Methotrexate in Combination or Alone for Early RA Remission?
Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial.
Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered.
Results Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, therapy-related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006).
Conclusions For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile.
While in the past patients with early rheumatoid arthritis (eRA) were treated conservatively, current guidelines recommend treating high-risk patients intensively, early and to target. A lot of interesting and important pioneering work has already been done, but many questions regarding the optimal dosage and combination of medication in the management of patients with eRA remain unaddressed.
Trials using early intensive combination strategies with classical disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) gave rise to the 'early window of opportunity' theory. This implies that if intensive treatment is initiated early in the disease process and disease activity is rapidly controlled, more patients will go into long-term remission with better functional and radiographic outcomes later on. Discussion still exists about the optimal way to rapidly induce remission at the individual patient level. Some patients might do equally well on methotrexate (MTX) monotherapy, and even in case of insufficient response, intensifying to triple DMARD therapy or a combination with a biological can rescue patients later on. A delay in optimal disease control might indeed not necessarily result in worse outcomes at standard evaluation time points, but unfortunately does not take into account the cumulative disease activity patients have to suffer before arriving at these endpoints. This illustrates that the patient perspective is still understudied in traditional eRA trials.
Guidelines suggest adapting treatment according to prognostic factors. Unfortunately, this does not guarantee a favourable outcome in daily practice. Until better prediction models become available, the most effective approach to use the window of opportunity is to combine classical DMARDs with rapid remission inducing agents like GCs or biologicals.
GCs are commonly used to bridge the onset of the therapeutic effect of DMARDs, to rapidly control inflammation and to prevent radiographic damage. During the difficult initial treatment weeks, GCs can relieve pain, stiffness and disability, allowing patients to take up again their role in society more rapidly and potentially preventing chronic disease behaviour. The perception on GCs, however, remains ambiguous in both the patient's and the physician's mind. Thus many rheumatologists hesitate to prescribe GCs due to fear for side effects. Little is yet known about the optimal initial dose, treatment duration and administration route.
Ample evidence indicates that compared with MTX monotherapy, biologicals combined with MTX are more efficacious in eRA. Unfortunately, insufficient clarity exists whether these agents can be used as remission induction agents in bridging strategies just as well as GCs since most trial protocols led to persistent biological use after the induction phase. Moreover, tumour necrosis factor-blocking agents did not demonstrate superior efficacy compared with induction regimes with GCs. Thus, administering GCs could avoid or postpone starting expensive long-term biological therapy.
The debate on the ideal DMARD content of initial RA treatment strategies is still ongoing. Triple therapy (MTX, sulfasalazine (SSZ) and hydroxychloroquine), combination therapy for early rheumatoid arthritis (COBRA)-like schemes (MTX±SSZ+GCs) or other DMARD combination therapies show excellent clinical efficacy compared with monotherapy. However, studies comparing different intensive treat-to-target regimens of classical DMARDs associated with a remission-inducing agent are scarce.
The aim of the current study was to compare in high-risk patients with eRA the efficacy and safety of different initial DMARD combinations and GC bridging schemes, 16 weeks after initiation.
Abstract and Introduction
Abstract
Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial.
Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered.
Results Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, therapy-related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006).
Conclusions For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile.
Introduction
While in the past patients with early rheumatoid arthritis (eRA) were treated conservatively, current guidelines recommend treating high-risk patients intensively, early and to target. A lot of interesting and important pioneering work has already been done, but many questions regarding the optimal dosage and combination of medication in the management of patients with eRA remain unaddressed.
Trials using early intensive combination strategies with classical disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) gave rise to the 'early window of opportunity' theory. This implies that if intensive treatment is initiated early in the disease process and disease activity is rapidly controlled, more patients will go into long-term remission with better functional and radiographic outcomes later on. Discussion still exists about the optimal way to rapidly induce remission at the individual patient level. Some patients might do equally well on methotrexate (MTX) monotherapy, and even in case of insufficient response, intensifying to triple DMARD therapy or a combination with a biological can rescue patients later on. A delay in optimal disease control might indeed not necessarily result in worse outcomes at standard evaluation time points, but unfortunately does not take into account the cumulative disease activity patients have to suffer before arriving at these endpoints. This illustrates that the patient perspective is still understudied in traditional eRA trials.
Guidelines suggest adapting treatment according to prognostic factors. Unfortunately, this does not guarantee a favourable outcome in daily practice. Until better prediction models become available, the most effective approach to use the window of opportunity is to combine classical DMARDs with rapid remission inducing agents like GCs or biologicals.
GCs are commonly used to bridge the onset of the therapeutic effect of DMARDs, to rapidly control inflammation and to prevent radiographic damage. During the difficult initial treatment weeks, GCs can relieve pain, stiffness and disability, allowing patients to take up again their role in society more rapidly and potentially preventing chronic disease behaviour. The perception on GCs, however, remains ambiguous in both the patient's and the physician's mind. Thus many rheumatologists hesitate to prescribe GCs due to fear for side effects. Little is yet known about the optimal initial dose, treatment duration and administration route.
Ample evidence indicates that compared with MTX monotherapy, biologicals combined with MTX are more efficacious in eRA. Unfortunately, insufficient clarity exists whether these agents can be used as remission induction agents in bridging strategies just as well as GCs since most trial protocols led to persistent biological use after the induction phase. Moreover, tumour necrosis factor-blocking agents did not demonstrate superior efficacy compared with induction regimes with GCs. Thus, administering GCs could avoid or postpone starting expensive long-term biological therapy.
The debate on the ideal DMARD content of initial RA treatment strategies is still ongoing. Triple therapy (MTX, sulfasalazine (SSZ) and hydroxychloroquine), combination therapy for early rheumatoid arthritis (COBRA)-like schemes (MTX±SSZ+GCs) or other DMARD combination therapies show excellent clinical efficacy compared with monotherapy. However, studies comparing different intensive treat-to-target regimens of classical DMARDs associated with a remission-inducing agent are scarce.
The aim of the current study was to compare in high-risk patients with eRA the efficacy and safety of different initial DMARD combinations and GC bridging schemes, 16 weeks after initiation.
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