Hydroxychloroquine

Antimalarial drugs, most commonly hydroxychloroquine (HCQ), have long been a cornerstone of treatment for systemic lupus erythematosus (SLE).1 Over the years, HCQ has been used primarily as adjunctive therapy for mucocutaneous, musculoskeletal and constitutional manifestations of SLE. However, recent studies suggest that HCQ may exert broader effects in SLE, including prevention of flares,2 ,3 protection against venous and arterial thrombosis,4 protection against neonatal lupus,5 and reduced mortality.6 ,7 These beneficial effects may be a consequence of the ability of HCQ to inhibit toll-like receptors 7 and 9 (TLR7 and TLR9) by preventing endolysosomal acidification.8 ,9 Although HCQ is inadequate to control disease activity in most lupus patients, its beneficial effects establish a benchmark that future therapies will have to exceed.

Cyclophosphamide

Pulse cyclophosphamide (CTX) became the standard of care for lupus nephritis almost 40 years ago,10 but it was not until quite recently that we began to get answers to the most fundamental questions about the treatment regimen. Over the course of the past decade, the Euro-Lupus Nephritis (ELN) group examined a low-dose, short-duration regimen that consists of 6 biweekly infusions of CTX (500 mg) followed by oral azathioprine (AZA).11 By virtually every measure, this regimen was as effective as the more aggressive treatment approach to which it was compared (high-dose CTX monthly for 6 months, followed by two additional doses at 3-month intervals, followed by oral AZA beginning at week 44), and it was less likely to cause adverse effects. Despite this important finding, many clinicians have been hesitant to adopt the ELN treatment regimen. Their reluctance is based on concern that the largely Caucasian, northern European patient population that was studied in the ELN trials may be easier to treat than other racial and ethnic populations that tend to experience more severe nephritis, and to be less responsive to therapy. It remains to be determined whether this regimen will be generalisable to diverse populations of lupus patients.

Mycophenolate mofetil

Concurrent with progress in understanding the use of HCQ and CTX, convincing evidence has emerged to support the use of mycophenolate mofetil (MMF) in lupus, particularly for patients with lupus nephritis.12–16 Although early studies suggested that MMF might be more effective than pulse CTX in the treatment of active lupus nephritis,14 subsequent larger studies did not support this hope.15 However, taken together, the accumulated evidence from several trials strongly suggests that MMF is comparable with pulse CTX in efficacy, and may actually be superior in patients of African descent.15

Two trials have compared MMF and AZA as maintenance therapy for patients with a history of lupus nephritis. The results of these trials, though not identical, are compatible. A trial conducted in a largely Caucasian northern European population showed no significant difference between MMF and AZA with regard to efficacy or safety.17 In contrast, a larger multinational trial showed a distinct efficacy advantage for MMF over AZA.16 The reason for the apparent discrepancy is not yet clear, but it could conceivably be explained by differences in the study design, the patient populations, and/or the statistical power.

Belimumab

Against the background of considerable progress in conventional therapies, belimumab recently became the first drug to meet the current approval standards of the US Food and Drug Administration for the treatment of SLE. Approval of belimumab was based on two trials, designated Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-52 and BLISS-76, both of which demonstrated benefit when belimumab was superimposed on standard-of-care.18 ,19 In order to evaluate belimumab across a broad range of manifestations of SLE, a novel primary outcome measure was employed, referred to as the SLE Responder Index (SRI). The SRI has three components: (1) the SLE Disease Activity Index (SLEDAI) to document that overall disease activity improved; (2) the British Isles Lupus Assessment Group tool to document that no aspect of the disease worsened and (3) a physician's global assessment to provide clinical confirmation. Based on positive results in both trials using this outcome measure, as well as a favourable safety profile, belimumab was approved for patients with many of the diverse manifestations of lupus. However, since patients with active nephritis and central nervous system involvement were excluded from the trials, belimumab is not approved for these indications.

Because of the success of the two BLISS trials, considerable attention has focused on the novel SRI endpoint. It may be worth noting, therefore, that these trials were successful not because of the unique features of the endpoint, but rather because the trials were sufficiently powered to demonstrate the effect of the drug. As shown in table 1, the SLEDAI alone would have been equally effective at distinguishing treatment from control.

When any new drug is approved, there are invariably more unanswered than answered questions. Belimumab is no exception. The majority of subjects in the belimumab trials had mucocutaneous and/or musculoskeletal manifestations of SLE. Therefore, for now, these are the manifestations for which the evidence is strongest for the use of belimumab. The BLISS trials were not powered to determine with confidence which of the other manifestations of SLE will respond, especially with regard to the manifestations that were explicitly excluded from the trials. Similarly, the trials were not powered to assess response rates in distinct patient subsets, but concerns have been raised about lower response rates in North Americans and in patients of African descent. Finally, the trials do not address whether belimumab is best suited to treatment of active disease, maintenance of remission, or both. Extensive new trials are being initiated to address these and other unanswered questions.

Rituximab

A peculiar conflict exists within the lupus community with regard to the use of rituximab in SLE. Numerous uncontrolled case series and anecdotal reports strongly suggest that some lupus patients benefit from rituximab. However, two large trials of rituximab have yielded negative results: the LUNAR trial in patients with lupus nephritis,20 and the EXPLORER trial in patients with other manifestations of SLE.21 There has been considerable difference of opinion about the reasons for the failure of the controlled trials to confirm widespread clinical impressions. It may well be that, despite the case series, rituximab does not work in SLE. However, there are also issues of study design, including study size, that may explain the discrepancy. For example, the magnitude of the difference between the treatment and control groups in LUNAR was comparable with the differences observed in the BLISS trials, but the statistical anlaysis of the smaller group sizes led to the opposite conclusion (table 2). Until and unless there are further studies of rituximab in SLE, the controlled trials do not support its routine use. However, until the controversy surrounding rituximab is definitively resolved, it is likely that clinicians will continue to consider its use when other options are exhausted or contraindicated.

Abatacept

There is a strong rationale for believing that inhibition of T cell co-stimulation might be effective in SLE.22–24 By inhibiting CD28 engagement on T cells,25 abatacept (CTLA4Ig) interferes with T cell co-stimulation. To date, there have been two trials of abatacept in lupus and, like the rituximab trials, both trials had negative outcomes. However, in a post-hoc analysis, it was shown that the failure of abatacept in the nephritis trial may have been due to misjudgments in the prespecified definition of complete response.26 Using outcome measures from other major lupus nephritis trials, we showed that there were substantial differences between the treatment and control groups, suggesting possible benefit for abatacept. These post-hoc findings will have to be confirmed by prospective trials, but at the moment, they provide hope that abatacept may yet prove to be effective for lupus nephritis. Until then, however, the literature does not support the use of abatacept in lupus.