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Rheumatology Advance Access originally published online on March 6, 2007
Rheumatology 2007 46(6):975-979; doi:10.1093/rheumatology/kem007
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Assessing remission in clinical practice

M. Mierau1, M. Schoels1, G. Gonda1, J. Fuchs1, D. Aletaha2 and J. S. Smolen1,2

12nd Department of Medicine – Centre for Rheumatic Diseases, Hietzing Hospital and 2Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria

Correspondence to: J. Smolen, MD, Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: josef.smolen{at}wienkav.at


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Remission constitutes the best achievable state in patients zwith rheumatoid arthritis. We aimed at evaluating sustained remission in a large cohort of patients followed prospectively in clinical practice and to evaluate available instruments to define remission for their stringency in defining this state.

Patients and Methods. We analysed remission and sustained remission in 621 patients who had two consecutive and complete clinical observations; the average period between the two visits was 92 days (median; quartiles: 82; 105). Remission was evaluated according to modified ACR (mACR), 28 Joint Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) criteria. Sustained remission was defined as remission at both consecutive visits. Patients were treated with traditional disease- modifying antirheumatic drugs, mainly methotrexate, and partly with biological agents (~11%).

Results. Remissions at any one of the two visits were seen in 33.5% of patients by SDAI or CDAI, 42.7% by DAS28, and 38.6% by mACR criteria (P < 0.01). Sustained remission was observed in much lower proportions of patients (between 16.7 and 19.6%, dependent on the instrument). Agreement between classifications of remission by {kappa}-statistics was very good for SDAI vs CDAI, good for DAS28 vs SDAI or CDAI, and only moderate for mACR vs the three other scores. Residual swollen joints were observed in 15% of patients in DAS28 remission (range 1–9), 6% of patients in mACR remission (range 1–8), but only ~5% of patients in CDAI or SDAI remission (range 1–2) (P < 0.01).

Conclusion. Sustained remission can be observed in 17–20% of patients in clinical practice. CDAI and SDAI remission criteria are more stringent than DAS28 and mACR criteria, since they allow for lesser residual disease activity. Consequently, smaller proportions of patients are classified as in remission by SDAI and CDAI than by DAS28 and mACR criteria. Sustained remission is an achievable goal in clinical practice even with the most stringent of the definitions studied.

KEY WORDS: Rheumatoid arthritis, Remission, Low disease activity, CDAI, SDAI, DAS28, Pinals


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. RA disease activity and progression can be controlled by treatment with disease-modifying antirheumatic drugs (DMARDs). Therapeutic goals and strategies have changed over the last decade with high dose weekly methotrexate (MTX) portending the change in the treatment landscape before the era of biological agents [1, 2]. Importantly, however, since high disease activity is associated with poor outcome of RA [3–6], therapies have recently aimed at achieving low disease activity. In fact, two very recent trials targeting low disease activity states by changing treatment in conjunction with tight control strategies have revealed that this concept, when compared with less stringent strategies, improves functional and radiographic outcomes over the short term [7, 8]. Nevertheless, even under such apparently ideal therapeutic settings, mean or median joint damage still increased significantly over time in states of low disease activity [7–10]. This suggests that such states might not constitute the optimal therapeutic aim. Indeed, a need to achieve remission has been recently advocated [11–13].

On the other hand, the term remission is still ill-defined, and the various remission criteria allow different degrees of disease activity to be called remission [14–19]. Nevertheless, remission as a reflection of no, or at the most, minimal disease activity ought to ensure maximal reversal, preferably normalization of functional impairment and minimal progression of joint destruction, ideally halt and even healing of joint destruction [10, 20–22]. This issue will need to be addressed thoroughly in future trials to learn if asymptomatic synovitis, which does exist according to sonographic studies [23], is also associated with progression of joint damage. However, the vast majority of patients with absence of clinically discernible synovitis do not progress individually [24] and as a group irrespective of the type of therapy [25].

Clinical trials are idealized situations in which, by virtue of study design and control of case record forms, adherence to study principles is high. Inclusion and exclusion criteria require studying a pre-selected group of patients, often greatly differing from most patients seen in clinical practice. In contrast, observational studies usually include all patients seen, irrespective of their disease activity, underlying comorbidity or therapy, and the data generated, therefore, reflect routine care situations. Routine clinical care is influenced by patient and physician preferences and potential biases. Thus, while controlled clinical trials provide first line evidence of efficacy and safety of a therapeutic or treatment strategy in a selected group of patients, observational studies inform on effectiveness in the long term [26]. Moreover, rather than allowing judgement on the relatively few patients engaged in successful arms of randomized controlled clinical trials, results of observational studies help understanding transpositions of new paradigms or treatment guidelines into daily care and the degree of benefit from such translation of study results into practice.

