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Rheumatology Xagena

Spondylarthritis: the process of ankylosis could become a separate therapeutic target


Any form of arthritis that affects one or more vertebral joints, spondylarthritis ( SpA ) represents a group of closely related disorders, including ankylosing spondylitis ( AS ), psoriatic arthritis ( PsA ), and arthritis associated with inflammatory bowel disease.
Aside from chronic inflammation, these conditions are all characterized by ankylosis, stiffness and fusion of bone in the spine and peripheral joints, provoked by abnormal cartilage and bone formation.

What triggers ankylosis remains unknown.

Currently, inhibition of Tumor Necrosis Factor alpha ( TNF-alpha ) is the most effective strategy for controlling the painful symptoms of spondylarthritis and slowing vertebral joint destruction. But does anti-TNF therapy do anything to reduce the incidence or severity of ankylosis ?

To answer this critical question, a quartet of researchers led by Frank P. Luyten, at University Hospitals, Leuven, Belgium, tested the effectiveness of Etanercept ( Enbrel ), an established TNF receptor, on animal models of arthritis.

A sample of male mice with spontaneous arthritis were caged together and observed from the age of 10 weeks. From week 12 to week 25, the mice were treated twice weekly with Etanercept, in a strength comparable to standard dosage for human patients, or a placebo. Mice were also scored twice weekly for signs of arthritis, including cartilage formation, bone formation, and joint ankylosis. The mice were killed at age 25 weeks, autopsied, and analyzed, through cell population staining, for the presence of TNF-alpha.

In a complementary experiment, another sample of mice was induced with arthritis, using methylated bovine serum albumin. Four days later, these mice were given a single injection of Etanercept. Three days later, on day seven, they were killed. Signs of arthritis were assessed and graded for cartilage destruction and bone erosion.

For the mice with induced arthritis, Etanercept had a significant impact on disease severity, inhibiting inflammation and cartilage and bone destruction. For the mice with spontaneous arthritis, however, Etanercept proved no more effective than placebo at inhibiting new cartilage or bone formation or ankylosis. What's more, TNF-alpha-positive cells were observed in the joint capsule, adjacent blood vessels and in new cartilage.

" Our observations strengthen our hypothesis that new bone formation in spondylarthritis is clinically relevant and largely independent of inflammation," Luyten states. Long-term results from clinical trials are required to corroborate this hypothesis in patients with spondylarthritis," he acknowledges, "and to define whether the process of ankylosis should become a separate therapeutic target."

Source: Arthritis & Rheumatism, 2007

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