Abstract

Objective. To study prospectively the daily practice effectiveness of a step-down early rheumatoid arthritis (RA) treatment strategy.

Methods. Patients with severe RA and no contra-indications were proposed step-down therapy, the others step-up. Step-down patients received a modified combination therapy in early RA (COBRA) regimen: sulphasalazine (SPS), 2 g daily, and methotrexate (MTX), 15 mg weekly, combined with step-down oral prednisolone (start 60 mg daily, fast tapering to 7.5 mg over 6 weeks, discontinuation from week 28). At week 40, patients were randomized to maintenance therapy with either SPS or MTX if disease activity score-28 (DAS28) was acceptably low. The step-up group started disease-modifying anti-rheumatic drug (DMARD) monotherapy. In both groups, treatment was adjusted at follow-up, based on DAS28. DAS28, functionality Health Assessment Questionnaire (HAQ), adverse events, DMARD changes and steroid use were registered 4-monthly for 2 yrs.

Results. Ninteen patients received step-down and 52 step-up treatment. More patients completed the first year without unplanned DMARD changes and without dosage adjustment and fewer had DMARD changes due to side effects or inefficacy in the step-down group compared with step-up, whereas the number of adverse events was comparable. MTX proved to be the most effective maintenance therapy after step-down. The DAS response, proportion of patients in remission, HAQ response and proportion of patients without disability at 4 months was higher in the step-down group.

Conclusions. In daily practice, a step-down treatment strategy for early RA is more effective than a step-up approach.

Introduction

The combination therapy in early rheumatoid arthritis (COBRA) trial was a milestone in the development of the present treatment paradigm for rheumatoid arthritis (RA) [1]. Meanwhile, although the importance of early intensive treatment has been confirmed and emphasized in numerous publications [2–4], there seems to be a discrepancy between theoretical acceptance and practical implementation of this strategy in the rheumatological community [5]. The most important reason why rheumatologists do not prescribe the COBRA scheme in daily practice seems to be a concern about their patient's opinion on the complexity of the scheme and the large amount of drugs they have to take. Patients indeed dislike corticosteroids and prefer newer drugs such as anti-tumour necrosis factor (TNF) agents, but this unfavourable perception seems to improve after steroid use [6]. In this study, we evaluated in daily practice the feasibility of using a step-down strategy based on the original COBRA scheme for early RA treatment. Efficacy and effectiveness were compared with a more classical step-up treatment.

Patients and methods

All newly diagnosed early RA patients at the rheumatology outpatient department of the University Hospitals Leuven were included in a structured care programme and received a pre-defined pharmacological treatment regimen depending on their physician's decision.

This decision was inspired by the prognostic profile at diagnosis: patients with at least one unfavourable prognostic factor, such as the presence of rheumatoid factor, anti-cyclic citrullinated peptide (CCP) antibodies or structural damage on X-ray and with a more severe disease, as assessed by the physician [formalized on a visual analogue scale (VAS)], were treated preferably according to a step-down strategy and the others according to a step-up approach. Some of the patients with severe disease were recruited in industry-sponsored early RA medication trials and could not participate in our study. Since this was a study in daily practice, factors such as the presence of comorbidities, child's wish and patient's preference had to be taken into account during treatment allocation. The step-down group received a modified COBRA treatment regimen: sulphasalazine (SPS), 2 g daily, and methotrexate (MTX), 15 mg weekly, combined with a step-down dosage of oral prednisolone, starting at 60 mg daily and decreasing weekly over a period of 6 weeks to 7.5 mg, with a further decrease till discontinuation from week 28. At week 40, patients were randomized to continue either SPS or MTX if their disease activity was acceptably low, in order to evaluate the effectiveness of these drugs as maintenance therapy during the second year. The step-up group started monotherapy with MTX, SPS, hydroxychloroquine or azathioprine.

