Giant cell arteritis (GCA) and Takayasu arteritis (TA) are chronic inflammatory diseases that mainly affect large elastic arteries. Although GCA is a disease of older people and TA is a disease of younger people, their shared predilection for causing vasculitis of large arteries and their nearly identical histopathologic changes suggest a possible link in pathophysiology and eventually in treatment response.

Response to glucocorticoids (GCs) is generally favorable in GCA and TA but relapses may occur while gradually tapering GCs. Physicians tend to start immunosuppressive (IS) agents together with GCs but there is no evidence showing which is the IS agent of choice.

Serum tumor necrosis factor-α (TNF-α) levels and IL-6 are increased in TA and GCA patients as well.1,2 Therefore, blocking TNF-α or IL-6 with biologic therapy (BT) has emerged as an attractive therapeutic alternative that would move the field forward and decrease the cumulative GC toxicity.

Here, we assessed the clinical, serological, and imaging outcomes of 10 patients with refractory TA and GCA who were administered BT.

Ten patients, 5 with TA and 5 with GCA under BT were included. Demographics and baseline ESR, CRP and GC dose are described in Table 1.

In TA, the most common lesion sites were supra-aortic arteries (in all cases). Abdominal aorta and its branches were affected in three patients but only 2 patients showed thoracic aorta involvement. Stenotic lesions were the most frequent vascular finding and only one patient presented with aneurismal lesions. Three patients required revascularization procedures prior to BT.

The main reason for starting BT in TA was the appearance of relapses upon GC tapering in all patients and lack of response to prior therapy; methotrexate (n=5), cyclophosphamide (n=3) and mycophenolate mofetil (n=3) were the most common IS agents added at some point to GC. One patient had received adalimumab prior to this study but remission was not achieved and BT was switched to TCZ. Four patients received IFX and 1 patient TCZ. Only one patient received IFX as monotherapy (patient 5) and the remaining four received methotrexate (n=3) 20.8±7.2mg/week (2 subcutaneous and 2 oral administration) or mycophenolate mofetil (n=1) 1000mg/day. Remission was observed before 6 months in all cases. Sustained remission was achieved in all cases during follow-up (mean follow-up 59.6±27.2 months) and GC daily dose was reduced by 79% (Table 1). In cases of sustained remission, careful down-titration was carried out without evidence of relapses. None of the patients developed a new arterial lesion while receiving BT. Furthermore, revascularization procedures were not required during follow-up. All patients tolerated BT without infusion reactions. Other AEs attributable to BT were recurrent infections (one patient with IFX) and mild neutropenia (one patient with TCZ). At last follow-up, 3 patients continued on BT, 1 patient was lost to follow up (moved to another country) and 1 patient discontinued IFX due to recurrent infections.

In GCA the main reason for starting BT was lack of response to prior therapy (MTX in 5 patients, AZA in 2 patients, MMF in 2 patients) and/or ≥2 relapses during GC tapering. Three patients started TCZ, one patient IFX and one patient ETN. Three patients received BT as monotherapy (patients 6–8) and the remaining two received MTX 15mg/week and leflunomide 20mg/day. The remission was observed before 3 (n=4) and 6 months (n=1). Only one patient had a relapse during follow-up (mean follow-up 37.8±33.8 months). This was the patient under ETN therapy who suffered a recurrence at 24 months of BT and six months after GC withdrawal. She presented with PMR, high CRP and ESR without any ischemic complication and resolved with GC reintroduction. Overall, the daily dose of GC in GCA was reduced by 60%. No changes in concomitant IS agents was required. One AE was attributable to IFX (anaphylaxis) and 1 AE attributable to TCZ (mild neutropenia). At last follow-up, 2 patients continued with BT, 1 patient discontinued ETN for sustained remission, 1 patient discontinued BT secondary to AE attributable to IFX and 1 patient died for reasons not attributable to BT.

There are no reported randomized controlled studies on the use of BT in TA. Hoffman et al. first published an open-label trial of anti-TNF therapy in TA (n=15) in 2004.4 Overall, the addition of anti-TNF therapy resulted in improvement in 14 patients and sustained remission in 10 cases. Anti-TNF treatment also allowed for the reduction or elimination of GC therapy in almost all of the patients. In 2008, Molloy et al. published their experience in 25 patients.5 Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10mg/day in additional 7 patients (28%). Schmidt et al. reported in 2012 a single center experience with the use of TNF inhibitors in 20 patients with TA.6 Disease remission was achieved in 18 (90%) but 33% of patients experienced disease relapse while receiving BT. In France, Mekinian et al. (n=15) confirmed also previous reports on the efficacy of TNF inhibitors in refractory TA.7

TCZ could be another option for refractory TA or patients failing to TNF-inhibitors. Abisror et al. retrospectively studied 5 patients from 3 French university hospitals and 39 cases from the literature.8 Clinical and biological activities significantly decreased within 3 months similarly to steroid dose and steroid-dependence rate. Remission was achieved in 33 cases (75%). Moreover, 9 out of 14 patients (65%) who had previously received TNF inhibitors achieved remission. Recently, Cañas et al. reported 8 refractory TA patients treated with TCZ who achieved remission in all cases and 85% GC reduction.9 Last, Loricera et al. published a study on 16 patients with inflammatory aortitis refractory to corticosteroids or to other biologic immunosuppressive drugs (14 cases were large vessels vasculitis), TCZ appeared to be effective and relatively safe.10 Most recently, the same study group evaluated the efficacy of TCZ in patients with refractory TA (n=8). Clinical and laboratory parameters improved in most cases.11 Both TCZ and TNF inhibitors seem to be effective in refractory TA but comparative studies to determine the better strategy for these biologics are lacking.

Despite the reported experience in TA with BT and the lack of clinical trials, GCA first published randomized trial was terminated prematurely due to lack of benefit with IFX.12 However, the protocol of steroid tapering used in this study could have negatively influenced the final results. Two subsequent controlled trials failed to demonstrate a steroid sparing effect of etanercept and adalimumab.13,14 However, the response in 2 of our patients suggests a potential role for these therapies in selected GC refractory cases. Regarding TCZ, our findings are in agreement with a recently published systematic review and meta-analysis of GCA patients treated with TCZ.15 All the 19 patients treated with TCZ plus prednisone achieved disease remission and a steroid sparing effect with complete discontinuation of GC in nine patients. Notably, 3 of our patients with GCA were successfully treated with TCZ monotherapy. Finally, TCZ therapy showed rapid and maintained improvement in patients with refractory GCA and/or with unacceptable AEs related to GCs in a multicenter open-label study of 22 patients.16

In spite of the limitations of a retrospective study and the small number of patients included, our data provide positive evidence on the potential benefit of TNF inhibitors and TCZ in patients with large vessels vasculitis refractory to conventional treatment. TNF inhibitors or TCZ have a role as steroid-sparing agents in refractory LVV patients, with acceptable safety profile. TCZ might be the first choice biologic therapy in refractory GCA patients. In the absence of randomized controlled trials addressing this specific clinical situation, this type of evidence can help in our daily clinical practice.

This research received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

RGV has received funding for research or teaching from MSD, Roche, BMS, Abbvie, and UCB; has participated on advisory boards for Actelion, BMS, UCB, Pfizer, Roche, Hospira, Janssen and Sandoz, has delivered presentations sponsored by Roche, BMS, Pfizer, UCB, Sandoz.