B cells have been targeted in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to the central role they play in the pathogenesis of these disorders. These cells play a critical role in host defence through their maturation into antibody-secreting plasma cells, secretion of proinflammatory cytokines, antigen presentation and co-stimulatory support for T cells. However, dysfunctional recognition of self-antigens as nonself-antigens results in autoantibody production, sustained by plasma cells derived from the B-cell lineage that survive for prolonged periods in the lymphoid tissues. B cells also participate in inflammatory reactions through antibody-independent mechanisms by acting as antigen-presenting cells and co-stimulation of T cells and other inflammatory cell types, although as yet there are no validated biomarkers that distinguish pathogenic from protective B-cell subsets. Reagents that specifically target pathogenic B-cell subsets are therefore not likely to be available in the near future. This reality provides the rationale for targeting B cells in patients with SLE, RA and other autoimmune diseases 1 2 3 4 5 .

B-cell-targeted immunotherapy was initially developed for the treatment of B-cell-related malignancies, which are associated with poor prognosis despite aggressive cytotoxic therapies. Of the many surface-expressed antigens on B cells studied as possible targets, CD20 - a transmembrane phosphoprotein expressed in normal B cells as well as 90% of lymphomas - is not shed or modulated, making it an attractive target. In 1994, Reff and colleagues reported a major (95%) and sustained (up to 90 days) B-cell depletion using a murine mAb (2B8) that targeted CD20 on B cells in nonhuman primates 6 . In 1997, a landmark study reported on both the safety and efficacy of rituximab, a chimeric (mouse-human) mAb directed against CD20, for the treatment of relapsed, refractory low-grade or follicular lymphoma 7 . In November 1997, rituximab was licensed for this indication. Rituximab is now a part of the standard therapeutic regimen in the management of B-cell malignancies and remains among the most successful therapeutic mAbs. Interestingly, the response rate is variable amongst individuals with the same histological type of lymphoma as well as the overall response rate between different histological types 8 . This suggests that B-cell depletion is not uniform across patients or indeed diseases for reasons yet to be fully understood, but Fcγ receptor function appears important with enhanced Fcγ receptor IIb expression being associated with reduced rituximab efficacy in lymphoma 9 . Intriguingly, polymorphisms of this receptor are associated with SLE, although their precise role in the disease and potential for targeted therapeutic intervention is not understood.

In 1999, Professor Edwards' group at University College London treated a small number of patients with refractory RA using rituximab, having been encouraged by the safety and efficacy profile of induced transient depletion of B cells in haematological malignancies. This study and subsequent studies of rituximab in RA, including a large phase II randomised controlled trial, indicated that the treatment was potentially safe and effective 10 11 12 13 . The regimen in these studies utilised two doses (1,000 mg) of rituximab given 2 weeks apart, with premedication including a single 100 mg intravenous dose of methylprednisolone and 10 mg chlorphenamine. In the original study, patients also received a course of high-dose prednisolone (60 mg for up to 3 weeks and then tapering over the next 3 to 4 weeks or maintaining at 5 mg a day). Responding patients were retreated at or just before predicted relapse. Initially, intravenous cyclophosphamide was used to accompany the rituximab 10 . The phase II study showed that cyclophosphamide could be replaced by methotrexate or rituximab on its own, although the response rates were better when rituximab was used in combination with methotrexate. Further, the assigned dose of prednisolone was reduced to 60 mg/day oral prednisone on day 2 and days 4 to 7 and 30 mg/day oral prednisone on days 8 to 14 11 .

The first open, uncontrolled study of rituximab for patients with SLE, by Professor Isenberg's group at University College London, showed improvements in both clinical and laboratory features of disease following treatment with rituximab in refractory SLE 14 ; these observations have been supported by the publication of many other similar open, nonrandomised studies 15 16 17 18 19 (Table 1). The University College London regimen employed premedication with 100 mg intravenous methylprednisolone in addition to 750 mg low-dose intravenous cyclophosphamide (for renal manifestations) 1 day prior to the first of two doses of rituximab, given 2 weeks apart. More recently just one dose of cyclophosphamide has been used, and any subsequent need for immunosuppressive therapy is adjusted based on the merits of clinical response and disease manifestation activity that can be assessed using well-validated tools such as the British Isles Lupus Assessment Group (BILAG) 2004 index (for example, using the BLIPS computer software program; LIMATHON, Sheffield, UK).

