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Amara N. Ezeonyeji, David A. Isenberg, Early treatment with rituximab in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen, Rheumatology, Volume 51, Issue 3, March 2012, Pages 476–481, https://doi.org/10.1093/rheumatology/ker337
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Abstract
Objectives. To assess the effectiveness of B-cell depletion therapy (BCDT) as a steroid-sparing treatment in newly diagnosed SLE patients.
Methods. Eight female SLE patients were treated with BCDT using a rituximab/CYC-based regimen aiming to avoid the routine use of oral steroids. Post-treatment, patients were given AZA. The BILAG disease activity index was used for clinical assessment. Serum anti-dsDNA, complement (C3), ESR, circulating B lymphocytes (CD19+) and protein : creatinine ratio were tested at 0, 1, 3, 6 and 12 months post-treatment. Disease activity and steroid requirement over the first 6 months of treatment were compared with three SLE patients treated conventionally, each carefully matched for ethnicity, sex, age at disease onset and disease duration at diagnosis.
Results. All patients achieved B-cell depletion (CD19 count <0.005 × 109/l). The mean decrease in global BILAG at 6 months for the BCDT patients was −12.0 vs 13.22 for the controls. Post-BCDT, no patient developed any significant deterioration, mean ESR fell from 70.12 to 17.14 mm/h at 6 months, mean serum anti-dsDNA antibody levels fell by >70% at 1 month and serum C3 level normalized in two patients by 6 months. There were no adverse events. The mean cumulative prednisolone dose at 6 months for the BCDT patients was 1287.3 mg (range 250–4501.8 mg) vs 2834.6 mg (range 0–6802.5 mg) for the controls.
Conclusion. Early treatment of SLE patients with BCDT is safe and effective and enables a reduction in the overall steroid burden.
Introduction
Rituximab (RTX) has been widely used in the treatment of patients with SLE who have failed to respond to conventional immunosuppression. Even though two double-blind controlled trials, Explorer [1] and Lunar [2], failed to meet their endpoints, increasingly large studies continue to indicate the utility of this approach [3, 4]. In an interesting extension of the use of B-cell depletion therapy (BCDT), Pepper et al. [5] reported the use of RTX in newly diagnosed biopsy-proven patients with LN. We have sought to extend their work by using RTX accompanied by AZA for patients with SLE whose principle clinical features have been non-renal. Our aims are similar to those of Pepper et al., namely to determine the effectiveness of a B-cell depletion regimen at diagnosis and to avoid the use of oral steroids, especially given their propensity for inducing damage in patients with SLE [6]. Damage is associated with an increased mortality in patients with SLE [6]. We now report on the first 6–12 months following treatment of eight newly diagnosed patients, describing their clinical features and response to treatment. We compared their disease activity and steroid requirement over the first 6 months of treatment with three carefully matched SLE patients treated conventionally.
Methods
Eight newly diagnosed SLE patients underwent BCDT between October 2008 and May 2010. All patients had four of the revised ACR criteria for SLE [7]; all patients gave informed consent to treatment. The standard BCDT treatment protocol used was a combination of 1 g of RTX on Days 1 and 14 and 750 mg of CYC on Day 2. Two patients did not receive CYC with their RTX treatment, and one patient received 500 mg of CYC with the second dose of RTX rather than the first, as she was neutropenic before treatment. One patient received a further 750 mg of CYC with the second RTX dose.
Methylprednisolone (MP) 100 mg i.v. was administered before each RTX dose. B-cell depletion was considered to have been achieved once the absolute CD19 count decreased to <0.005 × 109/l after treatment. One patient was taking AZA before BCDT for IBD. This was continued. Following the second dose of RTX, patients were started as soon as possible on AZA, increasing to a dose of 2 mg/kg. Where possible, oral steroids were avoided altogether and any regular oral steroids given before BCDT were rapidly tapered. Two patients were not given AZA post-RTX. One patient received AZA 2 months post-BCDT after a flare. Six of the eight patients received concomitant HCQ.
