Early aggressive treatment in SLE: are we there yet? Save

Early treatment with disease modifying anti-rheumatic drugs (DMARDs) has revolutionised the outcomes of patients with rheumatic arthritis. However, this concept has not been fully extrapolated to other autoimmune rheumatic diseases such as systemic lupus erythematosus (SLE) and Sjogren’s disease, since moderate to severe systemic features often develop gradually over time following detection of autoantibodies in some patients. However, since some patients also could turn up in the emergency floor with severe complications from SLE, should we employ aggressive treatment with immunosuppressive therapy at the onset? 

At the ACR 23 Conference in San Diego, California, Dr Ye (Abstr# 2490) presented data on multicentre, Phase 2 randomised controlled trial in China on early use of low dose mycophenolate mofetil 500mg BD (MMF) + hydroxychloroquine + glucocorticoids (prednisolone 0.5mg/kg/d) in newly diagnosed SLE patients with high titre of anti-dsDNA antibody (>300 iu/mL), and without major organ involvement (brain, heart, liver, kidney, lung, muscle and gastrointestinal tract). The comparator arm (control) was hydroxychloroquine + prednisolone 0.5mg/kg/d. Total number of participants was 130. At week 96, the primary endpoint, i.e., the proportion of severe flares as defined by SELENA-SLEDAI, was significantly lower in the low dose MMF group vs control, 10% vs 28% respectively. Additionally, more patients in the MMF group vs control never had a relapse, 34% vs 17% respectively. The rates of new development of lupus nephritis was 2% and 14% respectively. There was no significant reduction in prednisolone dose (mean 38mg/d to 4mg/d for the former, 34mg/d to 6mg/d for the latter) and adverse events at week 96 between both groups although numerically, these favoured the low dose MMF group. 

So what do these data tell us? 

Early use of combination immunosuppressive therapy appear effective in preventing severe flares, as well as development of lupus nephritis in a subset of patients who are considered high risk, i.e., strongly positive anti-dsDNA antibody. This approach appears safe with lower frequency of adverse events compared to the control group. However, there are several limitations and some refinement to this approach are warranted before this approach can be employed in practice.

First, for patients without major organ involvement, the use of quite a hefty dose of glucocorticoids at the onset in this trial appear excessive and may not be necessary. Initial short burst with rapid tapering would be more appropriate and could reduce some of the unwanted side effects, which may not be related to the MMF and hydroxychloroquine. Second, although this was a multicentre study, the participants were homogenous (i.e., Chinese). Data from a more diverse population are needed to capture the efficacy and tolerability more accurately for this disease with plenty of issues relating to heterogeneity. Lastly, the study only evaluated patients with a very high titre of anti-dsDNA antibody as prognostic stratification. In order to promote inclusive research and to extrapolate this approach to all newly diagnosed SLE for wider applicability, a more refined stratification to also include other poor prognostic routine immunological markers (e.g. low complement levels), clinical factors e.g. age, ancestry, disease activity score, etc. and other potential biomarkers could be incorporated as treatment stratification to yield a treatment effect. Alternatively, another strategy could be treat-to-target.