At follow-up, patients were evaluated by a rheumatologist after 4–6 weeks and at least once every 4 months thereafter. Treatment was adjusted if desirable and feasible, based on the disease activity score (DAS28 CRP), aiming at remission (<2.6) or at least low disease activity (<3.2). At every visit, adverse events, disease-modifying anti-rheumatic drug (DMARD) changes or dosage modifications due to side effects or lack of efficacy and the use of steroids were registered. Also, the non-pharmacological care of these patients was strictly organized. The implementation of specific aspects of daily care such as patient education and monitoring of drug treatment, socioprofessional functioning and psychological well-being was well standardized under the supervision of a rheumatology nurse specialist, who evaluated patients on most of their visits to the outpatient clinic during the first year of follow-up and in situations of crisis. At each visit, patients quantified their disease activity, pain and fatigue on a VAS. Disease activity (DAS28 CRP) and functionality Health Assessment Questionnaire (HAQ) were registered once every 4 months. This information was stored in an electronic medical file, with the possibility to generate cumulative reports.

This study was approved by the Ethics Committee of the University Hospitals Leuven and all patients gave written informed consent before inclusion.

The statistical analysis was performed with SPSS 14. Chi-squared tests were used for comparison of dichotomous variables and unpaired Student's t-tests or Mann–Whitney U-tests were used for continuous variables, depending on the distribution of the data.

The evolution of disease activity over time was analysed using Friedman test.

Results

Baseline data

Nineteen patients were included in the step-down group and 52 in the step-up group.

The physician's global assessment, tender joint count and swollen joint count were higher, more patients were RF-positive and more were anti-CCP-positive in the step-down group, reflecting the tendency to select patients with more severe disease for this treatment arm (Table 1). Besides this, the demographics differed only for age. Baseline disease activity scores (DAS28 CRP), functionality scores (HAQ), patients’ global assessments and evaluation of pain and fatigue were comparable (Table 1).

Table 1.

Baseline characteristics

 Step-down (n = 19) Step-up (n = 52) 
Gender, female (%) 63 65 
Mean (s.d.) age (yrs) 45 (17) 55 (15) 
RF+/anti-CCP+ (%) 79/84 52/54 
Erosive disease (%) 53 42 
Mean (s.d.) symptom duration (months) 10 (10) 8 (6) 
Mean (s.d.) disease duration (months) 0.7 (0.6) 0.8 (0.7) 
Mean (s.d.) TJC (68 joints) 20 (12) 13 (11) 
Mean (s.d.) SJC (66 joints) 17(11) 11(8) 
Mean (s.d.) phys. global assessment 53 (18) 35 (18) 
Mean (s.d.) DAS28 CRP 5.28 (1.59) 4.76(1.31) 
Mean (s.d.) HAQ 1.1 (0.6) 1.1 (0.8) 
Mean (s.d.) patient global assessment 51 (26) 54 (24) 
Mean (s.d.) patient pain assessment 49 (20) 50 (23) 
Mean (s.d.) patient fatigue assessment 40 (29) 42 (27) 
 Step-down (n = 19) Step-up (n = 52) 
Gender, female (%) 63 65 
Mean (s.d.) age (yrs) 45 (17) 55 (15) 
RF+/anti-CCP+ (%) 79/84 52/54 
Erosive disease (%) 53 42 
Mean (s.d.) symptom duration (months) 10 (10) 8 (6) 
Mean (s.d.) disease duration (months) 0.7 (0.6) 0.8 (0.7) 
Mean (s.d.) TJC (68 joints) 20 (12) 13 (11) 
Mean (s.d.) SJC (66 joints) 17(11) 11(8) 
Mean (s.d.) phys. global assessment 53 (18) 35 (18) 
Mean (s.d.) DAS28 CRP 5.28 (1.59) 4.76(1.31) 
Mean (s.d.) HAQ 1.1 (0.6) 1.1 (0.8) 
Mean (s.d.) patient global assessment 51 (26) 54 (24) 
Mean (s.d.) patient pain assessment 49 (20) 50 (23) 
Mean (s.d.) patient fatigue assessment 40 (29) 42 (27) 

TJC, total joint count; SJC, swollen joint count; phys, physicians.

