Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis

AUTREV-02162; No of Pages 11 Autoimmunity Reviews xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis Lillian Barra a,⁎, Grace Yang a, Christian Pagnoux b, The Canadian Vasculitis Network (CanVasc) a b

Department of Medicine, Division of Rheumatology, University of Western Ontario, London, Canada Vasculitis Clinic, Division of Rheumatology, Mount. Sinai Hospital, University of Toronto, Toronto, Canada

a r t i c l e

i n f o

Article history: Received 16 January 2018 Accepted 22 January 2018 Available online xxxx Keywords: Takayasu's arteritis Large vessel vasculitis Treatment Biologics Immunosuppressant

a b s t r a c t Background: Takayasu's Arteritis (TAK) affects mostly young women and causes significant morbidity. Most patients are refractory to glucocorticoids (GC) or relapse when GC doses are reduced. The objective of this study is to summarize the literature pertaining to the effectiveness of non-GC drugs for the treatment of TAK. Methods: MEDLINE and Embase were searched for English-language studies of TAK patients with a sample size N5. Studies were included if the effectiveness of non-GC drugs for the treatment of TAK was reported. Random effects meta-analyses of various effect measures were performed. Results: Of the 915 studies identified by the search, 14 of small molecule immunosuppressants (IS) and 25 of biologic therapies were included. Studies had a high risk of bias. Pooled remission rates were similar for both categories of non-GC drugs: 58% (95% CI: 40–74%) and 64% (95% CI: 56–72%), respectively. The relapse rate was 54% (95% CI: 39–68%) for IS therapies and 31% (95% CI: 22–41%) for biologics. Both significantly decreased GC doses and acute phase reactants. Observational studies suggested that anti-TNF agents were more effective than IS at maintaining remission. Randomized-controlled trials (RCTs) of biologics were of small sample size: abatacept was not effective and the trial of tocilizumab was underpowered to detect a difference in time to relapse versus placebo. Serious adverse events were uncommon. Conclusions: Non-GC agents were moderately effective in inducing remission in TAK, but relapse rates were high. Larger, better designed studies are required to determine the optimal treatment regimen for TAK. © 2018 Published by Elsevier B.V.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature search and study selection. . . . . . . . . . . . . . . . . . . . . 2.2. Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . 2.3. Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results and characteristics of included studies . . . . . . . . . . . . . 3.2. Effect of steroid-sparing agents on clinical outcomes in observational studies . . 3.3. Effect of steroid-sparing agents on ESR, CRP and imaging in observational studies 3.4. Results of RCTs of steroid-sparing agents . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Abbreviations: AZA, azathioprine; ADA, adalimumab; CYA, cyclosporine A; CYX, cyclophosphamide; ETN, etanercept; FK, tacrolimus; IFX, infliximab; IS, immunosuppressant; LFM, leflunomide; MMF, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab; TAK, Takayasu's Arteritis; TCZ, tocilizumab; TNF, anti-tumor necrosis alpha drug. ⁎ Corresponding author at: St. Joseph's Health Care, 268 Grosvenor St., Room D2-160, London N6A 4V2, Ontario, Canada. E-mail address: [email protected] (L. Barra).

https://doi.org/10.1016/j.autrev.2018.01.019 1568-9972/© 2018 Published by Elsevier B.V.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

2

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

1. Introduction Takayasu's Arteritis (TAK) is a rare large vessel vasculitis characterized by granulomatous inflammation of the aorta and its major branches causing claudication symptoms and potentially severe ischemic complications with major organ dysfunction [1]. TAK predominantly affects women and onsets before the age of 40, including children [2]. The disease is chronic, continuous or following a remitting-relapsing pattern, with decades of morbidity, disability and poor quality of life [3]. Mortality is 3 times higher than the general population [4]. The first-line treatment for active TAK is systemic glucocorticoids (GC), usually started at high doses followed by a tapering regimen [5,6]. Unfortunately, most patients either fail to achieve remission with GC or relapse on lower doses [7,8]. In addition, chronic GC therapy is associated with common and potentially severe adverse effects, such as infections, osteoporosis, cardiovascular disease, and growth restriction in children. For these reasons, effective treatment with small molecule immunosuppressants (IS) and/or biologic therapies would be highly beneficial [7,8]. There are no strong data available to date that favour one such drug over others that have been tried for the management of TAK [9]. Most evidence comes from small observational studies and case series. Consequently, the choice of any such non-GC therapy in TAK is often based on physicians' familiarity, patients' preferences, and trial-anderror. The primary goal of the present meta-analysis was to quantify the effectiveness of currently available non-GC treatments for TAK. Specifically, the outcomes of interest were (1) the proportion of patients with TAK achieving remission, (2) the proportion of patients with TAK with relapse over the follow-up period, (3) the magnitude of decrease in daily GC dose, (4) the magnitude of decrease in acute phase reactants (APR), and (5) the impact on imaging progression.

observational studies was assessed using the Newcastle-Ottawa score [11] and of RCTs using the Cochrane Risk of Bias tool [12]. 2.3. Meta-analysis Outcomes varied widely across studies. Random effects meta-analyses (DerSimonian and Laird method) were performed for the most commonly reported outcome measures: proportion of patients achieving remission, proportion relapsing or experiencing disease progression on imaging, change in prednisone dose, Erythrocyte Sedimentation Rate (ESR) or C-reactive protein (CRP). Composite disease activity scores were inconsistently reported in studies and not included in this meta-analysis. Small molecule and biologic therapies were analyzed separately; anti-TNF and tocilizumab were analyzed both separately and together. There were too few RCTs to include in the meta-analyses; results of these studies were described in the systematic review. The included studies defined remission as complete resolution of clinical symptoms and physical exam findings of TAK and no evidence of disease activity by acute phase reactants (ESR or CRP). Most studies also included stable or improved imaging in their definition of remission. Relapses were defined as new or recurrent TAK symptoms and/ or elevations in APR attributable to TAK as determined by the treating physician and/or disease progression on imaging. Details regarding the imaging modalities used, timing of the exam and specific imaging findings that were deemed to be indicative of active disease were inconsistently reported. Heterogeneity between studies was reported using the I2 and publication bias was assessed using funnel plots. All analyses were performed using Comprehensive Meta-Analysis (Biostat, Englewood, NJ). The design and conduction of this systematic review and meta-analysis followed the PRISMA statement [13]. 3. Results

2. Methods 3.1. Search results and characteristics of included studies 2.1. Literature search and study selection The literature review was conducted using Embase and MEDLINE covering the period from database inception to January 2018. The search included terms for TAK and non-GC drugs (small molecule IS and biologic therapies) (Table A.1). Studies enrolling adult and pediatric-onset TAK patients reporting the effectiveness of steroid-sparing agents were included. Studies that included patients with other types of vasculitis in addition to TAK were only included if outcomes were reported separately for TAK. Case reports, case series with b5 subjects and non-English language papers/abstracts were excluded. If there were multiple studies of the same cohort with the same outcomes, the largest study was included. Two authors (LB and GY) independently reviewed the studies for inclusion and exclusion criteria. 2.2. Data extraction and quality assessment Data extraction was performed by LB and GY independently using standardized forms. The following data were extracted: study design, age of study subjects and disease duration at study onset, gender, duration of follow-up, doses of steroid-sparing agents, duration of treatment, outcomes for drug effectiveness/efficacy and adverse events. Treatments were separated into two major categories: (1) small molecule steroid-sparing IS (cyclophosphamide (CYX), methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF), leflunomide (LFM), cyclosporine A (CSA), tacrolimus (FK), or others) and (2) biologic therapies (anti-tumor necrosis factor alpha (anti-TNF): infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab (CZP) or golimumab (GOL), tocilizumab (TCZ, anti-IL6), abatacept (ABA, antiCTLA4) and rituximab (RTX, anti-CD20)). For consistent reporting of outcomes, Hozo's method to estimate mean and standard deviation based on median, range and sample size was used [10]. The quality of

