AMSTERDAM, The Netherlands—New research outlines some drawbacks and limitations in the use of TNF-inhibitors among patients with ankylosing spondylitis (AS) and other forms of spondylarthritis.

"To prevent [antibodies to infliximab] formation that might inhibit the efficacy of infliximab, it might be helpful to increase the dosage of infliximab (as occurs in the treatment of rheumatoid arthritis with infliximab), to shorten the interval between infliximab infusions (as is currently the strategy in Crohn's disease), or to provide coadministration of other immunosuppressives (such as methotrexate)." —M. K. de Vries, MD.
TNF-inhibitors are effective in up to 70% of AS patients, and many of the nonresponders may never reach therapeutic levels of infliximab because anti-infliximab antibodies intervene, according to a pilot study in Annals of the Rheumatic Diseases,1 M. K. de Vries, MD, rheumatologist at VU University Medical Center, in Amsterdam, The Netherlands, reported that AS patients who did not respond to infliximab had low or undetectable serum trough infliximab levels and had antibodies to infliximab within 24 weeks. 

A second study,2 which appears in the February 2007 issue of Arthritis & Rheumatism, used a murine model of peripheral joint ankylosis to show that etanercept effectively targets inflammation in AS but does not affect ankylosis.

AS nonresponders have very low serum infliximab levels

The first study comprised eight AS patients who were treated with 5 mg/kg of intravenous infliximab at baseline, week 2, 6, 12, and every 6 weeks thereafter. Researchers collected blood at 12 and 24 weeks before infusion. At each visit, patients filled out questionnaires to see if they met the 20% response criteria of assessment in AS (ASAS). Researchers also conducted lab tests to check levels of inflammatory markers. They correlated these findings with disease activity levels, serum trough and antibody levels. Six responding patients showed a decline in the Bath Ankylosing Spondylitis Disease Activity Index, erythrocyte sedimentation rates, and levels of C-reactive protein, as well as high serum trough levels of infliximab and no antibodies to infliximab. 

Two patients, however, did not show detectable serum trough infliximab levels and developed infliximab antibodies after 12 and 24 weeks, respectively. One patient did not respond to treatment at all; another nonresponder arrived at the 20% response criteria of ASAS, but showed an increase in inflammatory markers. Both nonresponders had infusion reactions to infliximab.

The low serum levels may be due to enhanced clearance of immune complex formation between anti-infliximab antibodies and infliximab, the researchers speculate.

Personalized medicine for AS?

"To prevent [antibodies to infliximab] formation that might inhibit the efficacy of infliximab, it might be helpful to increase the dosage of infliximab (as occurs in the treatment of rheumatoid arthritis with infliximab), to shorten the interval between infliximab infusions (as is currently the strategy in Crohn's disease), or to provide coadministration of other immunosuppressives (such as methotrexate)," the researchers write.

If confirmed in a larger cohort, these data may allow researchers to develop "a more patient-specific treatment, which might predict the inefficacy of infliximab in an early stage and might prevent adverse reactions," the study authors conclude.

Why TNF-blockade may not halt X-ray progression in AS

In the second report, male mice with spontaneous arthritis were treated twice weekly with etanercept or placebo from week 12 to week 25. The mice were also scored twice weekly for signs of arthritis. In another experiment, mice were induced with arthritis using methylated bovine serum albumin. Four days later, these mice were given a single injection of etanercept. Signs of arthritis were assessed and graded for cartilage destruction and bone erosion. 

They found that etanercept had a significant impact on disease severity for the mice with induced arthritis. It inhibited inflammation and cartilage and bone destruction. In mice with spontaneous arthritis, however, etanercept was no more effective than placebo at inhibiting new cartilage or ankylosis. The researchers also found TNF-positive cells in the joint capsule, adjacent blood vessels, and new cartilage.

"Anti-TNF drugs are currently the best treatment available for AS patients to control their symptoms, as has become clear from different clinical trials. However, one issue that has not been resolved is the question of whether these drugs will also delay the progression of ankylosis in these patients," study author Frank P. Luyten, MD, rheumatologist at University Hospitals, in Leuven, Belgium, told CIAOMed.

In general, inflammation and TNF are associated with bone destruction, not bone formation, he noted. "Preliminary results of different cohorts suggest that radiographic progression may not be halted by anti-TNF," Dr. Luyten said. "Our data show no effect on ankylosis suggesting that it occurs independent of TNF and may therefore be a specific target [along with] control of inflammation."

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References

1. de Vries MK, Wolbink GJ, Stapel SO, et al, Inefficacy of infliximab in ankylosing spondylitis is correlated with antibody formation. Ann Rheum Dis. 2007;66:133-134.
2. Lories RJU, Derese I, De Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodelling in a mouse model of spondylarthritis, Arthritis Rheum. 2007;56:489-497.