Sir, Treatment of RA with rituximab (RTX) is established for patients with an inadequate response to anti-TNF-α therapy [1–3]. Previous RTX trials show an ACR-70 response in ∼15% of all patients after 24 weeks [2, 3]. Therefore, a significant fraction of RA patients cannot be treated sufficiently. Other trials showed that combinations of etanercept (ETN) and anakinra [4] or ETN and abatacept [5] were associated with severe infections and are not recommended. Current guidelines propose that patients with an inadequate response to one or more anti-TNF-α drugs should switch to RTX therapy [6]. Recently published data suggest a switch to RTX after inefficacy of the first anti-TNF-α drug [7]. Current practice for switching to RTX is to discontinue ETN for 2 weeks, adalimumab (ADA) for 4 weeks and infliximab for 4–8 weeks before RTX therapy. However, it is not clear whether this is necessary to prevent infections or whether discontinuation leads to disease exacerbation.

We describe a retrospective analysis of 18 consecutively selected patients with long-standing active RA according to the ACR 1987 classification criteria who received RTX therapy. The pro and contra for combination therapy was discussed with the patient and an informed patient consent was obtained for this study. Patients were previously treated with up to six DMARDs and three anti-TNF-α drugs, but still had significant disease activity. Patients were mostly treated with MTX, LEF or MTX + LEF in combination with ETN or ADA. Anti-TNF-α drugs were discontinued and 2 weeks later RTX therapy was initiated with two infusions of 1 g within 2 weeks. Pre-medication with 100 mg prednisone was used to prevent anaphylactoid reactions. Concomitant DMARDs were not changed. During the follow-up period intra-articular steroid injections and oral pulses with up to 40 mg prednisone were offered to patients with active synovitis. Follow-up visits were scheduled 4 and 8 months after the first RTX infusion or earlier if necessary. Two months after the first RTX infusion six patients did not achieve a satisfying clinical response and had persistently high CRP and ESR parameters. Results from the REFLEX study showed that the clinical benefit of RTX appears ∼4 weeks after the first infusion with a DAS-28 improvement of −1.6 after 4 weeks and −1.8 after 12 weeks [3]. Therefore, these six patients re-started anti-TNF-α therapy with ETN, which corresponds to an RTX + ETN combination because of the long-lasting depletion of B cells [8, 9]. ETN was used because of its short half-life and concerns about infections. After 2 months of RTX + ETN (4 months after the first RTX infusion) all clinical and serological parameters improved significantly. All patients gradually improved between 4 and 8 months. The second RTX cycle was started in both groups after re-occurrence of disease activity after ∼8 months. Patients who received RTX + ETN discontinued ETN 1 week before the next RTX infusion and continued ETN 1 week after the second RTX infusion in the second cycle. The interval between RTX infusions was 8.2 ± 1.8 months in the RTX group and 10.2 ± 6.9 months in the RTX + ETN group, respectively. The difference was due to a single patient and was not statistically significant. Patients in the RTX + ETN group were younger at disease onset, had a longer disease duration, received more DMARDs and biologics and had a longer duration of previous anti-TNF-α therapies (Table 1). Clinical parameters were not different in both groups at the time of the first RTX infusion. Inflammatory parameters were higher in the RTX + ETN group, which correlates to the selection procedure of these patients.

Table 1.

