Biologic treatments in Takayasu’s Arteritis: A comparative study of Tumor Necrosis Factor

inhibitors and Tocilizumab

Fatma Alibaz-Oner (1), Sema Kaymaz-Tahra (2), Özün Bayındır (3), Ayten Yazici (4), Burak
İnce (5), Kübra Kalkan (6), Nilüfer Alpay Kanıtez (7), Sinem Burcu Kocaer (8), Nazife Sule
Yaşar Bilgin (9), Ahmet Omma (10), Elif Durak (11), Can Ilgın (12), Servet Akar (11), Timuçin
Kaşifoğlu (9), Fatoş Önen (8), Hakan Emmungil (6), Murat İnanç (5), Ayşe Cefle(4), Kenan
Aksu (3), Gökhan Keser (3), Haner Direskeneli (1)

1) Marmara University, School of Medicine, Department of Internal Medicine, Division of

Rheumatology, Istanbul, Turkey

2) Sancaktepe Prof.Dr. Ilhan Varank Training and Research Hospital, Rheumatology, Istanbul,
Turkey
3) Ege University School of Medicine, Rheumatology, Izmir, Turkey
4) Kocaeli University School of Medicine, Rheumatology, Kocaeli, Istanbul
5) Istanbul University Istanbul School of Medicine, Rheumatology, Istanbul, Turkey
6) Trakya University School of Medicine, Rheumatology, Edirne, Turkey
7) Koc University School of Medicine, Rheumatology, Istanbul, Turkey
8)Dokuz Eylul University School of Medicine, Rheumatology, Izmir, Turkey
9)Osmangazi University School of Medicine, Rheumatology, Eskisehir, Turkey
10) Ministry of Health Ankara City Hospital, Rheumatology, Ankara, Turkey
11) Katip Celebi University School of Medicine, Rheumatology, Izmir, Turkey
12) Marmara University Faculty of Medicine, Department of Public Health, Istanbul, Turkey.
Corresponding author: Fatma Alibaz-Oner

Adress: Division of Rheumatology, Marmara University School of Medicine Hospital, Fevzi

Çakmak Mahallesi, Ust-Kaynarca, Pendik, Istanbul, Turkey

e-mail: falibaz@gmail.com Phone: +90-532-6318413

Introduction

Takayasu arteritis (TAK) is a rare, chronic granulomatous large vessel vasculitis mainly
affecting aorta and its major branches. Inflammation in the involved vessel wall leads to
segmental stenosis, occlusion, dilatation and/or aneurysm formation. Vascular stenosis may
also be a sign of disease-related damage due to scarring in the vessel wall. [1, 2] There are
only two randomized controlled studies (RCTs) not meeting the primary end points for the
treatment of TAK. Majority of current data comes from retrospective case series and open
studies. Glucocorticoids (GCs) are the mainstay of treatment. Conventional
immunosuppressive (IS) agents are usually added on GCs. According to the EULAR
recommendations, methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF)
or leflunomide (LEF) could be chosen as the first line IS agent. In refractory or relapsing
patients with first line IS agents, biologic treatments can be used. In EULAR recommendations,
tocilizumab (TCZ) or tumor necrosis factor-α (TNF) inhibitors are equally recommended in
refractory cases.[3] However, data is still limited for the comparative efficacy, safety, and drug
survival with biologic agents in patients with TAK. In this multicenter retrospective study from
experienced tertiary centers in Turkey, we aimed to compare treatment outcomes of TNF
inhibitors and TCZ in refractory patients with TAK. Besides, we also shared our limited data
with other less commonly used biologic agents.