Database searches identified 915 studies and 775 did not meet inclusion criteria as determined by title and abstract review. After full article review, an additional 96 studies were excluded due to lack of outcomes of interest and 9 due to low sample size of b5. In total, 35 observational studies [7,8,14–43] and 4 randomized controlled trials (RCTs) [44–47] were included in the systematic review (Fig. A.1). The characteristics of the observational studies are shown in Table 1. Twelve studies investigated small molecule IS: 2 CYX [14,15], 5 MTX [15–18,48], 1 AZA [19], 2 MMF [20,21], 1 LFM [22] and 2 with various drugs included but reported separately [7,8]. Twenty-three studies investigated biologics: 12 anti-TNF [8,23–31,33,48], 9 TCZ [35,36,38– 41,49], 1 RTX [42] and 2 both anti-TNF and TCZ reported separately [32,34]. All patients were treated with concomitant GC. For most studies, patients had been previously exposed to at least 1 other non-GC drug. Anti-TNF agents were frequently used in combination with MTX or AZA. The sample sizes ranged from 5 to 235 with the largest study consisting of 161 patients treated with MMF, 54 with AZA and 20 with MTX [7]. The ages of study subjects at the time of study enrolment ranged from 3 to 61 and 67–100% were females. The disease duration of subjects at the time of study enrolment varied widely across studies from new onset disease up to a median of 116 months. The duration of follow-up in the studies ranged from a median of 6 to 71 months. Using the Newcastle-Ottawa Score, the studies were of low or unclear quality: risk of selection bias was high or derivation of the cohort was not described, only two of the studies included a comparator group (and analyses did not account for confounders), blinding of outcome assessments was not performed or not reported and many studies did not adequately account for all participants at follow-up. There were 4 double-blind placebo-controlled RCTs included: 1 curcumin (N = 246) [44], 1 resveratrol (N = 220) [45], 1 TCZ (N = 36) [47] and 1 ABA (N = 26) [46](Table 2). The age of participants ranged

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

3

Table 1 Characteristics of included observational studies. Study Small molecules Shelhamer et al. 1985 Ozen et al. 2007

c

Design

Drug

Na

Age (years)b

% Female

Disease duration (months)b

Prior IS

Follow-up (months)b

Drug dose and duration

Prospective

CYX

7

27 (7–57)

100

0

No

56 (2−113)

Prospective

6

12 (10–15)

67

0

No

24 (0.1–84)

18

30 (13–56)

83

62 (12–144)

No

34 (16–58)

2 mg/kg/day Mean 27 months 1.5–1.7 mg/kg/day 12 weeks 0.3 mg/kg/week 1 year NR

Hoffman et al. 1994

Prospective

CYX MTX MTX

Boccacci et al. 2011d [abstract] Gokhale et al. 2013 [abstract] Kostina et al. 2014 [abstract] Valsakumar et al. 2003

Retrospective

MTX

16

12 (3–17)

88

0

No

59 (0.1–105)

Prospective

MTX

36

23 (SD8)

83

NR

No

6

Retrospective

MTX

36

3–16

NR

NR

NR

36

Prospective

AZA

15

28 (14–38)

100

13 (14–24)

No

12

Goel et al. 2010

Retrospective

MMF

21

32 (SD14)

91

36 (1−120)

No

Shinjo et al. 2007

Prospective

MMF

10

30 (18–40)

70

57.5 (SD 65.8)

Yes

De Souza et al. 2012

Prospective

LFM

15

36 (SD 13)

93

38 (29–73)

Yes

Ohigashi et al. 2017d,e

Prospective

Various

29

24 (SD 11)

93

60 (SD 40.8)

Yes

Goel et al. 2017d,f

Prospective

Various

235

29 (SD 12)

82

24 (6–70)

No

Biologics Hoffman et al. 2004

Prospective

TNF

15

28 (17–48)

93

72 (2–16)

Yes

12 (8–51)

Molloy et al. 2008

Retrospective

TNF

25

35 (15–64)

88

116 (39–344)

Yes

28 (2–48)

Boccacci et al. 2011 [abstract]d Mekinian et al. 2012

Retrospective

TNF

7

12 (3–17)

88

0

No

59 (0.1–105)

Retrospective

TNF

15

41 (17–61)

87

37 (6–365)

Yes

43 (4–71)

Schmidt et al. 2012

Retrospective

TNF

20

33 (SD10)

95

16 (2−33)

Yes

54 (34–82)

Comarmond et al. 2012 Case series

TNF

5

41 (19–58)

89

64 (0.1–262)

Yes

26 (3–72)

Novikov et al. 2013

Case series

TNF

9

(19–37)

100

74 (30–168)

Yes

36 (16–112)

Quartuccio et al. 2012

Retrospective

TNF

15

34 (16–40)

NR

39 (12–84)

Yes

71 (10–162)

Tombetti et al. 2013 [abstract] Serra et al. 2014

Retrosepctive

TNF

15

36

100

NR

Yes

46 (11–56)

Prospective

TNF

5

37 (34–40)

80

0

No

34

Mekinian et al. 2015e

Retrospective

TNF TCZ

35 14

42 (20–55)

80

NR

Yes

24 (2–95)

Gudbrandsson et al. 2017 Ohigashi et al. 2017c

Retrospective

TNF

32

NR

NR

36 (SD41)

Yes

Up to 60

Prospective

TNF

6

24 (SD 11)

93

60 (SD 40.8)

Yes

NR

Novikov et al. 2017 [abstract]

Retrospective

TNF TCZ

18 10

25 (18–56)

100

36 (30–180) 49 (29–146)

Yes

NR

Abisror et al. 2013

Case series

TCZ

5

37 (13–61)

80

NR

Yes

NR

Goel et al. 2013

retrospective

TCZ

10

25 (15–53)

90

26 (2–60)

Yes

6

15–25 mg/week NR NR

2 mg/kg/day 1 year 9.6 (SD6.4) NR Mean 9.6 months 23.3 (SD 2 g/day 12.1) Mean 23 months 9.1 20 mg/day Duration NR 52.8 (SD38.4) MTX: 13 (SD4) mg/kg/week CYA: 200 (SD55) mg/day FK: 5.4 (SD3.2) mg/day AZA: 80 (SD 27) mg/day Duration NR 42 (24–81) MMF: 2–3 g/day AZA: 2 mg/kg/day MTX: 15–25 mg/week Duration: NR

