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The initiation of recurrent
methotrexate (MTX) and various biologic agents has had such an influence on the
treatment of rheumatoid arthritis (RA) that a standard shift has appeared
towards earlier and more aggressive involvement with the goal of remission.
In rheumatoid arthritis (RA) patients with
inadequate response to methotrexate, tocilizumab in combination with methotrexate
suppressed the inflammation more rapidly than tocilizumab switched from
methotrexate, leading to superior clinical efficacy and prevention of joint
destruction.
The initiation of recurrent methotrexate (MTX) and various biologic agents has had such an influence on the treatment of rheumatoid arthritis (RA) that a standard shift has appeared towards earlier and more aggressive involvement with the goal of remission. Methotrexate is an anchor drug in the management of RA because of its long-term effectiveness and safety profile, but in poor responders of MTX, adjustment of treatment should be considered. This adjustment can include the introduction of another conventional disease modifying antirheumatic drug (DMARD) or a biological DMARD according to the absence/presence of poor prognostic factors. There can be two approaches of initiating a biological DMARD in MTX poor responders with low prognostic factors. The first one is combining a biological DMARD with MTX, and the other is swapping to a biological DMARD from MTX. Though many clinical studies provide the positive results of a combination treatment, the switch to a monotherapy is a debate for interleukin6 (IL6) blocking. Regarding tumor necrosis factor (TNF) inhibitors, results from many clinical studies have advised that the use of TNF inhibitors in combination with MTX is superior to TNF inhibitor monotherapy, and that adding TNF inhibitors to MTX is better than replacing MTX with TNF inhibitors in efficacy, while the safety is comparable among the groups. Tocilizumab (TCZ), humanized antihuman IL6 receptor monoclonal antibody, has been proven to be efficacious in RA patients, and its efficacy has been well validated, both as a combination therapy with MTX and as monotherapy. Tocilizumab monotherapy has been shown to be more efficacious than MTX monotherapy in MT naïve patients, in patients with an inadequate response to MTX and in patients with a history of MTX treatment more than 6 months before. Therefore, a question arises if addition of TCZ to MTX or a switch from MTX to TCZ is comparable.
Rationale behind research:
Objective:
To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active RA.
Study Endpoints:
Primary Endpoint: The primary outcome of this study was to determine the percentage of patients in remission according to the Disease Activity Score 28- erythrocyte sedimentation rate (DAS28-ESR) at week 24.
Other Endpoint: To assess the following parameters: tender joint count, swollen joint count, health assessment questionnaire disability index, patient global assessment using a VAS, evaluator global assessment using a VAS, creactive protein (CRP), ESR and matrix metalloproteinase. Radiographs of the hands and feet were obtained at baseline and at week 52. Each radiograph was assessed applying the van der Heijdemodified total Sharp scoring system (mTSS) by two independent readers who were blinded to treatment assignment and the patient's clinical status. At each visit, patients were monitored for physical signs, laboratory tests, and AEs.
Outcomes:
Baseline characteristics: There were no statistically or clinically significant differences between the two groups in baseline characteristics, except for the swollen joint count in the 66 joints.
Primary outcomes: DAS28ESR remission rates were significantly higher in the Add-on group than in the Switch group at weeks 4 and 24, but they became comparable at week 52. Remission rates according to the Simplified Disease Activity Index (SDAI) and the Crohn's Disease Activity Index (CDAI) were not significantly different between the two groups but showed a similar tendency.
Figure 1: Comparison of DAS28-ESR rates in add on group and switch group
Other outcomes: For other endpoints, including Boolean remission and ACR20/50/70, the differences between the two treatment groups were not significant, but there was a trend towards superiority of TCZ added to MTX to TCZ switched from MTX. The DAS28ESR remission rate was also significantly higher in the Add-on group at week 8, and this corroborated the finding that TCZ added to MTX was favorable for the 24 weeks. The clinical efficacy of TCZ switched from MTX could catch up by week 52.
At week 52, structural remission, defined as a change in mTSS from baseline ≤0.5, was achieved in 63 patients (66%) in the Add-on group and in 63 (64%) in the Switch group (p=0.92), and there was no significant difference in the median change (0 in both groups) between the two groups. Although the percentages of CRRP were not significantly different between the two groups (p=0.07), the mean change in mTSS in CRRP patients was significantly larger in the Switch group than in the Add-on group. The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group.
This study compared two different strategies in patients with RA who poorly responded to MTX. The results suggest that TCZ added to MTX is clinically and radiographically superior to TCZ switched from MTX. The switch strategy could catch up later to the add-on protocol with respect to clinical efficacy, but the structural damage progressed more in a year with the switch therapy.
Monotherapy of TCZ as well as its combination with MTX has been proven to be more efficacious than MTX monotherapy. The ACTRAY study comparing the efficacy and safety of TCZ in combination with MTX with TCZ monotherapy in a similar fashion to the present study showed no clinically relevant superiority of the add-on strategy over the switch strategy at 1 year. This suggested that TCZ monotherapy is a valuable treatment in RA patients with inadequate response to MTX. However, a modest difference favoring the add-on strategy in achieving low disease activity at week 24 and in suppressing radiographic progression at week 52 was observed. The present study underlined the trends showing the clinical superiority of the combination therapy for the first half of the follow-up period and radiological superiority at 1 year.
Rheumatoid arthritis patients who poorly respond to MTX, TCZ added to MTX suppresses inflammation more than TCZ switched from MTX, leading to superior clinical efficacy and prevention of joint destruction.
Ann Rheum Dis. 2016;75(11):19171923.
Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)
Yuko Kaneko et al.
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