Appreciating this robust clinical management focused on the individual patient - potentially involving multi-disciplinary expert opinion, including rheumatologists, dermatologists and renal physicians - is important when comparing the results with those from large multicentre randomised controlled trials with variable quality observations in a broad population.

Worthy of note is that the indication for rituximab at Professor Isenberg's centre is a combination of active disease (renal or nonrenal) (assessed by the BILAG 2004 index) poorly controlled despite at least two standard immunosuppressive agents (not including corticosteroids) used for sufficient time at optimal doses. To date, 100 patients have been treated at University College London with at least one cycle of rituximab and more than 30 patients have received repeated treatment. Although involving only small numbers, the observations from repeating the regimen showed that improvements in disease, including remission rates, were sustained in patients who responded to the initial treatment 20 . This same group has previously demonstrated following B-cell depletion therapy (BCDT) that anti-double-stranded DNA (anti-dsDNA) and anti-nucleosome antibodies reduce to 30 to 40% of baseline, whereas other autoantibodies such as anti-Ro and antibodies to pneumococcal polysaccharide (protective) remain unaltered. This observation would suggest that rapidly proliferating clones of B cells may give rise to short-lived plasma cells that produce these anti-dsDNA, anti-cardiolipin and anti-nucleosome antibodies and appear preferentially affected by BCDT 21 , whereas other autoantibodies such as anti-Ro and anti-RNP or protective antibodies, which develop following immunisation and are thought to be produced by long-lived plasma cells, remain unaltered.

In line with this experience, anti-dsDNA antibody levels tend to fall but not to normalise and these antibodies are probably produced by a combination of short-lived and long-lived plasma cells. Similar to these findings, a post-hoc analysis of the EXPLORER trial focusing on the biological effects of rituximab revealed a significant reduction in the levels of anti-dsDNA and anti-cardiolipin antibodies and a significant increase in complement levels and serum BAFF in the rituximab-treated group versus placebo. Analysis of the repopulation dynamics of subsets of B cells identified naïve cells as the primary phenotype detected first in circulation; however, the phenotype analysis was limited in that CD27^- memory cells were not examined in this study 22 . The changes in biological effects did not translate into clinical benefits at 1 year. Whether a long-term follow up with more detailed phenotype analysis at various time points would help predict response to rituximab therapy is not known. However, designing clinical trials to define the precise relationship between the biological effects that occur following BCDT and the clinical response in the long term (typically, 2 to 5 years) would be met with the potential challenge of maintaining remission in the placebo group with conventional immunosuppressants alone. The effects extend to global disease control including an improvement in lipid profile 23 , but such benefits are not necessarily captured in randomised controlled trials with a short duration of follow-up.

Recently, following the approach by a group at Imperial College (see later) in a pilot study, eight patients with active disease were treated at diagnosis with rituximab in an attempt to avoid the use of corticosteroids. Using this approach it was possible to reduce the cumulative dose of steroids substantially in five of the eight patients 24 , a major long-term advantage.

A recent review of the rituximab experience in approximately 200 patients with refractory SLE, from open studies and real clinical experience, indicated that many would respond at least partially to B-cell depletion 25 . Differences in determining endpoints for these studies make it difficult to establish formal median and range of improvements. In a phase I/II dose-escalation trial of the safety and efficacy of rituximab in addition to ongoing therapy in 18 patients with SLE, three dosing regimens of rituximab were studied as follows: six patients received a low dose, a single infusion of 100 mg/m²; six patients received an intermediate dose, a single infusion of 375 mg/m²; and five patients received a high dose, four infusions of 375 mg/m² administered 1 week apart. There was a significant improvement in the disease activity, as measured by systemic lupus activity measure scores, in all patients by 2 months, which persisted at 12 months regardless of a change in anti-dsDNA antibody and complement levels. Six of 17 patients developed human anti-chimeric antibodies, resulting in reduced serum rituximab levels and inefficient B-cell depletion and less impressive efficacy. Importantly, there were no significant adverse events 26 . The UK-BIOGEAS registry study of 164 patients with refractory or relapsing lupus nephritis reported a 67% partial or complete response rate to rituximab using standardised response criteria 27 .

Clinicians therefore continue to use rituximab for refractory lupus nephritis as well as nonrenal manifestations including haematological, skin and central nervous system manifestations where clinically useful responses have been reported 28 29 . There is thus extensive nonrandomised and retrospective experience of rituximab in the treatment of refractory SLE. A role for rituximab for this indication is supported by the consistency of the reports of improvement but differences in regimens, concomitant medications and endpoints remain, making it difficult to assess the extent of effectiveness of B-cell depletion accurately. Additionally, there is uncertainty as to how to reduce relapse risk after rituximab, and an unqualified recommendation for rituximab in refractory SLE will require higher quality evidence.

