Current Immunosuppressive Treatment for Takayasu Arteritis

Abstract

Takayasu arteritis (TAK) is a rare disease characterized by inflammation of large blood vessels, which results in vascular stenosis, occlusion, and aneurysm formation. The principal treatment has been glucocorticoids, but the recent emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), represented by tocilizumab (TCZ), has significantly changed the treatment landscape. Both cardiologists and cardiovascular surgeons will encounter patients receiving these drugs who require catheterization, other invasive procedures, or surgery. Several bDMARDs have shown promise against TAK in clinical studies and their use is expected to increase in the future. Janus kinase inhibitors may also be effective. Here, we review the evidence supporting the use of TCZ and other immunosuppressants in TAK and provides an update on their status as well as the relevant guidelines.

Takayasu arteritis (TAK) is a chronic inflammatory vasculitis of unknown etiology that affects large vessels and causes vascular stenosis, occlusion, and aneurysm formation.^1–3 In 2017, >7,000 patients were diagnosed with TAK in Japan, and this number has been increasing by 300 each year.⁴ Although glucocorticoids (GCs) are the principal treatment, tocilizumab (TCZ) is effective for patients with GC-refractory disease.^5,6 In the 2017 Japanese Circulation Society (JCS) guidelines for the management of vasculitis syndrome, TCZ is a Class I treatment recommendation for TAK.⁷ In the 2021 American College of Rheumatology (ACR)/Vasculitis Foundation guidelines, TCZ may be considered for patients who show an inadequate response to other immunosuppressive therapies such as methotrexate, tumor necrosis factor inhibitors (TNFi), and azathioprine.⁸ Since those guidelines were published, several studies have reported acceptable long-term safety and efficacy outcomes for TCZ in TAK patients refractory to other treatments.^9,10 Here, we describe current and future immunosuppressive therapies for TAK, focusing on TCZ, TNFi, other promising biological disease-modifying anti-rheumatic drugs (bDMARDs), and Janus kinase (JAK) inhibitors. Our aim is to help cardiologists and cardiovascular surgeons, who are occasionally involved in treating TAK patients, to better understand the disease and treatment.¹¹

Treatment

TCZ

Interleukin (IL)-6 is important in both the pathophysiology and disease activity of TAK.^12–14 TCZ is a recombinant humanized anti-IL-6 receptor monoclonal antibody, which case reports and case series since 2008 have reported as effective in refractory TAK.^6,15 Large-scale clinical trials investigating the efficacy of TCZ for TAK are presented in Table 1. In a large retrospective multicenter study of 46 TAK patients, TCZ reduced the median National Institutes of Health disease activity score and GC dose, and event-free survival was significantly better with TCZ than DMARDs.¹⁶ In the randomized double-blind placebo-controlled phase 3 Japanese Takayasu arteritis Treated with Tocilizumab study, the primary endpoint of time to relapse for TCZ vs. placebo was not met by a narrow margin while the background GC dose was tapered (hazard ratio 0.41; 95.41% confidence interval, 0.15–1.10; P=0.0596).⁵ It was on the basis of this evidence that TCZ was a Class I treatment recommendation in the 2017 JCS guidelines.⁷ However, TNFi were preferred to TCZ in the 2021 ACR recommendations.⁸ A more recent systematic review/meta-analysis reported equivalent efficacy for TCZ and TNFi.¹⁷

Table 1.

Large-Scale Clinical Trials Demonstrating the Efficacy of Tocilizumab

Study, year	Type of study	Comparative drug	Advantages of tocilizumab
Mekinian et al,16 2018	Retrospective	DMARDs	NIH score, GC dose, event-free survival
Nakaoka et al,5 2018	RCT	Placebo	GC dose
Mekinian et al,60 2020	Prospective	N/A	GC dose
Nakaoka et al,9 2020	RCT, open label	N/A	GC dose, improved disease on imaging
Alibaz-Oner et al,61 2021	Observational	TNFi	Equivalent
Mekinian et al,62 2022	Observational	TNFi	Equivalent
Nakaoka et al,18 2022	Post hoc	N/A	Stable disease on imaging
Harigai et al,10 2023	Observational	N/A	GC dose, safety concern
Yoshida et al,63 2023	Observational	GC alone	Relapse-free survival rate
Misra et al,17 2023	Meta-analysis	TNFi	Equivalent

DMARSs, disease-modifying anti-rheumatic drugs; GC, glucocorticoid; N/A, not available; NIH, National Institutes of Health; RCT, randomized controlled trial; TNFi, tumor necrosis factor inhibitor.