Methods

The study included 111 patients (age: 35.7±11.2 years; female/male: 98/13) fulfilling the
American College of Rheumatology (ACR) 1990 criteria for TAK [4] and followed in 10 tertiary
centers in Turkey. All patients were refractory to at least one conventional IS agent and were
treated with biologic agents. Conventional IS agents included AZA, MTX, LEF, MMF and
cyclophosphamide (CYC). Sixty-six patients (67%, 66/99) had used at least two IS agents before
the initiation of TNF inhibitors or TCZ (Table 1). Clinical, demographic, angiographic data and
treatment outcomes were acquired from the clinical charts. Physician global assessment (PGA)
was used as the gold standard definition of active disease in this study, however activity
defined according to Kerr et al (NIH definition) was also used, if available. Active disease by
PGA was defined by the attending physician as any new symptom that is associated with
disease activity such as malaise, weight-loss, myalgia, dizziness, or vascular insufficiency
including claudication, as well as new signs such as hypertension, syncope, bruits, or any
elevation in acute-phase response. Complete remission was defined as no new signs and
symptoms of vascular disease assessed by a physician, normalized acute phase reactants and
reduction of GC dose under 10 mg/d of prednisolone or its equivalent at the third month of
treatment. Partial response was defined as at least 50% decrease in PGA score and acute phase
response, and at least 50% reduction of initial GC dose at the third month.

All patients were screened for latent tuberculosis before the initiation of biologic agents
with either tuberculin skin test (purified protein derivative; PPD) or QuantiFERON test, as
suggested and used in routine practice in Turkey. Patients with PPD >5 mm and/or positive
QuantiFERON test were given 9 months of isoniazid (INH) prophylaxis. Sixty-seven (60%)
patients received INH prophylaxis before biologic treatments. Infliximab (IFX) was
administrated as an induction dose of 5 mg/kg at 0, 2 and 6 weeks followed by every 8 weeks
intravenously, adalimumab (ADA) as 40 mg every 2 weeks subcutaneously and certolizumab
(CTZ) as 200 mg subcutaneously every 2 weeks after three induction doses of 400 mg at 0, 2
and 4 weeks. TCZ was administered 8 mg/kg every 4 weeks intravenously or 162 mg
subcutaneously every week. Rituximab (RTX) courses were administered 1000 mg (2 repeated
doses with two weeks interval) every 6 months. The only patient with anakinra treatment
received anakinra at a dose of 200 mg/day. Ustekinumab was used 45 mg at 0 and 4. weeks
and increased to 90 mg every 12 months due to inefficacy.
As the routine practice, imaging for the follow-up of TAK is performed as clinically required to
assess active disease. Different imaging modalities according to the preferential approaches
of individual centers were chosen. Positive imaging was defined as a new vascular involvement
in a previously unaffected vessel, progression in luminal vascular lesions or increased vascular
uptake in positrone emission tomography (18-FDG-PET). The study was performed according
to the Declaration of Helsinki and approved by the local ethical committee of Marmara
University, Faculty of Medicine, Istanbul (No: 09.2020.372).

Statistical analysis
Statistical data were performed with Statistical Package for the Social Sciences 22.0 (SPSS,
Chicago, IL, USA) program. Results were expressed as means and standard deviations or as
median (minimum-maximum) according to the distribution of data. Mann–Whitney U-test,
independent-samples t test, Wilcoxon test and chi-square test were used for comparisons of
data. The drug survival of the biologic drugs was analyzed by the Kaplan-Meier method and
the influence of concomitant IS agent use on biological drug survival was evaluated with cox
regression analysis.

Patients given tocilizumab or TNF inhibitors as first-line biological treatment were matched
using three variables including age, gender, and aorta involvement. For the matching process,
these three variables were used alone or in combinations. Thus, a total of seven different
matching combinations with different number of matched patients were used, including ‘age’,
‘gender’, ‘aorta involvement’, ‘age+gender’, ‘age+ aorta involvement’, ‘gender + aorta
involvement’ and ‘age+gender+aorta involvement’.

Patients with distinct matching categories were compared according to the selected
outcomes: relapse during biological treatment, reducing the GC dose ≤ 5 mg/day
prednisolone or its equivalent or discontinuation of the GCs, need for surgery during biological
treatment and final activity status. Chi-square and Fisher's exact tests were used for the
analysis of cross tabulations, and a p value less than 0.05 was considered significant.

Results

One hundred and eleven (F/M: 98/13) patients were enrolled in the study. Before switching
to a biologic agent, conventional IS agents (median 2; ranging 1-5) were used initially in all
patients, except for two. In other words, biologic agents were chosen as first-line IS treatment
without trying conventional IS agents for only 2 patients.

