How is lupus treated?

Lupus is a chronic, autoimmune disease that can affect almost any organ in the body and has widely heterogenous clinical presentations.¹ Management of lupus is highly individualized given the variable clinical manifestations and requires frequent reassessment to guide therapy. Treatment of lupus centers on medications that decrease activity of the immune system with the goal of decreasing disease activity, preventing organ damage, and relieving symptoms.²

Corticosteroids

Corticosteroids are powerful immunosuppressive drugs used to treat acute flares of lupus or as a bridging treatment to another long-term medication.^2,9 Low-dose prednisone is commonly given in periods limited to weeks to months, until it can be tapered off, or it may be continued longer if necessary to manage disease activity. In a study examining corticosteroid use among a cohort of 1700 patients with lupus from 1999 to 2011, researchers found that 81.3% received oral glucocorticoids and 26.3% received parenteral glucocorticoids at some point in the study follow-up period, which had a mean duration of 7.26 years with a standard deviation of 3.82 years. Of those who received oral glucocorticoids, 32.8% received them for the entire follow-up period and 47.5% received them for part of it.³ Patients with major organ manifestations and severe, life-threatening disease may require higher doses of corticosteroids2. When corticosteroids cannot be successfully reduced (to less than 5 to 7.5 mg/day of prednisone) or eliminated, additional immunosuppressive medications are recommended.² This management recommendation stands regardless of major organ involvement because corticosteroids alone may not be enough to control disease activity and have long-term side effects, including diabetes, heart disease, and osteoporosis.²

Anti-Malarial Medications

First-line treatment for nearly all patients with lupus are antimalarial drugs, primarily hydroxychloroquine and chloroquine.⁴ These drugs have a long history of use and have been shown to have multiple benefits in the treatment of lupus, including improvement of constitutional, musculoskeletal, and mucocutaneous symptoms, and pregnancy outcomes.^5,6 A systematic review of 95 studies from 1982 to 2007 found a high level of evidence that anti-malarial drugs prevent acute lupus flares and promote long-term survival due to a consistent protective effect. According to propensity score analysis they reduced mortality by more than 50%.⁷ There is moderate evidence that these drugs also protect against permanent organ damage, thrombosis, and bone loss.⁷ A multiethnic cohort study in the United States found that hydroxychloroquine has a protective effect on survival with an odds ratio (OR) 0.128 (95% confidence interval [CI] [0.054 – 0.301]) and is well tolerated by most patients.⁸ The European League Against Rheumatism (EULAR) recommends that all patients with lupus be treated with hydroxychloroquine at a dose no greater than 5 mg/kg body weight, to minimize the risk of retinal toxicity.^9,10 Many patients with mild to moderate lupus involvement will experience full resolution of symptoms with long-term antimalarial treatment. However, these drugs take three to six months to reach full effectiveness, and many patients will require bridging treatment with corticosteroids.⁹

Conventional Immunosuppressive Therapies

Immunosuppressive medications used in the treatment of lupus include methotrexate, azathioprine, and mycophenolic acid (the active compound in mycophenolate mofetil and mycophenolate sodium). The choice of medication depends on the clinical presentation of the patient, consideration of adverse effects, and patient preference. In particular, methotrexate has been shown to be effective in managing the cutaneous and musculoskeletal symptoms of lupus.¹¹ A systematic review of the efficacy of methotrexate in treating lupus found that it is associated with significant reduction in disease activity, as measured by the lupus Disease Activity Index (SLEDAI) among treated patients compared with controls (OR 0.444, 95% CI [0.279 – 0.707], p=0.001), and decreased average corticosteroid dose requirement.¹² In patients with lupus nephritis, mycophenolate mofetil and cyclophosphamide are the preferred induction medications, and mycophenolate mofetil and azathioprine are used for maintenance therapy.¹³ Meta-analysis of clinical trials did not reveal significant evidence for a difference in efficacy between mycophenolate mofetil and azathioprine for long-term therapy of lupus nephritis.¹⁴ There is a lack of clinical trials comparing the treatment efficacy for other major organ manifestations of lupus, particularly neuropsychiatric lupus. In these cases, mycophenolate mofetil, azathioprine, or cyclophosphamide are often used, selected largely based on case reports.¹³

