VIENNA — Early results with biologic therapy for systemic lupus erythematosus show promise, but the results of controlled trials are needed before these drugs can be widely used in lupus, according to Dr. Martin Aringer of the department of rheumatology, Medical University of Vienna.
The complexity of lupus provides multiple potential targets for biologic response modifiers, including the B cell, which is quantitatively and functionally abnormal in lupus; the interface between B cells and T cells; and various cytokines involved in the inflammatory response, Dr. Aringer said at the 16th Congress of the European Academy of Dermatology and Venereology.
B cell-depleting therapies being evaluated in lupus include monoclonal antibodies against the surface antigens CD20 (rituximab) and CD22 (epratuzumab).
The first study of rituximab in lupus was an open-label trial that included 17 patients with longstanding, clinically active disease. Mean age was 37 years, prednisone dosage was 13 mg/day, and Systemic Lupus Activity Measure (SLAM) score was 8.8.
Patients received either a single infusion of 100 mg/m
A total of 11 patients achieved B-cell depletion, and in these patients SLAM scores improved significantly, with improvements persisting for 12 months (Arthritis Rheum. 2004;50:2580–9).
Only three patients showed a decline in autoantibody levels, which suggests that the role of B cells in lupus is autoantibody independent, Dr. Aringer said.
In another study that included six patients with refractory disease, rituximab was given as two infusions of 500 mg along with two infusions of 750 mg of cyclophosphamide and high-dose corticosteroids. One patient was lost to follow-up, but the remaining five all improved clinically and serologically, with decreases in anti-double-stranded DNA antibodies, erythrocyte sedimentation rate, and urinary protein-to-creatinine ratio (Arthritis Rheum. 2002;46:2673–7).
“B-cell depletion does seem to be one way to check autoimmunity,” Dr. Aringer said. “Either way is probably fine, with rituximab alone or in combination with cyclophosphamide. It's not clear which is better,” he said. This may be an option for patients who do not respond to other therapies, but controlled data are lacking at this point, he said.
B-cell immunotherapy using epratuzumab was evaluated in an open-label study that included 14 patients with moderately active lupus. After receiving four doses of 360 mg/m
“We can also target the contact between T cells and antigen-presenting B cells with the costimulatory blocker abatacept,” he said. “We don't yet have published human experience with this, but we have spectacular mouse data on the combination of abatacept and cyclophosphamide—better than anything that was used before in this mouse model,” he said. Two human trials are ongoing, one with the combination and the other with abatacept alone. “We will know very soon if this works.”
“Finally, our focus in the last couple of years has been on targeting the downstream inflammatory response using tumor necrosis factor blockade,” he said.
Despite the fact that tumor necrosis factor (TNF) is very high in the serum of patients with lupus and correlates with several measures of disease activity, the widely available tumor necrosis factor-α blockers have not been given much consideration in lupus.
One reason for this is that approximately 15% of patients with rheumatoid arthritis and Crohn's disease being treated with these drugs develop anti-double-stranded DNA and anticardiolipin antibodies, and some develop drug-induced lupus, according to Dr. Aringer. Also, some mouse models have suggested worsening of nephritis, although others have demonstrated delay in disease.
Despite this controversy, but with the reassuring observation that the antibodies clear on withdrawal of the drug, Dr. Aringer and his colleagues performed the first open-label trial of infliximab in lupus.
Six patients each received four infusions of 300 mg of infliximab on day 0 and at weeks 2, 6, and 10 in addition to immunosuppression with methotrexate or azathioprine.
Global disease activity decreased in all patients during the treatment period, and there were no flares in a follow-up period of 52 weeks, he said.
In the three patients who had arthritis, there was rapid improvement with no swollen joints being seen during treatment, although symptoms returned about 8 weeks after the final infusion (Arthritis Rheum. 2004;50:3161–9).
There was an increase in anti-double-stranded DNA antibodies in four patients, and one patient developed antiphospholipid and anticardiolipin antibodies and a deep venous thrombosis. “This was the only immunologic adverse event we saw,” he said.
Marked improvements were seen in longstanding proteinuria among all four patients with nephritis, with a decrease of 60% or more within a few weeks. “More than 3 years later these patients continue to have very low level proteinuria. We can't explain this, but we think it's important,” he said.