ETN: 25 mg 2× weekly IFX: 3-5 mg/kg/4–8 weeks Mean 20 months ETN: NR IFX: 4–10 mg/kg/4–8 weeks Duration NR NR IFX: 3–5 mg/kg/4–8 weeks Mean 43 months ADA: 40 mg/2 weeks ETN: 50 mg/week IFX: 3–7 mg/kg/4–6 weeks Mean 23 months IFX: 5 mg/kg Duration NR IFX: 3–5 mg/kg/4–6 weeks ADA: 40 mg/2 weeks Median 36 months IFX: 3–8 mg/kg/4–8 weeks Mean 74 months NR ADA: 40 mg/2 weeks IFX: 3 mg/kg/8 weeks 1 year ADA: 40 mg/2 weeks ETN: 25 mg/2× weekly IFX: 3–7 mg/kg/4–8 weeks TCZ: 8 mg/kg/month Mean 16 months Doses not reported Mean 42 months IFX: 4–6 mg/kg/6–8 weeks ETN: 50 mg/week Duration NR Dose NR TNF: 38 months TCZ: 20 months 4–8 mg/kg/month Duration NR NR (continued on next page)

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

4

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

Table 1 (continued) Study

Design

Drug

Na

Age (years)b

% Female

Disease duration (months)b

Prior IS

Follow-up (months)b

Drug dose and duration

Tombetti et al. 2013

Retrospective

TCZ

7

25 (23−30)

100

66 (17–82)

Yes

14 (10−33)

Yamazaki et al. 2013 [abstract] Canas et al. 2014

Prospective

TCZ

6

13 (7–17)

NR

94 (18–92)

Yes

6

Retrospective

TCZ

8

31 (12–43)

100

54 (12–372)

Yes

18 (9–36)

Loricera et al. 2016

Retrospective

TCZ

8

36 (7–56)

100

11 (1–168)

Yes

16 (6–24)

Zhou et al. 2017

Prospective

TCZ

16

27 (18–47)

33 (2–129)

Yes

11 (1−20)

Goel et al. 2017 [abstract] Pazzola et al. 2017

Retrospective

TCZ

44

NR

NR

NR

Yes 68%

NR

4 mg/kg/month Duration NR 8–10 mg/kg/2 weeks Duration NR 8 mg/kg/month Duration NR 4–8 mg/kg/2–4 weeks Mean 16 months 4–8 mg/kg/month 9 (1–20) NR

Retrospective

RTX

7

32 (SD 17)

86

57.6 (SD 92.4)

Yes

32 (12–72)

1 g week 1–2/6 months 1–4 courses

AZA = azathioprine; ADA = adalimumab; CYA = cyclosporine A; CTX = cyclophosphamide; ETN = etanercept; FK = tacrolimus; IFX = infliximab; IS = immunosuppressant; LFM = leflunomide; MMF = mycophenolate mofetil; MTX = methotrexate; RTX = rituximab; TNF = anti-tumor necrosis alpha drug; TCZ = tocilizumab. a Numbers are patients exposed to small molecule immunosuppressants and/or biologic therapies (patients on glucocorticoids alone are excluded). b Numbers are median (range) or mean (SD). c N = 4 received cyclophosphamide induction followed by methotrexate maintenance; N = 2 received methotrexate for entire course of study. d Demographics reported were for entire study population. e Data were included if ≥5 study subjects exposed to the small molecule; subjects could have been exposed to N1 drug, but not at the same time: N = 18 MTX, N = 12 CYA, N = 10 FK, N = 7 AZA; maximum drug doses were reported. f N = 161 MMF, N = 54 AZA, N = 25 MTX.

proportion of TAK patients achieving remission was 0.579 (95% CI: 0.400–0.740; I2 = 81%) (Fig. 1a). Relapse rates were reported in 4 studies with 6 treatment groups (total N = 251): 0.539 (95% CI: 0.388–0.684; I2 = 66%) (Fig. 1b). The pooled remission rate for biologic agents (12 studies with 15 treatment groups; total N = 233) was 0.641 (95% CI: 0.560–0.715; I2 = 23%) and the relapse rate (12 studies with 14 treatment groups; total N = 256) was 0.310 (95% CI: 0.222–0.413; I2 = 41%) (Fig. 2a, b). For small molecule IS (3 studies, N = 46) and biologic agents (12 studies with 14 treatment groups, N = 185) the prednisone dose significantly decreased after treatment: pooled mean change in dose of −17.2 mg/day (p b 0.0001; I2 = 0%) and − 11.1 mg/day (p b 0001; I2 = 61%), respectively (Fig. 3a, b). There was 1 case series of rituximab with 3/7 (43%) patients achieving remission. Prednisone doses significantly decreased with rituximab treatment: from 25 mg/day to 8.7 mg/day (p = 0.0122) [42]. Thirty-four serious adverse events (SAEs) were reported in 363 patients from 9 studies of small molecule IS. Amongst these SAEs, 17 led to drug discontinuation and 9 led to a dose reduction due to elevations in liver enzymes (MTX). SAEs included 1 pneumocystis pneumonia (MTX), 1 sepsis (MMF), 13 cases of cytopenias (12 AZA and 1 MTX) and various ones (1 herpes simplex virus infection, 7 reports of oligomenorrhea and 2 cystitis cases) in patients treated with CYX. Four

from 29 to 36 years and 55–89% were female. The TCZ and ABA trials followed patients for 12 months and the prednisone tapering regimen was the same in both the treatment arms; no other steroid-sparing agents were allowed. The TCZ trial included an open-label extension after the primary end-point of relapse was met in 19 patients. Therefore, some outcomes were not assessed blindly and this is a potential source of bias. Also, details regarding protocols in the open-label extension were not reported. The ABA trial included a pre-randomization phase in which all enrolled patients were treated with ABA and only those achieving remission were randomized to ABA or placebo; all patients were accounted for in the study. The overall risk of bias in the ABA trial was low. For the curcumin and resveratrol trials, the risk of bias was unclear. The use of GC and other IS in the curcumin and resveratrol trials were not described, other important clinical outcomes such as adverse events were not reported. The duration of follow-up for these 2 trials was short (1 and 3 months, respectively). 3.2. Effect of steroid-sparing agents on clinical outcomes in observational studies Seven studies with 12 treatment groups (total N = 344) examined the effects of small molecule IS on remission in TAK. The pooled

Table 2 Characteristics of included randomized controlled trials. Study

Design

Drug

Na

Age (years)b

% Female

Disease duration (months)b

Prior IS

Follow-up (months)b

Drug dose

Small molecules Shao et al. 2017c

DB RCT

36 (19–52) 36 (19–52) 32 (SD16) 35 (SD 15)

66 55 62 67

NR

1

300 mg daily

DB RCT

120 126 112 108

NR

Shi et al. 2017c

Curcumin Placebo Resveratrol Placebo

NR

NR

3

250 mg daily

Biologics Nakoaka et al. 2017d

DB RCT

31 (SD 18) 31 (SD 13) 30 (19–59) 29 (20–57)

89 83 82 87

6.5 (SD 7.4) 3.6 (SD 4) 61.2 (2.8–228) 11 (0–204)

12

162 mg s.c. weekly

DB RCT

18 18 11 15

NR

Langford et al. 2017d

Tocilizumab Placebo Abatacept Placebo

Yes

12

10 mg/kg i.v. monthly

DB RCT = double blind randomized controlled trial; NR = not reported. a Numbers are patients randomized to the study drug or placebo. b Numbers are median (range) or mean (SD). c Manuscript did not specify treatment arms were used in combination with glucocorticoids or other immunosuppressants. d Both treatment arms were used in conjunction with the same tapering regimen of prednisone; no other immunosuppressants were allowed.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