Since the phase 3 study in Japan, other studies have examined the long-term safety and efficacy of TCZ in TAK.^9,18 To summarize, 57% of patients did not show progression of arterial wall thickness; however, a few patients with refractory disease showed progression of arterial wall inflammation that resulted in dilatation/aneurysm or stenosis/occlusion. Hence, imaging surveillance should be performed in patients with refractory TAK treated with TCZ.

In a recent observational study of 120 TAK patients treated with TCZ, 83.0% of relapse-free patients were able to reduce their GC intake to 10 mg/day prednisolone dose equivalent or less.¹⁰ Although 9 patients (7.5%) reported serious infection, the result was comparable to the rate reported in a similar clinical trial involving patients with giant cell arteritis.¹⁹ Therefore, TCZ appears to be relatively safe in patients with TAK.

Because TAK mostly affects young women, the safety of TCZ during pregnancy is of considerable concern. A retrospective study of 61 pregnant women with rheumatic disease exposed to TCZ reported that the drug was not associated with increased rates of spontaneous abortion or congenital abnormalities.²⁰ The benefits of TCZ use during pregnancy in women with refractory TAK include relapse prevention and reduction of GC dose, which may outweigh the risk of immunosuppression in the fetus/neonate.^21,22 Therefore, TCZ use in pregnancy may result in a more favorable clinical course and outcome in these women; however, the JCS guidelines do not yet recommend it and further large-scale studies in pregnant women are warranted.

After TCZ therapy is discontinued, clinicians must be wary of the development of cytokine storm and/or TAK recurrence. We reported a patient who experienced both: marked increases in the IL-6 and TNF-α concentrations were observed after TCZ discontinuation, along with reappearance of the original symptoms.²³ TAK flare-up and cytokine storm can occur after acute cessation of TCZ, even when the disease activity seems to be controlled before discontinuing TCZ.

Perioperative TAK management in cardiovascular surgery patients receiving TCZ can be challenging.^24–26 At present, there are no guidelines or solid evidence of the optimal timing of preoperative TCZ discontinuation. However, according to the ACR guidelines for rheumatoid arthritis (RA) patients receiving weekly subcutaneous injections of TCZ, treatment should be stopped 2 weeks before surgery and can be resumed 2 weeks after surgery provided wound healing problems, surgical site infection, and systemic infection are absent.²⁷ In our case report, TCZ was stopped 5 weeks before coronary artery bypass grafting and had to be resumed to treat a TAK relapse before wound healing was complete.²⁸ More studies of the perioperative management of TAK patients treated with TCZ are needed.

As TAK progresses, aortic aneurysms may form and grow. Several cases of progression of aortic aneurysms in TAK patients despite TCZ administration have been reported.^29,30 Interestingly, gut dysbiosis (i.e., an increase in oral bacteria in the gut) appears to be associated with the formation and progression of aortic aneurysms in patients with TAK.³¹ Future large multicenter studies are needed to confirm this finding.

TNF-α Inhibitors

The serum TNF-α concentration is significantly higher in TAK patients than in controls.¹⁴ However, in TAK patients, the concentration does not differ between those with active and stable disease. TNFi were recommended in the 2021 ACR guidelines as a firstline treatment for TAK, as were methotrexate and azathioprine.⁸ In the 2017 JCS guidelines, use of TNFi in patients with refractory TAK was a Class IIa recommendation, despite not being covered by health insurance in Japan.⁷ Several studies have reported various benefits of TNFi in TAK patients, including safety, clinical and radiological improvements, and reduction in GC dose.^32–37 Recently, a randomized trial³⁸ compared the TNFi adalimumab and TCZ in patients with active and severe TAK; both drugs were administered in combination with GC and methotrexate. The efficacy rate at 6 months was higher in the adalimumab group, but at 12 months, the efficacy rate and rates of relapse and adverse events were comparable between groups.³⁸ Stronger evidence is needed for treating TAK patients with TNFi (NCT04564001).

