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Study Clears Gene Therapy in Death of Arthritis Patient

Posted on: 10 July 2009, source: MedPage Today
The death of a young patient participating in a gene-therapy trial for a rheumatoid arthritis drug was most likely the result of another arthritis drug, adalimumab (Humira), and not the novel gene therapy agent, a new study found. "The death of this young patient who was receiving multiple forms of TNF inhibitors highlights the risk of opportunistic infections in patients receiving such agents, and the importance of having a well-designed monitoring plan when a patient in a study becomes ill," Karen M. Frank, MD, of the University of Chicago Medical Center, and colleagues wrote in the July 9 issue of New England Journal of Medicine.
The patient, a 35-year-old woman with a 15-year history of rheumatoid arthritis, first presented three days after receiving a second injection on July 2, 2007, of the active gene-therapy agent, tgAAC94, a tumor necrosis factor alpha (TNF-α) antagonist. She was suffering from a range of symptoms that including fever, chills, abdominal pain, and vomiting.

Her symptoms worsened in the following days and she was hospitalized in a hospital that was not connected with the study, on July 12, with jaundice, abnormal liver-function test results, elevated white-cell count, and low platelet count. After suffering a large abdominal hematoma, liver damage, and kidney failure, she died on July 24, about three weeks after the injection of the trial gene-therapy agent. A subsequent investigation determined that her death was most likely caused by a widespread histoplasmosis, a normally harmless fungal infection that turned deadly as a result of immunosuppressant therapy. The new study concluded that her death was probably the result of her treatment with adalimumab, another TNF inhibitor, which she was taking while participating in the gene-therapy trial.

In an editorial, Elizabeth L. Hohmann, MD, of Partners Human Research Committee in Boston, wrote that the case offered a number of important lessons, notably the importance of endemic infections. As noted by Frank et al, the patient lived in an area in "which histoplasmosis is endemic, and her previous systemic immunosuppressive treatment was extensive. An oral temperature of 37.6°C (99.6°F) and a low positive result of a histoplasma-antigen test (performed after the patient's death on a serum sample from three weeks before her death) suggest that this illness was already present at the time of the second intraarticular injection."

Nonetheless, Dr. Hohmann wrote, "One cannot help but also wonder whether a zebra misled clinicians as the illness progressed; did they focus inappropriately on a possible direct effect of the AAV or on the AAV and a potential 'helper' herpes virus, which was found at low levels in this patient?"

TNF-α inhibitors have dramatically improved the treatment of rheumatoid arthritis, the authors wrote. The drugs, which act as a key mediator of inflammation, include the two antibodies, infliximab (Remicade) and adalimumab, and etanercept (Enbrel), a dimeric fusion protein that combines immunoglobulin and TNF-receptor regions. The trial in which the woman participated sought to evaluate the safety of a TNF-α inhibitor administered either as intraarticular therapy in patients with inflammatory arthritis who had persistent destructive synovitis in selected joints or as targeted treatment in patients with monoarticular or oligoarticular arthritis. The gene-therapy agent was carried by an AAV vector and altered patients' DNA so that it expressed a protein that inhibits TNF-α.

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