5

a Study name

Hoffman et al. 1994 Boccacci et al. 2011 [1] Goel et al. 2017 [1] Ohigashi et al. 2017 [1] Goel et al. 2017 [2] Ohigashi et al. 2017 [2] Shinjo et al. 2007 Goel et al. 2017 [3] Ozen et al. 2007 Ohigashi et al. 2017 [3] de Souza et al. 2012 Ohigashi et al. 2017 [4]

Statistics for each study Event rate

Lower limit

Upper limit

0.833 0.231 0.600 0.222 0.889 0.143 0.900 0.720 0.833 0.250 0.800 0.200 0.579

0.591 0.076 0.380 0.086 0.774 0.020 0.533 0.646 0.369 0.083 0.530 0.050 0.400

0.945 0.522 0.786 0.465 0.949 0.581 0.986 0.784 0.977 0.552 0.934 0.541 0.740

Drug

Event rate and 95% CI

Total 15 / 18 3 / 13 12 / 20 4 / 18 48 / 54 1/ 7 9 / 10 116 / 161 5/ 6 3 / 12 12 / 15 2 / 10

MTX MTX MTX MTX AZA AZA MMF MMF CYX CYA LFM FK -1.00

-0.50

0.00

0.50

1.00

b Study name

Drug Event Lower Upper rate limit limit

Total

Ozen et al. 2007

0.333 0.084 0.732

2/6

CYX

Hoffman et al. 1994

0.389 0.198 0.621

7 / 18

MTX

Goel et al. 2017 [1]

0.706 0.458 0.872 12 / 17 MTX

Valksakumar et al. 2003 0.031 0.002 0.350 Goel et al. 2017 [2] Goel et al. 2017 [3]

Event rate and 95% CI

0 / 15

AZA

0.698 0.563 0.806 37 / 53 AZA 0.585 0.502 0.663 83 / 142 MMF 0.539 0.388 0.684 -1.00

-0.50

0.00

0.50

1.00

Fig. 1. Clinical effectiveness of small molecule immunosuppressants. Meta-analysis of the proportion of patients achieving remission (a) and relapsing (b).

deaths were reported, 3 attributable to disease activity (pulmonary vasculitis, myocardial infarction and hypertensive urgency) and 1 due to gastrointestinal bleeding. Twenty studies of biologic agents (N = 208) reported adverse events, but not all described the types of SAEs that occurred. Overall, 41 SAEs were reported (11 led to drug discontinuation and two resulted in dose reduction), including infections, infusion reactions, 1 case of cutaneous systemic lupus erythematosus, 1 congestive heart failure and 4 reported cancers: lung cancer in a smoker, breast cancer in a patient with a family history, a case of pancreatic cancer and another case of breast cancer. No deaths were reported. 3.3. Effect of steroid-sparing agents on ESR, CRP and imaging in observational studies Four studies (N = 61) investigated the impact of small molecule IS on ESR and CRP. ESR (Fig. A.2a) and CRP (Fig. A.2b) decreased by an average of 16.3 mm/h (p = 0.021; I2 = 89%) and 14.1 mg/L (p = 0.023; I2 = 74%), respectively. In comparison, the ESR reduction for biologic therapies (7 studies, N = 75; Fig. A.3a) was 47.0 mm/h (p = 0.001; I2 = 96%). Because TCZ is an IL-6 inhibitor and directly effects CRP, reductions in CRP for anti-TNF agents (5 studies, N = 67; Fig. A.3b) was reported separately from TCZ (4 studies, N = 45; Fig. A.3c): 20.0 mg/mL (p b 0.0001; I2 = 51%) and 21.8 mg/mL (p b 0.0001; I2 = 30%), respectively. The proportion of patients with new angiographic lesions or progression of previously noted lesions were reported in 5 studies of small molecule IS (total N = 57) and 7 studies of biologics (total N = 98): 0.219 (95% CI: 0.072–0.504; I2 = 59% and 0.229 (95% CI: 0.121–0.390; I2 = 49%), respectively (Fig. A.4a, b).

3.4. Results of RCTs of steroid-sparing agents In Langford et al. 2017, 34 patients received ABA + GC: 1 patient failed to achieve remission, 5 remitted and relapsed, 1 patient was diagnosed with breast cancer and another patient withdrew from the study within the first 12 weeks of the study. The remaining 26 patients were randomized (double-blind) to ABA + GC vs. placebo + GC. The primary outcome of relapse free-survival was not met at 12 months follow-up in intention-to-treat analysis: 22% for ABA vs. 40% for placebo, p = 0.853. Reductions in prednisone dose and ESR/CRP and adverse events were not different between the two groups. The most common adverse event was infections (13 in ABA vs. 36 in placebo group); 2 patients developed thromboembolic events during ABA treatment. There was 1 RCT of 36 patients that investigated TCZ + GC vs. placebo + GC [47]. The double-blind first phase of this study started after patients had achieved remission with GC alone; the second phase was an open-label extension. In the intention-to-treat analysis, relapse free survival was not statistically significantly different for the 2 groups: 56% for TCZ and 23% for placebo. Nine TCZ patients had infections, 3 had gastrointestinal complaints, 6 had cutaneous non-severe adverse events and there was no difference compared to placebo; no serious adverse events were attributable to TCZ. Two double-blind RCTs investigated naturally occurring compounds that have TNFα-inhibiting properties: curcumin present in turmeric and resveratrol found in fruits vs. placebo. The studies were of short duration (b3 months) and showed significant decreases in ESR/CRP and TNFα. The only other clinical parameter reported was the Birmingham Vasculitis Disease Activity Score (BVAS) [50]. The mean score was very high at study onset and declined significantly over follow-up.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

6

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

a Study name

Biologic Event Lower Upper rate limit limit

Hoffman et al. 2004 0.667 Molloy et al. 2008 0.533 Boccacci et al. 2011 [2] 0.714 Quartuccio et al. 2012 0.733 Schmidt et al. 2012 0.900 Tombetti et al. 2013 [1] 0.533 Mekinian et al. 2015 [1] 0.697 Gudbrandsson et al. 2017 0.438 Ohigashi et al. 2017 [5] 0.833 Novikov et al. 2017 [1] 0.667 Goel et al. 2013 0.600 Tombetti et al. 2013 [2] 0.429 Mekinian et al. 2015 [2] 0.938 Loricera et al. 2016 0.750 Novikov et al. 2017 [2] 0.700 0.641

0.406 0.358 0.327 0.467 0.676 0.293 0.523 0.279 0.369 0.429 0.297 0.144 0.461 0.377 0.376 0.560

0.854 0.701 0.928 0.896 0.975 0.759 0.829 0.610 0.977 0.842 0.842 0.770 0.996 0.937 0.900 0.715

Event rate and 95% CI

Total 10 / 15 16 / 30 5/ 7 11 / 15 18 / 20 8 / 15 23 / 33 14 / 32 5/ 6 12 / 18 6 / 10 3/ 7 7/ 7 6/ 8 7 / 10

TNF TNF TNF TNF TNF TNF TNF TNF TNF TNF TCZ TCZ TCZ TCZ TCZ -1.00

-0.50

0.00

0.50

1.00

b Study name

Molloy et al. 2008 Quartuccio et al. 2012 Comarmond et al. 2012 Schmidt et al. 2012 Mekinian et al. 2015 [1] Novikov et al. 2017 [1] Ohigashi et al. 2017 [4] Abisror et al. 2013 Tombetti et al. 2013 [2] Canas et al. 2014 Mekinian et al. 2015 [2] Loricera et al. 2016 Goel et al. 2017 [4] Novikov et al. 2017 [2]