JAK Inhibitors

The JAK/signal transducer and activator of transcription (JAK/STAT) signaling pathway is critical in TAK pathogenesis.³⁹ Tofacitinib is the first commercially approved JAK inhibitor for treating RA.⁴⁰ According to the Japan College of Rheumatology guidelines, its use is limited to RA patients in whom methotrexate is inadequately effective.⁴¹ Several clinical trials have demonstrated their efficacy and safety in TAK.^42–45 In a recent prospective observational study of 27 TAK patients treated with tofacitinib, it was superior to methotrexate in inducing clinical remission, preventing disease relapse and tapering the GC dose.⁴³ Table 2 lists the large-scale clinical trials demonstrating the efficacy of tofacitinib for TAK. However, safety is a concern because of the association of tofacitinib with higher incidence rates of major adverse cardiovascular events and cancer compared with TNF-α inhibitors.⁴⁶ Because TAK patients are mostly young women and therefore cancer is a concern, studies with long-term follow-up are necessary. Several large-scale clinical trials in TAK patients are currently underway (NCT04299971, NCT05151848, NCT05749666, NCT05102448, NCT04161898).

Table 2.

Large-Scale Clinical Trials Demonstrating the Efficacy of Tofacitinib

Study, year	Type of study	Comparative drug	Advantages of tofacitinib
Kong et al,43 2022	Prospective	Methotrexate	GC dose, relapse-free rate
Wang et al,44 2022	Prospective	Leflunomide	GC dose, disease remission

GC, glucocorticoid.

Ustekinumab

The IL-12B gene is associated with TAK and the risk allele is associated with aortic regurgitation.⁴⁷IL-12B encodes IL-12/23 p40, which suggests that IL-12 and IL-23 play a crucial role in TAK pathogenesis, and the p40 protein is a subunit common to both ILs.

Ustekinumab is a monoclonal antibody against p40 that is used in Japan for patients with psoriasis vulgaris, Crohn’s disease, or ulcerative colitis. Several studies of ustekinumab in TAK patients have demonstrated improvement of symptoms and clinical markers,^48–50 but currently no new clinical trials are being conducted.

Abatacept

Abatacept is a soluble fusion protein comprising cytotoxic T lymphocyte-associated antigen 4 and the Fc portion of immunoglobulin G1.⁵¹ This drug prevents CD80/CD86 from binding to CD28 on the T-cell surface, which causes failure of the costimulatory signal required for T-cell activation. Abatacept is used in Japan for patients with RA or juvenile idiopathic arthritis. Combined with GC, abatacept did not improve relapse-free survival in TAK patients,⁵² and its efficacy against TAK has yet to be demonstrated. No new clinical trials are being conducted at this time.

Secukinumab

IL-17 is thought to be involved in TAK pathogenesis^53–55 and secukinumab selectively binds to IL-17A. It is used for patients with psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, ankylosing spondylitis, and axial spondyloarthritis. It has been shown to be effective in TAK patients who have not responded to GC and conventional immunosuppressive drugs.⁵⁶ However, more studies of secukinumab in TAK patients are needed.

Rituximab

Rituximab is a monoclonal antibody that binds to the differentiation antigen CD20 on the human B lymphocyte surface.⁵⁷ It is used to treat various diseases, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis polyangiitis, microscopic polyangiitis, refractory nephrotic syndrome, chronic idiopathic thrombocytopenic purpura, acquired thrombotic thrombocytopenic purpura, systemic scleroderma, intractable pemphigus vulgaris, and pemphigus foliaceus. Although a few case studies have reported its effectiveness in patients with refractory TAK, further evidence is required.^58,59

Discussion

Our aim was to provide an overview of current and promising TAK treatments. In the 2017 JCS guidelines, use of TCZ in TAK patients was a Class I recommendation and TNF-inhibitor use was a Class IIa recommendation; JAK inhibitors, ustekinumab, abatacept, secukinumab, and rituximab were not described.⁷ Nonetheless, these drugs may be effective and might be recommended in the future provided that supporting evidence emerges. Use of immunosuppressants such as methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, tacrolimus, and cyclosporine is a Class IIa or IIb recommendation for treating TAK in combination with GC therapy.⁷ However, we did not discuss these drugs in this article.

Among the bDMARDs, the evidence for treating TAK is greatest for TCZ. Its ability to enable GC dose reduction was demonstrated in a randomized controlled trial.⁵ Moreover, the long-term safety and efficacy of TCZ in patients with refractory TAK has been demonstrated.^9,10,18 However, further studies examining the efficacy of early TCZ administration with or without GC, as well as perioperative TCZ management and its administration in pregnant women, are necessary. We anticipate that the JCS guidelines will be revised in the future as new evidence accumulates.

Acknowledgments

We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (23FC1019) and the Japan Agency for Medical Research and Development (AMED) (JP23ek0109633).

Conflicts of Interest

Y.N. has received lecture fees and research grants from Chugai, research grants from AbbVie. The other authors have no conflicts of interest to disclose.

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