Assessment of clinical outcome
Follow-up occurred at 1, 3, 6 and 12 months post-BCDT. At each visit the patient was assessed using the BILAG activity index [8]. The BILAG index was used for both individual organ system assessment and also as a global index whereby an A score in any system = 12 points, B = 9, C = 5 and D/E = 0 [9]. Serological markers of disease activity, notably anti-dsDNA antibody titres measured by ELISA) (Sheild Diagnostics Dundee, normal <50 IU/ml) and serum complement (C3) levels [measured by laser nephelometry (normal 0.90–1.80 g/l)] were also performed. Clinical and laboratory data were collected prospectively. Treatment efficacy was evaluated on the basis of improvement in both clinical and laboratory features.
The control SLE patients were selected from the cohort of SLE patients diagnosed within the past 5 years who were under follow-up at University College Hospital and were treated conventionally. Where possible, each of the study patients was matched with three controls. In one case it was only possible to find two controls (Patient 6). The controls were carefully matched to the study patients for ethnicity, sex and duration of symptoms before diagnosis. Age at disease onset of the control patients was also within 5 years of their respective study patient. Change in the global BILAG score and cumulative steroid dose at 6 months were compared between the study patients and their controls.
Results
Eight female patients were treated with BCDT at the diagnosis of SLE. The mean age at the time of BCDT was 36.4 years (range 21–47 years) (Table 1). Mean symptom duration before SLE diagnosis was 58.9 weeks (range 4–384 weeks). One patient (Patient 6) had been under the care of dermatologists for 5 years with discoid lupus, RP and arthralgia. At this time there were no supporting laboratory investigations to make a diagnosis of SLE; however, after referral to rheumatologists with worsening symptoms, a diagnosis of SLE was confirmed. Data at baseline, 3 and 6 months were available for eight patients. Data at 12 months were available for two patients. All eight patients achieved B-lymphocyte depletion in the peripheral blood by 1 month (CD19 count <0.005 × 109/l). Patient 2 re-populated at 2 months (CD19 count 0.056 × 109/l). This coincided with a flare and arthritis that required treatment with oral prednisolone. Post-flare, the patient was commenced on AZA. Patient 3 also re-populated at 6 months, although did not flare. The remaining six patients remained depleted for at least 6 months. Patient 7 remained depleted for 1 year.
Patients’ baseline characteristics
| Patient . | Age, years . | Ethnicity . | Symptom duration before diagnosis, weeks . | Clinical features and serology at SLE diagnosis . | Cumulative dose pred at 6 months, mg . | Indication for pred . | CYC . | Mean pred dose controls, mg . | AZA post-BCDT . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 47 | Black African | 12 | Fever, headache, proteinuria rash, pleurisy, ANA, ↑ anti-dsDNA, ↑ anti-C1q, ↓C3 | 2495 | Active SLE at diagnosis | No | 1091.7 | No |
| 2 | 21 | Chinese | 4 | Rash, fevers, angioedema, arthritis, ANA,↑ anti-dsDNA, lymphopenia, ↓ C3 | 1060 | Active SLE at diagnosis and late flare | Yes (500 mg dose) | 3243.3 | Yes |
| 3 | 47 | Afro-Caribbean | 6 | Oral ulcers, rash (positive lupus band), alopecia, ANA, lymphopenia | 250a | With RTX only | Yes | 3588.3 | No |
| 4 | 44 | Caucasian | 4 | Livido reticularis, serositis, rash, oral ulcers, proteinuria, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3, ↑ ACL and LA | 4510.8 | Active SLE at diagnosis | Yes (two doses) | 1281.7 | Yes |