Currently, it is still insufficiently known how frequent patients achieve remission, this foremost desired state, under conditions of routine clinical care. Therefore, in the present study we aimed at determining remission by various validated indices among an observational RA patient cohort who underwent regular, prospective control examination employing mandatory use of a clinical database at every visit.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients and clinical assessment
Over a period of 12 months in 2005, 948 patients with RA according to the ACR classification criteria [27] were followed in our out-patient clinic prospectively using a database established for routine clinical CAre of RA (CARAbase). Of these patients, complete datasets for two consecutive visits were available in 621 patients within the 12-month period studied. Baseline demographic data of these patients are shown in Table 1. Except for a small number, all patients were treated with DMARDs and/or biologicals (Table 2); non-steroidal anti-inflammatory drug (NSAIDs) and/or corticosteroids were added when appropriate.


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  		TABLE 1. Patient characteristics (n = 621)

 

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  		TABLE 2. Therapies of patients assessed at the two consecutive visits (n = 621)

 
Clinical assessments comprised 28 joint counts for swollen and tender joints (SJC and TJC, respectively), pain visual analogue scale (VAS), evaluator and patient global assessments (EGA, PGA, respectively) by VAS, health assessment questionnaire disability index (HAQ), morning stiffness (MST), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Evaluation of remission
Patients were evaluated for the fulfilment of remission by the following criteria: modified ACR remission criteria (mACR) [14], 28 joint Disease Activity Score (DAS28) < 2.6 [14], Simplified Disease Activity Index (SDAI) ≤ 3.3 and Clinical Disease Activity Index (CDAI) ≤ 2.8 [17, 18].

The following formulae were used [14, 17, 18]: DAS28= 0.56x{surd}TJC28 + 0.28x{surd}SJC28 + 0.70xlognat(ESR) + 0.014xGH(PGA); SDAI = SJC + TJC + PGA (cm) + EGA (cm) + CRP (mg/dl); CDAI = SJC + TJC + PGA (cm) + EGA (cm); where SJC and TJC constitute swollen and tender joints using the 28 joint count. Fulfilment of the mACR remission criteria required four of the following five items to be met: MST ≤ 15 minutes, no joint pain by history, no joint tenderness, no swollen joints, and an ESR < 30 mm (female) or <20 mm (male); compared with the original Pinals criteria [15], fatigue was omitted [14]. In an exploratory analysis, we also looked at those patients who had a normal CRP and no swollen joints; although such ‘score’ has not been validated, many physicians might employ such simple definition and, therefore, this was compared with CDAI and SDAI to see if there were any stringency benefits of the composite indices over such even more simplified simple method of using just two of the five variables.

We defined sustained remission as fulfilment of the remission criteria at two consecutive visits, at least 1 month apart, with complete data sets.

Statistical analysis
We tested data of all variables for normal distribution using a one-sample Kolmogorov–Smirnov test. Wilcoxon test and Mann–Whitney U-test were applied to analyse differences in core set measures. Correlations were calculated using Spearman rank correlation. Agreement between classifications of remission was assessed by {kappa}-statistics. McNemar's test was applied to compare remissions achieved by the different indices. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, version 12.0, Chicago, IL, USA). P-values < 0.05 were regarded as significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Baseline characteristics
In Table 3, the individual baseline clinical and laboratory characteristics of all patients with complete data at the (two) consecutive visits (n = 621) are depicted.


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  		TABLE 3. Patients’ clinical characteristics (n = 621) at the two consecutive visits

 
The median (quartiles) interval between these consecutive visits was 92 (82,105) days and the range 1–8 months.

The median joint counts were very low (0–1 for both, SJC and TJC) and so were also other variables, such as CRP and ESR. Since this is a cross-sectional representation of the patients followed at our clinic and not an inception cohort, these low values of the core set variables indicate that many patients had reached at least a state of low disease activity on the treatment regimens shown in Table 2. This is also revealed in Fig. 1A and B, which shows that less than ~10% of the patients fall into the high disease activity categories of the three composite indices employed and that approximately 50–67% of the patients had reached low disease activity or remission, depending on the score used.


Figure 1
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  		FIG. 1. Proportion of patients (n = 621) in distinct disease activity categories by various indices. (A) Remission at visit 1, (B) Remission at visit 2. CDAI and SDAI remissions are consistently less frequent than DAS28 and mACR remissions.

