In the last decade the treatment of rheumatoid arthritis (RA) has changed dramatically. It has been shown that patients diagnosed with RA require treatment with disease modifying anti-rheumatic drugs (DMARDs) as soon as possible after diagnosis to preserve functional ability and to slow radiographic joint damage progression.1 Recently, new therapies have been developed, resulting in more treatment options for RA patients. In addition, studies focusing on tight control of disease activity in patients with active RA have shown improved outcomes compared to standard care.2^–4 To assess disease activity in clinical practice, the disease activity score (DAS) was composed and validated.5 6 In the Behandel Strategieën (BeSt) study, tight control of disease activity and early treatment initiation resulted in a large percentage of patients achieving a DAS ⩽2.4 or <1.6 after 2 years.7

The European League Against Rheumatism (EULAR) task force for the management of early arthritis recommends monitoring the disease activity every 1–3 months as long as remission is not achieved.8 It is unclear how intense monitoring should be once the treatment target is reached. Continued frequent monitoring can be time consuming and costly.

The treatment goal in the BeSt study was a DAS ⩽2.4 in all patients; the DAS was calculated every 3 months. Once the DAS was ⩽2.4, treatment was not changed; however treatment was increased again or changed if the DAS increased to >2.4. The objective of this analysis was to calculate the duration of a DAS ⩽2.4, and the probabilities of maintaining a DAS ⩽2.4 once this goal had been achieved, in order to discuss the optimal frequency of monitoring in daily practice.

METHODS

The BeSt study is a multi-centre, randomised clinical trial, designed to compare the clinical and radiological efficacy of four different treatment strategies in patients with recent onset RA: (1) sequential monotherapy (n = 126); (2) step-up combination therapy (n = 121); (3) initial combination therapy including a tapered high dose prednisone (n = 133); and (4) initial combination therapy including infliximab (n = 128). All patients met the following criteria: diagnosis of RA according to the American College of Rheumatology (ACR) 1987 criteria, active disease (⩾6 tender and ⩾6 swollen joints, erythrocyte sedimentation rate (ESR) ⩾28 mm/h or VAS global health ⩾20 mm) and disease duration shorter than 2 years.9

The EULAR response criteria based on the DAS (44 joint count)5 6 were used to monitor response to treatment and to provide guidelines for dosage adjustments, with the goal of achieving a DAS ⩽2.4 in all patients. Every 3 months, a trained research nurse who was blinded for study treatment calculated the DAS. Once a DAS ⩽2.4 was achieved, treatment remained stable for 6 months and was subsequently tapered to monotherapy in maintenance dose (usually methotrexate 10 mg/week) in case of a persisting DAS ⩽2.4. If the DAS increased >2.4, the rheumatologist adjusted the medication according to a fixed protocol.9 The present analysis, using 2-year follow-up data, included patients with at least 8 of 9 DAS calculations available.

The number and percentage of patients who achieved a DAS ⩽2.4 or <1.6 for the first time after treatment initiation was determined. To calculate the probability of maintaining a DAS ⩽2.4, the number of patients achieving a second and third consecutive DAS ⩽2.4 was determined. We also calculated the probability for a next DAS ⩽2.4 given one or two preceding DAS were <1.6. To study the influence of an intercurrent increase in disease activity, the number of patients who achieved a DAS ⩽2.4 for the second time after experiencing a flare of disease activity (DAS>2.4) was determined. The time needed to achieve a first DAS ⩽2.4, as well as the duration of low disease activity, was determined for patients in every treatment group.

Statistical analysis

Differences between groups were tested using the χ² test or a one-way analysis of variance (ANOVA) or the Kruskal–Wallis test depending on the tested variable. p Values less than 0.05 were considered significant.

RESULTS

We excluded 63 of the original 508 patients; 27 patients had dropped out and 36 patients had >1 missing DAS during follow-up (fig 1). The excluded patients were equally distributed among the treatment groups (p = 0.257). Demographic and disease characteristics at baseline did not differ significantly among the four treatment strategies (table 1). A total of 3963 DAS assessments for 445 patients were obtained during the 2-year study period. For 403 patients, all 9 DAS assessments were available; for 42 patients, 1 DAS assessment was missing.

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Figure 1 Flowchart of the study.

