As very effective targeted biological therapies have become available to treat rheumatoid arthritis (RA), remission is now the goal of treatment. Since 1981, efforts have been undertaken to develop criteria for clinical remission in RA. Although several different measures of disease activity have been proposed, many issues remain unresolved. Active joint inflammation, even if involving only a few joints, negatively impacts a patient’s quality of life and may ultimately result in structural damage. Thus, a low disease activity state (LDAS), which has been adopted as the target in clinical trials of ‘treat to target’, may not be the optimal treatment target in clinical practice. Similarly, the definitions of remission used in clinical trials may not be appropriate for use in daily clinical practice because some allow for the presence of several tender and swollen joints. Measures of disease activity do not necessarily correlate with structural remission, which implies halting progression of radiographic evidence of damage over time. Because no single measure of RA disease activity fully quantifies the global burden of disease, rheumatologists must follow multiple parameters to assess disease activity thoroughly and to adjust treatment optimally.
How can we assess disease to know if it is controlled?
Over the past decade, the availability of very effective, but expensive, targeted biological therapies to treat rheumatoid arthritis (RA) has underscored the need for rheumatologists to accurately assess disease activity to optimise the use of these agents. The current approach to treating RA is modelled upon that of diabetes mellitus, with tight control aimed towards achieving an objective outcome measure that reflects control of disease activity . The recent consensus of an international group of experts recommends a ‘treat to target’ approach for RA treatment based on objective measures of disease activity and aimed towards promptly achieving remission or a low disease activity state (LDAS) . This approach requires accurate and objective monitoring of disease activity to guide the advancement of drug treatment, according to level of disease activity .
Various instruments have been developed to measure disease activity in RA. These assess a range of disease characteristics, including elements of the physical examination, acute phase reactants, patient and physician global assessment of disease activity and patient assessment of pain and fatigue. Although originally developed for use in clinical trials of drug therapy for RA, some of these tools have been adopted for use in daily clinical practice.
To standardise these instruments, the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) and the World Health Organization/International League Against Rheumatism (WHO/ILAR) have proposed a ‘core’ set of variables that includes: swollen and tender joint counts, patient assessment of pain, patient global assessment, physician global assessment, measurement of functional status and laboratory measurement of acute phase reactants. Because different RA patients display distinctive clinical presentations, no single variable accurately reflects every patient’s disease activity at any given point in time. Thus, composite scores have been developed that integrate various individual core variables into a single number. The development and implementation of simplified joint assessments that require evaluation of only 28 joints has facilitated the adoption of these composite scores by rheumatologists to provide a continuous measure of disease activity in routine clinical practice . These composite indices, which include the disease activity score including a 28-joint count (DAS28) , the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) , can be used regularly to categorise disease activity into specific states, such as high, moderate and low disease activity or remission.
By contrast, dichotomous measures of disease activity such as the ACR and EULAR response criteria classify levels of response to treatment compared to a baseline visit. These are challenging to use in routine patient care, since a single baseline visit often is irrelevant when monitoring disease activity and response to therapy over time. It becomes difficult, in clinical practice, to choose an appropriate baseline visit for a patient who is being cared for over an extended period of time . Should it be the initial encounter between the patient and the rheumatologist or should it be that visit when a new medication was initiated? The baseline visit may change, depending upon the therapeutic intervention that is being assessed.
Patient-reported outcomes are independent of physician assessment of joint disease activity. Scores derived from these self-reported questionnaires reflect disease activity by providing a global measure of functional status. Such outcome measures do not include an objective assessment of swollen or tender joints. However, because a patient’s maximal physical function may be limited by long-standing structural damage, even in the absence of swollen or tender joints, a patient-reported outcome measure may not provide an accurate reflection of improvement in joint disease activity in response to treatment.