Statistics for each study Event rate

Lower limit

Upper limit

0.500 0.600 0.400 0.333 0.091 0.278 0.500 0.400 0.286 0.125 0.143 0.056 0.280 0.300 0.310

0.328 0.348 0.100 0.158 0.030 0.121 0.168 0.100 0.072 0.017 0.036 0.003 0.140 0.100 0.222

0.672 0.808 0.800 0.571 0.247 0.519 0.832 0.800 0.673 0.537 0.427 0.505 0.482 0.624 0.413

Biologic

Event rate and 95% CI

Total 15 / 30 9 / 15 2/ 5 6 / 18 3 / 33 5 / 18 3/ 6 2/ 5 2/ 7 1/ 8 2 / 14 0/ 8 7 / 25 3 / 10

TNF TNF TNF TNF TNF TNF TNF TCZ TCZ TCZ TCZ TCZ TCZ TCZ -1.00

-0.50

0.00

0.50

1.00

Fig. 2. Clinical effectiveness of biologic therapies. Meta-analysis of the proportion of patients achieving remission (a) and relapsing (b).

4. Discussion The optimal pharmacologic management of TAK based on currently available agents remains unclear; existing clinical practice guidelines recommend high dose GC for induction of remission with a slow taper and IS in relapsing patients [5,6]. Observational studies report that N70% of TAK patients fail GC monotherapy [8]. In clinical practice, there are wide variations in the type of IS drugs used, doses and duration of treatment [51]. This systematic review and meta-analysis summarizes the available data on the effectiveness and safety of various small molecule IS and biological therapies for the management of TAK. Overall, observational studies showed that approximately 60% of patients achieved remission with GC combined with small molecule IS or biologic therapies, without significant difference between these two treatment groups. Acute phase reactants declined significantly and steroid-sparing effects were reported with significant declines in daily prednisone doses over the course of follow-up. The pooled relapse rates were higher for the small molecules IS (54%) versus biologics (31%), which was not statistically significant, but studies of biologics included more refractory patients. Angiographic progression was rarely reported and affected at least 20% of the patients for both drug categories. The most frequently studied small molecule IS were MTX (7 studies), MMF (3 studies) and AZA (3 studies) and biologics were anti-TNF (13 studies) and TCZ (10 studies). In subgroup analyses, there were no significant differences in the rates of relapses amongst the different small molecule IS and between anti-TNF and TCZ (data not shown).

Two observational studies directly compared treatments. Goel et al. 2017 found no statistically significant differences amongst MMF, AZA and MTX [7]. Mekinian et al. 2015 found a higher 3-year relapse-free survival for biologic therapies (anti-TNF or TCZ) versus small molecule IS (mostly MTX) (91% and 59%, respectively; p = 0.0025) [32]. There was no difference in the effectiveness of anti-TNF and TCZ [32]. Nevertheless, the use of biologics drugs first-line was rarely investigated in studies largely because of availability and/or high costs. Three abstracts included in this meta-analysis reported drug effectiveness exclusively in pediatric patients (1 MTX, 1 anti-TNF, 1 TCZ) [18,37,48] and the results were similar to adult patients. In a study of 27 TAK pediatric patients, the 2-year relapse-free survival was higher for biologic therapies compared to other small molecule IS: 80% vs. 43%, p = 0.03 [52]. Larger studies are required to confirm results. Recently, 4 RCTs of therapies for TAK have been published. The RCT of ABA vs. placebo did not show a benefit in TAK despite including a pre-randomization phase where non-responders were excluded [46]. The trial of TCZ vs. placebo also failed to meet the primary outcome of time to relapse. TCZ had a higher rate of relapse-free survival (51%) vs. placebo (23%), but was not statistically significant [47]. A larger RCT would be helpful to determine the efficacy of this drug in TAK. Two other RCTs investigated naturally occurring compounds that inhibit TNF alpha. Although these studies reported significant improvements compared to placebo, the short duration of follow-up of b3 months and the lack of information regarding the use of other therapies in the two study arms makes interpretation of the results difficult [44,45].

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

7

a Study name

Statistics for each study

Drug

Difference in means and 95% CI

Difference Standard in means error p-Value Total Shinjo et al. 2007

-19.000

4.386

0.000

10

MMF

Goel et al. 2010

-17.000

4.416

0.000

21

MMF

De Souza et al. 2012

-16.000

3.864

0.000

15

LFM

-17.217

2.424

0.000 -30.00 -15.00

0.00

15.00 30.00

b Study name

Statistics for each study

Biologic

Difference in means and 95% CI

DifferenceStandard in means error p-ValueTotal Hoffman et al 2004 Malloy et al 2008 Comarmond et al 2012 Quartuccio et al 2012 Novikov et al 2013 Tombetti et al 2013 [1] Mekinian et al 2015 [1] Goel et al 2013 Tombetti et al 2013 [2] Canas et al 2014 Yamazaki et al 2013 Mekinian et al 2015 [2] Loricera et al 2016 Zhou et al 2017

-20.000 3.729 0.000 -19.000 1.947 0.000 -14.500 6.783 0.033 -7.500 2.255 0.001 -22.500 9.703 0.020 -10.300 4.441 0.020 -7.500 3.707 0.043 -18.600 4.622 0.000 -4.000 2.594 0.123 -9.000 1.054 0.000 -6.300 3.245 0.052 -8.000 3.722 0.032 -40.000 11.665 0.001 -5.000 1.502 0.001 -11.139 1.682 0.000

15 25 5 15 9 15 35 10 7 8 6 14 8 13

TNF TNF TNF TNF TNF TNF TNF TCZ TCZ TCZ TCZ TCZ TCZ TCZ -60.00

-30.00

0.00

30.00

60.00

Fig. 3. Effect of steroid-sparing agents on prednisone doses. Meta-analysis of the prednisone dose reduction (mg/day) at follow-up after initiation of small molecule immunosuppressants (a) or biologic therapies (b).

Serious adverse events for the investigated therapies were uncommonly reported; however, there was no defined protocol for data extraction with the potential for reporting bias. More SAEs leading to drug discontinuation were reported for AZA (cytopenias causing infections and hospitalizations) compared to MMF and MTX. The adverse events for biologic drugs were similar to what has been reported for other conditions treated with these therapies (infections, infusion reactions and cancer). Severe complications occurred with CYX, which was only used in patients with severe disease [14,15]. Long-term observational studies show that 5–10% of TAK patients have disease refractory to several drugs [7,8]. Although anti-TNF agents are often used in combination with MTX, the role of other combination therapies in these refractory TAK patients has not been reported separately or investigated. New agents such as ustekinumab may be an option in these refractory patients [53]. This meta-analysis is limited by the quality of the included observational studies. Given the rarity of the disease, most of the studies were of small sample size. Many studies did not recruit patients consecutively or the procedures for inclusion were not described, which can introduce selection bias. Standardized data extraction protocols were infrequently described and the risk of reporting bias was high. Definitions of outcome measures (remission, relapse, angiographic progression and adverse events) for drug effectiveness were not standardized across studies. Therapeutic studies in TAK can be challenging as there are no specific biomarkers to diagnose active disease and imaging modalities are suboptimal [54,55]. Future studies should use validated disease activity scores to allow for standardization [56,57]. Only 2 studies had a comparator group and these studies did not account for confounders in their analyses [7,32]. Many of the meta-analyses reported here showed