| 5 | 36 | Caucasian | 5 | Arthritis, fatigue, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3 | 625 | Active SLE at diagnosis | Yes | 0 | Yes |
| 6 | 31 | Mixed (Afro-Caribbean/Caucasian | 384 | Discoid lupus, malar rash, Raynaud's, alopecia, pleurisy, ↑ anti-dsDNA, lymphopenia | 857.5 | Active SLE at diagnosis | Yes | 3867.5 | Yes |
| 7 | 26 | Malaysian Chinese | 16 | Discoid lupus, alopecia, Raynaud's arthralgia, ANA, anti-SM, lymphopenia | 250a | With RTX only | No | 6802.5 | Yes |
| 8 | 39 | Caucasian | 40 | Arthritis, ANA, ↑ anti-dsDNA, lymphopenia, ↑ aCL | 250a | With RTX only | Yes | 2801.7 | Yes, already on AZA |
| Patient . | Age, years . | Ethnicity . | Symptom duration before diagnosis, weeks . | Clinical features and serology at SLE diagnosis . | Cumulative dose pred at 6 months, mg . | Indication for pred . | CYC . | Mean pred dose controls, mg . | AZA post-BCDT . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 47 | Black African | 12 | Fever, headache, proteinuria rash, pleurisy, ANA, ↑ anti-dsDNA, ↑ anti-C1q, ↓C3 | 2495 | Active SLE at diagnosis | No | 1091.7 | No |
| 2 | 21 | Chinese | 4 | Rash, fevers, angioedema, arthritis, ANA,↑ anti-dsDNA, lymphopenia, ↓ C3 | 1060 | Active SLE at diagnosis and late flare | Yes (500 mg dose) | 3243.3 | Yes |
| 3 | 47 | Afro-Caribbean | 6 | Oral ulcers, rash (positive lupus band), alopecia, ANA, lymphopenia | 250a | With RTX only | Yes | 3588.3 | No |
| 4 | 44 | Caucasian | 4 | Livido reticularis, serositis, rash, oral ulcers, proteinuria, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3, ↑ ACL and LA | 4510.8 | Active SLE at diagnosis | Yes (two doses) | 1281.7 | Yes |
| 5 | 36 | Caucasian | 5 | Arthritis, fatigue, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3 | 625 | Active SLE at diagnosis | Yes | 0 | Yes |
| 6 | 31 | Mixed (Afro-Caribbean/Caucasian | 384 | Discoid lupus, malar rash, Raynaud's, alopecia, pleurisy, ↑ anti-dsDNA, lymphopenia | 857.5 | Active SLE at diagnosis | Yes | 3867.5 | Yes |
| 7 | 26 | Malaysian Chinese | 16 | Discoid lupus, alopecia, Raynaud's arthralgia, ANA, anti-SM, lymphopenia | 250a | With RTX only | No | 6802.5 | Yes |
| 8 | 39 | Caucasian | 40 | Arthritis, ANA, ↑ anti-dsDNA, lymphopenia, ↑ aCL | 250a | With RTX only | Yes | 2801.7 | Yes, already on AZA |
aPred 250 mg is equivalent to MP 200 mg given with RTX. pred: prednisolone; aCL: anticardiolipin antibodies; LA: lupus anticoagulant; anti-SM: anti-Smith.
Patients’ baseline characteristics
| Patient . | Age, years . | Ethnicity . | Symptom duration before diagnosis, weeks . | Clinical features and serology at SLE diagnosis . | Cumulative dose pred at 6 months, mg . | Indication for pred . | CYC . | Mean pred dose controls, mg . | AZA post-BCDT . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 47 | Black African | 12 | Fever, headache, proteinuria rash, pleurisy, ANA, ↑ anti-dsDNA, ↑ anti-C1q, ↓C3 | 2495 | Active SLE at diagnosis | No | 1091.7 | No |
| 2 | 21 | Chinese | 4 | Rash, fevers, angioedema, arthritis, ANA,↑ anti-dsDNA, lymphopenia, ↓ C3 | 1060 | Active SLE at diagnosis and late flare | Yes (500 mg dose) | 3243.3 | Yes |
| 3 | 47 | Afro-Caribbean | 6 | Oral ulcers, rash (positive lupus band), alopecia, ANA, lymphopenia | 250a | With RTX only | Yes | 3588.3 | No |
| 4 | 44 | Caucasian | 4 | Livido reticularis, serositis, rash, oral ulcers, proteinuria, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3, ↑ ACL and LA | 4510.8 | Active SLE at diagnosis | Yes (two doses) | 1281.7 | Yes |
| 5 | 36 | Caucasian | 5 | Arthritis, fatigue, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3 | 625 | Active SLE at diagnosis | Yes | 0 | Yes |
