This report presents safety data from the global rituximab RA clinical trial programme in 3194 patients with 11 962 patient-years of follow-up. Compared with a previous analysis,17
this represents almost 7000 additional patient-years of follow-up with 20% more patients, and includes a placebo+MTX population for comparison. The inclusion of 627 patients with >5 years of observation, with some patients having received up to 17 rituximab courses over 9.5 years of observation, affords a high level of confidence in the data and increases the probability of detecting common and infrequent safety risks compared with previous studies.12
AE and SAE rates generally remained stable over time and over multiple courses, and the most common SAEs in the All Exposure population were typical of biological-treated RA patients.25
The overall SIE rate (3.94/100 patient-years) was within the range reported (3.0 to 5.2/100 patient-years) for long-term follow-up with other RA biologics.6
These observations are consistent with controlled rituximab trials10
and a meta-analysis of randomised controlled trials that did not identify a significant increase in SIE risk during rituximab treatment.28
Opportunistic infections were rare. No further cases of PML in the RA clinical trial programme have been reported other than the single case previously described.19
The occurrence of confirmed PML from spontaneous reporting and clinical trial sources remains very rare (six confirmed cases in estimated 188 228 RA patients treated with rituximab, as of November 2011 (Roche data on file)). Herpes zoster rates were consistent with placebo+MTX and general RA populations.20
Decreases in Ig levels were observed in some patients following rituximab treatment although the clinical consequences of this are unclear. Analysis of registry data has previously shown that a low IgG level (<6 g/l) before
rituximab treatment was associated with an increased risk of SIE.29
Low baseline IgG was an exclusion criterion in the RA clinical trials and therefore this observation could not be confirmed or refuted. Following rituximab treatment, low Ig concentrations (particularly IgM) were observed in some patients. Patients with low IgM had no increased risk of infections or SIE. It is well established that reduced IgG levels are inherently associated with an increased risk of infections.30
Nevertheless, for the small subgroup of patients with low IgG, a higher SIE rate was seen both before and after the development of low IgG compared with patients who never developed low IgG, suggesting that these patients had a higher inherent risk of developing SIE, possibly associated with demographical and/or clinical characteristics rather than with low IgG itself. Thus, for both Ig classes, SIE rates were similar before and after development of low levels. Limitations of the Ig analysis included low patient numbers in the IgG subgroup, lack of a placebo comparator and lack of correlation (due to protocol-defined Ig measurements) between SIE onset and recording of low Ig levels.
RA patients are known to be at an increased risk of cardiovascular disease.31
Consistent with this, MI was the most frequent cardiac AE reported in rituximab-treated patients. Most patients experiencing MI had at least one conventional risk factor, although it has been reported that cardiovascular morbidity in RA patients cannot be fully explained by such risk factors and that RA-associated inflammation and underlying disease may also be a contributing factor.32
The MI rate reported for rituximab-treated patients is consistent with epidemiological data from a general RA population receiving TNF inhibitors or DMARDs (0.48 to 0.59/100 patient-years)31
and there was no evidence to suggest an increased risk of MI associated with rituximab treatment. The rate of stroke was also consistent with published data in RA patients.31
As might be expected in a predominantly female study population with a mean age of 51 years, the most common solid tumour was breast cancer. Age- and sex-matched standardised incidence ratios for all confirmed malignancies and breast cancer did not indicate an increased risk of malignancy for rituximab-treated RA patients compared with the general US population (SEER database)23
and with published data in adults with RA.21
The rate of fatal AEs remained consistent through the observation period and there was no evidence of an increased rate of any type of fatal event with prolonged rituximab exposure. The overall death rate observed in the rituximab RA clinical development programme was within the expected range for patients receiving a biological therapy36
and leading causes of death were also consistent with those expected in such a population.
The analysis has potential limitations. Data were pooled from diverse studies in which rituximab doses, retreatment regimens and prior or active disease status could differ. Notably, two of the studies limited patients to receive one or two rituximab courses, thus reducing the overall number of patients receiving higher numbers of courses. In addition, clinical trial data are heavily influenced by the fact that patients are selected at baseline to exclude significant comorbidities, and only those who did well clinically remained in the study. Finally, the mean observation period of patients in the placebo+MTX population was considerably shorter than that of patients in the All Exposure population, and this should be borne in mind when making comparisons. Notwithstanding these limitations, the key strength of this analysis is the long observation and follow-up period in a population of patients with active RA, which included frequent assessments, including those performed after study withdrawal or completion (minimum 1 year) and during extended periods of peripheral B cell depletion. In addition, the overall number of patients withdrawing due to AEs was low (6% in total).
In summary, evidence from the RA clinical trial data of up to 9.5 years of follow-up of 3194 patients treated with rituximab, including a substantial number of patients with >5 years’ observation, revealed no new safety signals. Rituximab has remained generally well tolerated over time and over multiple courses, with a safety profile consistent with published data of patients with moderate-to-severe RA. These findings also indicate that repeated peripheral B cell depletion with rituximab did not give rise to any increased safety risk over time or increased reporting rates of any types of AEs (including infections, cardiovascular events, malignancies or fatal AEs) in the global RA clinical trial programme. Overall, these results are encouraging and should provide clinicians with reassurance regarding the long-term safety of rituximab in RA.