Methotrexate in Combination or Alone for Early RA Remission?
In patients with eRA with unfavourable classical prognostic factors such as RF, ACPA, erosions and/or high-disease activity, MTX associated with a moderate step-down dose of GCs was as effective as DMARD combination therapies with moderate or high step-down GC doses, for remission induction at 16 weeks. Furthermore, the short-term safety profile of MTX associated with a moderate step-down dose of GCs was more favourable.
This finding has two implications. First, in association with a moderate or high GC dose, the combination of MTX with other DMARDs does not seem to be more effective compared with MTX alone, at least in the early treatment stage. Until now only a few studies have addressed the question whether DMARD combinations are superior to MTX monotherapy independent from additional GC bridging in eRA. The tREACH trial showed that DMARD combination was better than MTX monotherapy, both in association with low-dose GC bridging. In our trial, the COBRA-like moderate-dose or high-dose GC scheme bridged the time lag before full DMARD efficacy, probably erasing any difference between the different DMARD schedules. As a consequence, less medication is needed over time, which might impact AE and possibly also patients' adherence to treatment. The tight control setting could also correct swiftly for any suboptimal treatment regimen, explaining some of the good efficacy of COBRA Slim. However, only MTX dose adjustment and no step up to combination therapy could be implemented before W16. Furthermore, the proportion of treatment adjustments between the three arms was not significantly different.
Second, a high-dose GC scheme starting at 60 mg prednisone does not seem to improve early clinical outcomes compared with a moderate-dose scheme starting at 30 mg prednisone, regardless of the DMARD strategy used. Thus, a lower cumulative GC dose is still equally effective, perhaps avoiding long-term AEs. Furthermore, the possibility to use a lower dose of GCs, while having the same efficacy, could benefit the implementation of COBRA-like strategies. Rheumatologists appear more reluctant to administer complex therapies with high dosages of GCs, although we showed that this approach is feasible in daily practice. den Uyl et al reported similar results comparing an attenuated COBRA regimen with the original one in a moderately active eRA population. However, this study lacked decisive evidence, the MTX dose in the classical scheme was suboptimal and the GC scheme in the attenuated COBRA version was cumulatively comparable with the classical one.
Many rheumatologists use low-dose GCs in association with DMARDS for eRA in daily practice, much to their own and their patients' satisfaction. They have, however, doubts about the need for higher GC dosages and prolonged use. The potential advantage of a COBRA-like schedule over low-dose GCs is two-sided. First, a high or moderate dose could have a more radical biological effect on the disease process favouring 'real' remission induction. Low-dose GCs show only a slow genomic effect, while higher dosages show both slow genomic and faster non-genomic effects. Second, compared with using GCs only short term and discontinuously, it can be more effective to bridge systematically the entire time window before maximum DMARD efficacy, taking up to 6 months. DMARD combinations could therefore have a short-lived advantage over DMARD monotherapy in trials using GCs not systematically, at a too low dose or for a too short period of time.
The analysis of the AUC of disease activity reinforced the study findings at every visit, illustrating that the disease burden was the same during the first 16 weeks of treatment over the three treatment arms. A delayed targeted therapy as proposed by others would result in a much higher cumulative disease activity. This study only presents the first 16 weeks of the CareRA trial, but this initial treatment period, the so-called 'window of opportunity', is crucial for longer-term outcome at the biological and probably also at a psychosocial level. Long-term disease control and patient-reported outcomes after 1 and 2 years are awaited in CareRA.
The safety analysis strengthened the efficacy outcomes further. The proportion and number of related AEs was comparable in Classic and Avant-Garde, while Slim patients had half the related AEs. GC dosage does not make any difference in the frequency or type of related AEs at this stage. Remarkable are the comparable number of AEs of the combination therapies with different GC dose, underscoring again the prejudice against GC dosage and lack of knowledge of GC side effects.
The first two limitations are related to the design of this study, although unavoidable in a pragmatic trial aiming to reflect daily clinical practice. First, medication adherence was not measured. However, if adherence was lower in a certain trial arm, the same could be expected from this treatment regimen in daily clinical practice. Second, no blinding was implemented. Rheumatologists could have been biased towards a certain therapy and therefore report less therapy-related AEs. Certain patients could also be more motivated for certain treatment regimens than for others.
Another limitation was the superiority design of this study. We opted for this design because in a non-inferiority trial the number of patients needed would be doubled. Hence, we can only state that COBRA Classic and COBRA Avant-Garde are non-superior to COBRA Slim, which is not the same as claiming non-inferiority.
In conclusion, the data presented are positioning classical MTX therapy with bridging GCs at a lower dose than in the original COBRA study as a highly effective and safe remission induction therapy in more than 70% of high-risk patients with eRA and this in a close to daily practice setting applying a treat-to-target strategy.