Over 2 years, 421 patients (95%), equally distributed among the four treatment groups, achieved a DAS ⩽2.4 at least once. Patients treated with initial combination therapy, including either prednisone or infliximab, achieved a DAS ⩽2.4 significantly earlier than patients treated with initial monotherapy (table 2). Of the patients who reached a DAS ⩽2.4, 69–79% (74% overall) had a second DAS ⩽2.4. Of patients who achieved two consecutive DAS ⩽2.4, 75–90% (85% overall, p<0.05 for group 3 vs groups 1 and 4) had a third DAS ⩽2.4 without therapy adjustment. The percentage of patients who maintained a DAS ⩽2.4 was comparable among the four treatment strategies, although patients treated with initial combination therapy including a tapered high dose prednisone appeared to have a lower probability of achieving a third, consecutive, low DAS. The median duration of maintaining a DAS ⩽2.4 was 12 months for patients in groups 1–3 and 18 months for patients in group 4 (p = 0.016). A total of 52% of patients with low disease activity experienced a flare (DAS>2.4) at least once. Flares occurred within 3 months in 26% of patients, between 3–12 months in 20% of patients and after >12 months in 6% of patients (table 2). No flares after a first DAS ⩽2.4 were observed in 48% of patients (median (IQR) duration of low disease activity 21 (18–24) months). These patients had a significant lower baseline DAS (4.26 vs 4.47) and HAQ (1.26 vs 1.43) and were more often males (40% vs 27%) than the patients who experienced a flare. Of the patients with a disease flare (DAS>2.4 after initial good response), 89% achieved a next DAS ⩽2.4 after therapy adjustment and 73% achieved a second consecutive DAS ⩽2.4 without therapy adjustment, which is similar to patients who had not experienced a disease flare.

Although the treatment target in the BeSt study was a DAS⩽2.4, 314 patients (71%) equally distributed among the four treatment groups, achieved a DAS<1.6 at least once during the 2-year study period. Patients treated with initial combination therapy (including either prednisone or infliximab) achieved a DAS<1.6 significantly earlier than patients treated with initial monotherapy (table 2). Of the patients who reached a DAS<1.6, 84–91% (88% overall) had a next DAS ⩽2.4. Of patients who recorded two consecutive DAS<1.6, 97% had a subsequent DAS ⩽2.4 without therapy adjustment.

DISCUSSION

This subanalysis of the BeSt study shows that once patients with recent onset RA achieve a DAS ⩽2.4, the probability of continued low disease activity without treatment changes is high, regardless of treatment strategy.

The BeSt study uses thrice-monthly DAS calculations and aims at achieving a DAS ⩽2.4, with a protocol that requires treatment adjustments if the DAS is >2.4, but stable (and after 6 months tapering off) medication as long as the DAS is ⩽2.4. Once a DAS ⩽2.4 is achieved, the probability of the next DAS also being ⩽2.4 is 74%. Interestingly, if after an intermediate disease flare a DAS ⩽2.4 is achieved again, the probability for the next DAS to be ⩽2.4 is the same as before the disease flare. Patients initially treated with a combination including prednisone had significantly more flares, possibly due to a lower initial methotrexate dose (7.5 mg/week) in this group. On average, patients who achieved a DAS ⩽2.4 retained such a low DAS for median 12 months. The probability of the next DAS also being ⩽2.4 is even higher when 1 or 2 preceding DAS calculations are <1.6. These results support the EULAR recommendations to intensely monitor disease activity as long as remission is not achieved.8

Intense monitoring is time consuming and can be costly. Our results suggest that independent of treatment, once DAS remission or recurrent low disease activity is achieved, the chances for prolonged low disease activity are so high that scheduled monitoring could be more flexible. Self-assessment tools could help patients estimate when the disease activity increases,10^–12 however, experience with the use of such tools in clinical practice is limited and it is unknown if these tools would help patients distinguish between a DAS ⩽2.4 or >2.4. Careful instruction should aim to prevent underreporting of increased symptoms.

In conclusion, patients with recent onset RA benefit from early interventions based on tight monitoring of disease activity. Once a DAS ⩽2.4 is achieved with intense therapy, patients retain a low disease activity without further treatment adjustments for on average 12 months. These results may influence the implementation of frequent monitoring in daily practice after a state of low disease activity or remission has been achieved.