A total of 173 courses of biologic treatments were given (77 IFX, 49 TCZ, 33 ADA, 9 CTZ, 3 RTX,
1 ustekinumab and 1 anakinra). Seventy-one (64%) patients were treated with a single biologic
agent, 25 (23%) with two biologic agents, 10 (9%) with three biologic agents, 4 (4%) with four
biologic agents and 1 (0.9%) patient with six biologic agents. The median treatment duration
for all biologic agents was 44 (3-130) months. Twenty-three patients (21%) received TCZ and
88 patients (79%) received TNF inhibitors (67 IFX, 18 ADA, 3 CTZ) as first-line biologic agent.
Ustekinumab was chosen for a single patient as the 4th biologic agent and switched to CTZ
after 8 months due to inadequate disease control. Anakinra was used in a single patient as the
3rd-line biologic treatment for 7 months and switched to IFX because of active disease. Analysis
of three patients who used RTX showed that, treatment was changed to TCZ in one patient
due to persistent disease activity, while a patient deceased after four courses of RTX
treatment because of congestive heart failure. The remaining patient was still on RTX
treatment at the last visit.

Among whole group of biologics, concomitant IS agent use was noted in 63% (70 patients),
with no difference between TNF inhibitors vs TCZ (42% vs 57%, p=0.47). Distribution of IS
agents showed that 21 (19%) patients were given AZA, 11 (10%) LEF and 38 (35%) MTX.

The median treatment duration was 21 (1-370) months (TNF inhibitors vs TCZ: 24 (1-370) vs
18 (1-81) months, p=0.048) for the first biologic agent. Remission was achieved in 83% of TNF
inhibitor group and 74% of TCZ group during the follow-up (p=0.13). Remission rate was 86%
in biologic monotherapy group and 82% in patients with concomitant IS use (p=0.54). At the
3rd month of the treatment, 30% of the patients in the TNF inhibitor group and 18% of the
patients under TCZ treatment were in complete remission (p=0.34). Partial response was
observed in 40% in the TNF inhibitor group compared to 50% in the TCZ group (p=0.84).
Complete remission (TNF inhibitors vs TCZ: 50% vs 50%, p=0.75) and partial response (TNF
inhibitors vs TCZ: 25% vs 11%, p=0.20) rates were similar between the groups at the end of
the follow-up (Table 2).

For convenience, GC doses are given as methyl prednisolone equivalents. In TNF inhibitor
group, baseline median GC dose decreased from 16 (6-32) mg to 4 (0-16) mg/d at the 3rd
month of follow-up (p<0.01). Median GC dose did not change in TNF inhibitor group until the
last visit. In TCZ group, a significant decrease was also observed in GC dose between baseline
and the 3rd month visit (GC dose baseline vs 3rd month: 20 (8-32) vs 8 (4-16), p=0.001). No
significant change was observed between 3rd month and last visit GC dose in the TCZ group
(GC dose 3rd month vs last visit: 8 (4-16) vs 4 (0-32), p=0.32). Decrease in the GC dose was
similar in TNF inhibitors and TCZ groups at the 3rd month of the treatment (TNF inhibitors vs
TCZ: 5 (0-60) vs 12 (0-24), p=0.064). In one (2%, 1/56) patient using a TNF inhibitor the GC
dose was increased to 6 mg/d at the 3rd month of the treatment by the physician. None of the
patients in the TCZ group had a GC dose increase at the 3rd month visit. GC treatment was
discontinued or ≤ 4 mg daily in 75% (55/77) of the patients in the total group. GC dose was ≤
4 mg in 78% of patients in TNF inhibitors group and 59% of patients in TCZ group at the last
visit (p=0.125).

At the end of the follow-up, GC dose increased in three (5%, 3/56) patients (median 8 (6-26)
mg/d increase) in the TNF inhibitor and in one (7%, 1/15) patient (20 mg increase) in TCZ
group. GC dose decreased median 6 (0-64) mg in TNF inhibitor group and 16 (0-30) mg in TCZ
group (p=0.054). GC was stopped in 25% in the total group. Patients in whom GC could be
discontinued were more frequent in TNF inhibitor group, although not statistically significant
(TNF inhibitors vs TCZ: 29% vs 12%, p=0.21).

