Giant Cell Arteritis: Ustekinumab Shows Activity in Early Trial

Janis C. Kelly

May 12, 2016

Blocking interleukins 12 (IL-12) and IL-23 may be a novel way to control or even partly reverse the symptoms and vascular damage associated with refractory giant cell arteritis (GCA), according to a small proof-of-concept trial of the IL-12/IL-23 blocking monoclonal antibody ustekinumab.

Ustekinumab "permitted a significant reduction in glucocorticoid dose and cessation of other immunosuppressants in patients with refractory GCA" and justified further evaluation of the drug in a randomized controlled trial, Richard Conway, MD, and colleagues report in an article published online May 9 in a letter to Annals of the Rheumatic Diseases. Dr Conway is from the Department of Rheumatology, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin Academic Medical Centre, Ireland.

The single-center, uncontrolled, unblinded trial included 14 patients with GCA enrolled in a prospective registry and managed according to British Society for Rheumatology guidelines. All met the American College of Rheumatology 1990 Classification Criteria for GCA and had refractory disease requiring at least 10 mg/day glucocorticoids to prevent GCA symptoms.

Patients received 90 mg ustekinumab subcutaneously at week 0 and week 4 and then every 12 weeks. The primary outcome measure was the median glucocorticoid dose required to maintain disease control, and median follow-up was 13.5 months. Secondary outcomes included physician-assessed GCA relapse and change in acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein).

None of the 14 patients relapsed while taking ustekinumab. Median prednisolone dose at last follow-up was 5 mg vs 20 mg at baseline (P = .001). The researchers intensified ustekinumab dosing from every 12 weeks to every 8 weeks in five patients because of persistent symptoms and elevated acute phase reactants. Symptoms resolved and acute phase reactants normalized in three of these patients and were attributed to other causes in the remaining two.

Computed tomography angiography had been used for evaluation of large vessel vasculitis in seven patients before ustekinumab treatment. Five of these patients underwent repeat imaging at a median of 13 months after beginning ustekinumab. All five showed improvement of wall thickening, and two of the five patients had full resolution. None had new stenosis or aneurysms.

Adverse events included one case each of urinary tract infection, tinea pedis, dental abscess, lower respiratory tract infection, alopecia, and nondermatomal limb paresthesias. Three patients stopped treatment because of adverse events.

The authors note that the prolonged, high-dose glucocorticoids that are the mainstay of GCA treatment are associated with serious complications in 86% of patients, and that results with methotrexate and infliximab have been "disappointing." They suggest that ustekinumab might provide a safer and more effective therapy.

Tanaz Kermani, MD, director of the Vasculitis Program at the University of California/Los Angeles Medical Center, Santa Monica, told Medscape Medical News that there is an unmet need for alternatives to glucocorticoids in GCA as a result of the high levels of associated morbidity and adverse effects.

"The study by Conway et al explores another biologic medication, ustekinumab, which targets a molecule that may be important in the pathogenesis of giant cell arteritis, and therefore may be beneficial for these patients," said Dr Kermani, who was not involved in the ustekinumab study. "However, the study is a small proof-of-concept study, and therefore conclusions that can be drawn are limited. Clinical trials are necessary."

Dr Kermani noted that all patients had relapsing disease, that most had tried one prior immunosuppressive therapy to get to lower doses of prednisone, and that the median glucocorticoid dose at entry was moderate (20 mg).

"However, despite the addition of ustekinumab, only 29% were able to stop prednisone therapy, though the steroid doses were lower after 13.5 months than when they started the medication," Dr Kermani explained. "The authors say there were no relapses during treatment with the medication, but the frequency of the study drug had to be increased in about one third of subjects because of persistent symptoms or elevated markers of inflammation. Side effects including infections were observed, and three of 14 patients had to discontinue ustekinumab due to adverse effects."

Dr Kermani concluded, "Based on these preliminary data, this may be a medication worth pursuing and which may offer patients an alternative to glucocorticoids."

The authors have disclosed no relevant financial relationships. Dr Kermani is principal investigator for the SIRRESTA study of sirukumab, supported by GlaxoSmithKline.

Ann Rheum Dis. Published online May 3, 2016. Extract

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