RituximabEdwards et al.

Because the open-label pilot trials of rituximab in RA patients had demonstrated encouraging results, a randomized, double-blind, controlled study was conducted. A total of 161 patients with active RA that was inadequately controlled by conventional DMARDs, including at median doses of 12.5 to 15 mg/week, were recruited into the study. The baseline characteristics and measures of disease activity were similar in all four treatment groups (Table 2).

Patients were randomly assigned to receive one of four treatments: oral 10 mg weekly; rituximab 1,000 mg on days 1 and 15; rituximab plus IV cyclophosphamide 1,000 mg on days 1 and 15 and 750 mg on days 3 and 17, respectively; or rituximab 1,000 mg on days 1 and 15 plus oral methotrexate at a dose of 10 mg weekly. They were allowed to take NSAIDs at stable doses or corticosteroids at doses that did not exceed 12.5 mg/day of prednisolone, and they were followed for 48 weeks.

Table 2 Baseline Characteristics of Patients

Methotrexate (N = 40) Rituximab(N = 40) Rituximab/ Cyclophosphamide (N = 41) Rituximab/ Methotrexate(N = 40)

Age (years)

54 ±11 54 ± 10 53 ± 10 54 ± 12

Female sex (%)

80 73 83 75

Duration of disease (years)

11 ±7 9 ±6 10 ± 6 12 ± 7

Previous DMARDs (No.)

2.6 ± 1.3 2.5 ± 1.6 2.6 ± 1.4 2.5 ± 1.4

Swollen joints (No.)

19 ± 10 21 ±11 19 ± 10 23 ± 13

Tender joints (No.)

32 ± 13 34 ±15 33 ± 14 32 ± 16

Serum C-reactive protein (mg/liter)

32 ± 43 26 ± 22 40 ± 40 29 ± 32

Erythrocyte sedimentation rate (mm/hour)

52 ± 32 47 ± 23 55 ± 29 53 ± 23

The primary endpoint of the study was the proportion of patients with an ACR 50 response at week 24. Secondary outcomes included ACR 20 and ACR 70 responses (20% and 70% improvement, respectively, according to the ACR criteria).

The proportion of patients achieving an ACR 50 response at week 24 was greater (P = .005) in the groups of patients receiving the regimens of ritux-imab in combination with either metho-trexate or cyclophosphamide than in the control group. The ACR 50 response with rituximab monotherapy was numerically higher than the response for the control group (which received only methotrexate), but the difference did not reach statistical significance (P = .059). The proportions of patients achieving ACR 20 and ACR 70 responses at week 24 were higher for the rituximab patients than for the controls.

Exploratory analyses at week 48 revealed ACR 70, ACR 50, and ACR 20 responses in 0%, 5%, and 20% of patients in the canadian methotrexate control group, respectively, compared with 15%, 35%, and 65% of patients in the rituximab/ methotrexate group (P = .03, P = .02, and P < .001, respectively).

In the rituximab/cyclophosphamide group, 27% of patients had ACR 50 responses and 49% achieved ACR 20 responses (P = .01 for both comparisons). All other comparisons of ACR responses at week 48 favored rituximab therapy, but this difference did not reach statistical significance.

ADVERSE DRUG EVENTS

Safety evaluations from the Edwards study showed that rituximab was generally well tolerated in patients with RA. The treated patients demonstrated a similar overall incidence of ADEs, with 73% to 85% of patients reporting at least one ADE; 30% to 45% of patients in each group experienced ADEs associated with the first infusion (Table 3). During the initial 24 weeks, a total of 16 serious ADEs were reported in 14 patients, with the highest incidence among patients receiving rituximab plus cyclophosphamide.

Table 3 Summary of Adverse Drug Events

Adverse Event

Methotrexate(N = 40) Rituximab(N = 40) Rituximab/ Cyclophosphamide (N = 41)

Rituximab/ Methotrexate

(N = 40)

Any event

Up to week 24 Up to week 48

No. of Patients (%) 32 (80) 34 (85) No. of Patients (%) 32 (80)36 (90) No. of Patients (%) 30 (73)35 (85)

No. of Patients (%)

34             (85)

35             (88)

Serious adverse event Up to week 24 Up to week 48

3                  (8)

4                  (10)

2 (5)4 (10)

6                  (15)

7                  (17)

3    (8)4    (10)

Any event associated with the first infusion

12 (30) 18 (45) 13 (32)

13 (33)

Specific event Hypotension*

7 (18) 12 (30) 12 (29)

7 (18)

Exacerbation of RA

16 (40) 6 (15) 6 (15)

2 (5)

Hypertension*

6 (15) 6 (15) 3 (7)

10 (25)

Nasopharyngitis

6 (15) 4 (10) 2 (5)

4 (10)

Arthralgia

3 (8) 3 (8) 1 (2)

4 (10)

Rash

1 (3) 4 (10) 4 (10)

1 (3)

Back pain

2 (5) 4 (10) 3 (7)

0

Cough Pruritus Nausea Dyspnea

0 0

1 (3)

0

5 (13) 4 (10) 2 (5) 4 (10) 1 (2) 4 (10) 4 (10)0

2 (5)

0 0 0

During the extended observation to week 48, three patients withdrew from the trial because of ADEs: one control and two rituximab monotherapy patients. The profile of ADEs remained the same as those observed during the initial 24 weeks. It was concluded that because using rituximab in combination with either or metho-trexate led to substantial clinical responses—yet did not result in an observed increased risk for developing life-threatening infections—this treatment approach should be considered a viable option for refractory RA.

CONCLUSION

B cells have an important role in the pathogenesis of RA. This is documented not only by in vitro data but also by in vivo data of B-cell-depleting biological agents. The therapeutic efficacy of ritux-imab in RA suggests that this agent affects B cells in the synovium and causes clinically significant disruption of the inflammatory process. According to the published studies, patients do not appear to become immunocompromised by short-term treatment with anti-CD20 antibody. However, treatment is likely to involve maintenance doses after the proposed two induction doses and, possibly, additional treatment with immunosuppressive or immunomodulatory agents. canadian antibiotics

Many unanswered questions exist regarding response rates, optimal dosing, comparative long-term efficacy, and placement in the RA treatment algorithm. Further controlled trials need to be conducted to answer these questions.