Abstract

Objectives. Rituximab has recently been shown to be effective in suppressing disease activity in patients with rheumatoid arthritis (RA) who fail anti-TNF therapy. We present our experience of treating patients with long-standing, multi-DMARD and anti-TNF resistant RA with rituximab in ‘real-life’ setting.

Methods. Patients with RA resistant to more than two anti-TNF drugs and with persistent disease activity (DAS28 > 5.1) were considered for treatment with rituximab (two infusions 1000 mg each, a fortnight apart). DAS28 and HAQ scores were performed at baseline, 3 and 6 months post-treatment. Response to rituximab was defined as per the EULAR response criteria. Re-treatment with a second cycle of rituximab was offered if they had responded to the earlier one but flared.

Results. Twenty patients received rituximab. Median disease duration was 16 yrs (range 5–39) and 90% were rheumatoid factor positive. Median number of biologics received pre-treatment was two (range 2–4). Rituximab treatment led to a significant reduction in DAS28 score (P < 0.0001) at 3 months and various other disease parameters. The benefit was sustained at 6 months. Moderate-to-good EULAR response was seen in 85% of patients at 3 months and 60% at 6 months. No significant side effects were observed. 50% of the patients flared and received re-treatment. Interval to re-treatment varied from 6 to 18 months. The majority of the RA patients responded to re-treatment with rituximab and no major side effects were observed.

Conclusion. Rituximab was effective in controlling disease activity in anti-TNF therapy resistant RA patients in ‘real-life’ setting. Rituximab was safe with no major side effects. Re-treatment with rituximab was safe and efficacy was maintained.

Uncontrolled rheumatoid arthritis (RA) results in significant pain and disability, leading to increased morbidity and mortality [1]. The introduction of anti-tumour necrosis factor (TNF) therapy for RA has had a significant impact in improving disease outcome [2–4]; however, up to 30% of patients fail to respond [5]. Disease control in these ‘difficult-to-treat’ patients is a therapeutic challenge. Rituximab (an anti-CD20 chimeric monoclonal antibody) has recently been shown to be effective in suppressing disease activity in RA. Randomized trials have demonstrated efficacy both in methotrexate-resistant [6] and in anti-TNF therapy resistant patients [7, 8]. It is well known that patients treated in ‘real-life’ setting may differ from those treated in clinical trials. Hence data from real-life experience are important to reaffirm the results from trials. In this article we present our experience of treating patients with long-standing multi-DMARD and multi-anti-TNF drug resistant RA with rituximab.

Methods

Patients with RA (1987 American College of Rheumatology criteria [9]) who were resistant to more than two anti-TNF agents (treated with each agent at least for 3 months) and had persistent disease activity were considered for treatment with rituximab. Persistent disease activity was defined as disease activity score (DAS 28) >5.1 despite anti-TNF therapy.

Patients received two intravenous infusions of rituximab (1000 mg each) and methylprednisolone (100 mg each) 2 weeks apart. No changes were made to their DMARDs or anti-inflammatory drugs.

DAS28 and health assessment questionnaire (HAQ) scores were performed at baseline, 3 and 6 months post-treatment.

Response to rituximab therapy was defined as per the EULAR response criteria [10] (moderate response = DAS28 > 3.2, ≤5.1 plus improvement of >0.6, ≤1.2 or DAS28 > 5.1 plus improvement >1.2; good response = DAS 28 < 3.2 plus improvement >1.2; also EULAR defines low disease activity as DAS28 ≤ 3.2 and remission as DAS28 < 2.6). Patients were offered re-treatment with a second cycle of rituximab if they had responded to the earlier one but flared. Drug toxicity was carefully monitored.

Statistical methods

Results were presented as medians and range. Responses to rituximab at 3 and 6 months post-treatment were compared with baseline. Non-parametric statistical analysis (Wilcoxan signed ranks test) was performed and a P value <0.05 was considered significant.