high heterogeneity and high publication bias (data not shown). Potential sources of heterogeneity include: differences in duration of treatment and follow-up of outcomes, disease severity, GC regimens and the prior exposure to other steroid-sparing agents. Because of incomplete reporting, these factors could not be accounted for in analyses. 5. Conclusions The effectiveness of available non-GC drugs for patients with TAK is limited: remission rates are approximately 60% and relapses occur in N30% when they are given in combination with GC. There is insufficient evidence to recommend one non-GC drug over others. In one small RCT, ABA was not effective in maintaining remission in TAK. Although, some observational studies suggest a benefit of anti-TNF agents or TCZ over small molecule IS, a small RCT of TCZ did not show a statistically significant benefit of TCZ with GC compared to GC alone. Larger multi-national studies with standardized definitions of disease characteristics and outcomes and more consistent reporting of important outcomes are crucial to improve management of this challenging disease. Disclosures The authors declare no conflicts of interest pertaining to this study. Dr. L. Barra has received honoraria from Roche, UCB, Amgen and Pfizer. Dr. C. Pagnoux has received speaker fees from Roche and consulting fees (advisory boards) from Roche, Sanofi and ChemoCentryx. This work was partially funded by a grant from the Canadian Initiative for Outcomes in Rheumatology cAre (CIORA) – 2015 campaign, main applicant: Dr. C. Pagnoux.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

8

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

(Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada), Nader Khalidi (St Joseph's Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada), Majed Khraishi (Memorial University of Newfoundland, St John's, Newfoundland, Canada), Christian Pineau (McGill University, MUHC Lupus and Vasculitis clinic, Montréal, Québec, Canada), Dax G Rumsey (Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada), David Robinson (University of Manitoba, Arthritis Centre, Winnipeg, Manitoba, Canada), Regina Taylor-Gjevre (Royal University Hospital, University of Saskatchewan, Saskatoon, Canada), Tanveer Towheed (Queen's University, Kingston, Ontario, Canada), Judith Trudeau (CHAU de Lévis, Lévis, Quebec, Canada) and Rae Yeung (the Hospital for Sick Children, Toronto, Ontario, Canada).

Acknowledgements Study conception and design: LB, CP; lit search, review, study selection, data extraction and quality assessment: LB, GY; statistical analyses: LB. All authors interpreted data and reviewed and approved the final manuscript. The authors would like to acknowledge Kevin Lee for his help with the literature search. CanVasc collaborators are Volodko Bakowsky (Nova Scotia Rehabilitation Centre and Dalhousie University, Halifax, Nova Scotia, Canada), Simon Carette (Mount Sinai Hospital, Toronto, University of Toronto, Ontario, Canada), Natasha Dehghan (University of British Columbia, Vancouver, British Columbia, Canada), Leilani Famorca (Langs Community Centre, Cambridge, Ontario, Canada), Michele Goulet Appendix A

915 studies aer duplicates eliminated

755 excluded for irrelevance

96 without outcomes of interest excluded

29 case series with sample size < 5 excluded

35 observaonal studies and 4 RCTs included Fig. A.1. Search results. Studies identified by database searches with reasons for exclusion and number of observational and randomized controlled trials included in the systematic review and meta-analysis.

a Study name

Statistics for each study Difference in means

Standard error

Drug

p-Value

Valsakumar et al. 2003

-32.000

7.729

Shinjo et al. 2007

-12.000

4.873

0.014 MMF

Goel et al. 2010

-25.000

7.404

0.001 MMF

-2.000

0.693

0.004 LFM

-16.326

7.046

0.021

De Souza et al. 2012

Difference in means and 95%CI

0.000 AZA

-50.00 -25.00 0.00 25.00 50.00

b Study name

Statistics for each study

DrugDifference in means and 95% CI

Difference Standard in means error p-Value Total Valsakumar et al. 2003

-43.000

12.508

0.001

15

Shinjo et al. 2007

-12.800

4.365

0.003

10

MMF

Goel et al. 2010

-13.700 1079.498

0.990

21

MMF

15

LFM

De Souza et al. 2012

-5.000

1.733

0.004

-14.147

6.217

0.023

AZA

-100.00 -50.00

0.00

50.00 100.00

Fig. A.2. Effect of small molecule immunosuppressants on acute phase reactants. Meta-analysis of the reduction in ESR (mm/h) (a) and CRP (mg/L) at follow-up after initiation of small molecule immunosuppressants.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

9

a Study name

Statistics for each study

Biologic

Difference in means

Standard error

p-Value

Mekinian et al. 2011

-50.000

23.195

0.031

15

TNF

Novikov et al. 2013

-60.000

25.874

0.020

9

TNF

Tombetti et al. 2013 [1]

-13.000

4.439

0.003

15

TNF

-111.000

7.141

0.000

5

TNF

-30.000

6.982

0.000

10

TCZ

Serra et al. 2014 Goel et al. 2013 Loricera et al. 2016

-37.000

Zhou et al. 2017

10.995

Difference in means and 95%CI

Total

0.001

8

TCZ

-33.000

5.795

0.000

13

TCZ

-46.955

14.713

0.001 -150.00

b

Study name

Statistics for each study

-75.00

0.00

75.00

150.00

Difference in means and 95% CI

Biologic

Difference Standard in means error p-ValueTotal Comarmond et al. 2012

-28.000

9.931 0.005 5 TNF

Novikov et al. 2013

-16.000

6.900 0.020 9 TNF

Tombetti et al. 2013 [1]

-13.000

3.629 0.000 15 TNF

Serra et al. 2014

-25.550

2.967 0.000 5 TNF

-21.000

10.262 0.041 33 TNF

Mekinian et al. 2015 [1]

-19.983

3.551 0.000 -50.00

-25.00

0.00

25.00

50.00

c Study name

Statistics for each study

Biologic

Difference in means

Standard error

-6.900

8.580

0.421

10

TCZ

Mekinian et al. 2015 [2]

-24.000

11.053

0.030

14

TCZ

Loricera et al. 2017

-29.400

9.568

0.002

8

TCZ

Zhou et al. 2017

-28.400

8.529

0.001

13

TCZ

-21.751

5.579

0.000

Goel et al. 2013

Difference in means and 95% CI

p-Value Total

-50.00

-25.00

0.00

25.00

50.00

Fig. A.3. Effect of biologics on acute phase reactants. Meta-analysis of the reduction in ESR (mm/h) at follow-up after initiation of biologics (a); meta-analysis of the reduction in CRP (mg/L) at follow-up after initiation of anti-TNF agents (a) or TCZ (b).

a Study name

Drug Event Lower Upper rate limit limit

Total

Shelhamer et al 1985

0.333

0.084

0.732

2 / 6 CYX

Ozen et al 2007

0.800

0.309

0.973

4 / 5 CYX

Hoffman et al 2014

0.125

0.031

0.386 2 / 16 MTX

Valsakumar et al 2003 0.031

0.002

0.350 0 / 15 AZA

De Souza et al 2012

Event rate and 95% CI

0.133

0.034

0.405 2 / 15 LFN

0.219

0.072

0.504 -1.00

-0.50

0.00

0.50

1.00

b Study name

Biologic

Event rate and 95% CI

Event Lower Upper rate limit limit Total Hoffman et al 2004

0.333

0.146

Quartuccio et al 2012

0.154

0.039

0.451 2 / 13 TNF

Gudbrandsson et al 2017 0.094

0.031

0.254 3 / 32 TNF

Goel et al 2013

0.400

0.158

0.703 4 / 10 TCZ

Tombetti et al 2013 [2]

0.571

0.230

0.856 4 / 7 TCZ

Loricera et al 2016

0.125

0.017

0.537 1 / 8 TCZ

Zhou et al 2017

0.594 5 / 15 TNF

0.077

0.011

0.391 1 / 13 TCZ

0.229

0.121

0.390 -1.00

-0.50

0.00

0.50

1.00

Fig. A.4. Effect of steroid-sparing agents on angiographic disease progression. Meta-analysis of the proportion of patients experiencing new angiographic lesions or progression of existing lesions by various imaging modalities at follow-up after initiation of small molecule immunosuppressants (a) or biologics (b).

