Centre for Rheumatology, University College London, London, UK.
Correspondence to: D. Isenberg, Centre for Rheumatology, University College London, 4th Floor, Arthur Stanley House, 4050 Tottenham Street, London W1T 4NJ, UK. E-mail: d.isenberg{at}ucl.ac.uk
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Abstract |
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Methods. An open study of 24 patients with severe SLE followed for a minimum of 3 months is reported. In the majority of patients (19 out of 24), 6 months follow-up data are described. Disease activity in these patients was assessed every 12 months using the British Isles Lupus Assessment Group (BILAG) system and estimates of anti-double-stranded DNA antibodies and serum C3 levels. During the follow-up period, significant side-effects were sought and the reduction in oral prednisolone was recorded. It was our general practice to stop concomitant immunosuppression (e.g. azathioprine, mycophenolate) when B-cell depletion was given (in most cases in the form of two 1 g intravenous infusions of rituximab 2 weeks apart accompanied by two 750 mg intravenous cyclophosphamide infusions and two methylprednisolone infusions of 250 mg each).
Results. Twenty-two patients were female and two male. At the time of B-cell depletion, the mean age was 28.9 yr (range 1749) and the mean disease duration was 7.9 yr (range 118). The global BILAG score (P < 0.00001), serum C3 (P < 0.0005) and double-stranded DNA binding (P < 0.002) all improved from the time of B-cell depletion to 6 months after this treatment. Only one patient failed to achieve B-lymphocyte depletion in the peripheral blood. The period of B-lymphocyte depletion ranged from 3 to 8 months except for one patient who remains depleted at more than 4 yr. Analysis of the regular BILAG assessments showed that improvements occurred in each of the eight organs or systems. The mean daily prednisolone dose fell from 13.8 mg (S.D. 11.3) to 10 mg (S.D. 3.1).
Conclusion. In this open study of patients who had failed conventional immunosuppressive therapy, considerable utility in the use of B-cell depletion has been demonstrated. Our data provide strong support for the performance of a full double-blind control trial.
KEY WORDS: SLE, Rituximab, B-cell depletion
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Introduction |
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There is therefore a continuing need to identify new, more effective therapies for severely affected patients, with fewer side-effects. As reviewed elsewhere, recent interest has focused on the utility of removing C20-positive B lymphocytes in patients with SLE with rituximab, a chimeric monoclonal antibody directed to CD20 that is very effective in depleting normal and malignant B lymphocytes in vivo [4, 5]. Some encouraging early results have now been published [6, 7].
The notion that B-cell depletion might be useful as a form of treatment for patients with an autoimmune rheumatic disease, rheumatoid arthritis, was first demonstrated in an open study [8, 9]. A large double-blind multicentre controlled trial has recently confirmed the value of B-cell depletion in rheumatoid arthritis [10]. These early results were obtained by using a combination of rituximab, a chimeric monoclonal antibody recognizing the CD20 marker, together with corticosteroids (orally or intravenously) and intravenous cyclophosphamide or oral methotrexate.
In our first report of six patients with SLE given rituximab, intravenous cyclophosphamide and corticosteroids [6], we described both clinical improvement and a lowering of double-stranded DNA (dsDNA) antibody levels and an increase in C3 in some of the patients. We now report a long-term follow-up study of up to 4 yr in 24 patients treated with B-cell depletion.
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Patients, materials and methods |
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The clinical assessment of these patients, most of whom were followed every 12 months in our lupus clinic, was undertaken using the British Isles Lupus Assessment Group (BILAG) disease activity index [12]. This index distinguishes disease activity in eight organs or systems using the principle of the physician's intention to treat. A combination of clinical features and a small number of blood test results allows the distinction of patients from the most active, grade A, to the never active, grade E, in that organ or system. A global BILAG numerical score can be derived using the following notation: A = 9 points, B = 3 points, C = 1 point, and D/E = 0 points. The patients routine full blood count, serum creatinine, C3 (laser nephelometry), total immunoglobulin and dsDNA binding (Shield Diagnostics, Dundee, UK; normal <50 units/ml) and urine protein to creatinine ratio were tested in the hospital routine laboratories. Paired t-tests or Wilcoxon matched-pairs signed-rank tests were used to compare global BILAG scores and key laboratory test results prior to and 3 months and 6 months after B-cell depletion.
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Results |
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Only one patient (patient 18) failed to achieve B-lymphocyte depletion in the peripheral blood (i.e. CD 19 count <0.005 x 109/l). The period of B-lymphocyte depletion ranged from 3 to 8 months, except for one patient who remains depleted at more than 4 yr (patient 3).