To evaluate the safety and efficacy of rituximab in SLE in a clinical trial setting, two double-blind, randomised, placebo-controlled trials (DBRCTs) investigating renal (LUNAR study) and nonrenal (EXPLORER study) manifestations were undertaken (Table 2). Both trials addressed the hypothesis that the addition of rituximab to the standard of care, corticosteroids and immunosuppressants was superior to addition of placebo for the control of SLE activity.

In the EXPLORER study, the safety and efficacy of rituximab in moderate-to-severe active nonrenal SLE was evaluated 30 (Figure 1). This study included 257 patients with ≥1 BILAG A score (>50% of patients at entry) or ≥2 BILAG B scores despite ongoing stable-dose immunosuppressant therapy with either azathioprine (100 to 250 mg/day), mycophenolate (1 to 4 g/day) or methotrexate (7.5 to 25 mg/week), which was continued during the trial. Background immunosuppressive therapy was evenly distributed. A key feature of treatment in this study was the additional course of high-dose corticosteroids patients received early in the study. Corticosteroids were given at initial doses of 0.5 mg/kg, 0.75 mg/kg or 1 mg/kg depending on severity (by BILAG score) and type of disease manifestations, followed by a taper regimen. Of the overall population, >50% were classed as steroid dependent, and ≥60% of patients received an average 45.9 ± 16.4 mg prednisolone and then attempted to reduce to a target dose of <10 mg/day over the 10-week taper period and ≤5 mg/day at week 52.

Patients were randomised at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo. Eighty-eight patients received placebo and 169 patients received rituximab (two doses given 14 days apart) on days 1, 15, 168, and 182. The majority (≥50%) of patients in both groups had musculoskeletal and mucocutaneous disease.

The primary endpoint of the EXPLORER study was stringent, with complete and partial response definitions as follows.

To classify as a complete/major response, at week 24 an improvement in all organ systems with a BILAG C score or better was required. Further, this response was to be sustained at week 52, without experiencing a severe or moderate/severe flare during the period to week 24 and week 52, respectively. A severe flare was defined as a BILAG A score or as two new domains with BILAG B scores 31 .

Patients were considered to have attained a partial response if: there was an improvement in all organ systems with a BILAG C score or better, which was sustained for 16 consecutive weeks; a BILAG B score in no more than one organ system at week 24 without a new BILAG A or BILAG B score to week 52 was achieved; and, at week 24, no more than two BILAG B scores were achieved without new BILAG A or BILAG B scores provided the baseline BILAG score was one A score plus ≥2 B scores, ≥2 A scores, or ≥4 B scores.

The secondary endpoints included the time-adjusted area under the curve minus the baseline BILAG score over 52 weeks, the proportion of patients who achieved a major and partial clinical response, the proportion of patients who achieved a BILAG C score in all organ systems at week 24, the time to the first moderate to severe disease flare, improvement in quality of life as measured by the Lupus Quality of Life, and the proportion of patients who achieved a major clinical response with a prednisolone dose <10 mg/day from week 24 to week 52. In addition, serological activity parameters including levels of autoantibodies, complement, immunoglobulins, T-cell and B-cell counts and human anti-chimeric antibody were monitored.

In the intent-to-treat analysis of 257 patients, approximately 70% of patients completed the study in both arms and the safety and tolerability was similar in both groups. There was no difference between the addition of placebo and rituximab to the standard of care in the primary and secondary efficacy endpoints, including the BILAG-defined response, in terms of both area under the curve and other analyses.

A preplanned subgroup analysis, however, detected a beneficial effect of rituximab in the primary endpoint in the African American and Hispanic patients, a major clinical response in 13.8% and a partial response in 20% when compared with 9.4% and 6%, respectively. Notably, these patients had more active disease and more refractory disease as previously reported 32 . There were significant biological effects in the rituximab-treated group, with greater falls in anti-dsDNA levels and rises in complement levels compared with placebo. Interestingly, up to 9.5% of patients did not achieve complete B-cell depletion, but analysis without these patients did not change the primary outcome. This phenomenon has been observed in autoimmune prone mice 33 34 . A recent study investigating the role of highly sensitive flow cytometry detected a correlation between clinical response and B-cell numbers 35 .