Results

The baseline characteristics of the cohort are outlined in Table 1. Our patient cohort had longstanding DMARD and biologic-resistant RA. Fourteen patients (70%) had previously tried three or more DMARDs and the rest had tried at least two. Concomitant DMARDs history included—six patients on methotrexate, two on intramuscular gold, two on hydroxychloroquine, one each on azathioprine, cyclosporine, leflunomide and seven patients were not on any. Ten patients (50%) had failed all three anti-TNF drugs (infliximab, adalimumimab, etanercept), five of these had failed anakinra in addition and the others had failed at least two anti-TNF drugs. Apart from one patient with atlanto-axial disease, none of the other patients had any major extra-articular disease at the time of initiating rituximab. Follow up data were available on all 20 patients at 3 months and 15 at 6 months. The response to first cycle of rituximab is shown in Table 2.

Table 1.

Baseline characteristics

Total number of patients 20 
Male/female 4/16 
Age (yrs): median (range) 54 (33–80) 
Disease duration (yrs): median (range) 16 (5–39) 
Rheumatoid factor positive: n (%) 18 (90) 
Number of pre-treatment DMARDs: median (range) 3 (2–8) 
Number of pre-treatment biologics: median (range) 2 (2–4) 
Prednisolone therapy: n (%) 12 (60) 
Prednisolone dosage (mg): median (range) 10 (5–20) 
Total number of patients 20 
Male/female 4/16 
Age (yrs): median (range) 54 (33–80) 
Disease duration (yrs): median (range) 16 (5–39) 
Rheumatoid factor positive: n (%) 18 (90) 
Number of pre-treatment DMARDs: median (range) 3 (2–8) 
Number of pre-treatment biologics: median (range) 2 (2–4) 
Prednisolone therapy: n (%) 12 (60) 
Prednisolone dosage (mg): median (range) 10 (5–20) 
Table 2.

Median (range) of various parameters with rituximab treatment

Parameter Baseline (n = 20) 3 months (n = 20) 6 months (n = 15) 
Tender joint count (TJC) 26 (2–28) 7* (0–27) 8** (0–28) 
Swollen joint count (SJC) 13 (0–26) 4* (0–22) 4** (0–23) 
Erythrocyte sedimentation rate (ESR mm/h) 56 (14–125) 37** (5–115) 31** (5–124) 
C-reactive protein (CRP mg/l) 32 (3–174) 23 (3–135) 26 (3–132) 
Patient global score (VAS 0–100 mm) 78 (20–100) 35** (0–84) 39** (0–85) 
DAS28 7.2 (5.3–9) 5.6* (2.11–8.55) 5.5** (2.8–8.2) 
HAQ 2.63 (0.75–3) 2.13 (0.63–2.88) 1.86 (1–3) 
Parameter Baseline (n = 20) 3 months (n = 20) 6 months (n = 15) 
Tender joint count (TJC) 26 (2–28) 7* (0–27) 8** (0–28) 
Swollen joint count (SJC) 13 (0–26) 4* (0–22) 4** (0–23) 
Erythrocyte sedimentation rate (ESR mm/h) 56 (14–125) 37** (5–115) 31** (5–124) 
C-reactive protein (CRP mg/l) 32 (3–174) 23 (3–135) 26 (3–132) 
Patient global score (VAS 0–100 mm) 78 (20–100) 35** (0–84) 39** (0–85) 
DAS28 7.2 (5.3–9) 5.6* (2.11–8.55) 5.5** (2.8–8.2) 
HAQ 2.63 (0.75–3) 2.13 (0.63–2.88) 1.86 (1–3) 

*P < 0.0001 **P < 0.05 P = not significant.

Moderate EULAR response was seen in 11 of 20 patients (55%) at 3 months and 8 of 15 (53.33%) at 6 months; good response was seen in 6 of 20 (30%) at 3 months and 1 of 15 (6.66%) at 6 months; no response was seen in 3 of 20 (15%) at 3 months and 6 of 15 (40%) at 6 months. Five patients achieved low disease activity at 3 months after rituximab and one patient at 6 months. One patient achieved EULAR remission criteria at 3 and 6 months. There was no reduction in dose of prednisolone or DMARDs following rituximab therapy. No clinically significant side effects from rituximab were observed.