Effectiveness data

During the study, two patients (10.5%) were lost to follow-up in the step-down group (both during the second year) and six (11.5%) in the step-up group (three in the first year and three in the second) (Fig. 1).

Fig. 1.

Patient disposition table. This figure depicts the number of patients included in each treatment arm, the number of patients lost to follow-up, with corresponding timing and reasons for loss to follow-up.

Fig. 1.

Patient disposition table. This figure depicts the number of patients included in each treatment arm, the number of patients lost to follow-up, with corresponding timing and reasons for loss to follow-up.

More patients completed the first year of treatment without unplanned DMARD changes (84.2 vs 60%; P = 0.051) and without adjustment of the DMARD dosage (73.7 vs 44%; P = 0.048) in the step-down group compared with the step-up group.

During the first year, fewer patients had DMARD changes due to side effects [not significant (10.5 vs 30%; NS)] or inefficacy (10.5 vs 40%; P = 0.053), and there were fewer DMARD changes per patient due to side effects [mean (s.d.)] [0.11 (0.31) vs 0.38 (0.63); P = 0.02] or inefficacy [0.16 (0.50) vs 0.48 (0.65); P = 0.034] in the step-down group.

Over the complete 2-yr follow-up period, the proportion of patients without unplanned DMARD changes (73.3 vs 55%; NS) and without adjustment of the DMARD dosage (40 vs 30%; NS) tended to remain higher in the step-down group.

During the first year, 100% of the patients in the step-down group received steroids according to the protocol, whereas 56% needed steroids in the step-up group. A short course of low-dose oral steroids was initiated in the step-up group in 14 patients (27%) at baseline, as a bridging therapy before the onset of the DMARD treatment effect. In both groups, very little or no intra-articular injections were given, but according to the treating physician's decision, oral steroids (<10 mg prednisolone) were given in case of disease flares and were tapered as soon as possible. Six patients (12%) in the step-up group and none in the step-down group received steroids continuously throughout the 2-yr study period. The mean (s.d.) number of days on steroids was 255 (84) days in the step-down group and 191 (260) days in the step-up group. During the second year of follow-up, fewer patients needed steroids to keep disease activity under control in the step-down group compared with the step-up (20 vs 40%) and the proportion of patients using steroids was lower in this group at each time point from month 12 onwards (Fig. 2).

Fig. 2.

Effectiveness of step-down treatment compared with step-up. The proportion of patients in need of steroids during the second year tended to be higher in the step-up group. Differences between groups were analysed by chi-squared tests. Asterisks correspond to P-values <0.05.

Fig. 2.

Effectiveness of step-down treatment compared with step-up. The proportion of patients in need of steroids during the second year tended to be higher in the step-up group. Differences between groups were analysed by chi-squared tests. Asterisks correspond to P-values <0.05.

The mean (s.d.) cumulative steroid dose (in prednisolone equivalents) was 2603 (211) mg in the step-down group and 997 (1423) mg in the step-up group. Over the 2-yr study period, the mean (s.d.) daily steroid dose (in prednisolone equivalents) in the step-down group was 3.6 (0.3) mg compared with 1.4 (1.9) mg in the step-up group.

The mean (s.d.) number of adverse events per patient during the first year of treatment was comparable between groups [2 (0.94) step-down vs 1.8 (0.99) step-up; NS].

Also, during the second year, the mean (s.d.) number of adverse events per patient did not differ between groups [1.6 (0.99) step-down vs 1.88 (0.94) step-up; NS].

In the step-down group, there were three serious adverse events (SAEs) during the first year of treatment: two suicide attempts by the same patient and a severe bronchitis episode requiring hospitalization. During the second year, there were four SAEs: a malign melanoma, an acute myeloid leukaemia, a cerebrovascular accident (same patient with bronchitis in the first year) and a hospitalization for atypical thoracic pain.