 
Reaching remission depends on score employed
When looking at remission at any one of the two consecutive visits analysed, the proportions of patients in remission were highest for the DAS28 (43%), followed by mACR (39%), SDAI and CDAI (34% each) (Fig. 2). This application of the remission criteria showed that significantly more patients had reached DAS28 remission than mACR, SDAI or CDAI remission (P < 0.01 McNemar test). Importantly, however, sustained remission (at two consecutive visits) was seen in only <20%, ranging from 16.7% (CDAI) to 19.6% (DAS28) (Fig. 2).


Figure 2
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  		FIG. 2. Remissions among 621 patients at any one of the two consecutive visits (left) and sustained remission, i.e. remission at both visits (right) as assessed by the different disease activity indices. Remissions were significantly (P < 0.01) more frequent when categorized by DAS28 than by CDAI and SDAI criteria.

 
In an exploratory analysis, we also evaluated patients who had no swollen joint and no increase in CRP: 40% were classified as in remission at any one of the two visits, revealing that SDAI and CDAI criteria, which also comprise tender joints and global assessments, were more stringent than the use of just two of the SDAI variables; although this figure was close to that obtained for DAS28 remission, a significant number of patients in DAS28 remission had residual swollen joints (see subsequently).

In Table 4, the values of disease activity indices at the non-remission visits of those patients who failed to sustain remission are shown. For patients fulfilling mACR, CDAI or SDAI remission criteria only once, the ranges of the DAS28, SDAI and CDAI at the non-remission visit reached well into the moderate and occasionally even into the high disease activity categories. Consequently, the mean disease activity of the non-remission visits was significantly higher than of visits in remission (P < 0.01). Interestingly, when comparing the non-remission visits according to the DAS28 with the non-remission visits according to the SDAI the DAS28-non-remission visits had higher disease activity than the SDAI-non-remission visits (P < 0.01 for comparison of the respective SDAI and CDAI values; Table 4). These data suggested that disease activity in DAS28 remission might be generally higher than disease activity in remission by the other scores, as will be shown subsequently.


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  		TABLE 4. Medians, quartiles and ranges of values of disease activity indices in the non-remission visits (of patients with one visit in remission)

 
Rates of concordance of classification of remission by the different remission criteria
The agreement of classification into remission was—not surprisingly—best for SDAI and CDAI ({kappa} = 0.89, P = 0.0001) and good for DAS28 and SDAI or CDAI ({kappa} = 0.63 and 0.58, respectively, P = 0.0001), but only moderate for the concordance of mACR criteria with any of the other ones ({kappa} = 0.36 for SDAI and CDAI, and 0.40 for the DAS28, P = 0.001). Interestingly, significantly (p < 0.01) more patients fulfilling DAS28 remission criteria (<2,6) had CDAI values in low disease activity rather than remission (>2.8) than vice versa of values 37% very similar results were observed when SDAI and DAS28 cutpoints for remission were compared (data not shown). In contrast, a thus, the CDAI and SDAI criteria are more specific for remission than the respective ones for the DAS28.

Residual joint counts in remission
It has been previously discussed that patients in DAS28 remission may have relatively large numbers of residual joint counts, especially swollen joints [16, 17, 19]. Therefore, as a surrogate of residual disease activity, we evaluated the joint counts that were still found in remission according to the various criteria. Indeed, when looking at patients in sustained remission, residual swollen joints were seen in 13% of patients in DAS28 remission (range 1–4), in 7% of patients in mACR remission (range 1–6), but in only 5% of patients in SDAI and CDAI remission (range 1–2). When looking at all remissions in all patients seen during the observation period (Table 5), 15% of the visits classified as in DAS28 remission had one or more swollen joints ranging up to nine involved joints, while the joint counts were significantly lower (P < 0.01) in SDAI or CDAI remissions; 6% of the visits in remission by mACR criteria showed ≥1 swollen joint with a range of 1–8.


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  		TABLE 5. Residual 28 SJCs in remission defined by composite scores (available visits: 2904)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In the present study we have revealed that ~50–70% of RA patients followed in routine clinical care achieve a state of low disease activity or remission and that less than ~10% of the patients fall into the high disease activity categories according to the various composite scores. This is further confirmed by the very low median joint counts of 0–1 in the total observed patient population with two swollen joints comprising the upper quartile. This success of the recent days is in line with observations by others [28] and provides evidence for the therapeutic advances made by using new DMARDs including biological agents and novel treatment strategies. On the other hand, since even patients in low disease activity suffer from significant progression of joint damage [3, 5, 6, 9, 29], which in turn transpires into irreversible disability over time [20, 30], remission rather than low disease activity may have to be the therapeutic goal of our time. In this context it will be important to consider in future investigations that even patients with no clinical evidence of joint swelling may have (subclinical) synovitis [23].

