Following on from last nights section on APS here is the section on SLE from the above Medscape abstract on PubMed.
Latest Advances in Connective Tissue Disorders
Simon Bowman, PhD, FRCP, Vijay Rao, MRCP
Ther Adv Musculoskel Dis. 2013;5(4):234-249.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) typically affects women (circa 9:1 female:male ratio) in the 16–55 age group [Ballou et al. 1982]. It is commoner among patients of African/Afro-Caribbean, South Asian or Chinese/other Asian ethnic groups. It ranges from a mild to a life-threatening or fatal disorder [Petri et al. 2012a]. Active disease is associated with raised anti-dsDNA antibodies and reduced levels of complement C3 and/or C4 levels. Current therapy is, in fact, very effective for most patients. In mild to moderate disease, hydroxychloroquine is now commonly used as steroid-sparing therapy for all patients. For patients with active disease, corticosteroids are at the heart of current therapy, often combined with steroid sparing agents such as azathioprine, methotrexate, leflunomide, ciclosporin or mycophenolate. In patients with severe or life-threatening renal, nervous system or pulmonary disease, oral or pulsed intravenous cyclophosphamide has been typically used over the past 20 years [Boumpas et al. 1992]. As a consequence, the survival rate for SLE has steadily increased. In a review of this topic [Urowitz et al. 2008] the authors point out that since the 1950s, SLE has changed from a disease with a 50% mortality at 5 years to one of over 90% 5-year survival.
The challenge, in recent years, has been less about finding drugs with greater efficacy than corticosteroids and cyclophosphamide and more about developing drug regimes with lower toxicity. Corticosteroids, in particular, have been associated with higher rates of infection, cardiovascular and bone disease [Ruiz-Irastorza et al. 2012; Petri et al 2012b]. Cyclophosphamide is associated with increased infection risk and with infertility [Hickman and Gordon, 2011].
This challenge is now being met following a series of clinical trials over the past few years exploring corticosteroid/cyclophosphamide sparing agents to treat SLE, especially the more severe forms of SLE such as lupus nephritis.
The American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) in collaboration with the European Renal Association–European Dialysis and Transplant Association have recently brought out guidelines for the management of lupus nephritis [Hahn et al. 2012; Bertsias et al. 2012]. Both guidelines use renal biopsy as a starting point for therapeutic regimens that include either mycophenolate or 'low-dose' cyclophosphamide regimes. These guidelines are broadly similar. To summarize, in patients with mild renal disease (class I) and in patients with advanced kidney damage without significant inflammation (class VI), immunosuppression is not generally indicated. In class II disease with proteinuria (mesangioproliferative lupus nephritis) the EULAR guidelines are more inclined to recommend therapy (low to moderate dose glucocorticoids with or without azathioprine) than the ACR guidelines. In class III–IV lupus nephritis (focal or diffuse inflammation with proliferation), or class V (membranous nephritis) a study of 370 patients by the Aspreva Lupus Management Study Group demonstrated equivalent efficacy of mycophenolate mofetil (MMF) 3 g/day compared with intravenous cyclophosphamide (monthly pulses of 0.5–1 g/m2) for 6 months [Appel et al. 2009]. Tapered doses of prednisolone were used in both arms of the study. The Euro-Lupus Nephritis Trial group demonstrated that, in general, shorter courses of lower dose cyclophosphamide given more frequently (e.g. 500 mg intravenously every 2 weeks for a total of six doses) are as effective as traditional 'high-dose' (500—1000 mg/m2 monthly for 6 months) National Institutes of Health regimes [Houssiau et al. 2002]. The ACR guidelines suggest that lower doses of MMF may be required in Asian patients and that African-American and Hispanic patients may respond less well to cyclophosphamide than other groups.
Patients whose condition fails to respond to the initial regime can be tried with the alternative (MMF in those who have failed to respond to cyclophosphamide and vice versa). In refractory patients, rituximab, ciclosporin, tacrolimus or other therapies can be considered. For maintenance, either mycophenolate or azathioprine are recommended as preferred therapies [Dooley et al. 2011; Houssiau et al. 2010].
The two sets of guidelines have also highlighted other aspects of good practice such as the initial use of three intravenous methylprednisolone pulses and good control of hypertension (e.g. with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers) and other cardiovascular risk factors.
Other important issues to pay close attention to include adjunctive use of hydroxychloroquine and statin therapy if appropriate; the use of aspirin/anticoagulation when there is a thrombosis risk; annual and other immunization with nonlive vaccines; consideration of annual measurement of immunoglobulins; the use of bone protection agents, particularly in patients on corticosteroids; appropriate sun protection and annual cervical smear tests for female patients. Vitamin D supplementation may also reduce disease activity in SLE [Bello et al. 2012].
