SAN DIEGO — A single infusion of pamidronate resulted in immunologic changes that, at least theoretically, could lead to a reduction in collagen production and fibrosis in scleroderma, Dr. Kenneth J. Warrington reported at the annual meeting of the American College of Rheumatology.
Immune activation plays a central role in the complex pathogenesis of scleroderma, with upregulation of certain profibrotic cytokines such as interleukin-4 (IL-4), IL-13, and transforming growth factor-β (TGF-β)
Pamidronate is an aminobisphosphonate that inhibits bone resorption and is indicated for the treatment of hypercalcemia associated with malignancy as well as for bone metastases and Paget's disease. In recent years it has come to light that this agent also has immunomodulatory properties, acting as a ligand for a subset of T cells that express the γΔ-T-cell receptor.
When this subclass of T cells is activated by pamidronate, an alteration in the cytokine pattern occurs. There is an increase in production of interferon-γ (IFN-γ, a cytokine that has antifibrotic properties. Upregulation of IFN-γ might alter the extracellular matrix deposition of collagen, said Dr. Warrington of the University of Tennessee, Memphis. “Therefore, administration of pamidronate could potentially restore the cytokine balance in scleroderma,” he said.
This hypothesis was tested in a small pilot study that included 19 patients, three-quarters of whom were women and whose mean disease duration was 11 years. They were given a single intravenous dose of 60 mg pamidronate and followed for 6 months, with cytokine production and lymphocyte activation being measured at 48 hours and at weeks 4, 8, 12, and 24 post infusion using enzyme-linked immunosorbent assay and flow cytometry.
At 48 hours there was a statistically significant increase in activated CD4 and CD8 lymphocytes; by week 4 the percentage of activated lymphocytes had returned to baseline levels. At weeks 4 and 8 a decrease in production of the profibrotic cytokine TGF-β was observed in vitro, along with an increase in the production of tumor necrosis factor-α (TNF-α, which regulates the transcription of type 1 collagen.
And with a specialized cytokine secretion assay it was noted that the γΔ-T-cell subset was indeed directly activated by pamidronate to produce IFN-γ. Cytokines from these T cells may then act indirectly on other cell subsets, inducing further activation downstream, Dr. Warrington said.
Safety was monitored throughout, and the drug was well tolerated. Four patients reported transient flulike symptoms at the 48-hour visit, a finding that has been reported previously with pamidronate. Clinical parameters overall were unchanged.
The findings of this study provide a basis for a follow-up study in which pamidronate would be infused repeatedly, with the goal of inducing sustained antifibrotic modulation of IFN-γ, TNF-α, and TGF-β, according to Dr. Warrington. This work was supported by grants from the Scleroderma Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.