Patient characteristics and response to treatment

 RTX RTX + ETN t-test 
Patients, n 12  
Female, n (%) 7 (58) 4 (67)  
Juvenile RA, n (%) 0 (0) 3 (50)  
Age at disease onset, mean ± S.D., yrs 46.4 ± 10.9 30.0 ± 16.5 0.06 
Disease duration, mean ± s.d., yrs 9.1 ± 6.1 17.0 ± 4.8 0.01 
Age at first RTX, mean ± s.d., yrs 55.5 ± 11.8 47.0 ± 14.1 0.2 
RF positive, n (%) 9 (75) 3 (50) 0.4 
CCP positive, n (%) 8 (67) 3 (50) 0.4 
ANA positive, n (%) 3 (25) 5 (83) 0.4 
Previous DMARDs, mean ± s.d., n 3.9 ± 2.2 6.0 ± 1.5 0.04 
Previous biologics, mean ± S.D., n 2.2 ± 0.9 3.0 ± 0 0.01 
Previous TNF-α duration, mean ± s.d., months 26.9 ± 17.0 51.5 ± 21.1 0.04 
Pre/post first cycle RTX Pre Post t-test Pre Post t-test 
DAS-28, mean ± s.d., n 6.3 ± 1.0 4.1 ± 1.6 0.001 6.5 ± 0.7 4.3 ± 1.0 0.002 
SDAI, mean ± s.d., n 38.0 ± 13.7 18.2 ± 13.0 0.002 35.7 ± 9.2 13.3 ± 7.1 0.001 
Tender joint count, mean ± s.d., n 12.9 ± 6.1 4.3 ± 5.3 0.001 11.2 ± 8.4 4.3 ± 2.3 0.05 
Swollen joint count, mean ± s.d., n 8.1 ± 5.7 3.8 ± 3.9 0.04 7.0 ± 2.1 2.0 ± 2.4 0.01 
CRP, mean ± s.d., mg/l, normal range <5 36.4 ± 33.0 18.5 ± 18.5 0.2 55.0 ± 26.3 9.6 ± 7.1 0.003 
ESR, mean ± s.d., mm/h, normal range <15 45.3 ± 19.3 31.0 ± 24.1 0.1 70.0 ± 17.7 33.0 ± 14.9 0.01 
 RTX RTX + ETN t-test 
Patients, n 12  
Female, n (%) 7 (58) 4 (67)  
Juvenile RA, n (%) 0 (0) 3 (50)  
Age at disease onset, mean ± S.D., yrs 46.4 ± 10.9 30.0 ± 16.5 0.06 
Disease duration, mean ± s.d., yrs 9.1 ± 6.1 17.0 ± 4.8 0.01 
Age at first RTX, mean ± s.d., yrs 55.5 ± 11.8 47.0 ± 14.1 0.2 
RF positive, n (%) 9 (75) 3 (50) 0.4 
CCP positive, n (%) 8 (67) 3 (50) 0.4 
ANA positive, n (%) 3 (25) 5 (83) 0.4 
Previous DMARDs, mean ± s.d., n 3.9 ± 2.2 6.0 ± 1.5 0.04 
Previous biologics, mean ± S.D., n 2.2 ± 0.9 3.0 ± 0 0.01 
Previous TNF-α duration, mean ± s.d., months 26.9 ± 17.0 51.5 ± 21.1 0.04 
Pre/post first cycle RTX Pre Post t-test Pre Post t-test 
DAS-28, mean ± s.d., n 6.3 ± 1.0 4.1 ± 1.6 0.001 6.5 ± 0.7 4.3 ± 1.0 0.002 
SDAI, mean ± s.d., n 38.0 ± 13.7 18.2 ± 13.0 0.002 35.7 ± 9.2 13.3 ± 7.1 0.001 
Tender joint count, mean ± s.d., n 12.9 ± 6.1 4.3 ± 5.3 0.001 11.2 ± 8.4 4.3 ± 2.3 0.05 
Swollen joint count, mean ± s.d., n 8.1 ± 5.7 3.8 ± 3.9 0.04 7.0 ± 2.1 2.0 ± 2.4 0.01 
CRP, mean ± s.d., mg/l, normal range <5 36.4 ± 33.0 18.5 ± 18.5 0.2 55.0 ± 26.3 9.6 ± 7.1 0.003 
ESR, mean ± s.d., mm/h, normal range <15 45.3 ± 19.3 31.0 ± 24.1 0.1 70.0 ± 17.7 33.0 ± 14.9 0.01 

We were concerned about infections in patients receiving RTX + ETN. The six patients were exposed to RTX + ETN for a mean of 18.5 months and overall 111 patient-months, respectively. No serious infections requiring an i.v. therapy or hospitalization were observed up to now (October 2008). One non-serious infection occurred in a patient in the RTX + ETN group, who had a re-exacerbation of perioral herpes simplex. The doses of LEF and prednisone were reduced and the lesions rapidly resumed. A second patient had suffered from frequent mild respiratory infections in the past which did not exacerbate during RTX + ETN therapy. A third patient received total finger joint replacement 2 yrs before and some protheses had to be explanted in the past because of infection. We did not observe an infection of the remaining devices during RTX + ETN therapy.

Depletion of B cells and anti-TNF-α therapy target different pathways of inflammation and therefore probably act synergistically. TNF-α is one of the most powerful pro-inflammatory cytokines and is produced by monocytes. RTX treatment virtually depletes B cells in the circulation, but synovial B cells are only depleted in patients with RA who show a good response to RTX therapy [10]. An inflammatory network with multiple cell types, cytokines and chemokines contributes to synovitis. Elimination of one specific mediator might be bypassed by other mechanisms.

This is the first report which shows that the combination of RTX + ETN and DMARDs might be safe and effective in patients with RA.

graphic

Disclosure statement: R.M. has received financial/material support from Wyeth and Roche (less than 5000 Euro). H.-M.L. has received grants/research support from Abbott, MSD, Sanofi-Aventis, Roche, Wyeth, Bristol Myers Squibb, Novartis, Essex (less than 5000 Euro each). N.B. was supported by Wyeth and Roche (less than 5000 Euro each). All other authors have declared no conflicts of interest.

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