The LUNAR study investigated the safety and efficacy of 2 × 1,000 mg rituximab, at both 0 and 6 months, as compared with placebo in addition to background therapy with high-dose glucocorticoids and mycophenolate mofetil 3 g/day in 144 patients with proliferative lupus nephritis, classes III and IV (Figure 2).

The primary endpoint of the study was the proportion of patients with a complete or partial remission of nephritis at 12 months. Complete response was defined as, at week 52: serum creatinine improving from abnormal to normal level or from normal to ≤115% of baseline normal; a fall in the urine protein-creatinine ratio to <0.5; and urine sediment containing <5 red blood cells in a high-power field without casts. Patients who did not meet complete response were considered to have achieved a partial response if: serum creatinine reduced to ≤115% of abnormal baseline; the number of red blood cells/high-power field reduced to ≤50% baseline without red blood cell casts; and a reduction in urine protein-creatinine ratio from ≥3.0 to ≤3.0 or to <1 from ≤3.0.

The secondary endpoints were: complete renal response sustained from week 24 to week 52; time to first complete renal response; and, at week 52, the urine protein-creatinine ratio improving from >3 to <1, the time-adjusted area under the curve minus the BILAG global score, and a change in the physical function of SF-36 health survey. As in the EXPLORER study, serological indices, human anti-chimeric antibodies and B-cell depletion were monitored.

The response rates for rituximab and placebo were 26% and 30% for complete renal response and 30% and 15% for partial renal response, respectively. At week 52, more patients in the placebo arm (8 patients vs. 0 patients) received rescue cyclophosphamide therapy. Improvement in proteinuria was 32% and 9% for rituximab and placebo, respectively. Analogous to the findings in the EXPLORER study and the ALMS trial, a greater proportion of black patients responded favourably, although this was not statistically significant. There was a greater reduction in anti-dsDNA levels in the rituximab-treated group. Whether the response noted in patients of African ancestry is attributable to the disease severity alone or whether there are potential differences in B-cell responsiveness to rituximab therapy in these patients is as yet unclear. In this respect, it is worth noting that ethnicity might influence the clinical response to treatment even with conventional immunosuppressants as noted in the ALMS study. Our own data (D Isenberg, unpublished observations) has not indicated a clearly different outcome at 12 months post BCDT comparing Caucasians, Afro-Caribbean or Asian patients. Drawing any firm conclusions based on the disease severity alone would therefore be difficult.

However, overall this was a negative study in that there was no significant difference between the rituximab group and the placebo group. The absolute difference in response was 11%, with 54% and 43% responding in the rituximab and placebo groups, respectively 36 . This value was less than the planned 23% difference, which in retrospect looks over-optimistic especially considering the analysis at only 12 months in this population. Again, differences in serological markers between groups were found and a subsequent analysis found greater falls of proteinuria in the rituximab group. More African patients in the rituximab group responded and cyclophosphamide rescue was required more frequently in the placebo group. Therefore, despite some clear signals of efficacy and safety, this study did not meet its primary or secondary endpoints.

Why did these two DBRCTs fail to meet their endpoints? As discussed earlier, there are several confounding factors that may have masked the ability to accurately quantify any significant clinically meaningful beneficial effects of rituximab (Table 3), perhaps the most important being the aggressive background immunosuppressive therapy in the placebo and rituximab-treated groups. High-dose corticosteroids, in particular, may have prevented the full extent of efficacy of rituximab becoming evident, a factor that warrants due consideration in the design of future clinical trials for any investigational agent. The dilemma for trial designers is how rapidly to reduce glucocorticoid in patients with organ-threatening SLE. Trials with duration beyond 12 months would have greater chance of demonstrating the specific treatment effect that could be attributed to rituximab if corticosteroids are reduced to low levels during the first 6 months. Corticosteroid dosing could also be included in the threshold for response in trial endpoints. For example, standard treatment should allow low-dose prednisolone and the proportion of patients requiring >7.5 mg/day prednisolone could be classed as a failure. In the open studies, response was defined with such stringent criteria. Furthermore, applying such criteria would not detect organ-specific improvement; for example, a significant sustained improvement in a severe haematological abnormality but concurrent minor or moderate flare in skin or mucocutaneous disease would be classified as a failure.

