Lupus update: Perspective and clinical pearls
ABSTRACTPatients with systemic lupus erythematosus (SLE, lupus) have a markedly better survival rate today than they did 50 years ago, but they face a greater risk of cancer, cardiovascular disease, and osteoporosis at early ages. With better understanding of the immunological mechanisms of the disease, new avenues of therapy are emerging.
KEY POINTS
- Lupus is often misdiagnosed. A person may be given a diagnosis based on a positive antinuclear antibody (ANA) test, a finding that alone is not sufficient to establish the diagnosis. In contrast, some patients with lupus may go several years and see numerous physicians before the proper diagnosis is made.
- One of the major mechanisms for lupus involves defective clearance of apoptotic cells, which act as a source of self-antigens. Because sun exposure can result in massive cell death of keratinocytes (skin cells), protection from the damaging effects of ultraviolet light plays an important role in the management of lupus.
- Patients at any age with SLE should have their modifiable cardiovascular risk factors managed.
- Drugs on the horizon for treating SLE inactivate B cells or their actions.
ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT
Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.
Buyon et al15 randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.
Petri et al16 randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.
A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.
TREATMENTS ON THE HORIZON?
In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.
Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.
Ginzler et al,17 in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m2, increased to 1.0 g/m2). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.
The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m2 in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.
The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.
Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.
New drugs target B cells
Many new drugs for lupus target B cells.
Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.
The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.
B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.
Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.
The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.
Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.
