1) baseline clinical characteristics
Thirteen patients with active TA applied TCZ to induce remission were identified. All patients were female, with a median age of 25 years (13 to 61 years) and a median duration of disease of 24 months (6 to 60 months). Among them, 8 patients were treatment-naïve, 3patients suffered disease relapse, and 2 patients did not respond to high-dose GC treatments.
The clinical manifestations included fatigue in 6 patients (46.2%), fever in 3 patients .(23.1%), weight loss in 2 patients (15.4%), dizziness in 8 patients (61.5%), stroke in 5 patients (38.5%), transient amaurosis in 5 patients (38.5%), neck pain in 4 patients ( 30.8%), chest and/or back pain in 3 patients (23.1%), unequal bilateral brachial artery blood pressure in 10 patients(76.9%, radial artery pulse disappearance in 3 patients༈23.1%, hypertension in 5 patients༈38.5%), intermittent claudication in 6 patients (46.2%).
Laboratory test showed elevated CRP level (> 8mg/L) in 5 patients (38.5%), mean 22.2 ± 28.3 mg/L, elevated ESR (> 20mm/first hour) in 7 patients (53.8%), mean 47.5 ± 44.9mm/first hour (Table 1).
Table 1
Clinical data of 13 patients with active TA treated by tocilizumab.
patient | Gender/age (years) | Disease duration (months) | clinical features | ESR | CRP | NIH score | ITAS-A score | Involved arteries (CTA\MRI\ultrasound\PET-CT) | Previous therapy | Duration of TCZ (months) | Concurrent treatment | Response at week 24 | GC dosage at 24 weeks |
1 | Female/24 | 6 | Intermittent claudication, stroke, unequal bilateral brachial artery blood pressure | 20 | 1.45 | 2 | 17 | LCCA, LICA, LECA, LMCA, LACA, LSCA, LVA; | N | 6 | MTX | CR | 0 |
2 | Female/52 | 1 | Hypertension, unequal bilateral brachial artery blood pressure | 60 | 4.84 | 3 | 3 | AOA, BCT, bilateral CAA, RSCA, SMA, AA | N | 6 | MTX | CR | 0 |
3 | Female/61 | 12 | Hypertension | 7 | 1.12 | 2 | 5 | LICA, LACA, BCCA, SCA, AA, CA, bilateral RA SFA, CIA, DA | Prednisone 50mg/MTX | 6 | MTX/ prednisone 5mg | CR | 0 |
4 | Female/28 | 84 | Hypertension, Dizziness, Transient amaurosis, Chest pain, Stroke | 3 | 0.16 | 2 | 14 | CCA, LICA, LECA, RRA, LM, LAD, LCX, DA | Prednisone 60mg | 3 | MTX/prednisone 40mg | CR | 5mg |
5 | Female/26 | 48 | Intermittent claudication, Transient amaurosis, Fever, Fatigue, Weight loss, Neck pain, dizziness, unequal bilateral brachial artery blood pressure | 108 | 59.4 | 4 | 11 | BCCA, AOA, BCT, LSCA, | Prednisone 50mg, TNFi | 3 | MTX/prednisone 30mg | CA | 30mg |
6 | Female/21 | 60 | Dizziness, Transient amaurosis, Stroke, unequal bilateral brachial artery blood pressure | 62 | 25.2 | 2 | 3 | AAO, AOA, DA, PA, BCCA, RSCA, CA, BRA | Prednisone 40mg, AZA | 6 | MTX/prednisone 5mg | CR | 5mg |
7 | Female/25 | 144 | Dizziness, Fatigue, Transient amaurosis, Strock, Intermittent claudication, radial artery pulse disappearance, unequal bilateral brachial artery blood pressure | 26 | 5.65 | 2 | 13 | BCCA, BCT, RSCA, AA, CA, SMA | N | 6 | MTX | CR | 0 |
8 | Female/37 | 1 | Stroke, unequal bilateral brachial artery blood pressure | 2 | 0.16 | 2 | 16 | RCCA, BCT, RSCA, AA, CA, SMA, LRA | N | 6 | MTX | CR | 0 |
9 | Female/33 | 7 | Intermittent claudication, fatigue, neck pain, chest pain, hypertension, dizziness, unequal bilateral brachial artery blood pressure | 17 | 3.94 | 2 | 22 | BCCA, BSCA, BCT, AOA | N | 6 | MTX | CR | 0 |
10 | Female/15 | 24 | Dizziness, Transient amaurosis, radial artery pulse disappearance, intermittent claudication, neck pain, fatigue | 120 | 48.9 | 3 | 19 | BCCA, BSCA, BCT, LVA, RAXA, RRA | N | 1 | MTX | CA | 10mg |
11 | Female/19 | 24 | Fever, hypertension, radial artery pulse disappearance, dizziness, unequal bilateral brachial artery blood pressure | 8 | 1.25 | 2 | 9 | LCCA, RAXA, RSCA, BRA, AA | N | 6 | MTX | CR | 0 |
12 | Female/13 | 6 | fatigue, weight loss, dizziness, intermittent claudication, unequal bilateral brachial artery blood pressure | 120 | 73.8 | 3 | 16 | BCCA, RSCA, BCT, CA, SMA, AOA, AAO, DA, AA | N | 6 | MTX | CR | 0 |