First-line biologic treatment was discontinued or switched to another biologic treatment

in 44 (50%) patients in TNF inhibitor group and in 12 (52%) patients in TCZ group (p=0.72). The
main reason for discontinuation was disease activity in 29 patients (TNF inhibitors vs TCZ: 25
(56%) vs 4 (33%) patients), remission in 3 patients (TNF inhibitors vs TCZ: 1(2%) vs 2 (17%)
patients), infection in 3 patients (TNF inhibitors vs TCZ: 3 (7%) vs 0 (0%) patients), allergic
reactions in 4 (TNF inhibitors vs tocilizumab: 3 (7%) vs 1 (8%) patient), non-adherence to
treatment in …….. (TNF inhibitors vs tocilizumab: 3 (7%) vs 2 (17%) patients), pregnancy in 4
(TNF inhibitors vs tocilizumab: 3 (7%) vs 1(8%) patient) and other reasons including worsening
of heart failure, new-onset proteinuria, worsening in concomitant ankylosing spondylitis in 8
patients (TNF inhibitors vs tocilizumab: 6 (14%) vs 2 (17%) patients) (Figure 1). None of the
patients had tuberculosis infection during biologic treatment.

Radiographic progression was similar among two groups (TCZ vs TNF inhibitors: 9 (39%)
vs 17 (19%) patients, p=0.13). Vascular Damage Index (VDI) scores at baseline and last visit
were similar in both TNF inhibitors (Baseline vs last visit VDI: 2 (2-3) vs 2 (2-7), p=0.14) and TCZ
(Baseline vs last visit VDI: 0 (0-5) vs 0 (0-5), p=0.41) groups. During follow-up, a
revascularization procedure was performed in 1 (2%) patient in the 4 th month of TCZ
treatment and in 5 (4%) patients at median 11.5 (5-36) months of TNF inhibitors treatment
(all 5 patients were using IFX). Three (2.7%) patients deceased (1 RTX, 1 ADA, 1 IFX) during
follow-up because of congestive heart failure, myocardial infarction, and mesenteric ischemia,
respectively.

Drug survival under TNF inhibitors or tocilizumab treatment was similar (Drug survival
rate TNF inhibitors vs TCZ: 54% vs 50%, p=0.22) (Figure 2). Also, no difference in drug retention
was observed in patients with or without concomitant IS use (HR =0.78, 95% CI =0.42-1.43,
p=0.42). One hundred and five (105/108, 97%) patients who were alive at the last visit were
still on biologic treatment (71 TNF inhibitors, 35 TCZ, 2 RTX). Overall, biologic agents were
discontinued with sustained remission in 7 patients (4 IFX, 2 TCZ, 1 ADA). One of the patients
(50%), who discontinued TCZ, was still in remission after 66 months of follow-up. The other
patient (50%) had a relapse after 26 months after discontinuation. Among TNF inhibitor group
2 patients (40%) were on remission after 12 and 18 months of discontinuation. Three patients
(60%) in TNF inhibitors discontinuation group had a relapse after 18 (7-60) months after
biologic agent discontinuation.

Table 1. The demographic and clinical features of Takayasu’s arteritis patients

Total First-line TNF First-line

group inhibitor tocilizumab p
(n=111) (n=88) (n=23)
Age current, years 35.7±11.2 36.4±10.8 33.0±12.4 0.06
Age symptom onset, years 25.6±9.1 25.4±8.3 26.7±12.1 0.51
Age diagnosis, years 28.2±9.8 28.2±8.9 28.2±13.1 0.21
Gender, female, n (%) 98 (88) 76 (86) 22 (95) 0.29
Hata angiographic classification, 45 (40) 37 (42) 8 (35) 0.86
type 5, n (%)
Duration of first-line biologic 21 (1-370) 24 (1-370) 18 (1-81) 0.048
treatment, months
Number of previous ISs 2 (0-5) 2 (1-4) 2 (0-5) 0.42
70 (63) 57 (65) 13 (57) 0.42
Combined IS, present, n (%)
Baseline disease activity

