Introduction

Rheumatoid arthritis (RA) is an autoimmune systemic disease characterized by destructive polyarthritis. Major impacts on RA patients’ functional capacity may occur due to persistently active disease. Adjusting disease-modifying antirheumatic drugs (DMARDs) aiming for the lowest disease activity level has been demonstrated to improve RA treatment outcomes in various treat-to-target (T2T) and tight control studies [1–12]. Disease activity tight control strategy prevents joint destruction and disability in RA [13–15].

However, feasibility of the intensive therapy exclusively with synthetic DMARDs still remains to be confirmed. Although strict use of synthetic DMARDs has been proved to be efficacious in clinical trials [3, 7, 11, 16, 17]; real-world data is scant [4, 8, 18]. Since pragmatic studies reflect real clinical scenario better than efficacy trials [19], our objective was to prospectively study the daily practice feasibility and effectiveness of treating RA to target strategy with synthetic DMARDs aiming for remission or low disease activity according to 28-joint disease activity score (DAS28) and clinical disease activity index (CDAI).

Patients and methods

From 2006 through 2007, 241 consecutive adult patients with RA from Hospital de Clínicas de Porto Alegre were followed in the outpatient clinic of the Rheumatology Division. Patients were diagnosed according to the ACR criteria [20] and had established RA. Patients with other systemic inflammatory conditions were excluded. This study was approved by the institutional Ethics Committee, and before inclusion, all patients gave written informed consent according to Declaration of Helsinki.

During follow-up, patients were evaluated by a rheumatologist at least once every 3–4 months. At each visit, clinical assessments comprised 28-joint counts of swollen and tender joints (SJC and TJC, respectively), pain visual analog scale (VAS), evaluator and patient global assessments (EGA, PGA, respectively) by VAS, health assessment questionnaire disability index (HAQ) [21], morning stiffness (MST), and routine blood tests, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The patient’s disease activity was quantified by performing DAS28 and CDAI [22].

The therapy of all patients was prescribed strictly according to a step-up strategy based on the use of synthetic DMARDs. Since this was a daily practice study, factors such as the presence of comorbidities, child’s wish, and patients’ preferences had to be taken into account during treatment choice. Treatment was adjusted if desirable and feasible based on DAS28 and CDAI, aiming for remission (<2.6 and <2.8, respectively) or at least low disease activity (<3.2 and <10, respectively) [23, 24]. At every visit, adverse events, DMARD changes, or dosage modifications due to side effects or lack of efficacy and the use of steroids were registered. Some of the patients with severe disease or persistently high DAS28 and CDAI (>5.1 and >22, respectively) were allocated to use anti-TNF alpha as a separate protocol study. At the end of the study, in order to evaluate treatment effectiveness, all drugs under use and disease activity status were recorded.

The statistical analysis was performed with SPSS 20. Chi-squared tests were used for comparison of dichotomous variables and paired Student’s t test or Wilcoxon’s test was used for continuous variables, depending on data distribution. Correlations between DAS28, CDAI, and HAQ were calculated by Spearman’s and Pearson’s correlation coefficients. The agreement between disease activity categories by both scores was calculated by kappa statistics.

Results

Patients were predominantly women (84.7 %) of mean (±SD) age 54.9 (±11.9) years old with 11.1 (±7.4) years of disease duration. After 14.3 (±5.6) months, at visit 4, T2T intervention significantly reduced DAS28 (mean ± SD) (4.6 ± 1.6 vs. 4.0 ± 1.5; p < 0.005), CDAI [median (IQR)] [17.8 (8.2–28.7) vs. 12.6 (5.1–22.5); p < 0.001], and HAQ (1.5 ± 0.9 vs. 1.3 ± 0.8; p = 0.002) (Table 1). There was a statistically significant decrease in the number of swollen and tender joints, patient’s global disease, and pain visual analog scales (VAS) (p < 0.05). There were no significant changes in physician’s VAS and erythrocyte sedimentation rates during follow-up. Compared to the baseline scores, more patients at the end of the study achieved remission by DAS28 (11.6 vs. 18.6 %; p < 0.001) and CDAI (8.1 vs. 13.6 %; p < 0.001) and also low disease activity by DAS28 (9.8 vs. 13.0 %; p < 0.001) and CDAI (23.9 vs. 28.4 %; p < 0.001) (Fig. 1).

