Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation, joint destruction and functional disability.1

Rituximab is a chimeric, anti-CD20, B-cell-depleting monoclonal antibody composed of a human and a murine portion. It has been approved for use in combination with methotrexate in patients with moderately or highly active RA who have not responded satisfactorily to anti-tumor necrosis factor (anti-TNF) therapy.1 A number of studies have demonstrated that changing to rituximab rather than to another anti-TNF agent may prove to be more effective.2–4Although biological treatments represent an important advance in the control of RA, their potential toxicity and high cost should be taken into account. Given both their elevated price and the costs of administration, monitoring, prophylaxis and treatment of the toxicity, they are cost-effective only in certain situations.5–7 Although the price per dose of rituximab is higher than that of the anti-TNF agents, as the treatment with the former requires fewer courses, in the end, it is the less expensive of the two.

The authorized dose of rituximab is 2 infusions of 1000mg separated by 15 days for each treatment course, and repeat treatments are administered every 6 months.8 However, at the present time, patient management is being generalized by means of “tight control” and “treat to target” strategies. These strategies require frequent adjustments of the treatment intensity and have opened the door to modifications of the doses and regimens recommended in the specifications, depending on the clinical status of the patient. Moreover, the authorized rituximab doses have been found to be only slightly superior in the prevention of radiation damage, but there was no clear clinical superiority in the major phase 3 trials with rituximab.9–16As a consequence of these approaches, studies have been conducted in the attempt to determine whether the same therapeutic benefit is obtained in patients receiving rituximab at a dose of 500mg, rather than the standard dose of 1g.14–16 The results suggest that, in some patients, the reduced dose can exhibit the same efficacy, as was observed in the DANCER study,9 SERENE trial,10 TAME study,11 MIRROR trial12 and IMAGE trial.13

On the other hand, in the clinical trials that evaluate the efficacy of rituximab for the treatment of RA, it has been observed that the most frequent adverse events are associated with reactions to infusion of the drug and the rate of infusion. This suggests that a reduction in the doses might also be accompanied by a lower incidence of adverse events.

Finally, it is not known whether or not a decrease in the dose of rituximab is associated with a higher frequency of retreatment when it is administered at the discretion of the treating physician. This datum is relevant as regards the efficacy of this drug, as a reduction in the dose could be accompanied by a reduced effectiveness and an even higher cost, should retreatment be required more frequently.

In short, clinical practice studies that evaluate the true efficacy of the use of rituximab in regimens of this type would be necessary.

Our objective was to investigate whether there were differences in efficacy in terms of effectiveness (measured by the treatment retention time and retreatment rates), safety and final cost among patients treated with different regimens and doses of rituximab.

From July 2006 to December 2012 (inclusive), 57 patients with RA were treated with at least 1 course of rituximab. Five patients were excluded because less than 3 months had elapsed since their first rituximab course when enrollment in the study was concluded. The final analysis included 52 patients with a total follow-up of 135.34 patient-years.

The patients were divided into 3 groups according to the doses of rituximab they received in the first course and thereafter (Fig. 1). Group 2 was the largest of the 3 and showed the longest treatment retention time.

Fig. 1.

Diagram showing treatment groups and sequence.

(0.21MB).

The baseline clinical characteristics of the patients are shown according to group in Table 1. The majority of the patients were women with a mean age of 61 years, were seropositive and had erosive disease. The proportion of women in group 1 was lower than in the other 2 groups. There were no significant differences between the 3 groups with respect to the median disease activity score in 28 joints (DAS28) at baseline. Three months after the first infusion, the median DAS28 (calculated from the available data) had decreased in all 3 groups (group 1=3.4; group 2=3.2; group 3=3.94), again without significant differences (P=.16).

The majority of the patients began rituximab therapy after having received at least 1 anti-TNF agent (Table 2). The drugs most frequently administered with rituximab as concomitant treatment during the first course were methotrexate and corticosteroids.

The economic impact of RA is largely due to the cost of treatment. A great part of this expense corresponds to biological therapy.18 For this reason, we consider that the choice of therapy should depend not only on its efficacy, but on its efficiency, as well. Another aspect that is equally important is the safety profile of the drug.