We focussed on evaluation of sustained remission defined as remission at two consecutive visits with a mean inter-visit period of ~3 months. At both these visits, a similar proportion of patients fulfilled the individual remission criteria (~25–31%, depending on the instrument employed); interestingly, patients achieving remission at one time point had not only low but frequently moderate or even high disease activity at the other assessed visit. However, only a much smaller proportion of patients (<20%) exhibited sustained remission, i.e. remission at both of the two consecutive visits. Thus, while remission at an individual point in time may be achieved quite frequently, sustained remission is a less common event. In the present study, most patients were treated with traditional DMARDs, mainly MTX, while about 11% of all patients received biological agents. Thus, it seems that given our current treatment possibilities, there is substantial reserve capacity for achieving even higher remission rates in routine care of patients with RA. At the same time, a single visit showed not to be sufficient to specifically characterize the state of remission, as varying disease activity might cause some patients to occasionally fulfil criteria for remission.

The remission criteria analysed, namely mACR, DAS28, SDAI and CDAI, led to different proportions of remission with good agreement between SDAI or CDAI and DAS28 criteria, but only moderate agreement between mACR and remission according to the other three instruments. Among the various remission criteria the most stringent ones appeared to be the SDAI and CDAI criteria, since patients in SDAI and CDAI remission had the lowest mean residual joint counts and joint count ranges. Consequently, SDAI and CDAI criteria were fulfilled by the lowest proportion of patients. Although the CDAI allows to be employed even in the absence of laboratory values, the proportions of patients in remission by CDAI criteria were very similar to those by the SDAI criteria. In contrast, by virtue of the different construction of the score, patients in DAS28 remission (DAS28 < 2.6) had up to nine swollen joints in over 15% of visits in remission; this was the case in only 5% of patient visits in CDAI/SDAI remission with joint counts not exceeding two. Also patients fulfilling the mACR remission criteria presented with up to eight swollen joints, since only four of the five components of these criteria need to be fulfilled. The low stringency of the DAS28 remission criteria, especially in relation to residual joint counts, has already been addressed in previous studies [16, 19] and is also apparent from the difference between the proportions of patients with a single visit in remission and that of patients in sustained remission; this indicates a high frequency of ‘false positives’ for remission using the DAS28 criteria. Interestingly, the SDAI/CDAI criteria could not be replaced by merely looking at patients with no joint swelling and normal CRP, supporting previous notions on the importance of composite scores for disease activity assessment [31, 32].

The fact that some remission criteria allow for a high number of residual swollen joints deserves special mention. Synovitis and thus joint swelling is the major manifestation of the pathophysiological process underlying RA, and swollen joint counts are the major determinant of joint destruction [6, 29]. Therefore persistence of joint swelling will translate into progression of RA. It has not been shown hitherto that joint swelling ceases to have an impact on disease progression if present in a low or minimal disease activity category by composite scores when compared with higher ones. This aspect is of particular importance because of several recent reports on achievement of remission in the context of clinical trials [33–35], suggesting that up to 40% of patients reach remission by DAS28 criteria despite the inclusion of a large fraction of patients with considerable residual disease activity [19]. On the other hand, it appears that at least upon therapy with MTX, joint damage progresses in low disease activity, while only remission prevents its progression [25].

In summary, sustained remission is seen in a significant proportion of patients under routine clinical care. However, different remission criteria have different stringencies and the SDAI and CDAI criteria appear to be the most stringent ones currently validated, allowing for only minimal residual joint counts and thus reflecting a state of no active disease more closely than other scores. Given that remission constitutes the state with the least likelihood of disease progression, it is not only an important therapeutic goal clearly achievable in patients treated in clinical practice, but one that needs to be aimed for more vigorously using the best therapies and treatment strategies.

The authors have declared no conflicts of interest.


Figure 3
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  		FIG. 3. Scatter plot of CDAI (y-axis) and DAS28 (x-axis) values of patients in CDAI and Das28 remission. (lower left quadrant). Low night quadrant: CDAI remission but not DAS28 remision; upper left qudrant CDAS28 remission, but not CDAI remission.

 


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 9 August 2006; revised version accepted 3 January 2007.
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