In the step-up group, six SAEs were reported during the first year of treatment: two hospitalizations for elective surgery, one for a gastric ulcer, one for a trauma, one for a ruptured Baker cyst and one for a myocardial infarction requiring coronary artery bypass graft (CABG). In this group, there was one SAE during the second year of follow-up: a hospitalization for a herpes zoster infection.

At baseline, all step-down patients received a modified COBRA regimen. In the step-up group, 59.6% received MTX and 36.5% SPS (Table 2). As a consequence of the randomization procedure at week 40, by month 12, more patients were taking SPS monotherapy in the initial step-down group (31.6%) than in the step-up group (10.2%). One patient receiving SPS monotherapy in the step-down group developed acute leukaemia and was lost to follow-up at month 16. Of the other patients randomized to SPS, two (40%) had to be switched to another DMARD within the next year, whereas this was not the case in any of the patients randomized to MTX.

Table 2.

Treatment distribution at different time points

Baseline Step-down (n = 19) Step-up (n = 52) 
    Other DMARD, n (%) 0 (0) 2 (4) 
    Sulphasalazine, n (%) 0 (0) 19 (36) 
    Methotrexate, n (%) 0 (0) 31 (60) 
    COBRA, n (%) 19 (100) 0 (0) 
Month 12 Step-down (n = 19) Step-up (n = 49) 
    No treatment, n (%) 1 (5) 3 (6) 
    Other DMARD, n (%) 0 (0) 1 (2) 
    Sulphasalazine, n (%) 6 (32) 5 (10) 
    Methotrexate, n (%) 8 (42) 35 (71) 
    Leflunomide, n (%) 0 (0) 1 (2) 
    COBRA, n (%) 3 (16) 0 (0) 
    Combination DMARD, n (%) 0 (0) 3 (6) 
    Anti-TNF + MTX, n (%) 1 (5) 1 (2) 
Month 24 Step-down (n = 17) Step-up (n = 42) 
    No treatment, n (%) 1 (6) 1 (2) 
    Other DMARD, n (%) 0 (0) 3 (7) 
    Sulphasalazine, n (%) 3 (18) 3 (7) 
    Methotrexate, n (%) 11 (65) 33 (79) 
    Leflunomide, n (%) 0 (0) 1 (2) 
    Combination DMARD, n (%) 1 (6) 1 (2) 
    Anti-TNF + MTX, n (%) 1 (6) 0 (0) 
Baseline Step-down (n = 19) Step-up (n = 52) 
    Other DMARD, n (%) 0 (0) 2 (4) 
    Sulphasalazine, n (%) 0 (0) 19 (36) 
    Methotrexate, n (%) 0 (0) 31 (60) 
    COBRA, n (%) 19 (100) 0 (0) 
Month 12 Step-down (n = 19) Step-up (n = 49) 
    No treatment, n (%) 1 (5) 3 (6) 
    Other DMARD, n (%) 0 (0) 1 (2) 
    Sulphasalazine, n (%) 6 (32) 5 (10) 
    Methotrexate, n (%) 8 (42) 35 (71) 
    Leflunomide, n (%) 0 (0) 1 (2) 
    COBRA, n (%) 3 (16) 0 (0) 
    Combination DMARD, n (%) 0 (0) 3 (6) 
    Anti-TNF + MTX, n (%) 1 (5) 1 (2) 
Month 24 Step-down (n = 17) Step-up (n = 42) 
    No treatment, n (%) 1 (6) 1 (2) 
    Other DMARD, n (%) 0 (0) 3 (7) 
    Sulphasalazine, n (%) 3 (18) 3 (7) 
    Methotrexate, n (%) 11 (65) 33 (79) 
    Leflunomide, n (%) 0 (0) 1 (2) 
    Combination DMARD, n (%) 1 (6) 1 (2) 
    Anti-TNF + MTX, n (%) 1 (6) 0 (0) 

By month 24, treatment regimens were comparable between groups, with a large majority of patients on MTX. Only one patient in each group was treated with an anti-TNF agent during the study. The patient in the step-down group continued anti-TNF treatment by month 24 and the one in the step-up group stopped anti-TNF at month 20, after reaching remission (Table 2).