PGA, active, n (%) 91 (98) 72/73 (99) 19/19 (100) 0.60

Kerr, active, n (%) 91 (98) 71/73 (97) 20/20 (100) 0.45
ITAS2010 5 (0-21) 5 (3-9) 9 (0-12) 0.67
Remission with first-line biologic, 90 (81) 73 (83) 17 (74) 0.13
ever, n (%)
Time to remission, months 3 (1-35) 3 (1-35) 3 (1-12) 0.79

Table 2. Comparison of the outcomes of TNF inhibitors and tocilizumab treatments patients
during follow-up
 Baseline visit 3rd month of Last visit
p treatment p P

Complete TNF inhibitors - 16/52 (30) 0.34 28/61 (50) 0.75

Remission, n (%) Tocilizumab - 3/16 (18) 9/18 (50)
Partial Response, TNF inhibitors - 21/52 (40) 0.84 15/61 (25) 0.20
n(%) Tocilizumab - 8/16 (50) 2/18 (11)
PGA remission, n(%) TNF inhibitors 1/73 (1) 0.60 32/56 (57) 0.17 34/48 (71) 0.058
Tocilizumab 0/19 (0) 7/18 (39) 5/12 (42)
Kerr remission, n(%) TNF inhibitors 2/73 (3) 0.45 43/59 (73) 0.41 53/72 (74) 0.74
Tocilizumab 0/20 (0) 12/19 (63) 14/20 (70)
ESR, mm/h TNF inhibitors 42 (10-120) 0.85 18 (2-80) 0.65 19 (2-103) 0.06
Tocilizumab 46 (11-109) 8 (4-112) 9 (2-118)
CRP, mg/L TNF inhibitors 35 (17-62) 0.22 11 (6-22) 0.25 9 (6-79) 0.54
Tocilizumab 34 (14-98) 17 (8-118) 20 (6-72)
GC dose, mg/d TNF inhibitors 16 (6-32) 0.01 4 (0-16) 0.001 4 (0-40) 0.14
Tocilizumab 20 (8-32) 8 (4-16) 4 (0-32)
Decrease in GC TNF inhibitors - 5 (0-60) 0.064 6 (0-64) 0.054
dose, mg/d Tocilizumab - 12 (0-24) 16 (0-30)
VDI TNF inhibitors 2 (2-3) 0.21 - 2 (2-7) 0.15
Tocilizumab 0 (0-5) - 0 (0-5)

60% 56%

50%

40%
33%
30%

20% 17% 17% 17%

14%
10% 7% 7% 8% 7% 7% 8%
2% 0%
0%

TNFi TCZ

Figure 1. The discontinuation reasons for biologic treatments in TAK patients.

 Figure 2. Drug survival in Takayasu arteritis patients under tocilizumab and TNF inhibitor treatments.

Supplementary table 1. Comparison of first-line TNF inhibitors and tocilizumab treatment for
the treatment of TAK patients with match analysis.

