SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.
"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Michael H. Pillinger
Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.
Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.
The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).
The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).
Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.
In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).
Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.
Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.