The planned efficacy margin in the LUNAR study was influenced by the 55% complete and partial response rate in the ALMS trial at 6 months using either mycophenolate or cyclophosphamide and corticosteroids. This suggested that 45% did not respond to standard of care; however, reasons for failure in the ALMS trial included death, severe adverse events, drug intolerance and patient/physician preference. One can estimate that true treatment failure was closer to 25% than 45%. A further factor in nephritis trials is the delayed response of the outcome measure, proteinuria, to reduction in histological activity in the kidney. The true time to remission of proteinuria is up to 2 years. Had the LUNAR trial aimed for a 12% efficacy difference and involved a 2-year duration, the study may have met its endpoint despite a small sample size.

One should also note that to date there is insufficient evidence to support the routine use of rituximab therapy for patients with specific neuropsychiatric manifestations. However, in a study of 10 patients with a range of neuropsychiatric manifestations (including cognitive dysfunction, psychosis and seizures) refractory to conventional immunosuppressants, including intravenous cyclophosphamide, there was a significant improvement, measured by the Systemic Lupus Erythematosus Disease Activity Index score at 28 days after treatment with rituximab, in all patients - and in five patients the response lasted for more than 1 year 28 .

The other anti-CD20 mAb investigated in clinical trials for SLE is ocrelizumab (a humanised anti-CD20 mAb). In rheumatoid arthritis, ocrelizumab (two regimens used: 200 mg and 500 mg ×2 every 6 months) was effective in reducing signs and symptoms and joint damage when added to a stable dose of methotrexate 37 38 . However, a detailed analysis of results from four DBRCTs investigating the safety and efficacy of ocrelizumab for RA indicated that an increase in serious infections associated with ocrelizumab compared with placebo were dose dependent and occurred more frequently in Asia (particularly Japan) 39 .

Two simultaneous clinical trials were initiated to study the safety and efficacy in lupus. Ocrelizumab was dosed differently from the RA and the rituximab SLE studies, at either 400 or 1,000 mg intravenously ×2 at entry with repeat, single dosing every 4 months. This regimen was designed to induce and maintain B-cell depletion throughout the trial periods. The BEGIN study for nonrenal SLE was cancelled early. The BELONG study for proliferative lupus nephritis compared 1,000 mg or 400 mg ocrelizumab at 1 day and 15 days, then repeated with a single dose every 4 months on a background of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide dosed according to the EUROLUPUS protocol (Figure 1). Although the study was designed to continue for to at least 2 years, the primary endpoint was the proportion of patients achieving partial or complete nephritis remission at 48 weeks. A total of 381 patients were recruited before the trial was stopped early due to an imbalance in the rate of serious infections in the ocrelizumab patients receiving mycophenolate. The 221 patients who had passed the 32-week treatment point were assessed. The absolute difference in renal response was 12%, with 63% and 51% for the combined ocrelizumab and placebo groups prospectively. However, it is worth noting that in the subgroup analysis there was a greater treatment effect of ocrelizumab when combined with the EUROLUPUS cyclophosphamide regime (renal response of 65.7% for ocrelizumab vs. 42.9% for EUROLUPUS alone) than with mycophenolate mofetil (renal response of 67.9% for ocrelizumab vs. 61.7% for mycophenolate alone), which was largely explained by a higher response rate in general with mycophenolate mofetil whilst perhaps again reflecting the outcome seen with rituximab in the LUNAR study 40 (Table 4).

Efficacy of the BCDT has also been demonstrated in another autoimmune condition, relapsing-remitting multiple sclerosis. A recent phase II randomised clinical trial investigating the safety and efficacy of ocrelizumab (given together with pre-infusion steroids only) in multiple sclerosis showed a significant reduction in neurological lesions compared with placebo as assessed by gadolinium-enhanced magnetic resonance images. Serious adverse events occurred in three of 55 patients receiving 2,000 mg ocrelizumab (one of 55 patients receiving 600 mg ocrelizumab, and two of 54 patients each in the placebo group and the IFNβ-1a group) 41 . These results also support the notion that treatment regimens of BCDT continue to have the potential to be safe in the wider context of treatment for chronic refractory autoimmune diseases.

Although not the principal focus of this review, it is notable in two trials involving >800 patients in each trial that belimumab (Benlysta), an anti-BLyS antibody, met its primary endpoint with a 10% and 14% absolute response difference over placebo 42 43 . The primary endpoint was a composite score, the SLE Responder Index, comprising a fall in Systemic Lupus Erythematosus Disease Activity Index of 4 points, no new BILAG A or B scores, and no change in the physician's global assessment. The comparisons were made at the start of the study, and at 52 or 76 weeks. These studies demonstrate: the need for larger trials looking for small but meaningful treatment effects; the potential efficacy of B-cell-targeted therapy; a similar magnitude of response to that seen in the LUNAR and BELONG studies, which collectively raises the question of defining a clinically meaningful treatment effect in SLE trials; and a new approach to defining a primary endpoint, the SLE Responder Index.