| 6 | 31 | Mixed (Afro-Caribbean/Caucasian | 384 | Discoid lupus, malar rash, Raynaud's, alopecia, pleurisy, ↑ anti-dsDNA, lymphopenia | 857.5 | Active SLE at diagnosis | Yes | 3867.5 | Yes |
| 7 | 26 | Malaysian Chinese | 16 | Discoid lupus, alopecia, Raynaud's arthralgia, ANA, anti-SM, lymphopenia | 250a | With RTX only | No | 6802.5 | Yes |
| 8 | 39 | Caucasian | 40 | Arthritis, ANA, ↑ anti-dsDNA, lymphopenia, ↑ aCL | 250a | With RTX only | Yes | 2801.7 | Yes, already on AZA |
| Patient . | Age, years . | Ethnicity . | Symptom duration before diagnosis, weeks . | Clinical features and serology at SLE diagnosis . | Cumulative dose pred at 6 months, mg . | Indication for pred . | CYC . | Mean pred dose controls, mg . | AZA post-BCDT . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 47 | Black African | 12 | Fever, headache, proteinuria rash, pleurisy, ANA, ↑ anti-dsDNA, ↑ anti-C1q, ↓C3 | 2495 | Active SLE at diagnosis | No | 1091.7 | No |
| 2 | 21 | Chinese | 4 | Rash, fevers, angioedema, arthritis, ANA,↑ anti-dsDNA, lymphopenia, ↓ C3 | 1060 | Active SLE at diagnosis and late flare | Yes (500 mg dose) | 3243.3 | Yes |
| 3 | 47 | Afro-Caribbean | 6 | Oral ulcers, rash (positive lupus band), alopecia, ANA, lymphopenia | 250a | With RTX only | Yes | 3588.3 | No |
| 4 | 44 | Caucasian | 4 | Livido reticularis, serositis, rash, oral ulcers, proteinuria, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3, ↑ ACL and LA | 4510.8 | Active SLE at diagnosis | Yes (two doses) | 1281.7 | Yes |
| 5 | 36 | Caucasian | 5 | Arthritis, fatigue, ANA, ↑ anti-dsDNA, lymphopenia, ↓ C3 | 625 | Active SLE at diagnosis | Yes | 0 | Yes |
| 6 | 31 | Mixed (Afro-Caribbean/Caucasian | 384 | Discoid lupus, malar rash, Raynaud's, alopecia, pleurisy, ↑ anti-dsDNA, lymphopenia | 857.5 | Active SLE at diagnosis | Yes | 3867.5 | Yes |
| 7 | 26 | Malaysian Chinese | 16 | Discoid lupus, alopecia, Raynaud's arthralgia, ANA, anti-SM, lymphopenia | 250a | With RTX only | No | 6802.5 | Yes |
| 8 | 39 | Caucasian | 40 | Arthritis, ANA, ↑ anti-dsDNA, lymphopenia, ↑ aCL | 250a | With RTX only | Yes | 2801.7 | Yes, already on AZA |
aPred 250 mg is equivalent to MP 200 mg given with RTX. pred: prednisolone; aCL: anticardiolipin antibodies; LA: lupus anticoagulant; anti-SM: anti-Smith.
The baseline BILAG global scores for Patients 1–8 were 13, 33, 7, 41, 11, 20, 16 and 7, respectively (median 14.5, range 7–41). Change in global BILAG score at 6 months for the patients treated with BCDT compared with the matched controls is outlined in Fig. 1A. The mean decrease in global BILAG at 6 months for the BCDT treated patients was −12.0 and for the matched control group was −13.22.
Graphs showing change in global BILAG score and cumulative prednisolone dose at 6 months. (A) Change in global BILAG score at 6 months in study patients that have received BCDT vs matched controls treated conventionally. (B) Cumulative prednisolone dose at 6 months in study patients following BCDT vs the mean cumulative steroid dose of the corresponding matched controls. *Patient 8: data at 3 months only.
Sustained improvement following BCDT of at least two BILAG grades, i.e. A→D, A→C, B→D and B→C, in each of the eight organ systems is shown in Table 2. Manifestations such as rash, arthritis, fatigue, mouth ulcers and pleuritis responded well. Patient 5 had a BILAG B score from C in the general category at 6 months and Patient 4 went from C to B at 6 months in the renal category. No patient developed any major or sustained deterioration (i.e. new A or D→B scores). Patient 2 had a persistent B score in the haematological category at 6 months; however, this improved to a C score by 12 months. There were no infections or serious adverse events in patients given BCDT.