It has been known for over 10 years that high levels of circulating B-lymphocyte stimulator (BlyS also known as B-cell activating factor or BAFF) are seen in patients with SLE and correlate with immunoglobulin G (IgG) levels, suggesting that inhibition of BlyS could be therapeutic [Cheema et al. 2001; Zhang et al. 2001].
Belimumab is a human IgG1 lambda monoclonal antibody that binds soluble BlyS and inhibits its function. There have been two large-scale phase III studies of belimumab in SLE; the BLISS-52 and BLISS-76 studies [Manzi et al. 2012]. In BLISS-52, 865 patients with active SLE were treated with standard care along with 10 mg/kg belimumab, 1 mg/kg intravenous belimumab or placebo at 0, 14 and 28 days and then every 28 days until week 48 with review at week 52. More patients in the belimumab groups achieved an SLE Responder Index (SRI) response than in the placebo group. For belimumab 1 mg/kg the number of responders was 148/288 (51%) [odds ratio (OR) 1.55; 95% confidence interval (CI) 1.10–2.19; p = 0.0129], for the 10 mg/kg dose 167/290 (58%) (OR 1.83; 95% CI 1.30–2.59; p = 0.0006) and for placebo 125/287 (44%) at week 52 [Navarra et al. 2011]. Belimumab at both doses was well tolerated, it reduced the flare rate, improved serologic markers in patients with serologically active disease and reduced corticosteroid use. Adverse events were similar to those of the placebo group. In BLISS-76 a similar trial design in 819 patients generated SRI response rates for belimumab 1 mg/kg, 10 mg/kg and placebo at 52 weeks of 40.6%, 43.2% and 33.5% (p = 0.017 for 10 mg/kg versus placebo and p = 0.089 for 1 mg/kg versus placebo). Again the rate of flares was less in the belimumab groups with no increase in adverse event rate [Furie et al. 2011]. These studies excluded patients with active lupus nephritis or severe central nervous system involvement. Patients with higher disease activity clinically or serologically had greater benefit [van Vollenhoven et al. 2012]. The US Food and Drug Administration (FDA) approved belimumab for the therapy of SLE in 2011. Belimumab is also approved in Europe and Canada, although the National Institute for Health and Clinical Excellence in the UK is not currently recommending its use on cost-effectiveness grounds.
Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and has been effective therapy in B-cell non-Hodgkin lymphoma, rheumatoid arthritis and antineutrophil cytoplasmic antibody-positive vasculitis. In the EXPLORER study, of 257 patients with moderately active SLE assessed, 88 received placebo and 169 received 1 g rituximab (1:2 ratio) at week 0, 2, 24 and 26 with evaluation at week 52. Intravenous methylprednisolone 100 mg was given with each infusion. Oral prednisolone was tapered in both groups according to a preset protocol and background therapy with azathioprine, mycophenolate or methotrexate was continued. The study failed to demonstrate benefit for rituximab as additive therapy in this situation [Merrill et al. 2011].
In the second major trial of rituximab in SLE, the Lupus Nephritis Assessment with rituximab Study (LUNAR), 144 patients with active class III or class IV lupus nephritis were randomized to receive 1 g rituximab (n = 72) or placebo (n = 72) at weeks 0, 2, 24 and 26 with the primary outcome an assessment of renal status at week 52. Intravenous methylprednisolone 1 g was given prior to the first infusion and within 3 days and a further 100 mg was given prior to the subsequent infusions. Oral prednisolone up to 60 mg was given daily up to day 16 and then tapered. Mycophenolate 1.5 g/day increased up to a maximum of 3 g/day in divided doses was also given. The overall renal response rates were 56.9% in the patients receiving rituximab and 45.8% among those receiving placebo (p = 0.18). Eight patients in the placebo group required cyclophosphamide rescue therapy compared with none of the rituximab-treated patients. The rituximab-treated group had a greater reduction in anti-dsDNA antibody levels (p = 0.007). Rituximab also had a greater beneficial effect in patients of African-American or Hispanic ethnicity. Nevertheless, as in the EXPLORER study, the primary outcome was not met [Rovin et al. 2012].
In both the EXPLORER and LUNAR studies, the widely held expert view is that the relatively effective background therapy with corticosteroids obscured the underlying value of rituximab as a nonsteroid therapy for SLE and lupus nephritis and that further studies designed to reflect this will demonstrate this in the future [Weidenbusch et al. 2012; Isenberg, 2012; Gregersen and Jayne, 2012; Pepper et al. 2009]. Another consideration is that although the effect size was comparable to that observed in the belimumab studies, the smaller numbers of participants in the rituximab studies made it more difficult to achieve the primary outcomes.
Furthermore, there are some data that regimes for lupus nephritis that include rituximab with pulsed steroids followed by maintenance therapy with MMF and no further steroid use could even replace corticosteroid-based regimes in the future [Lightstone, 2012].