Both composite disease activity scores and patient-reported outcome assessments are valid measures of RA disease activity. When used in combination, they capture multiple dimensions of a patient’s clinical status . In addition, to assess for progression of joint cartilage space narrowing and bony erosions, plain radiographs of the hands and feet should be obtained at least every 2 years . In clinical trials, plain radiographs are formally scored using the Sharp scoring method , or the van der Heijde or Genant modifications of this method. Other imaging modalities, such as magnetic resonance imaging (MRI) and ultrasonography with power Doppler, demonstrate synovitis; however, there is no consensus as to how these should be incorporated into routine monitoring of RA disease activity.
Clinical measures of disease activity
ACR response criteria
The ACR response criteria were developed to distinguish the results of treatment of RA with an active drug from that with placebo in randomised controlled clinical trials . These criteria require at least a 20%, 50% or 70% improvement in the number of tender and swollen joints and a similar level of improvement in three of five other criteria: patient and physician global assessment of disease activity, patient assessment of pain, patient assessment of physical function using the Health Assessment Questionnaire (HAQ), and laboratory measurement of an acute phase reactant (erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)). Because these dichotomous measures compare disease activity between two discrete points in time, it is difficult to use them to monitor disease activity in routine clinical practice.
Disease Activity Scores (DAS)
The DAS and DAS28 can be used both in clinical trials and in daily clinical practice to quantify disease activity at any individual point in time or longitudinally . These continuous numerical measures include objective assessments of joint pain and swelling, patient subjective assessment of disease activity, and a laboratory measurement of an acute phase reactant. Because the formula for each of these continuous variables is complex, calculation of the DAS or DAS28 requires the use of a computational device.
The original DAS uses the Ritchie articular index (RAI) to enumerate tenderness in 53 joints and swelling in 44 joints . The DAS28 employs a simplified 28-joint count that includes only the shoulders, elbows, wrists, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands, thumb interphalangeal joints and knees and excludes the hips, ankles and feet. The validity of this modified DAS including a 28-joint count has been compared to the DAS calculated using more comprehensive joint counts in multiple studies . Possible scores for both the DAS and the DAS28 range from 0 to 9.
Disease activity categories of both the DAS and the DAS28 are remission and low, moderate and high disease activity ( Table 1 ). Based upon a formula that converts DAS to DAS28, remission characterised by DAS28 < 2.6 correlates with that characterised by DAS <1.6 . Patients with DAS28 scores in the remission range (DAS28 < 2.6) can still have up to 28 swollen, or 21 tender, or nine swollen and tender joints (excluding the ankles and feet, which are not included in the 28-joint count used to calculate the DAS28). Thus, the DAS28 is a less accurate reflection of remission of RA disease activity than the DAS (insufficient construct validity) . However, patients who had DAS28 < 2.6 in the setting of swollen or tender ankle or metatarsophalangeal (MTP) joints still reported higher global assessment of disease activity than RA patients without active disease in those joints .
| Calculation |
| DAS28 (ESR) = 0.56 × √ (TJC 28) + 0.28√ (SJC 28) + 0.70 × ln(ESR) + 0.014 × GH |
| (range: 0 – 9) |
| DAS28 (CRP) = 0.56 × √ (TJC28) + 0.28 √ (SJC 28) + 0.36 × ln(CRP+1) + 0.014 × GH + 0.96 |
| (range: 1 – 9) |
| Categories |
| Low disease activity > 2.6 and ≤ 3.2 |
| Moderate disease activity > 3.2 and ≤ 5.1 |
| High disease activity > 5.1 |
| 28 tender-joint count (TJC28) |
| 28 swollen-joint count (SJC28) |
| Acute-phase reactant: ESR or CRP |
| Patient global assessment of disease activity (GH) on visual analogue scale (0–100 mm) |
EULAR response criteria
The EULAR response criteria define ‘good’ and ‘moderate’ responses and non-response using a matrix that takes into account both the absolute decrease in disease activity and the level of disease activity at the treatment end point, using either the DAS or the DAS28 ( Table 2 ). To achieve a EULAR ‘good’ response, a patient must be in a state of ‘low’ disease activity or ‘remission’ at the treatment end point and exhibit a reduction in DAS or DAS28 of ≥1.2. If a patient is in a state of ‘moderate’ or ‘high’ disease activity at the treatment end point, he or she must demonstrate a reduction in DAS or DAS28 of ≥1.2 to achieve a EULAR ‘moderate’ response. Similarly, if the patient’s state of disease activity is ‘moderate’ or lower at the treatment end point, he or she must display evidence of a reduction in DAS or DAS28 of >0.6 and ≤1.2 to achieve a EULAR ‘moderate’ response. The EULAR response criteria have shown better construct validity than the ACR response criteria, thereby more accurately reflecting improvement in RA disease activity . However, as with the ACR response criteria, these dichotomous measures also require comparison of disease activity at two discrete time points, which renders them difficult to use to monitor response to drug treatment in clinical practice.