n P
No Yes
Age_ match
Relapse Tocilizumab (n=15) 10 5 0.59
TNF inhibitors (n=14) 8 6
Glucocorticoid treatment Tocilizumab (n=15) 6 9 0.58
(<5mg or discontinue) TNF inhibitors (n=11) 4 7
Surgery during biologic Tocilizumab (n=20) 19 1 0.87
treatment TNF inhibitors (n=16) 15 1
Mortality Tocilizumab (n=20) 20 0 0.23
TNF inhibitors (n=19) 17 2
Aorta_match
Relapse Tocilizumab (n=16) 11 5 0.82
TNF inhibitors (n=18) 13 5
Glucocorticoid treatment Tocilizumab (n=18) 7 11 0.29
(<5mg or discontinue) TNF inhibitors (n=14) 3 11
Surgery during biologic Tocilizumab (n=22) 21 1 0.55
treatment TNF inhibitors (n=22) 20 2
Mortality Tocilizumab (n=22) 22 0 0.51
TNF inhibitors (n=23) 22 1
Gender_match
Relapse Tocilizumab (n=16) 11 5 0.61
TNF inhibitors (n=17) 13 4
Glucocorticoid treatment Tocilizumab (n=18) 7 11 0.27
(<5mg or discontinue) TNF inhibitors (n=16) 3 13
Surgery during biologic Tocilizumab (n=22) 21 1 0.94
treatment TNF inhibitors (n=20) 19 1
Mortality Tocilizumab (n=22) 22 0 0.48
TNF inhibitors (n=23) 21 2
Age+aorta_match
Relapse Tocilizumab (n=6) 3 3 0.60
TNF inhibitors (n=10) 7 3
Glucocorticoid treatment Tocilizumab (n=8) 5 3 0.11
(<5mg or discontinue) TNF inhibitors (n=8) 1 7
Surgery during biologic Tocilizumab (n=11) 11 0 0.30
treatment TNF inhibitors (n=11) 10 1
Mortality Tocilizumab (n=11) 11 0
TNF inhibitors (n=11) 11 0
Age+gender_match
Relapse Tocilizumab (n=13) 8 5 0.81
TNF inhibitors (n=14) 8 6
Glucocorticoid treatment Tocilizumab (n=13) 5 8 0.80
(<5mg or discontinue) TNF inhibitors (n=9) 3 6
Surgery during biologic Tocilizumab (n=17) 16 1 0.88
treatment TNF inhibitors (n=14) 13 1
Mortality Tocilizumab (n=17) 17 0 0.31
TNF inhibitors (n=17) 16 1
Aorta+gender_match
Relapse Tocilizumab (n=15) 10 5 0.22
TNF inhibitors (n=16) 14 2
Glucocorticoid treatment Tocilizumab (n=18) 7 11 0.42
(<5mg or discontinue) TNF inhibitors (n=12) 3 9
Tocilizumab (n=21) 20 1 0.59
Surgery during biologic TNF inhibitors (n=19) 17 2
treatment
Mortality Tocilizumab (n=21) 21 0 0.48
TNF inhibitors (n=22) 20 2
Age+gender+aorta_match
Relapse Tocilizumab (n=7) 3 4 0.61
TNF inhibitors (n=9) 6 3
Glucocorticoid treatment Tocilizumab (n=21) 5 3 0.11
(<5mg or discontinue) TNF inhibitors (n=22) 1 6
Surgery during biologic Tocilizumab (n=11) 11 0 0.47
treatment TNF inhibitors (n=10) 9 1
Mortality Tocilizumab (n=11) 11 0 0.30
TNF inhibitors (n=11) 10 1

Discussion

In the present study, considering all matched comparisons, we found no significant difference
between TNF inhibitors and TCZ groups, regarding relapse rate, decrease in GC dose 5
mg/daily or lower, surgery need and mortality outcomes (Supplementary Table 1). Overall,
TNF inhibitors and TCZ seemed to have equivalent efficacy and safety in our study population.
Both agents reached good short-term outcomes as partial/complete remission. However, high
discontinuation rates (nearly 50%) after mean follow-up of 21 months suggested that efficacy
and safety issues might limit the use of long-term biologic agents in TAK patients.

Before discussing the role of biologic agents in management of TAK, it should be noted that
these agents are generally used in patients resistant or intolerant to GC’s and IS agents. GCs
are still the mainstay for the treatment of TAK, and initial high dose of prednisolone 1
mg/kg/day or its equivalent (maximum 60 mg/day), induces remission in most of the patients.
However, EULAR recommends the use of an additional IS agent in all patients with TAK to
avoid risk of GC-associated complications with long term usage and to decrease disease
activation during tapering of GCs, despite the lack of any RCT showing additional benefit of
adding IS agents in TAK [5]. Relapse rate was detected around 80% in 8-16 weeks with quick
GC tapering regimens in randomized controlled trials (RCTs) of TCZ and abatacept.[6, 7] and
there are no studies comparing different GC tapering protocols in TAK. In our inception cohort
of patients with TAK, almost half of the patients (45%) relapsed during a follow-up of mean
25.7 months with an additional IS agent with GC.[8] This lower relapse rate compared to GCs
alone suggests that conventional ISs should be added at the onset of disease course.