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

10

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx Table A1 Search Terms for MEDLINE and Embase 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

References [1] Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med 1994;120:919–29. [2] Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from cross-country research in Japan: age and sex specificity. Circulation 2015;132:1701–9. https://doi.org/10.1161/CIRCULATIONAHA. 114.012547. [3] Yilmaz N, Can M, Oner FA, Kalfa M, Emmungil H, Karadag O, et al. Impaired quality of life, disability and mental health in Takayasu's arteritis. Rheumatology (Oxford) 2013;52:1898–904. https://doi.org/10.1093/rheumatology/ket238. [4] Schmidt J, Kermani TA, Bacani AK, Crowson CS, Cooper LT, Matteson EL, et al. Diagnostic features, treatment, and outcomes of Takayasu arteritis in a US cohort of 126 patients. Mayo Clin Proc 2013;88:822–30. https://doi.org/10.1016/j.mayocp.2013. 04.025. [5] Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009; 68:318–23. https://doi.org/10.1136/ard.2008.088351. [6] Guideline for management of vasculitis syndrome (JCS 2008). Japanese circulation society. Circ J 2011;75:474–503. [7] Goel R, Danda D, Joseph G, Ravindran R, Kumar S, Jayaseelan V, et al. Long-term outcome of 251 patients with Takayasu arteritis on combination immunosuppressant therapy: single centre experience from a large tertiary care teaching hospital in southern India. Semin Arthritis Rheum 2017. https://doi.org/10.1016/j.semarthrit. 2017.09.014. [8] Ohigashi H, Tamura N, Ebana Y, Harigai M, Maejima Y, Ashikaga T, et al. Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. J Cardiol 2017;69:774–8. https://doi.org/10. 1016/j.jjcc.2016.07.009. [9] Keser G, Direskeneli H, Aksu K. Management of Takayasu arteritis: a systematic review. Rheumatology (Oxford) 2014;53:793–801. https://doi.org/10.1093/rheumatology/ket320. [10] Hozo SP, Djulbegovic BHI. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13.

Takayasu Arteritis Aortitis or/1–2 Methotrexate Azathioprine Mycophenolic Acid MTX AZA MMF Cyclophosphamide Cyclosporine Tacrolimus FK Mycophenolate mofetil Leflunomide Antirheumatic Agents Drug Therapy DMARD Biologics Antibodies, Monoclonal Anti-TNF Anti-Tumor Necrosis Factor-alpha TNF inhibitor Anti-interleukin 6 Tocilizumab Anti-IL6 IL-6 inhibitor Dmard Infliximab IFX Adalimumab Etanercept ETN Rituximab Anti-cd20 Golimumab Certolizumab Abatacept Or/4–45 3 and 39 case reports 40 not 41

[11] Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Hosp Res Inst 2013:1–4. [12] Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. [13] Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4(1). [14] Shelhamer JH, Volkman DJ, Parrillo JE, Lawley TJ, Johnston MR, Fauci AS. Takayasu's arteritis and its therapy. Ann Intern Med 1985;103:121–6. [15] Ozen S, Duzova A, Bakkaloglu A, Bilginer Y, Cil BE, Demircin M, et al. Takayasu arteritis in children: preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate. J Pediatr 2007;150:72–6. https://doi.org/10. 1016/j.jpeds.2006.10.059. [16] Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37:578–82. [17] GY, BK, KA, JL. Response of takayasu arteritis (TA) to prednisolone and methotrexate: an open label study. Indian J Rheumatol 2013;8:S27. [18] Kostina YOLG. Takaysu arteritis treatment in children. Pediatr Rheumatol 2014; 2014:12. [19] Valsakumar AK, Valappil UC, Jorapur V, Garg N, Nityanand S, Sinha N. Role of immunosuppressive therapy on clinical, immunological, and angiographic outcome in active Takayasu's arteritis. J Rheumatol 2003;30:1793–8. [20] Goel R, Danda D, Mathew J, Edwin N. Mycophenolate mofetil in Takayasu's arteritis. Clin Rheumatol 2010;29:329–32. https://doi.org/10.1007/s10067-009-1333-6. [21] Shinjo SK, Pereira RMR, Tizziani VAP, Radu AS, Levy-Neto M. Mycophenolate mofetil reduces disease activity and steroid dosage in Takayasu arteritis. Clin Rheumatol 2007;26:1871–5. https://doi.org/10.1007/s10067-007-0596-z. [22] de Souza AWS, da Silva MD, Machado LSG, Oliveira ACD, Pinheiro FAG, Sato EI. Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study. Scand J Rheumatol 2012;41:227–30. https://doi.org/10.3109/ 03009742.2011.633553.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019