The mean BILAG global score fell from a mean of 13.9 (S.D. 5.8) at baseline to 6.8 (S.D. 4.7) at 3 months and 5.0 (S.D. 2.3) at 6 months. Table 2 shows more detailed data on sustained improvement of at least two BILAG grades, i.e. A D, A
C and B
D, and also B
C in each of the eight organs or systems. It is clear that B-cell depletion was able to improve some aspects of lupus activity in every organ and system. In contrast, no lupus patient developed any major sustained deterioration (i.e. new A scores or D
B scores) before B-cell repopulation of the peripheral blood occurred. Manifestations such as fatigue, arthralgia/arthritis, serositis, nephritis, thrombocytopenia and haemolytic anaemia responded particularly well to the treatment. It should be noted that relatively few patients with major CNS disease were treated (n = 3). No clear differences in outcome were detected between patients treated with different protocols. The mean daily dose of prednisolone before treatment was 13.8 mg (S.D. 11.3) and for those completing 6 months of follow-up (n = 21) it had fallen to 10 mg (S.D. 3.1).
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The mean follow-up is now 23 months (range 351). At present, 13 patients (patients 2, 3, 6, 8, 9, 13, 14, 15, 16, 17, 21, 23 and 24) remain well enough not to have had to restart other immunosuppressive therapy (follow-up ranging from 7 to 51 months). Seven patients have been retreated (eight treatments). One patient failed to deplete on retreatment due to a documented specific human anti-chimeric antibody (HACA) response (described elsewhere [13]).
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Discussion |
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Whilst B-cell depletion using a combination of rituximab, cyclophosphamide and prednisolone is unlikely to be a cure for lupus, the fact that the majority of our patients were substantially improved in spite of having failed years of conventional immunosuppression is notable. Our key observations are that: the treatment regimens we have used almost always achieve a substantial depletion of B cells in the peripheral blood (>99%); the overwhelming majority of patients in whom this depletion is achieved improved clinically, some going into remission; the periods of B-cell depletion in the peripheral blood ranged from 3 to 11 months, except for one patient who remains depleted at more than 4 yr; disease flare does not occur until or a variable period of time after the CD20-positive B cells return to the peripheral blood; and the treatment was well tolerated in the majority of patients. We did, however, note that one patient had a severe infusion reaction and that another patient with very aggressive disease died of pancarditis 5 months after being treated. B-cell repopulation of the peripheral blood was already detectable before she died. In this small, heterogeneous group of patients, we have not been able to detect clear differences between the different protocols. We would advise against using a smaller dose of rituximab (2 x 500 mg) as this might predispose to the development of HACAs. In our experience, the period of B-cell depletion in the peripheral blood in patients with SLE is frequently shorter than in patients with rheumatoid arthritis treated with the same protocol or than what has been reported for patients with lymphoma. It is likely that these differences are accounted for by variation in the pharmacokinetics and effectiveness of the mechanisms of depletion of CD20-positive B cells by rituximab.
The mean daily dose of prednisolone before treatment was 13.8 mg (S.D. 11.3) and for those completing 6 months of follow-up (n = 21) it had fallen to 10 mg (S.D. 3.1). Oral prednisolone was only decreased slowly and progressively once clinical improvement was clear. Patients who remained well after 6 months continued to decrease the dose of prednisolone further.
The serological data are also of great interest. We have shown in this report that antibodies to dsDNA and serum C3 levels are significantly improved following B-cell depletion. This improvement matches the global and individual BILAG organ/system scores. Looney et al. [14] also reported a significant improvement in the global disease activity of 11 out of 17 of the patients they treated (using the SLAM activity index) in the absence of a significant change in anti-dsDNA antibody or complement levels. In the same trial these authors report a significant decrease in anti-dsDNA antibody levels in four out of eight patients in whom effective B-cell depletion was obtained and in whom elevated levels of anti-DNA antibodies at baseline were noted, even though a significant decrease was not found in the group as a whole [15]. It should be noted that this was a phase I/II dose escalation trial and patients were given three different doses of rituximab, two below the recommended dose, and unaccompanied by cyclophosphamide or methylprednisolone. Their results also confirm the safety of B-cell depletion as a therapeutic approach.
In summary, these encouraging long-term results on 24 patients with lupus severely active despite years of immunosuppression strongly encourage the view that removal of CD20-positive B cells may be a very useful way of treating patients with active lupus. It is now timely to undertake a large double-blind randomized control trial of this treatment.
D.A.I. declares that in lieu of payment for a consultancy undertaken for Roche, they have paid a fee into a back arthritis charity of which he is one of the trustees. The other authors have declared no conflict of interest.
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References |
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