: 1.1	May be influenced by chronic pain.	No
PAS-II	Modest floor effect	Not assessed	Content: Contains 3 ACR core measures. Criteria: Fair agreement with DAS28-ESR, CDAI. Construct: Moderate agreement with EuroQOL.	Not assessed	Not established	May be influenced by chronic pain.	No
RADAI	Mild floor effect	Excellent internal consistency and test-retest reliability.	Content: Contains 3 ACR core measures. Joint count is patient assessed. Criterion: Moderate to strong correlation with other RA disease activity measures. Discriminates DAS28 disease activity categories. Construct: Correlates with PrGA, HAQ, and CRP.	Large responsiveness (SES 1.36–1.58). Correlates with changes in other RA disease activity measures.	MCID: 1.0–1.4	May be less reliable in pregnancy. May be influenced by chronic pain disorders.	No
RADAI-5	Mild floor effect	Excellent internal consistency.	Content: Contains 3 ACR core measures. Joint count is patient assessed. Criterion: Moderate to strong correlation with other RA disease activity measures. Construct: Moderate agreement with MDHAQ.	SRM not assessed. Correlates with changes in other disease activity measures.	Not established	May be influenced by chronic pain disorders.	No
RAPID3	Modest floor effect	Excellent internal consistency and test-retest reliability.	Content: Contains 3 ACR core measures. Criterion: Moderate to strong correlation and fair agreement with other RA disease activity measures. Predicts functional and radiographic outcomes. Construct: RAPID3 correlates with hand function and quality of life.	Large responsiveness (SRM 1.24–1.46). Less responsive than CDAI in a RCT with TNFi use.	Good response: decrease >3.6 and achieve score <6.	May be higher in osteoarthritis.	Used in one RCT
RAPID4	Not assessed	Not assessed	Content: Contains 4 ACR core measures. Includes a patient joint count. Criterion: Moderate to strong correlation with other RA disease activity measures. Construct: Not assessed.	Not assessed	Not assessed	May be affected by chronic pain and osteoarthritis.	No
RAPID5	Not assessed	Not assessed	Content: Contains 5 ACR core measures. Includes a patient joint count. Criterion: Slightly stronger correlation with other disease activity measures compared to RAPID3/4. Construct: Not assessed.	Not assessed	Not assessed	May be affected by chronic pain and osteoarthritis.	No
SDAI	Possible floor effect	Poor to moderate internal consistency. Excellent test-retest reliability.	Content: Contains 5 ACR core measures. CRP accounts for only 5% of variance. Criterion: Strong correlation and agreement with DAS28-ESR and DAS28-CRP. SDAI remission more stringent than DAS28. Predicts radiographic progression. Construct: Associated with measures of physical function and quality of life.	Large responsiveness (SRM 0.97–1.33).	MCII: 13	May be elevated in females. Acute phase reactants may be influenced by obesity.	Yes

Abbreviations: CRP, C reactive protein; HAQ, Health Assessment Questionnaire; MCID, minimal clinically important difference; MCII, minimal clinically important improvement; MCIW, minimal clinically important worsening; MDHAQ, Multi-Dimensional Health Assessment Questionnaire; MID, minimally important difference; PrGA, provider global assessment; RA, rheumatoid arthritis; RCT, randomized controlled trial; SES, standard effect size; SF-36, Short Form 36; SRM, standardized response mean; TNFi, tumor necrosis alpha inhibitor.

Glossary

CDAI

Clinical Disease Activity Index

DAS

Disease Activity Score

DAS28-ESR & DAS28-CRP

Disease Activity Score with 28-Joint Counts

HUPI

Hospital Universitario La Princesa Index

MBDA

Multi-Biomarker Disease Activity score

PAS

Patient Activity Score

PAS-II

Patient Activity Score-II

RADAI

Rheumatoid Arthritis Disease Activity Index

RADAI-5

Rheumatoid Arthritis Disease Activity Index 5

RAPID3, RAPID4, & RAPID5

Routine Assessment of Patient Activity Index

SDAI

Simplified Disease Activity Index