Efficacy data

The disease activity score improved more from baseline to month 4 in the step-down group compared with the step-up group (P = 0.04, Mann–Whitney U-test) and although patients in the step-down group started with slightly higher DAS28 CRP scores (NS), the median DAS28 CRP reached a significantly lower level (P = 0.014) compared with the step-up group by month 4 (Fig. 3).

Fig. 3.

Evolution of median (interquartile range) DAS28 CRP over time in the step-down group compared with the step-up. Baseline DAS28 CRP was slightly higher in the step-down group, although this difference was not statistically significant. Nevertheless by month 4, the median DAS28 CRP had become significantly lower in the step-down group compared with step-up. During further follow-up, DAS scores were similar in both the groups. P-values are the results of Mann–Whitney U-tests for between-group comparisons at each time point. The median DAS28 CRP score improved significantly over time in both the groups (P < 0.0001, Friedman test).

Fig. 3.

Evolution of median (interquartile range) DAS28 CRP over time in the step-down group compared with the step-up. Baseline DAS28 CRP was slightly higher in the step-down group, although this difference was not statistically significant. Nevertheless by month 4, the median DAS28 CRP had become significantly lower in the step-down group compared with step-up. During further follow-up, DAS scores were similar in both the groups. P-values are the results of Mann–Whitney U-tests for between-group comparisons at each time point. The median DAS28 CRP score improved significantly over time in both the groups (P < 0.0001, Friedman test).

By month 4, more patients achieved a good European League Against Rheumatism (EULAR) response (70.6 vs 42.9%; P = 0.054) (Fig. 4A) and more patients were in remission (63.2% vs 36.4%; P = 0.049) (Fig. 4B) in the step-down group. The differences became less impressive at month 8, and by month 12, the results were comparable. During the second year, the proportion of patients in remission was higher in the step-down group, but without significant differences.

Fig. 4.

Evolution of the disease activity and functionality over time. The proportion of patients achieving a good EULAR response (A) and the proportion in remission (DAS28 CRP <2.6) (B) at month 4 was higher in the step-down group compared with step-up. The proportion of patients achieving a clinically meaningful HAQ response (HAQ change >0.22) (C) and the proportion without functional impairment (HAQ = 0) (D) was higher in the step-down group compared with step-up. Differences between groups were analysed by chi-squared tests. Asterisks correspond to P-values <0.05.

Fig. 4.

Evolution of the disease activity and functionality over time. The proportion of patients achieving a good EULAR response (A) and the proportion in remission (DAS28 CRP <2.6) (B) at month 4 was higher in the step-down group compared with step-up. The proportion of patients achieving a clinically meaningful HAQ response (HAQ change >0.22) (C) and the proportion without functional impairment (HAQ = 0) (D) was higher in the step-down group compared with step-up. Differences between groups were analysed by chi-squared tests. Asterisks correspond to P-values <0.05.

The HAQ score improved more from baseline to month 4 (P = 0.009, Mann–Whitney U-test) in the step-down group compared with the step-up group.

After 4 months of treatment, more patients showed a clinically meaningful (CM) improvement of the HAQ score (88.9 vs 52.9%; P = 0.010) (Fig. 4C) and more patients tended to have no functional impairment (52.6 vs 37.8%; NS) (Fig. 4D). By month 12, significantly more patients achieved the state of absence of functional impairment in the step-down group (61.1 vs 31.8%; P = 0.033) (Fig. 4D).

During the second year of follow-up, the proportion of patients achieving a CM HAQ response and the proportion without functional impairment remained higher in the step-down group, but without significant differences (except CM HAQ response at month 16; P = 0.010).

Discussion

In this study, we demonstrated that a step-down treatment strategy for early RA based on a modified COBRA regimen is feasible in daily practice and more effective than a step-up.