Biologics

Biologic therapies are agents that target underlying immune disease pathways and have potential utility for the treatment of lupus. In one case series rituximab, a B-cell-depleting chimeric monoclonal antibody, was been shown to be effective in treating some refractory patients with severe renal and hematologic features.¹⁵ However, two separate clinical trials did not find a significant difference in outcomes of treatment with rituximab versus controls, with further studies ongoing.^16,17 In the first of these trials, patients with background treatment evenly distributed between methotrexate, mycophenolate mofetil, and azathioprine received four infusions of rituximab or placebo and were assessed over a 52-week period using the British Isles Lupus Assessment Group (BILAG) score to measure baseline disease activity and clinical response rate. No significant difference was found between the placebo group overall response rate (28.4%) versus that of the rituximab group (29.6%, p=0.975), and the median time to first moderate or severe flare over 52 weeks was approximately four months in both groups with a hazard ratio of 0.974 (95% CI, [0.650 – 1.460], p=0.8979).¹⁶ The Lupus Nephritis Assessment with Rituximab Study found that rituximab did not improve clinical response compared to a placebo group among patients with class III or IV lupus nephritis (n=144) on concomitant therapy with mycophenolate mofetil and corticosteroids. Complete clinical response was defined as normal serum creatinine level (if baseline was abnormal) or a serum creatinine level of ≤115% of baseline (if baseline was normal), plus inactive urinary sediment (<5 RBCs/hpf and no RBC casts) and UPC ratio <0.5.¹⁷ Complete renal response occurred in 26.4% of the treatment group and 30.6% of the control group (p=0.55).¹⁷

Another biologic, belimumab, is a monoclonal antibody that targets the B lymphocyte stimulator. In a two-year clinical trial that compared intravenous belimumab to placebo when added to standard therapy with mycophenolate mofetil or cyclophosphamide–azathioprine in adults with lupus nephritis, patients in the belimumab group were found to have a significantly greater primary efficacy renal response (43% vs. 32%; OR 1.6, 95% CI [1.0 – 2.3], p=0.03) and complete renal response (30% vs. 20%; OR 1.7, 95% CI [1.1 – 2.7], p=0.02) compared to patients in the placebo group.¹⁸ The primary efficacy renal response was defined as an eGFR better than 20% of the pre-flare value, a urine protein to creatinine (UPC) ratio less than or equal to 0.7, and no use of rescue therapy. Complete renal response was defined as an eGFR better than 10% of the pre-flare value, a UPC less than 0.5, and no use of rescue therapy. ¹⁸ Belimumab was subsequently approved as a therapy for adult patients with lupus refractory to standard treatment as well as for lupus nephritis.²

Anifrolumab is an interferon monoclonal antibody that was recently approved for the treatment of moderate to severe lupus. A clinical trial studied clinical response, as measured by the British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA), among patients treated with anifrolumab in addition to standard therapy compared to placebo over 52 weeks and found that patients in the anifrolumab group had a 47.8% BICLA response rate versus 31.5% in the placebo group (difference, 16.3 percentage points; 95% CI, 6.3 to 26.3; P=0.001).¹⁹ Development and study of further biologic treatments for lupus are ongoing.

Calcineurin Inhibitors

Calcineurin inhibitors, like cyclosporine and tacrolimus, are another category of medication useful in the management of lupus nephritis. The American College of Rheumatology recommends that calcineurin inhibitors be considered in refractory cases where other therapies (e.g., corticosteroids plus cyclophosphamide or mycophenolate mofetil) fail to adequately treat the nephritis, and in cases when other medications are contraindicated (e.g. pregnancy).²⁰  A prospective clinical trial comparing tacrolimus to cyclophosphamide showed equivalent rates of both partial and complete remission of lupus nephritis at six months, with complete remission defined as proteinuria with protein excretion <0.3 g/24 h, serum albumin ≥3.5 g/dL, normal urinary sediment, and normal or stable serum creatinine.²¹ Another prospective trial comparing cyclosporine to azathioprine found that both medications limited flares of lupus nephritis at similar rates over a four-year period, with nephritic flares defined as an increase in serum creatinine of ≥30% above baseline plus an increase in proteinuria, reduction in serum C3 and C4, and/or an increase in anti-dsDNA antibody levels, and proteinuric flares defined as an increase of proteinuria by at least 2 g/day or doubled if it had previously been more than 3.5 g/day.²² Recent data supports the use of the novel calcineurin inhibitor voclosporin, as a multicenter, double-blinded phase three clinical trial found that treatment with voclosporin in addition to mycophenolate mofetil and steroids led to a clinically and statistically significant renal response rate compared to treatment with mycophenolate mofetil and steroids alone (OR 2.65, 95% CI [1.64 – 4.27], p<0.0001), with complete renal response defined as a UPC of or less than 0.5 mg/mg, eGFR ≥60 mL/min/1.73 m² or no decrease in eGFR more than 20% from baseline, and no rescue therapy.²³ Further trials are ongoing but current evidence supports the role of calcineurin inhibitors in lupus nephritis management.

References:

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