TCZ and TNF inhibitors can be equally considered in cases of relapsing or refractory disease
despite conventional IS treatment according to the EULAR recommendations.[3] In
chronologic order, TNF inhibitors are the first group of biologic agents showed as an effective
treatment option mainly for treatment of refractory TAK patients. However, all data comes
from open-label studies and retrospective case series. [9-13] A recent retrospective,
longitudinal follow-up cohort from Norway reported less angiographic progression at 2 years
in TAK patients receiving TNF inhibitors (10%), compared to conventional IS agents (40%). In
this study, angiographic progression rate was 90% in patients receiving GC treatment only.[14]
In another large series including 120 refractory TAK patients receiving TNF inhibitors, IFX was
the mostly preferred agent (80%). The remaining patients had used either ETN or adalimumab
(ADA). Overall response rate was 80%. In over 40% of these patients, GC dose could be
decreased or discontinued. During follow-up, relapses developed in 37% of patients. About
50% of relapsing patients needed an increase in total dose or frequency, or were switched to
another TNF inhibitor.[15] Certolizumab [16, 17] and golimumab [18] were also reported as
effective TNF inhibitors in selected cases.

The clinical efficacy of TCZ which is an IL-6 blocking agent, was first reported in TAK by
Nishimoto et al. in 2008.[19] Then, many open case series reported the efficacy of TCZ in
refractory TAK. In a recent systematic review of 105 patients, clinical improvement was
observed within 3 months in 90 (85.7 %) and GC dose could be decreased in 75 patients.
Imaging results were available in 66 patients with 43 (65.2%) having radiological
improvement. Relapse under TCZ treatment was observed in 7 (9%) patients, in 6 after TCZ
discontinuation with a median time of five months. Side effects were noted in 18%, with TCZ
interruption in seven cases.[20]. This review confirmed that TCZ was a safe and effective agent
in refractory TAK, but relapses seemed an important issue after TCZ discontinuation in almost
half of the patients. TCZ was recently studied in a double-blind RCT for the treatment of TAK
in Japan. In this study, 36 patients which relapsed within the last 12 weeks and gone into
remission with oral GC treatment, were enrolled. Although the primary endpoint (intention-
to-treat analysis: HR for time to relapse 0.41, 95% CI 0.15 to 1.10; p=0.0596) was not reached,
a trend favouring TCZ over placebo was observed (per protocol set: HR 0.34, 95% CI 0.11 to
1.00; p=0.0345). [6] In open-label extension phase of this RCT in 28 patients continuing TCZ
for 96 weeks, 46.4% of patients reduced their GC dose to <0.1 mg/kg/day with no safety
concerns.[21] In a recent open-prospective multi-center French trial, TCZ achieved 80%
remission rate and 54% remission rate without GCs at 6 months in treatment-naive TAK
patients.[22]
Indirect comparison of small retrospective series showed that all parameters such as disease
activity, acute phase response and surgical interventions were found similar between TNF
inhibitors and TCZ.[23] In another retrospective study of 86 biologic courses in 50 patients,
drug survival rate of TNF inhibitors was significantly higher than TCZ (67.2% vs 41.1 %,
p=0.028). Concomitant conventional IS use at baseline had a positive effect on drug survival
rate (HR = 3.79, 95% CI = 1.49-9.60, p=0.005) in this study.[24]

In conclusion, TNF inhibitors or TCZ can be both chosen as the first-line biologic agent in
patients with TAK with similar efficacy and safety. Whether a RCT comparing these two agents
may show a difference in affectivity, safety or drug survival is debatable. We believe that,
aiming for a lower GC dose (<5 mg/d) should still be a priority for long-term management of
TAK to decrease GC-associated side effects in these patients. Therefore, prospective RCTs are
still required with both conventional ISs and biologic agents to better assess the disease course
and to optimize the management of TAK.
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