Changes in BILAG categories following BCDT
| BILAG score . | Gen . | Muco . | Neuro . | Musculo . | Cardioresp . | Vasc . | Renal . | Haem . |
|---|---|---|---|---|---|---|---|---|
| Total BILAG A/B scores at baseline | 4 | 6 | 0 | 4 | 1 | 0 | 2 | 2 |
| Total change at 6 months post-BCDT | ||||||||
| A→B | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→C | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→D | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| B→C | 2 | 1 | 0 | 3 | 0 | 0 | 0 | 0 |
| B→D | 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 |
| BILAG scores remaining unchanged at 6 months post-BCDT | ||||||||
| A | – | – | – | – | – | – | – | – |
| B | – | – | – | 1 | – | – | – | 2 |
| C | – | – | – | 1 | 1 | – | – | 1 |
| BILAG score . | Gen . | Muco . | Neuro . | Musculo . | Cardioresp . | Vasc . | Renal . | Haem . |
|---|---|---|---|---|---|---|---|---|
| Total BILAG A/B scores at baseline | 4 | 6 | 0 | 4 | 1 | 0 | 2 | 2 |
| Total change at 6 months post-BCDT | ||||||||
| A→B | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→C | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→D | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| B→C | 2 | 1 | 0 | 3 | 0 | 0 | 0 | 0 |
| B→D | 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 |
| BILAG scores remaining unchanged at 6 months post-BCDT | ||||||||
| A | – | – | – | – | – | – | – | – |
| B | – | – | – | 1 | – | – | – | 2 |
| C | – | – | – | 1 | 1 | – | – | 1 |
Gen: general; muco: mucocutaneous; neuro: neurological; cardioresp: cardiorespiratory; vasc: vasculitis; haem: haematological.
Changes in BILAG categories following BCDT
| BILAG score . | Gen . | Muco . | Neuro . | Musculo . | Cardioresp . | Vasc . | Renal . | Haem . |
|---|---|---|---|---|---|---|---|---|
| Total BILAG A/B scores at baseline | 4 | 6 | 0 | 4 | 1 | 0 | 2 | 2 |
| Total change at 6 months post-BCDT | ||||||||
| A→B | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→C | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→D | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| B→C | 2 | 1 | 0 | 3 | 0 | 0 | 0 | 0 |
| B→D | 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 |
| BILAG scores remaining unchanged at 6 months post-BCDT | ||||||||
| A | – | – | – | – | – | – | – | – |
| B | – | – | – | 1 | – | – | – | 2 |
| C | – | – | – | 1 | 1 | – | – | 1 |
| BILAG score . | Gen . | Muco . | Neuro . | Musculo . | Cardioresp . | Vasc . | Renal . | Haem . |
|---|---|---|---|---|---|---|---|---|
| Total BILAG A/B scores at baseline | 4 | 6 | 0 | 4 | 1 | 0 | 2 | 2 |
| Total change at 6 months post-BCDT | ||||||||
| A→B | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→C | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| A→D | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| B→C | 2 | 1 | 0 | 3 | 0 | 0 | 0 | 0 |
| B→D | 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 |
| BILAG scores remaining unchanged at 6 months post-BCDT | ||||||||
| A | – | – | – | – | – | – | – | – |
| B | – | – | – | 1 | – | – | – | 2 |
| C | – | – | – | 1 | 1 | – | – | 1 |
Gen: general; muco: mucocutaneous; neuro: neurological; cardioresp: cardiorespiratory; vasc: vasculitis; haem: haematological.
Mean ESR fell from 70.12 to 23.75 mm/h at 3 months and 17.14 mm/h at 6 months (n = 7). Six of the eight patients had elevated serum anti-dsDNA antibody levels at baseline. Mean serum anti-dsDNA antibody levels fell from 2230 to 597.5 IU/ml at 1 month and 189.2 IU/ml at 3 months (excluding Patient 2, who flared at 2 months with an increase in serum anti-dsDNA antibody).