13 | Female/20 | 60 | Fever, neck pain, chest pain, fatigue, unequal bilateral brachial artery blood pressure | 65 | 62.9 | 4 | 4 | BCCA, LSCA, BCT, AOA, AA | Prednisone 60mg/MTX/CTX/AZA/CzA | 1 | MTX / prednisone 5mg | CA | 20mg |
BCCA: bilateral common carotid artery LCCA: left common carotid artery, RCCA: right common carotid artery, SCA: subclavian artery, VA: vertebral artery, ICA: internal carotid artery, ECA: external carotid artery, MCA: middle cerebral artery, ACA: anterior cerebral artery, AAO: ascending aorta, AOA: aortic arch, DA: descending aorta BCT: brachiocephalic trunk, SMA: superior mesenteric artery, AA: abdominal aorta, RA: renal artery, CA: celiac axis, SFA: superficial femoral artery, CIA: common iliac artery, DA: descending aorta, LM: Left main trunk, LAD: left anterior descending, LCX: left circumflex, PA :pulmonary arteries, AXA: axillary artery |
The involvement of the common carotid artery was observed in all 13 patients (100%). Subclavian artery involvement was present in 12 patients (92.3%), while brachiocephalic trunk involvement was found in 9 patients (69.2%). Aortic Arch involvement occurred in 7 cases (53.8%), thoracic aorta involvement in 3 cases (23.1%), and abdominal aorta involvement in 7 cases (53.8%). Celiac trunk stenosis was detected in 5 cases (38.5%) and superior mesenteric artery stenosis in 4 cases (30.8%). Renal artery involvement was seen in 6 cases (46.2%), whereas vertebral artery and external carotid artery involvement in 2 patients (15.4%), internal carotid artery and anterior cerebral artery were involved three cases reported (23.1%), middle cerebral artery were involved in 1 case, coronary artery was involved in 1 case. Pulmonary artery occlusion was revealed in 1 case (Table 1). According to the imaging classification, 3 cases were brachiocephalic (Type I) and 10 cases were mixed (Type V).
Thirteen patients had a median score of 2 (2–4) by the NIH score, all of them fulfilled the definition of active disease; and 14 (3–22) by the ITAS-A score, one patient scored 3 (case 6 in Table 1) due to no symptom presented but presented elevated ESR and CRP and newly onset of stenosis of renal artery, the scores of all other patients fulfilled the definition of active disease.
Twelve of 13 patients underwent vascular ultrasound and contrast-enhanced ultrasound of the carotid artery. Among them, 11 patients exhibited significant contrast enhancement in the thickened intima of the carotid artery, indicating vascularization at the inflammatory site. One patient showed no contrast enhancement in the carotid artery; however, newly onset bilateral renal artery stenosis was detected supporting the diagnosis of active disease (case 6 in Table 1). In one patient who did not undergo contrast-enhanced ultrasound examination of the carotid artery, PET-MRI revealed thickening and enhancement of aortic walls and bilateral carotid and subclavian arteries along with increased FDG uptake suggesting active inflammation (case 12 in Table 1). Two other patients also underwent PET-CT showed increased FDG uptake in carotid artery wall suggesting the active inflammation (case 3 and 5 in Table 1).
2) Treatment
All patients received TCZ (8mg/kg) combined with MTX 10-15mg weekly. For 8 treatment-naive patients no GC or other immunosuppressants were applied. Three relapsed cases and two patients inadequately responded to GC were previously treated with high-dose prednisone (1 mg/kg/d) to induce remission; three of them were treated with multiple immunosuppressive agents, including methotrexate (MTX), cyclophosphamide (CTX), azathioprine (AZA), and cyclosporine (CsA); one was treated with adalimumab. When TCZ treatment began, GC was tapered to 5 mg/d in 3 relapsed patients, and two inadequate responded patients using prednisone 30 mg/d and 40 mg/d respectively (Table 1). Three patients maintain 5mg/d prednisone, and for two inadequately responded patients, the dose of prednisone was tapered at the time of TCZ treatment. All of these five patients discontinued all other immunosuppressants except MTX.
