State of the Art REVIEW
for induction, and mycophenolate mofetil for maintenance; the optimal duration of maintenance treatment is unknown but should not be less than four years. Importantly, guidelines now recommend reduced starting doses of intravenous and subsequent oral glucocorticoids compared with historical practice and tapering to 7.5 mg/day prednisolone (or equivalent) or less within six months for most patients. 189 190 For severe organ threatening disease in other systems, treatment approaches are frequently derived from guidelines for lupus nephritis. 179 Biological treatments and calcineurin inhibitors The first biological widely used in the treatment of systemic lupus erythematosus is the anti-CD20 B cell depleting chimeric monoclonal antibody, rituximab. After multiple case reports suggesting benefit, randomized trials of rituximab in both systemic lupus erythematosus and lupus nephritis were performed, but both were negative. 120 149 Despite these results, the volume of anecdotal reports and multiple case series showing responses in refractory patients treated with rituximab 191 192 mean that the drug is widely used in patients unresponsive to immunosuppressants; generally, when other treatments have failed. In recent years, three new treatments have been approved for systemic lupus erythematosus after several decades without new lupus medicines ( fig 2,table 2 ). The BAFF monoclonal antibody belimumab had a negative phase 2 trial in systemic lupus erythematosus, but post hoc analysis allowed the investigators to derive a novel outcome measure, the systemic lupus erythematosus responder index (SRI), 193 which was used in the two phase 3 trials that led to regulatory approval. Belimumab was shown to be superior to placebo for attainment of SRI in two randomized trials of 867 and 819 patients 123 124 ( table 2 ); a similar efficacy was confirmed in trials of a subcutaneous form, 194 195 and notably, in a randomized trial in 93 children with systemic lupus erythematosus. 196 A recent systematic review of these trials and several postmarketing and registry based studies concluded that belimumab was effective in patients with serologically active disease (ie, in the presence of anti-dsDNA antibodies or low serum complement), reduces organ damage accrual, and is well tolerated. 197 Reduced damage accrual in response to belimumab treatment was suggested in a study comparing data from the phase 3 trials of belimumab with propensity matched data from a large single center cohort. 198 Most recently, a phase 3 trial of belimumab in 448 patients with lupus nephritis showed superiority to placebo over two years, 151 with both arms also receiving induction treatment with either mycophenolate mofetil or cyclophosphamide, leading to its approval for this indication by the US Food and Drug Administration in 2020. These studies confirm the pathogenic role of BAFF, and hence of B cells, in systemic lupus erythematosus. Of note, belimumab is considered
in as many as 80% of patients with systemic lupus erythematosus. 181 182 Unfortunately, in addition to predictable dose dependent Cushingoid metabolic adverse effects, glucocorticoids are associated with increased accrual of irreversible organ damage. 183 184 As a result, lowering glucocorticoid exposure is a major goal of systemic lupus erythematosus management. However, a trial in which 124 patients with quiescent disease were randomized to continue or stop oral glucocorticoids found that flares were less frequent in those who did not stop glucocorticoids (risk ratio 0.2, 95% confidence interval 0.1 to 0.7). 185 This result suggests that new treatments are needed to allow patients to stop using steroids. Immunosuppressants Immunosuppressants used in systemic lupus erythematosus, including mycophenolate mofetil and mycophenolate sodium, azathioprine, and less commonly used agents such as methotrexate are almost always used in combination with glucocorticoids and antimalarials. Other than for lupus nephritis, the specific choice of immunosuppressants in different presentations lacks evidence from high quality studies, but increasingly mycophenolate mofetil is seen as the first line immunosuppressant for systemic lupus erythematosus. A randomized trial comparing mycophenolate mofetil with azathioprine in 240 patients with non- renal systemic lupus erythematosus showed that enteric coated mycophenolic acid was superior in attainment of remission (32.5% v 19.2%, treatment difference 13.3, 95% confidence interval 2.3 to 24). 186 A prospective cohort study of over 700 visits in 50 patients with childhood onset systemic lupus erythematosus suggested that early introduction of mycophenolate was associated with increased attainment of treatment goals and lower overall exposure to glucocorticoids, as evidenced by mycophenolate mofetil usage being associated with reaching a lupus low disease activity state (LLDAS) within six months on multivariable analysis, and 53% of children achieving clinical remission on treatment versus only 22% achieving clinical remission off immunosuppressants. 187 The optimal duration of immunosuppressant treatment in systemic lupus erythematosus is poorly evidenced, but a recent multinational cohort study of over 3000 patients suggested that treatment retention as a surrogate for efficacy and tolerability is poor for both azathioprine and mycophenolate mofetil, with cessation of 25% of treatment episodes with mycophenolate mofetil occurring by 175 days; treatment retention, however, is better for mycophenolic acid (387 days to discontinue 25% of treatment episodes). 188 Treatment guidelines for lupus nephritis are regularly updated by an international glomerulonephritis working group, with the most recent guidelines recommending treatment of histological class III or IV lupus nephritis with mycophenolate mofetil or cyclophosphamide
the bmj | BMJ 2023;383:073980 | doi: 10.1136/bmj-2022-073980
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