We carried out a retrospective observational study to evaluate the efficiency of reduced rituximab doses for the treatment of RA based on our clinical practice.

We chose this retreatment scheme because many patients in clinical practice remain stable for periods of over 6 months.19 Moreover, this approach makes it possible to reduce expenses and the number of treatment courses accumulated throughout their lives. At the present time, we have no conclusive data on the long-term safety of repeated courses, and there is no evidence of differences in terms of the safety between the fixed treatment scheme and treatment at the discretion of the treating physician.20

A number of factors influence the retention time of a drug, such as its effectiveness, its toxicity, the availability of other treatment alternatives, the severity of the disease and adherence to treatment.21 However, due to the fact that there are now different options for biological therapy in RA, a longer treatment retention time usually translates into its greater effectiveness and safety.

In our study, there were no differences in the baseline clinical characteristics of the 3 treatment groups, with the exception of sex. In all 3 groups, rituximab was used most often as the second line of biological treatment but, in group 1, there was a high percentage of patients who received it as first-line therapy. As the effectiveness is usually greater with a first line of treatment and in men, these differences should be taken into account when interpreting the results. There were no differences between first courses and repeated courses in terms of concomitant treatment, although 6% of the patients discontinued corticosteroid therapy.

The results of our study show that when the 3 treatment groups were compared using the IRR, repeated treatments with full doses, as in group 1, were associated with a lower rate of retreatment as opposed to groups 2 and 3, in which the repeat courses consisted of reduced doses. This finding could be due to the fact that treatment with full-dose rituximab achieved longer periods of remission or low disease activity. However, we should not overlook the fact that, in group 1, there was a higher proportion of men and of patients receiving rituximab as first-line biological treatment, although, as we have seen, this did not result in a longer retention time. In fact, the longest rituximab treatment retention time was recorded in group 2, in which the initial course consisted of the full dose and subsequent courses of the reduced dose. These findings may indicate that retreatment courses with the lower dose of rituximab are as effective as courses with the full dose—provided that the only purpose of treatment is to fulfill the objectives of achieving and/or maintaining remission or low disease activity; in addition, a lower rate of adverse effects can be expected.

Group 3 received the highest number of courses, corrected for follow-up, and had the worse rituximab treatment retention. Thus, the administration of reduced doses of 500mg from the beginning may be less effective than starting with a full dose. We can assume that this discrepancy between group 3 and group 2 is due only to the initial dose; therefore, we can hypothesize that, to achieve satisfactory effectiveness, the first course should always consist of 1000mg. The latter point could be the subject of future studies.

We should not lose sight of the fact that the greater the number of courses, the greater the risk of infusion reactions,22 as well as other adverse reactions related to immunosuppression. This was not the case in our study; despite receiving the least number of courses after adjustment for time, it was in group 1 that the highest numbers of both overall and severe adverse effects were recorded. Despite the latter observation, these data suggest that the number of adverse effects does not depend so much on the number of courses, but on the dose utilized in each. In our study, there were fewer overall adverse effects in comparison with other studies.23 This could be due to differences in methodology and the number of patients.

Factors that clearly influence the cost of rituximab are the size of the doses and number of courses required to achieve and maintain complete remission or a low level of disease activity. Despite the differences in the doses and numbers of courses administered in our 3 groups, there were no great differences in the cost. Thus, the impact of this factor should not be considered too important when choosing a treatment regimen.

The limitations of this study are due to its design (retrospective cohort), as well as to the differences between the groups in terms of duration of follow-up and the proportions of men to women and of patients who received rituximab as first-line treatment to those who did not.

Taking into account the above-mentioned limitations, we could conclude that, despite the fact that the patients treated from the start with full doses required a lower rate of repeat treatments/patient-year, the administration of full doses in the first course and reduced doses thereafter appears to be the most effective option, and is only slightly more costly. Reducing the dose does not result in great savings with respect to full doses when compared with the savings produced with administration “on demand”, that is, at the discretion of the treating physician. The rate of adverse effects may be higher in patients treated with full rituximab doses in comparison with those treated with reduced doses, although these differences could be biased, in part because of the higher proportion, in group 1, of patients who received biological agents as first-line treatment. The incidence rate of serious infections is similar to that expected with a biological treatment as the first option.

The authors declare they have no conflicts of interest.