Ten of the twenty patients (50%) flared (median time to flare 368.5 days, range 195–587) and received re-treatment with a second cycle of rituximab. Four (40%) patients flared 6 months after their first infusion, three (30%) after 12 months and three (30%) after 18 months. Following a second cycle of rituximab, 6 of the 10 patients (60%) responded (five moderate and one good EULAR response) at 3 months, two patients did not respond and follow-up data was missing on two others. Statistical tests were not performed in view of the small number of patients. No major side effects were seen after re-treatment with rituximab.

Discussion

In this article we have described our experience with the use of rituximab in a cohort of patients with multi-drug-resistant RA. This is the first report described outside formal clinical trials from the United Kingdom, which gives a real-life experience. Our cohort of patients differed from those seen in the clinical trials [7, 8] and had a longer disease duration—mean 19.5 yrs (data not shown) compared with 10 yrs in the DANCER group [8] and 12 yrs in REFLEX group [7], greater functional impairment—mean pre-treatment HAQ 2.32 (data not shown) compared with 1.9 in the REFLEX group and had failed more biologic drugs (including anakinra)—mean of 2.6 compared with 1.5 in the REFLEX group. Methotrexate was the only concomitant DMARD allowed in both clinical trials [7, 8] whereas our patients were taking various other DMARDs, which reflects clinical practice.

Rituximab therapy was effective in suppressing disease activity as evidenced by a reduction in DAS28 scores from baseline by 2.06 at 3 months (P < 0.0001) and 1.68 at 6 months (P < 0.05). Major improvements were also seen in various other parameters of disease activity including tender joint count (P < 0.0001 at 3 months, P < 0.05 at 6 months), swolen joint count (P < 0.0001 at 3 months, P < 0.05 at 6 months), ESR (P < 0.05), CRP (P = NS) and patient global health (P < 0.05). A reduction in HAQ score by 0.22 results in meaningful clinical improvement and has been determined as minimum important difference [11]. A reduction in HAQ score by a median of 0.5 at 3 months and 0.87 at 6 months was observed suggesting major improvement in daily life activities.

Results from the REFLEX trial [7] showed a mean DAS28 change of approximately −2.0, mean HAQ change of −0.4 at 24 weeks and moderate-to-good EULAR responses in 65% of patients after rituximab therapy. Even though direct comparison between clinical studies is not always possible due to differences in patient demographics, assessment criteria, strict exclusions and treatment protocols, our results are very encouraging (mean scores equal to median and data not shown). Moderate-to-good EULAR responses were seen in 60% of our patients at 6 months and even higher (85%) as early as 3 months.

These observations show that rituximab is effective in suppressing disease activity and improving functional outcome in a difficult-to-treat cohort of RA patients. B-cell depletion therapy is therefore an effective option when patients fail anti-TNF therapy.

A proportion of patients (50%) required re-treatment with rituximab. It is very encouraging to note that despite resistant long-standing RA, disease activity continued to be suppressed in a majority of patients. Published evidence for efficacy and safety of repeat treatment course of rituximab is lacking and restricted to abstracts from international meetings [12–14]. Although rituximab has been shown to be effective on repeat treatment from these data, the median interval between infusions is still not clear. The most approximate time interval to re-treatment appears to be between 6 and 12 months as shown in our cohort although disease activity was controlled for as long as 18 months in a few patients. Data from larger clinical trials will be necessary in order to confirm our findings.

Conclusion

Rituximab was effective in controlling disease activity in a cohort of difficult-to-treat patients who were refractory to multiple DMARDs and biologic therapy. Rituximab therapy was also safe with no reports of major side effects. A repeat course of rituximab was found to be efficacious and safe.

Acknowledgements

Departmental research grants were received from Roche, Schering-Plough, Wyeth and Abbott pharmaceuticals. K.G. received an honorarium from Roche pharmaceuticals for attending an advisory board meeting. Prof Scott received an honorarium from Roche pharmaceuticals for lecturing.

graphic

M.S. received Department grants from all pharmaceutical companies (Roche, Schering, Wyeth Abbott).

The authors have declared no conflicts of interest.

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