| DAS at endpoint | DAS28 at endpoint | Improvement in DAS or DAS28 from baseline | ||
|---|---|---|---|---|
| ≤1.2 | >0.6 and ≤1.2 | ≤0.6 | ||
| ≤2.4 | ≤3.2 | Good | ||
| >2.4 and ≤3.7 | >3.2 and ≤5.1 | Moderate | ||
| >3.7 | >5.1 | None | ||
Simplified and clinical disease activity indices
The SDAI and CDAI both use a 28-joint count to enumerate swollen and tender joints . The SDAI consists of the numerical sum of the four components of the DAS28, with the addition of a physician global assessment of disease activity ( Table 3 ). The CDAI omits the CRP, thereby allowing for its calculation at the time of the patient encounter without waiting for laboratory determination of an acute phase-reactant level. The cut-off points for remission are SDAI < 3.3 and CDAI < 2.8. Because acute phase-reactant levels are not readily available at the time of most patients’ outpatient visits, the CDAI is a more practical measure for rheumatologists to use when following patients in clinical practice. The CDAI can be calculated immediately and thus can be used in real time to make informed management decisions . Because CRP values correlate with other core set measures and often are within the normal range, despite the presence of swollen and tender joints, the validity of the CDAI is not affected by excluding the CRP . The SDAI and CDAI are more stringent measures of disease activity than is the DAS28, because the SDAI and CDAI remission criteria allow for the fewest number of tender and swollen joints . The longer a patient remains in either SDAI or CDAI remission, the lower is that patient’s risk of exhibiting progression of structural damage on plain radiographs .
| SDAI | CDAI |
|---|---|
| Tender-joint count of 28 joints Swollen-joint count of 28 joints C-reactive protein Patient global assessment of disease activity on visual analogue scale Evaluator global assessment of disease activity on visual analogue scale SDAI is the numerical sum of the above components (range: 0 − 86) Categories Remission ≤ 3.3 Low disease activity > 3.3 and ≤ 20 Moderate disease activity > 20 and ≤ 40 High disease activity > 40 Major improvement: decrease of 22 or more Minor improvement: decrease of 10 to 21 | Tender-joint count of 28 joints Swollen-joint count of 28 joints Patient global assessment of disease activity on visual analogue scale Evaluator global assessment of disease activity on visual analogue scale CDAI is the numerical sum of the above components (range: 0 − 76) Categories Remission ≤ 2.8 Low disease activity > 2.8 and ≤ 10 Moderate disease activity > 10 and ≤ 22 High disease activity > 22 |
Clinical measures of disease activity
ACR response criteria
The ACR response criteria were developed to distinguish the results of treatment of RA with an active drug from that with placebo in randomised controlled clinical trials . These criteria require at least a 20%, 50% or 70% improvement in the number of tender and swollen joints and a similar level of improvement in three of five other criteria: patient and physician global assessment of disease activity, patient assessment of pain, patient assessment of physical function using the Health Assessment Questionnaire (HAQ), and laboratory measurement of an acute phase reactant (erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)). Because these dichotomous measures compare disease activity between two discrete points in time, it is difficult to use them to monitor disease activity in routine clinical practice.
