Research

17 Sep 2015
  • Research Result

Therapeutic effects of ustekinumab (anti-IL-12/23 p40 monoclonal antibody) on Takayasu arteritis

Assis Prof Yoshifuji

In a pilot study led by two Kyoto University researchers -- Program-Specific Assistant Professor Chikashi Terao of the Center for Genomic Medicine (currently a research fellow at Harvard University) and Assistant Professor Hajime Yoshifuji of the Dept of Rheumatology and Clinical Immunology -- ustekinumab (UST), a monoclonal antibody against IL-12/23 p40, was shown to improve symptoms and inflammatory markers in three patients suffering from Takayasu arteritis (TAK), a rare refractory disease.

It was the first time that the antibody was demonstrated to be effective against the condition. IL-12/23 p40, which can be blocked by UST, is encoded by the IL-12B gene, and the researchers had previously identified this gene as being associated with susceptibility to TAK.

Background

Takayasu arteritis (TAK) is categorized as vasculitis and causes stenosis or aneurysm of the aorta and its main branches. It is a rare condition with an incidence of around 1:20,000 in the Japanese population. Young females are the most susceptible. Glucocorticoids (GCs) are used as a standard treatment. However, the disease recurs in about half of patients during tapering of GC dosage. Refractory or recurrent cases may involve serious complications, such as aortic regurgitation, visual loss, and cerebral infraction, as well as side effects of long-term GC treatment. At the moment, there are no established treatments specific to TAK except for GCs.

In 2013, Assistant Professor Yoshifuji's team performed a genome-wide association study using DNA samples, collected from 379 patients with the assistance of several medical institutes and a TAK patient group (Akebono kai). The results showed that the IL-12B gene is associated with the onset of TAK (odds ratio: 1.75, CI: 1.42-2.16, p = 1.7x10-13, Terao et al, Am J Hum Genet, 2013) and that the risk allele is associated with aortic regurgitation, an important complication of TAK. The IL-12B gene encodes IL-12/23 p40, and p40 is a molecule important for the differentiation and maturation of helper T cells. This implied that p40 is crucial in the pathophysiology of TAK.

Ustekinumab (UST), a monoclonal antibody against p40, was developed as an agent to treat psoriasis vulgaris, a skin disease whose mechanism is also related with p40, and has thus far been administered to about 200,000 patients. p40 is also associated with susceptibility to inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn's disease, and UST has been tried in IBD patients as well. In another study, the team reported that UC and TAK share common susceptibility-associated genes (Terao et al, Arthritis Rheum, 2015). Although there had been no reports of using UST for TAK, the group hypothesized from the above evidence that UST might be beneficial, and designed a pilot study to evaluate its effectiveness and safety in three patients who were refractory to conventional therapies.

Methods and results

The group obtained approval from Kyoto University's medical ethics committee and written consent from the study participants. These three TAK patients suffered from neck pain and other symptoms that had not improved following treatment with GCs combined with one or more oral immunosuppressant drugs. The patients were injected with 45 mg of UST twice with an interval of four weeks. After one to three months, their symptoms, such as headache, neck pain, and easy fatigability, showed clear improvement, as did their inflammatory markers, such as C-reactive protein levels and the erythrocyte sedimentation rate (figure 1). No serious side effects were observed during the study. However, imaging evaluation showed no improvement of vascular inflammation, indicating the need for further examination to assess UST's long-term effects on the prognosis of TAK.

Significance of the study

This pilot study was the first to demonstrate the possibility that UST may be used as a therapeutic agent for TAK, a finding that may lead to a larger-scale clinical study. It is also one of the very few studies conducted to date in which researchers collected DNA samples of a genetically multifactorial disease, identified a gene associated with the condition's onset, and showed that a drug that can inhibit this gene can be effective against the disease's symptoms.

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Figure 1. Inflammatory markers (A) and clinical scores (B) before (left) and after (right) the treatment with ustekinumab

Paper Information

"Ustekinumab as a therapeutic option for Takayasu arteritis: from genetic findings to clinical application"
Chikashi Terao, MD, PhD; Hajime Yoshifuji, MD, PhD; Toshiki Nakajima, MD; Naoichiro Yukawa, MD, PhD; Fumihiko Matsuda, PhD; Tsuneyo Mimori MD, PhD
Center for Genomic Medicine, Center for the Promotion of Interdisciplinary Education and Research, Dept of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Scandinavian Journal of Rheumatology