The successful implementation of an intensive treatment regimen for early RA depends on effective communication between patients and health care providers, especially in the difficult first phase after diagnosis; this requires time and continuity of care. The number of patients declining to receive the COBRA regimen was surprisingly low. As a matter of fact, the decision not to start a step-down treatment where it would strictly have been indicated was almost always made after a long discussion with the patient and in mutual agreement, taking into account medical and personal objections as long as they were rational. Patients in this study were participating in an outpatient care programme, coordinated by a clinical nurse specialist, which facilitated the initial treatment organization in comparison with a busy private practice. However, in contrast to the general concern, during follow-up, the complexity and intensity of the medication scheme did not cause more adverse events than a more classical step-up regimen. On the contrary, during the first year of treatment, less unplanned treatment changes had to be made because of the side effects or lack of efficacy and throughout the follow-up year, fewer patients were in need of steroids to achieve the pre-set treatment goals. These results are in line with the observations in the BeSt (Behandel Stratezieen) study [7].

We confirmed the potent remission induction capacity of the modified COBRA regimen.

As in the original COBRA trial, more patients achieved a good response or even remission within the first 4 months of treatment, whereas the treatment results became comparable with the step-up regimen during the following months [8]. This difference is remarkable because in our study patients in the step-down group had the worst prognostic profile and their physicians’ global assessment of disease activity was significantly higher before treatment. Moreover, all patients were tightly monitored and, if desirable and feasible, treatment adjustments were made based on the disease activity score (DAS28 CRP), aiming at remission (<2.6) or at least low-disease activity (<3.2). Such a strategy of tight control is known to be very efficacious and, in our study, probably has favoured the step-up group especially, where more treatment adjustments were made, including the addition of steroids if necessary [7, 9].

As could be expected in an early RA population, the functionality scores closely followed the evolution of disease activity, with more patients achieving a clinically meaningful HAQ response or a state of absence of disability within the first months in the step-down group compared with the step-up group. The fast effect of a step-down approach on disease activity and functionality has of course important immediate consequences for a patient's quality of life, but on top of that, evidence has accumulated for the existence of a therapeutic window of opportunity, which means that important aspects of the disease course, such as the chance to achieve remission and the evolution of radiological joint damage, are determined by the delay in successful treatment [2, 10–12]. Treatment effectiveness during the first few months of follow-up, when patients are most vulnerable, also has a crucial effect on their psychosocial and professional functioning, which could determine their degree of socioprofessional participation in the following years [13]. We hypothesize that in early RA a delay in treatment effect can also have a negative influence on disease perception, a factor known to have a major impact on functionality, pain and depression in RA patients [14, 15].

We recently showed that a combination of MTX with intravenous methylprednisolone pulse therapy was clinically at least as effective as MTX combined with infliximab [16]. For this study, we used a modified COBRA regimen including a higher dosage of MTX and the original high oral step-down dosage of prednisolone. It would be of interest to compare, in a randomized trial, different DMARD combinations and different dosages of steroids to determine the best remission induction regimen. The results of our study, in which patients were randomized following induction of remission, suggest that MTX monotherapy is a more effective maintenance therapy than is SPS monotherapy. Given patients’ preference for newer drugs and often irrational dislike of corticosteroids, stimulated by media and public opinion, step-down regimens using classical DMARDS and steroids will probably only become popular in daily practice with the more general support of the rheumatological community.

In conclusion, our study advocates a more frequent use of a step-down treatment strategy for early RA in daily practice because it is not only more efficacious but also more effective than a step-up approach. In our centre, a step-down approach using the modified COBRA regimen remains the standard treatment strategy for severe early RA. A long-term prospective follow-up of our cohort is ongoing and patient numbers are growing. On top of the classical outcome parameters, more patient-centred outcomes are measured during follow-up and the patients’ perspective will be included in future effectiveness analyses.

graphic

Acknowledgements

Funding: P.V. is supported by a Clinical PhD Grant of the Research Foundation Flanders (FWO Vlaanderen).

Disclosure statement: The authors have declared no conflicts of interest.

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