Discussion
In patients with eRA with unfavourable classical prognostic factors such as RF, ACPA, erosions and/or high-disease activity, MTX associated with a moderate step-down dose of GCs was as effective as DMARD combination therapies with moderate or high step-down GC doses, for remission induction at 16 weeks. Furthermore, the short-term safety profile of MTX associated with a moderate step-down dose of GCs was more favourable.
This finding has two implications. First, in association with a moderate or high GC dose, the combination of MTX with other DMARDs does not seem to be more effective compared with MTX alone, at least in the early treatment stage. Until now only a few studies have addressed the question whether DMARD combinations are superior to MTX monotherapy independent from additional GC bridging in eRA. The tREACH trial showed that DMARD combination was better than MTX monotherapy, both in association with low-dose GC bridging. In our trial, the COBRA-like moderate-dose or high-dose GC scheme bridged the time lag before full DMARD efficacy, probably erasing any difference between the different DMARD schedules. As a consequence, less medication is needed over time, which might impact AE and possibly also patients' adherence to treatment. The tight control setting could also correct swiftly for any suboptimal treatment regimen, explaining some of the good efficacy of COBRA Slim. However, only MTX dose adjustment and no step up to combination therapy could be implemented before W16. Furthermore, the proportion of treatment adjustments between the three arms was not significantly different.
Second, a high-dose GC scheme starting at 60 mg prednisone does not seem to improve early clinical outcomes compared with a moderate-dose scheme starting at 30 mg prednisone, regardless of the DMARD strategy used. Thus, a lower cumulative GC dose is still equally effective, perhaps avoiding long-term AEs. Furthermore, the possibility to use a lower dose of GCs, while having the same efficacy, could benefit the implementation of COBRA-like strategies. Rheumatologists appear more reluctant to administer complex therapies with high dosages of GCs, although we showed that this approach is feasible in daily practice. den Uyl et al reported similar results comparing an attenuated COBRA regimen with the original one in a moderately active eRA population. However, this study lacked decisive evidence, the MTX dose in the classical scheme was suboptimal and the GC scheme in the attenuated COBRA version was cumulatively comparable with the classical one.
Many rheumatologists use low-dose GCs in association with DMARDS for eRA in daily practice, much to their own and their patients' satisfaction. They have, however, doubts about the need for higher GC dosages and prolonged use. The potential advantage of a COBRA-like schedule over low-dose GCs is two-sided. First, a high or moderate dose could have a more radical biological effect on the disease process favouring 'real' remission induction. Low-dose GCs show only a slow genomic effect, while higher dosages show both slow genomic and faster non-genomic effects. Second, compared with using GCs only short term and discontinuously, it can be more effective to bridge systematically the entire time window before maximum DMARD efficacy, taking up to 6 months. DMARD combinations could therefore have a short-lived advantage over DMARD monotherapy in trials using GCs not systematically, at a too low dose or for a too short period of time.
The analysis of the AUC of disease activity reinforced the study findings at every visit, illustrating that the disease burden was the same during the first 16 weeks of treatment over the three treatment arms. A delayed targeted therapy as proposed by others would result in a much higher cumulative disease activity. This study only presents the first 16 weeks of the CareRA trial, but this initial treatment period, the so-called 'window of opportunity', is crucial for longer-term outcome at the biological and probably also at a psychosocial level. Long-term disease control and patient-reported outcomes after 1 and 2 years are awaited in CareRA.
The safety analysis strengthened the efficacy outcomes further. The proportion and number of related AEs was comparable in Classic and Avant-Garde, while Slim patients had half the related AEs. GC dosage does not make any difference in the frequency or type of related AEs at this stage. Remarkable are the comparable number of AEs of the combination therapies with different GC dose, underscoring again the prejudice against GC dosage and lack of knowledge of GC side effects.
The first two limitations are related to the design of this study, although unavoidable in a pragmatic trial aiming to reflect daily clinical practice. First, medication adherence was not measured. However, if adherence was lower in a certain trial arm, the same could be expected from this treatment regimen in daily clinical practice. Second, no blinding was implemented. Rheumatologists could have been biased towards a certain therapy and therefore report less therapy-related AEs. Certain patients could also be more motivated for certain treatment regimens than for others.
Another limitation was the superiority design of this study. We opted for this design because in a non-inferiority trial the number of patients needed would be doubled. Hence, we can only state that COBRA Classic and COBRA Avant-Garde are non-superior to COBRA Slim, which is not the same as claiming non-inferiority.
In conclusion, the data presented are positioning classical MTX therapy with bridging GCs at a lower dose than in the original COBRA study as a highly effective and safe remission induction therapy in more than 70% of high-risk patients with eRA and this in a close to daily practice setting applying a treat-to-target strategy.
SHARE
