NEW YORK — Increased understanding of the natural history and pathogenic cellular events associated with Takayasu arteritis has only begun to translate into improvements in treatment, and the condition remains exceedingly difficult to manage, according to Dr. Gary S. Hoffman, who has been following a cohort of these patients at the Cleveland Clinic since 1992.

Corticosteroids have long been the cornerstone of therapy for the granulomatous vasculitis first described by Japanese ophthalmologist Dr. Mikito Takayasu in 1908. The disease affects the aorta and its primary branches and can lead to segmental stenosis, occlusion, and aneurysm formation, but with high doses, almost all patients improve—temporarily.

Among the 30 patients in Dr. Hoffman's longitudinal cohort, 28 were able to achieve disease remission of any duration, but only 8 have had sustained remissions of 6 months or more and have been able to taper their steroids to 10 mg/day or less.

Relapses ultimately have been seen in 27 while steroids were being tapered, and 8 relapsed while on steroids plus two immunosuppressive agents, said Dr. Hoffman, who is Harold C. Schott professor of medicine at Case Western Reserve University, Cleveland, and founder of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. “A further testimony to how ineffective our treatment has been is that half of the patients we followed required on average more than two surgical procedures,” he said.

“Initially, we were excited about the results with surgery, but when we looked at long-term follow-up, we found recurrences with 14 angioplasties and 16 vascular bypass/reconstruction procedures. The results were even worse with stents, which has led us to avoid conventional stenting,” Dr. Hoffman said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

One area that has seen improvement is long-term survival. In an earlier series from the National Institutes of Health, four patients died, while in the Cleveland Clinic series, there was one death. “I feel proud of our mortality data,” he said. However, in both of these cohorts, the rates of disability were “stunning,” with 25 patients in the Cleveland cohort and 44 patients in the NIH series being disabled (Ann. Intern. Med. 1994;120:919–29).

“And the mean age of these patients was only 26 years,” he said.

Clearly, better therapies are needed, and recent efforts have focused on potential roles for biologic agents. In a pilot study that included 15 patients with relapsing Takayasu arteritis, 14 patients improved with etanercept or infliximab and 10 achieved complete remission that persisted for up to 3 years without steroids (Arthritis Rheum. 2004;50:2296–304).

A total of 28 patients now have been treated with anti-tumor necrosis factor (TNF) drugs, most commonly infliximab, and long-term follow-up data are available on 20. Mean follow-up is 28 months, with the longest being 6.5 years. Steroid-free, long-term remissions have been seen in 12. Marked improvements have been seen in an additional six. Only two patients have been unable either to discontinue steroids or to cut them to less than 10 mg/day.

“We are encouraged by this open-label experience, and I think it's possible that anti-TNF therapy may be useful in the treatment of Takayasu arteritis,” Dr. Hoffman said at the meeting sponsored by the Hospital for Special Surgery.

But randomized, controlled trials are sorely needed, he added.

Another biologic agent that may prove helpful is the interleukin (IL)-6 inhibitor tocilizumab. Serum levels of the inflammatory cytokine IL-6 are elevated in this disorder and correlate with disease activity, and it is also strongly expressed in patients' affected aortic tissue.

Benefits were seen with tocilizumab in a recent case report of a 20-year-old woman with Takayasu arteritis and Crohn's disease whose disease activity could not be suppressed with high doses of corticosteroids plus multiple immunosuppressants. After a single 4-mg/kg dose of tocilizumab, her C-reactive protein level fell within a week from 126 mg/L to 26 mg/L, and by week 46, after 26 doses of the drug, her serum IL-6 level had decreased from 1,720 pg/mL to 114 pg/mL (Arthritis Rheum. 2008;58:1197–200).

Further experimental investigations include a trial of abatacept sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, expected to begin shortly, that will enroll 66 patients with Takayasu arteritis or giant cell arteritis.

Another possibility is fontolizumab, an anti-interferon-gamma antibody previously tested for Crohn's disease (Gut 2006;55:1131–7). “If it turns out that interferon-gamma is a key player in Takayasu arteritis I'll be interested to see what this drug would do,” Dr. Hoffman said.

Dr. Hoffman has previously disclosed having no conflicts of interest.

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Mononuclear cells, left, infiltrated the aortic arch, leading to a 5.0-cm aneurysm, right. Corticosteroids have long been the cornerstone of therapy for Takayasu arteritis. Images courtesy Dr. Gary S. Hoffman

Takayasu Arteritis Still a Therapeutic Challenge