Table 1 Clinical features of patients with RA in baseline and after T2T strategy
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Fig. 1
figure 1

Disease activity level distribution at baseline and at the end of the study according to CDAI and DAS28

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The minimal clinically important difference (MCID) [22] for HAQ (0.22) was achieved in 27.1 % of patients at visit 4, for DAS28 (1.2) in 28.3 % and for CDAI (8.05) in 35 %.

Both average doses of sulfasalazine and methotrexate at visit 4 were higher (1.375 vs. 1.621 mg, p = 0.024; and 14.5 vs. 16.5 mg, p < 0.001, respectively). More patients were on combination therapy at the end of the follow-up (48.2 vs. 52.3 %; p < 0.001). There were no significant changes in average prednisone doses (4.8 vs. 5.6 mg; p = 0.57).

Discussion

Treating RA with synthetic DMARDs to a target of remission or low disease activity is effective and feasible in daily practice. In our long-standing RA cohort, patients improved their disease activity level and functional capacity with intensive synthetic DMARDs adjustment.

The proportion of patients reaching remission in our study was similar to a cross-sectional single-center [18] and a multicenter [25] real-world studies but smaller than treat-to-target clinical trials [12], probably because our treatment goal included low disease activity. Remission is the primary outcome in most early RA trials; however, low disease activity may be acceptable in some particular clinical scenarios, mainly in long-standing disease and in patients with concomitant fibromyalgia. Alternatively, imaging remission could be a target for these patients as suggested by ultrasound studies [26, 27].

In QUEST-RA study, Sokka et al. demonstrated a DAS28 remission rate for usual care of 19.6 %, which is comparable to our findings. Similarly to our study, patients in QUEST-RA were not in a tight control or clinical trial setting, and therefore, remission was not as prevalent as it would be expected in a more intensive treatment strategy [25]. Recently, Santos-Moreno et al. reported that 51 % of long-standing RA patients with moderate or high disease activity treated with synthetic DMARDs under a T2T strategy achieved remission by DAS28 after 6 months of follow-up [28]. In this study, participants had to be moderately or highly active to be included and could not have been treated with three or more synthetic DMARDs previously. Possibly, the sample selection criteria adopted and the shorter follow-up may explain the greater remission rate found by the researchers [28].

Fransen et al. studied 384 patients in 24 centers randomized to either follow a DAS28-oriented intensive or a usual care strategy. After 24 weeks, more patients in the DAS28-oriented centers achieved remission or low disease activity compared to the usual care centers (31 vs. 16 %; p < 0.03) [4]. Similarly, in our cohort, more patients were at lower disease activity levels after following the T2T strategy. However, the magnitude of this difference was smaller, most likely due to our longer observation time. In addition, the average disease duration of our sample was at least twice higher than in this randomized trial. Joint deformities could dampen disease activity assessment and masquerade a greater improvement.

Despite the lack of radiographic scoring, our study demonstrated that RA patients significantly improved HAQ, a predictor of joint damage. According to our data, even in long-standing disease, intensive synthetic DMARDs use to the lowest RA activity levels improves functionality in 27.1 % of patients over time. As no biologic DMARDs were prescribed, the gain in functional capacity comes with lower drug-related direct medical costs.

In conclusion, our cohort study indicates that T2T strategy in long-standing RA patients with synthetic DMARDs aiming at remission or low disease activity level is effective and feasible in daily practice. Further real-world studies may contribute to better understanding clinical and social impacts of the intensive T2T approach to RA patients.