Treatment with rituximab 2×1000 mg in combination with MTX has previously been shown to result in significant inhibition of PJD over 1 year in MTX-naïve patients with early, active RA.12
The current analysis reports that these effects, including significant reductions in mTSS and erosion score, are maintained over 2 years of treatment with rituximab 2×1000 mg+MTX. Exploratory analysis also suggested that rituximab 2×500 mg+MTX slowed joint damage over 2 years.
The proportion of patients showing no progression of joint damage after 2 years was significantly higher in the rituximab dose groups compared with the placebo+MTX group. The figure of 57% observed for the 2×1000 mg dose was almost identical (56.8%) to that seen at 2 years in a similar population treated with abatacept+MTX.17
The majority of joint damage progression in the current study was observed within the first 6 months, with further damage almost entirely prevented thereafter; the reasons for this are unknown.
Over 2 years, both doses of rituximab continued to demonstrate significant improvements over placebo in relieving the signs and symptoms of RA, as exemplified by significantly higher proportions of patients achieving ‘high-hurdle’ end points, such as ACR70 and ACR90, major clinical response, EULAR good response and DAS28 remission. In addition, improvements in physical function were maintained, with significantly greater mean changes in HAQ-DI observed in both rituximab groups than in the placebo group throughout the observation period.
This study was not powered to compare rituximab doses, but exploratory results generally show that numerically greater responses for radiographic outcomes were achieved with the higher dose, while clinical outcome responses were generally numerically similar for both doses. In addition, the disconnect between radiographic and clinical responses with rituximab 2×500 mg+MTX previously observed at 1 year was reduced at 2 years—an effect attributed to a slower onset of radiographic inhibition during the initial 6 months of treatment with the 500-mg dose. A recent consensus statement18
discussed the optimal dose of rituximab in patients with RA. The authors proposed that the 500-mg dose may provide equivalent clinical and radiographic benefits to 1000 mg; however, the 500-mg dose is not approved and has not been studied in the licensed TNF-IR patient population. Consequently, further analysis would be required to confirm any equivalence of doses. In the present study, while both rituximab doses provided benefit in improving clinical signs and symptoms, data suggest that the higher dose slows PJD sooner, an observation that is relevant to an early population with RA (data presented in online supplementary table S1).
As at 1 year, and consistent with observations made in other patient populations,19–21
patients in the small subgroup who were seronegative for both RF and ACPA showed limited evidence of radiographic or clinical improvement with rituximab+MTX or placebo+MTX treatment. Conversely, radiographic and clinical responses among patients seropositive for RF and/or ACPA were significantly improved for rituximab compared with MTX alone.
The 2-year safety profile is consistent with that observed at 1 year12
and with previously reported data in TNF-IR patients7
and pooled data from long-term rituximab studies.22
The incidence of serious infections remained low and consistent with previously reported rates,22
and no further opportunistic infections were reported beyond those observed up to week 52. Infusion-related reactions remained the most common safety event overall; however, their incidence generally declined following the first infusion of the first course.
No cases of PML were reported in this trial, and the overall reporting incidence of PML in patients with RA receiving rituximab is very rare (5 cases in 129,000 patients with RA).23
The IMAGE trial was conducted in MTX-naïve patients with early disease, and many alternative treatment options are available for these patients; therefore, following a spontaneous report of a case of PML in a rituximab-treated patient not previously exposed to biological treatment,24
the sponsors took the decision to discontinue dosing with rituximab in the IMAGE trial.
Rituximab 2×1000 mg is currently licensed in combination with MTX for patients with RA who have had an IR or intolerance to other disease-modifying antirheumatic drugs, including one or more TNF inhibitor treatments. Rituximab is not approved for use in the MTX-naïve population described here, but these data demonstrate the value of rituximab+MTX in preventing progression of structural joint damage, a key goal of treatment. Furthermore, under recent recommendations and guidelines, patients often now receive their second and subsequent biological treatment much sooner after RA diagnosis.3
Consequently, the positive results presented here for the IMAGE trial, in which patients were treated on average 1 year after RA disease onset, may be relevant to a TNF-IR patient who initiates treatment with rituximab.
In conclusion, this 2-year analysis of the IMAGE study demonstrates that rituximab 2×1000 mg+MTX led to sustained and significant inhibition of joint damage progression and significant improvements in clinical signs and symptoms of RA and functional ability compared with MTX alone in an early population of patients with RA.