Four patients had low complement levels at baseline. Serum C3 level normalized in Patient 1 by 1 month and in Patient 5 by 6 months. Patients 3 and 5 remained hypocomplementaemic at 6 months. Serum creatinine was stable throughout in all patients. Patient 1 had a mildly elevated urinary protein : creatinine ratio (PCR) of 66 mg/mmol at baseline (normal <13 mg/mmol). This remained stable at 6-month follow-up. PCR was 127 mg/mmol at baseline in Patient 4. This rose to 236 mg/mmol by 3 months, but remained stable at 126 mg/mmol at 6 months with the patient taking a combination of AZA and low-dose prednisolone.
Oral daily prednisolone dose at baseline for patients 1, 3, 4, 5, 6, 7 and 8 was 40, 0, 40, 7.5, 5, 0 and 0 mg, respectively. Patient 2 had received an i.m. depomedrone 120 mg injection 2 months before BCDT therapy. The cumulative prednisolone dose for Patients 1–8 at 6 months compared with the mean cumulative steroid dose of their respective matched controls is outlined in Fig. 1B. At 6 months post-BCDT, the mean cumulative prednisolone dose for the study patients was 1287.3 mg (range 250–4501.8 mg) and the cumulative mean of the matched controls was 2834.6 mg (range 0–6802.5 mg).
Patients 3, 5 and 8 only received steroids as part of the RTX/CYC induction regimen. Two patients received significantly higher doses of steroids than anticipated. Patient 1 presented initially to another hospital with active SLE, having been under our care with an undifferentiated autoimmune rheumatic disease. At this hospital she was given high-dose oral steroids for a period of 2 weeks before being transferred to our department for BCDT. The patient remained on low-dose prednisolone 5 mg post-treatment in addition to AZA for persistent proteinuria and an elevated PCR. After review by a renal physician, it was felt that a renal biopsy was not indicated.
Patient 4 had a delayed admission for BCDT due to hospital logistics. Unfortunately, she was admitted as an emergency with active SLE and a concurrent lower respiratory tract infection. She was treated with antibiotics and i.v. MP 750 mg thrice, but was discharged prematurely before she could receive BCDT. Induction treatment with RTX and CYC was eventually given as an outpatient, but following treatment she was re-admitted with arthritis, fatigue and severe pericarditis requiring treatment with oral prednisolone 40 mg daily. BCDT was completed as an inpatient and following this she was started on AZA and her steroids weaned. She remained on prednisolone 5 mg maintenance for persistent proteinuria and an elevated PCR. Eventually, she underwent renal biopsy that showed focal proliferative GN.
Discussion
Survival of SLE patients has improved dramatically over the past 50 years primarily through the judicious use of CSs, immunosuppressive drugs and the introduction of dialysis and renal transplant [10]. Unfortunately, many of the causes of morbidity in SLE reflect the accumulation of damage occurring as a direct result of the cumulative dose of CSs over time [11].
Although the Lunar and Explorer trials failed to show superiority of RTX-treated SLE patients over those treated more conventionally, many smaller open-labelled studies have shown a good response to RTX [10]. Ours is the first group to use BCDT early in the treatment of principally non-renal SLE as a means of reducing the overall steroid burden of the patient. Pepper et al. [5] used MMF as a steroid-sparing agent following RTX. We have used AZA, which is less expensive, and encouragingly our regimen has shown similar efficacy at 6-month follow-up compared with carefully matched patients that were treated with standard therapy. Strikingly, there was also a clear trend to a lower cumulative steroid dose in the RTX-treated patients at 6 months compared with the control group, although this did not reach statistical significance. However, two RTX-treated patients had inadvertently been given much higher doses than anticipated, as explained above. Had it been possible to treat these two patients strictly according to our steroid sparing regimen, we may have seen an even better outcome. We believe the data are sufficiently reassuring to encourage the establishment of a formal trial comparing BCDT with conventional therapy at the time of SLE diagnosis.
Conclusion
BCDT is an effective therapy when used early in the disease and offers a useful method of reducing the cumulative steroid burden in patients with predominantly non-renal SLE.

Acknowledgements
Thanks to the patients who were involved in this study.
Disclosure statement: D.A.I. has consulted for Roche, but takes no personal honoraria. The support is given to a local arthritis charity in lieu. The other author has declared no conflicts of interest.


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