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Takayasu arteritis (TAK) is a form of large vessel vasculitis resulting in thickening and stenosis of the large-sized arteries, particularly the aorta and its main branches. Ulcerative colitis (UC) is a major complication of TAK, sharing some genetic background and pathogenesis.1 Serum levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), are potential biomarkers to reflect disease activity of TAK. Thus, IL-6 or TNF-α inhibitors have been used for treating refractory TAK. A randomised controlled trial suggested clinical efficacy and safety of tocilizumab in patients with refractory TAK, although the trial failed to achieve its primary endpoint.2 We here present a patient in whom tofacitinib (TOF), a Janus kinase (JAK) inhibitor, successfully induced a remission of TAK and UC resistant to both TNF-α and IL-6 inhibitors.
A 32-year-old Japanese female with a medical history of TAK and UC visited our hospital complaining of chest pain, abdominal pain and diarrhoea. TAK developed with fever and chest pain when she was 25 year old. TAK was diagnosed based on elevated serum C-reactive protein (CRP) levels and thickening of the thoracic aorta on contrast-enhanced CT images, was successfully treated with prednisolone (PSL) at 40 mg/day. UC developed with abdominal pain and diarrhoea when she was 31 year old during the maintenance therapy with PSL at 10 mg/day. We increased PSL up to 30 mg/day and started adalimumab to treat UC. However, fever and chest pain recurred with increased serum CRP levels. The adalimumab therapy for 1 month was ineffective against both UC and TAK. Switching to tocilizumab rapidly decreased serum CRP levels, but did not improve her symptoms. The tocilizumab therapy for 6 months was also ineffective, and we administered TOF at 20 mg/day to treat the refractory TAK and UC concomitantly with PSL at 10 mg/day (figure 1A).
At baseline, contrast-enhanced CT images displayed wall thickening of the brachiocephalic artery, left subclavian artery and descending aorta. Abnormal fluorodeoxyglucose (FDG) uptake was shown in the same arterial walls by 18F-FDG-positron emission tomography, and a colonoscopy showed redness and swelling of the mucosa from cecum to rectum, indicating active state of TAK and UC (figure 1B). Three months after TOF therapy, FDG uptake in those arterial walls were disappeared, and a colonoscopy showed normal mucosa from cecum to rectum (figure 1C). All her symptoms were dramatically ameliorated. The remission has been sustained on TOF at 10 mg/day and PSL at 8 mg/day without apparent adverse effects.
Recent studies have shown that increased Th1 and Th17 responses are predominant in the pathophysiology of TAK.3 Pro-inflammatory cytokines recruit the lymphocytes within the vascular wall. Th1 cells induced by the IL-12 drive the formation of giant cells through the production of interferon-gamma (IFN-γ) and activation of macrophages, while Th17 cells guided by the IL-23 activate infiltration of neutrophils via IL-17 production. Expressions of IFN-γ, IL-6, IL-12 and IL-17 are increased in the aorta from TAK patients.4 TAK is associated with a single nucleotide polymorphism encoding a common component of IL-12 and IL-23. TOF acts as multi-cytokine blockers by inhibiting the enzyme JAKs, which are involved in signal transduction of various cytokines including IL-6, IL-12, IL-23 and IFN-γ. TOF ameliorated experimental large vessel vasculitis in mice by decreasing Th1 and Th17-related cytokines such as IFN-γ and IL-17.5 TAK is a multi-cytokines disease, especially involved in Th1 and Th17 pathways. TOF could be a promising option for treating refractory TAK beyond the single-cytokine inhibiting therapies.
We especially thank the patient, who made this case report possible. We also thank Dr Yuhei Shibata, Dr Atsuko Miyoshi and Dr Masato Tarumi for their clinical contributions.
Handling editor Josef S Smolen
Contributors SK provided the figure and wrote the manuscript. ST participated in follow-up, edited the manuscript. SM collected the clinical data of colonoscopy. HN and TH contributed to the discussion and edited the manuscript. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.