The failure of clinical trials in SLE has introduced palpable uncertainty whilst providing some invaluable lessons regarding expectations for potential new therapies, carefully planned trial designs and appropriate endpoints for the particular agent/regimen in question. It is relevant to note that most preliminary data used rituximab for refractory SLE when standard agents had failed. This is in contrast to the randomised trials, which added rituximab on top of standard therapy for nonrefractory patients. Several factors specific to SLE increase the complexity in designing successful trials. RA is a less heterogeneous disease and is much better understood when compared with SLE and when arthritis is the main manifestation, despite the potential for other organs to be involved. Moreover, there exists a good deal more standardisation for clinical trials including validated endpoints - for example, Disease Activity Index, 28-joint Disease Activity Score. Conducting large-scale studies in a relatively short period of time is therefore possible - particularly as RA is more common and patient access is better, making statistically powered studies of relatively short duration feasible. For lupus, including nephritis, we are still some distance from achieving the same level of understanding and standardisation in the clinical trial setting.

In an attempt to improve the lupus patient's great unmet need, the European League Against Rheumatism has made a few suggestions to help researchers design successful trials 44 . The main points for the future design of clinical trials are to use strictly evaluated (a surrogate of therapeutic success against mortality or end-organ failure) outcome measures, including the disease activity indices, and to follow a standardised approach towards recording adverse events that could be used to measure benefit-to-risk ratios from interventions, comparable between trials. Increasingly important in future trials, when comparing the interventional drugs, is the real difference there may be in their potential to cause harm in the long term.

The aims of randomised controlled trials are to be defined to test robust hypotheses generated based on the available evidence from the open studies and clinical experience. Further, careful attention needs be paid when considering important factors, patient selection and sample size, the therapeutic agent or regimen and its potential effectiveness (and meaningful treatment delta vs. control), the disease outcome measures and disease activity indices, adequate follow-up and the adverse events (Tables 5 and 6). These variable factors contribute to a great element of uncertainty in predicting the probability of the success of clinical trial design in SLE.

• B-cell depletion with rituximab continues to be used in clinical practice for the treatment of refractory SLE, on the basis of a considerable number of publications describing the safety and efficacy data from small open studies and clinical experience whilst noting that it has not been approved by health authorities for the treatment of lupus.

• Contributing features that may have led to the failure of DBRCTs with anti-CD20-mediated B-cell depletion or at least identifying any true treatment effect size probably include concomitant use of high-dose steroids, stringent and nonorgan-specific clinical response criteria, too short a follow-up, and, from a statistical perspective, the sample size. However, the trials confirm the safety of repeated treatment with rituximab.

• A better response to rituximab detected in patients of African-American and Hispanic ancestry highlights the importance of preplanned subgroup analysis and the need to better understand the potential disease drivers of a treatment effect when compared with a standard-of-care regimen in a trial setting.

• The significant biological effects seen with rituximab need to be monitored to assess clinical benefit and risk in the long term.

• Future clinical trial design in SLE and lupus nephritis may be guided by the key working groups of experts, including the European League Against Rheumatism task force, in order to achieve standardisation and to continually apply lessons from both clinical and trial experience.

BAFF: B-cell activating factor belonging to the TNF family; BCDT: B-call depletion therapy; BILAG: British Isles Lupus Assessment Group; DBRCT: double-blind: randomised: placebo-controlled trial; dsDNA: double-stranded DNA; mAb: monoclonal antibody; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus.

DJ has received research grants from Roche/Genentech and Viforpharma, and consulting fees from BIOGEN, Boehringer, GSK, Roche/Genentech and UCB. DC is an employee of MedImmune Ltd and a former employee of Roche Products Ltd. DI has consulted for Roche, asking that his fee is donated to a local research charity. VR declares that he has no competing interests.

This article has been published as part of Arthritis Research & Therapy Volume 15 Supplement 1, 2013: B cells in autoimmune diseases: Part 2. The supplement was proposed by the journal and content was developed in consultation with the Editors-in-Chief. Articles have been independently prepared by the authors and have undergone the journal's standard peer review process. Publication of the supplement was supported by Medimmune.