Findings from a small, open-label trial in Austria, recently published in Arthritis & Rheumatism, show that treatment with tumor necrosis factor-α (TNF-α ) blockade is safe and appears to promote clinical improvement of systemic lupus erythematosus (SLE).1

The treatment appeared to result in a reduction of SLE disease activity both in the joints and kidneys and no serious adverse events (AEs) were observed. The investigating team, led by Martin Aringer, MD, of the Medical University of Vienna, Vienna, Austria, is calling for larger clinical trials to study the use of TNF-α blocker therapy in SLE patients.

"This study may have a significant impact on treatment of patients with systemic lupus erythematosus who are not responding to traditional treatments," Scott Zashin, MD, clinical assistant professor of medicine, University of Texas Southwestern Medical School, told CIAOMed.

Although the treatment created higher levels of antibodies, clinical effects from this were not seen, Dr. Zashin noted. "The study is encouraging, but the treatment must be used with caution until larger clinical trials are available," he added. "This is a very small study and lupus patients already have a higher risk of infection."

Among the 6 patients with moderately active SLE who were participating in the trial, 4 had lupus glomerulonephritis and 3 had severe polyarticular lupus arthritis refractory to other therapies (one of the latter group also had nephritis). The patients were given 4 infusions of infliximab (RemicadeÂR) 300 mg, a chimeric antiâ€"TNF-α antibody, over a 10-week period, in addition to immunosuppression with azathioprine or methotrexate. The 6 cases were followed for 52 weeks and patient medical records for the previous 12 months served as controls.

All 3 patients with joint involvement experienced remission of arthritis. Joint swelling and tenderness subsided during treatment and did not relapse until 8 to 11 weeks after the last infusion. The 4 patients with nephritis had more than a 60% decrease in proteinuria within 1 week of therapy and levels remained low until the end of the observation period. TNF, which is markedly increased in the blood of SLE patients, is present in renal tissue in lupus nephritis and correlates with SLE disease activity, according to the study investigators.

Significant findings for AEs included urinary-tract infections in 3 patients, one of which was accompanied by Escherichia coli bacteremia and another by a prolonged febrile episode, putatively of viral origin. All participants had experienced similar infectious conditions in the past. None had to terminate treatment.

TNF-α blockade therapy has been used effectively in the treatment of rheumatoid arthritis; however, blocking TNF-α in this disease has led to the formation of antinuclear antibodies, autoantibodies in double stranded (ds)DNA, and anticardiolipin (aCL) antibodies.2

Although 4 patients in the Vienna study formed anti-dsDNA antibodies and increases in aCL antibodies occurred in 3 patients, none experienced a deterioration of underlying disease or a drug-induced lupus-like syndrome.

The study indicates that anti-TNF therapy could suppress local tissue destruction in SLE; however, this may lead to increased anti-DNA autoantibody formation.3 These 2 effects combined with sustained improvement in renal disease suggest that anti-TNF agents only should be used as a rescue therapy in patients with refractory forms of SLE.

"Despite the observed efficacy, these data must be interpreted with all necessary caution," the current study's authors wrote, adding that no firm conclusions can be drawn.

The trial "represents an important step forward in exploring a new approach to the treatment of SLE," John C. Davis Jr., MD, assistant professor of medicine, University of California at San Francisco, wrote in an accompanying editorial.4 "Determining the risk:benefit ratio in patients with SLE is crucial to this approach and to what the future holds now that the ice has been broken," he observed.

Prior resistance to exploring the use of TNF-α inhibitors to treat SLE has reflected a growing awareness of this cytokine's complicated actions and a concern that blocking it to promote disease-improving activity might actually result in the opposite effect. The conclusions of the present study are tentative but encouraging, Dr. Davis wrote.

References:

  1. Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor blockade α in systemic lupus erythematosus. An open-label study. Arthritis Rheum. 2004; 50:3161-3169.
  2. Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in an open label and randomized placebo-controlled trial. Arthritis Rheum. 2000;43:2383-2390.
  3. Pisetsky DS Tumor necrosis factor alpha blockers and the induction of anti-DNA autoantibodies. Arthritis Rheum. 2000;43:2381-2382.
  4. Davis JC, Jr. Breaking the ice: testing tumor necrosis factor α blockade in lupus. Arthritis Rheum. 2004;50:3061-3063.