This study was conducted to identify predictors for achieving and sustaining remission and to investigate the relationship between time-to-remission and sustained remission according to two different remission criteria in a cohort of early RA patients treated in daily practice between 1985 and 2005. According to the results of this study, the number of patients achieving remission was comparable during the whole time frame of the cohort. Predictors to achieve more rapidly DAS remission were male gender, younger age and a low DAS or HAQ at baseline. Sustained remission was only and mainly determined by time-to-remission; the chance of sustained remission increased significantly with decreasing time-to-remission. Over time, reflecting more intensive treatment, the time-to-remission tended to shorten, the occurrence of sustained remission tended to increase, but the relation between time-to-remission and sustainability remained fairly constant. This indicates that the relation between time-to-remission and sustainability does not heavily depend on the type or strategy of DMARDs given. Results obtained with the mACR remission criteria were similar.
This study is the first daily care study showing the influence of time-to-remission at sustained remission. In earlier studies on evaluation of remission in daily practice, comparable predictors have been identified for achieving remission in patients with early RA [20
]. Rheumatoid factor [11
] and anti-cyclic citrullinated peptide (anti-CCP) antibody status [22
], level of CRP[23
] and presence of erosions at baseline[20
] have also shown to be predictive for not achieving remission rapidly. Further, the early start of DMARDs combination therapy[24
] or anti-TNFα agents plus MTX [5
] in RA patients emerged to be predictive for sustained remission.
Since treatment in patients with RA has shifted towards a more early and aggressive treatment strategy, higher remission rates and more sustainability of remission are expected these days. Remarkably in this study, the association between time-to-remission and sustained remission was present in all cohort patients, irrespective of date of inclusion. Therefore, early remission seems to be essential for sustained remission, and thus the further course of RA. Earlier studies have already confirmed this implication. In addition, the frequency of remission after one year was significantly higher among responders than among the non-responders [11
] and achieving low disease activity within three months of treatment was associated with low disease activity or remission at one year[12
Several criteria of (sustained) clinical remission are available and remission results of studies may for this reason depend on the remission criterion used [3
]. This study applied both DAS and mACR as remission criteria, which resulted in similar predictors for attaining and sustaining remission. Moreover, the relationship between time-to-remission and sustained remission remained significant. Reaching and sustaining mACR remission was only more difficult than DAS remission. Additionally, a great proportion of patients (23%) who attained DAS remission did not fulfill mACR remission. Since mACR remission criteria include absence of both tender and swollen joints, remission according to mACR is regarded as very strict[27
For the aim of this study, we used cohort data from the Nijmegen inception cohort. Cohort data have the advantage to be closely related to daily practice care[28
] and, therefore, the patients included in this study are supposed to be representative of the general RA population attending outpatient clinics. Moreover, the inception cohort from this study is regarded as a very valuable and complete cohort since this cohort includes a long time span, started from 1985 and still ongoing, and clinical variables are systematically collected every three months.
However, a limitation of using data from daily practice is that medication use differs for each patient and changes over time. For that reason, medication use cannot be analyzed as would it be an effect-modifier and studying medical treatment may be complicated using cohort data. Therefore, medication use in this study was regarded as an intermediate variable and was described for each sub-cohort to get more insight into time-trends of medication. Further, we have demonstrated that despite medication adjustments at the discretion of rheumatologists, the treatment strategy applied was mostly a sequential or step-up strategy (with or without glucocorticoids), starting with either MTX or SASP and the prescription of anti-TNF agents was low.
The number of anti-TNF users in this study was low. On the one hand the study includes the period 1990-2000 when anti-TNF was not available, on the other hand because in the Netherlands, anti-TNF is used after failure on at least two DMARDs. The results of this study, therefore, do not automatically generalize to patients treated with anti-TNF. Leaving out the patients treated with anti-TNF from the analysis did not change the results (not shown). Further research should be necessary to investigate, and even generalize, the relationship between time-to-remission and sustained remission in patients using (their first) anti-TNF treatment.
In some patients, joint damage may proceed despite clinical remission [29
], However, low levels of inflammation and specifically remission are associated with less (further) progression of joint damage [31
]. Clinical remission and ultimately the halt of progression of joint damage is regarded as the current treatment goal in RA[1
]. In clinical trials, remission has already shown to be attainable [7
] and striving for a sustained state of (drug-free) remission has become the ultimate aim in RA[35
]. However, the rate of achieving and sustaining (mACR) remission in daily practice is still very low. The results of this study have shown that within three years, 53% and 30% of the patients achieved at least one visit in DAS or mACR remission, which are comparable (or even higher) to those found in other daily care studies [2
]. A state of sustained clinical remission was in this study difficult to reach (23-36%), which was also demonstrated in previous studies [11
Despite the relatively low percentage of sustained remission, there are arguments to believe that substantial increases in sustained remission rates are these days expected. Additionally, treatment strategies with conventional DMARDs can be improved considerably by applying tight control of disease activity, including a medication protocol with regular assessments of disease activity and a threshold (remission) to determine whether treatment has to be changed [9
]. Moreover, in clinical trials the early introduction of DMARDs in combination with prednisone or anti-TNF, applied as a 'step-down' strategy [5
], has shown to be very effective. However, in daily practice this is not a common treatment strategy. Therefore, starting anti-TNF therapy more rapidly, in DMARDs failures and patients with poor prognosis at baseline in particular, may be necessary for achieving higher remission rates.