After first infusion of TCZ, two patients (case 10, case 5) suffered from deteriorated neck pain and one patient (case 13) experienced intensified chest and back pain. Two of them (case 10 and case 5) applied second dose of TCZ about 3 days after first infusion, as neck pain persisted, intravenous methylprednisolone 80mg once and non-steroid anti-inflammatory drug (NSAID) were applied for symptom-relieving. For patient with chest and back pain, NSAID and intramuscular dexsamethasone 2mg once were applied with limited effects on symptom.
One patient (case 10) abandoned TCZ due to persistent neck pain and lack of effectiveness and applied prednisone 45mg/d (1mg/kg/d) with MTX since 4-week after TCZ treatment. Two patients with pain of artery area and discontinued TCZ after 12-week treatment, both applied high-dose GC again, one (case 13) with MTX and one (case 5) with MTX and cyclosporine. With 12-week TCZ treatment, 10 patients relieved. Among them, one patient (case 4 in Table 1) changed the treatment to tofacitinib for economic reasons along with MTX and prednisone tapered to 5mg/d, and 9 patients completed TCZ plus MTX for 6 months. Two of them (case 3 and 6 in Table 1) maintained 5mg/d prednisone.
3) Effectiveness of TCZ
After TCZ treatment, the acute reactants level and disease activity score were significantly decreased in 13 patients with active TA (Fig. 1).
The treatment of TCZ was effective in 10 cases who fulfilled the definition of remission, the overall remission rate was 76.9% (10/13). About 87.5% (7/8) of treatment-naïve patients and 60% (3/5) of relapsed or inadequate responded patients were effective. The inflammation markers decreased quickly, four weeks after TCZ treatment, CRP level decreased from 11.8 ± 23.0 mg/L to 0.32 ± 0.30 mg/L, and ESR from 32.5 ± 37.7mm/h to 6.0 ± 7.76mm/h. After 12-week treatment of TCZ and MTX, symptoms were alleviated in these 10 patients and both NIH scores and ITAS-A scores were assessed as inactive. All of them remained stable after 24-week of treatment including the patient changed the treatment to tofacitinib.
The TCZ treatment was ineffective in three patients (patient 5, 10, and 13 in Table 1). They stopped TCZ due to persistent pain of artery area 4 weeks (case 13) and 12 weeks (case 10 and case 5) after treatments. Although all of them subsequently changed to high-dose GC, at the time of 24-week follow-up when the dose of GC tapered, disease was still active in all of them according to ITAS-A score (7 points, 20 points, and 5 points) (red line in Fig. 1C and 1D).
Before TCZ treatment, all three ineffective patients experienced pain in artery area (3/3, 100%), which was significantly higher compared to the group that responded well to treatment (2/10, 20%) (p = 0.035). The baseline CRP level in the ineffective TCZ treatment group (57.1 ± 7.3mg/L) was significantly higher than that of the effective treatment group consisting of ten patients (11.8 ± 23.0mg/L) (p = 0.043), and ESR level in the ineffective TCZ treatment group (97.7 ± 28.9mm/h) was significantly higher than that of the effective treatment group (32.5 ± 37.7mm/h, p = 0.034). In addition, baseline median NIH score of the ineffective TCZ treatment group was 4(3–4), significantly higher than that of the effective group (p = 0.006) (Table 2).
Table 2
The baseline level of inflammation markers and disease activity scores of patients with different response to TCZ.
| TCZ non-responder | TCZ responder | p |
Pain(case) | 3/3(100%) | 2/10(20%) | 0.035* |
ESR(mean ± SD) | 97.7 ± 28.9mm/h | 32.5 ± 37.7mm/h | 0.034* |
CRP(mean ± SD) | 57.1 ± 7.3 mg/L | 11.8 ± 23.0 mg/L | 0.043* |
NIH score(median) | 4(3–4) | 2(2–3) | 0.006* |
ITAS score(median) | 11(4–19) | 13.5(3–22) | 0.692 |
*statistically significant |
4) Safety of TCZ plus MTX in patients with active TA
None of the 13 patients required interventions (such as stent placement or angioplasty) or surgical treatment due to disease progression during follow-up, and none of the complications associated with TA, such as stroke, occurred. No serious adverse events and infection of hepatitis B, tuberculosis and fungus were found in all patients.