Disease Activity Scores (DAS)
The DAS and DAS28 can be used both in clinical trials and in daily clinical practice to quantify disease activity at any individual point in time or longitudinally . These continuous numerical measures include objective assessments of joint pain and swelling, patient subjective assessment of disease activity, and a laboratory measurement of an acute phase reactant. Because the formula for each of these continuous variables is complex, calculation of the DAS or DAS28 requires the use of a computational device.
The original DAS uses the Ritchie articular index (RAI) to enumerate tenderness in 53 joints and swelling in 44 joints . The DAS28 employs a simplified 28-joint count that includes only the shoulders, elbows, wrists, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands, thumb interphalangeal joints and knees and excludes the hips, ankles and feet. The validity of this modified DAS including a 28-joint count has been compared to the DAS calculated using more comprehensive joint counts in multiple studies . Possible scores for both the DAS and the DAS28 range from 0 to 9.
Disease activity categories of both the DAS and the DAS28 are remission and low, moderate and high disease activity ( Table 1 ). Based upon a formula that converts DAS to DAS28, remission characterised by DAS28 < 2.6 correlates with that characterised by DAS <1.6 . Patients with DAS28 scores in the remission range (DAS28 < 2.6) can still have up to 28 swollen, or 21 tender, or nine swollen and tender joints (excluding the ankles and feet, which are not included in the 28-joint count used to calculate the DAS28). Thus, the DAS28 is a less accurate reflection of remission of RA disease activity than the DAS (insufficient construct validity) . However, patients who had DAS28 < 2.6 in the setting of swollen or tender ankle or metatarsophalangeal (MTP) joints still reported higher global assessment of disease activity than RA patients without active disease in those joints .
| Calculation |
| DAS28 (ESR) = 0.56 × √ (TJC 28) + 0.28√ (SJC 28) + 0.70 × ln(ESR) + 0.014 × GH |
| (range: 0 – 9) |
| DAS28 (CRP) = 0.56 × √ (TJC28) + 0.28 √ (SJC 28) + 0.36 × ln(CRP+1) + 0.014 × GH + 0.96 |
| (range: 1 – 9) |
| Categories |
| Low disease activity > 2.6 and ≤ 3.2 |
| Moderate disease activity > 3.2 and ≤ 5.1 |
| High disease activity > 5.1 |
| 28 tender-joint count (TJC28) |
| 28 swollen-joint count (SJC28) |
| Acute-phase reactant: ESR or CRP |
| Patient global assessment of disease activity (GH) on visual analogue scale (0–100 mm) |
EULAR response criteria
The EULAR response criteria define ‘good’ and ‘moderate’ responses and non-response using a matrix that takes into account both the absolute decrease in disease activity and the level of disease activity at the treatment end point, using either the DAS or the DAS28 ( Table 2 ). To achieve a EULAR ‘good’ response, a patient must be in a state of ‘low’ disease activity or ‘remission’ at the treatment end point and exhibit a reduction in DAS or DAS28 of ≥1.2. If a patient is in a state of ‘moderate’ or ‘high’ disease activity at the treatment end point, he or she must demonstrate a reduction in DAS or DAS28 of ≥1.2 to achieve a EULAR ‘moderate’ response. Similarly, if the patient’s state of disease activity is ‘moderate’ or lower at the treatment end point, he or she must display evidence of a reduction in DAS or DAS28 of >0.6 and ≤1.2 to achieve a EULAR ‘moderate’ response. The EULAR response criteria have shown better construct validity than the ACR response criteria, thereby more accurately reflecting improvement in RA disease activity . However, as with the ACR response criteria, these dichotomous measures also require comparison of disease activity at two discrete time points, which renders them difficult to use to monitor response to drug treatment in clinical practice.
| DAS at endpoint | DAS28 at endpoint | Improvement in DAS or DAS28 from baseline | ||
|---|---|---|---|---|
| ≤1.2 | >0.6 and ≤1.2 | ≤0.6 | ||
| ≤2.4 | ≤3.2 | Good | ||
| >2.4 and ≤3.7 | >3.2 and ≤5.1 | Moderate | ||
| >3.7 | >5.1 | None | ||
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