L. Barra et al. / Autoimmunity Reviews xxx (2018) xxx–xxx [23] Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P. Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 2004;50:2296–304. https://doi.org/10.1002/art.20300. [24] Molloy ES, Langford CA, Clark TM, Gota CE, Hoffman GS. Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up. Ann Rheum Dis 2008;67:1567–9. https://doi.org/10.1136/ard.2008.093260. [25] Mekinian A, Neel A, Sibilia J, Cohen P, Connault J, Lambert M, et al. Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study. Rheumatology (Oxford) 2012;51:882–6. https://doi.org/10.1093/rheumatology/ ker380. [26] Schmidt J, Kermani TA, Bacani AK, Crowson CS, Matteson EL, Warrington KJ. Tumor necrosis factor inhibitors in patients with Takayasu arteritis: experience from a referral center with long-term followup. Arthritis Care Res 2012;64:1079–83. https://doi.org/10.1002/acr.21636. [27] Comarmond C, Plaisier E, Dahan K, Mirault T, Emmerich J, Amoura Z, et al. Anti TNFalpha in refractory Takayasu's arteritis: cases series and review of the literature. Autoimmun Rev 2012;11:678–84. https://doi.org/10.1016/j.autrev.2011.11.025. [28] Novikov PI, Smitienko IO, Moiseev SV. Tumor necrosis factor alpha inhibitors in patients with Takayasu's arteritis refractory to standard immunosuppressive treatment: cases series and review of the literature. Clin Rheumatol 2013;32:1827–32. https://doi.org/10.1007/s10067-013-2380-6. [29] Quartuccio L, Schiavon F, Zuliani F, Carraro V, Catarsi E, Tavoni AG, et al. Long-term efficacy and improvement of health-related quality of life in patients with Takayasu's arteritis treated with infliximab. Clin Exp Rheumatol 2012;30:922–8. [30] T E, B E, F S, M F, A P, Csd G. Efficacy of anti-TNF therapy in 15 patients with refractory takayasu's arteritis: long term unicentric follow-up. Ann Rheum Dis 2013;71. https://doi.org/10.1136/annrheumdis-2012-eular.2174. [31] Serra R, Grande R, Buffone G, Scarcello E, Tripodi F, Rende P, et al. Effects of glucocorticoids and tumor necrosis factor-alpha inhibitors on both clinical and molecular parameters in patients with Takayasu arteritis. J Pharmacol Pharmacother 2014;5: 193–6. https://doi.org/10.4103/0976-500X.136101. [32] Mekinian A, Comarmond C, Resche-Rigon M, Mirault T, Kahn JE, Lambert M, et al. Efficacy of biological-targeted treatments in Takayasu arteritis: multicenter, retrospective study of 49 patients. Circulation 2015;132:1693–700. https://doi.org/10.1161/ CIRCULATIONAHA.114.014321. [33] Gudbrandsson B, Molberg O, Palm O. TNF inhibitors appear to inhibit disease progression and improve outcome in Takayasu arteritis; an observational, populationbased time trend study. Arthritis Res Ther 2017;19:99. https://doi.org/10.1186/ s13075-017-1316-y. [34] NP, SI, ZE, EA, MS. Retrospective study of biologic agents in Takayasu arteritis. Rheumatol (United Kingdom) 2017:56. [35] Abisror N, Mekinian A, Lavigne C, Vandenhende M-A, Soussan M, Fain O. Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review. Autoimmun Rev 2013;12:1143–9. https://doi.org/10.1016/j.autrev.2013.06.019. [36] Tombetti E, Franchini S, Papa M, Sabbadini MG, Baldissera E. Treatment of refractory Takayasu arteritis with tocilizumab: 7 Italian patients from a single referral center. J Rheumatol 2013;40:2047–51. https://doi.org/10.3899/jrheum.130536. [37] Yamazaki K, Kikuchi M, Nozawa T, Kanetaka T, Hara R, Imagawa T, et al. Tocillizumab for patients with takayasu arteritis in childhood refractory to conventional therapy. Pediatr Rheumatol 2013:11. [38] Canas CA, Canas F, Izquierdo JH, Echeverri A-F, Mejia M, Bonilla-Abadia F, et al. Efficacy and safety of anti-interleukin 6 receptor monoclonal antibody (tocilizumab) in Colombian patients with Takayasu arteritis. J Clin Rheumatol 2014;20:125–9. https://doi.org/10.1097/RHU.0000000000000098. [39] Loricera J, Blanco R, Hernandez JL, Castaneda S, Humbria A, Ortego N, et al. Tocilizumab in patients with Takayasu arteritis: a retrospective study and literature review. Clin Exp Rheumatol 2016;34:S44–53.

11

[40] Zhou J, Chen Z, Li J, Yang Y, Zhao J, Chen H, et al. The efficacy of tocilizumab for the treatment of Chinese Takayasu's arteritis. Clin Exp Rheumatol 2017;35(Suppl. 1): 171–5. [41] Goel RSG. Long term outcome of tocilizumab therapy for management of Takayasu arteritis. Indian J Rheumatol 2017;12:S15. [42] Pazzola G, Muratore F, Pipitone N, Crescentini F, Cacoub P, Boiardi L, et al. Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature. Rheumatology (Oxford) 2017. https://doi.org/10.1093/rheumatology/kex249. [43] BSBAZDDF R, NP, HM, KS, Takayasu S. Arteritis: clinical features and treatment outcome in 16 pediatric patients. Clin Exp Rheumatol 2011;29:403. [44] Shao N, Jia H, Li Y, Li J. Curcumin improves treatment outcome of Takayasu arteritis patients by reducing TNF-alpha: a randomized placebo-controlled double-blind clinical trial. Immunol Res 2017;65:969–74. https://doi.org/10.1007/s12026-017-8917z. [45] Shi G, Hua M, Xu Q, Ren T. Resveratrol improves treatment outcome and laboratory parameters in patients with Takayasu arteritis: a randomized double-blind and placebo-controlled trial. Immunobiology 2017;222:164–8. https://doi.org/10.1016/j. imbio.2016.10.008. [46] Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, et al. A randomized, double-blind trial of Abatacept (CTLA-4Ig) for the treatment of Takayasu arteritis. Arthritis Rheumatol (Hoboken, NJ) 2017;69:846–53. https://doi. org/10.1002/art.40037. [47] Nakaoka Y, Isobe M, Takei S, Tanaka Y, Ishii T, Yokota S, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis 2017. https://doi.org/10.1136/annrheumdis-2017-211878. [48] B S, B A, Z D, D F, N P, H M, et al. Takayasu arteritis: clinical features and treatment outcome in 16 pediatric patients. Clin Exp Rheumatol 2011;29:403. [49] Goel R, Danda D, Kumar S, Joseph G. Rapid control of disease activity by tocilizumab in 10 “difficult-to-treat” cases of Takayasu arteritis. Int J Rheum Dis 2013;16:754–61. https://doi.org/10.1111/1756-185X.12220. [50] Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis activity score (BVAS) in systemic necrotizing vasculitis. QJM 1994;87:671–8. [51] Barra L, Liang P, Benseler SM, Cabral DA, Fifi-Mah A, Li Y, et al. Variations in the clinical practice of physicians managing Takayasu arteritis: a nationwide survey. Open Access Rheumatol Res Rev 2017;9:91–9. https://doi.org/10.2147/OARRR.S132080. [52] Aeschlimann FA, Eng SWM, Sheikh S, Laxer RM, Hebert D, Noone D, et al. Childhood Takayasu arteritis: disease course and response to therapy. Arthritis Res Ther 2017; 19:255. https://doi.org/10.1186/s13075-017-1452-4. [53] Terao C, Yoshifuji H, Nakajima T, Yukawa N, Matsuda F, Mimori T. Ustekinumab as a therapeutic option for Takayasu arteritis: from genetic findings to clinical application. Scand J Rheumatol 2016;45:80–2. https://doi.org/10.3109/03009742.2015. 1060521. [54] Aydin SZ, Merkel PA, Direskeneli H. Outcome measures for Takayasu's arteritis. Curr Opin Rheumatol 2015;27:32–7. https://doi.org/10.1097/BOR.0000000000000129. [55] Barra L, Kanji T, Malette J, Pagnoux C, Vasc C. Imaging modalities for the diagnosis and disease activity assessment of Takayasu's arteritis: a systematic review and meta-analysis. Autoimmun Rev 2017. https://doi.org/10.1016/j.autrev.2017.11.021. [56] Misra R, Danda D, Rajappa SM, Ghosh A, Gupta R, Mahendranath KM, et al. Development and initial validation of the Indian Takayasu clinical activity score (ITAS2010). Rheumatology (Oxford) 2013;52:1795–801. https://doi.org/10.1093/rheumatology/ ket128. [57] Sreih AG, Alibaz-Oner F, Kermani TA, Aydin SZ, Cronholm PF, Davis T, et al. Development of a Core set of outcome measures for large-vessel Vasculitis: report from OMERACT 2016. J Rheumatol 2017;44:1933–7. https://doi.org/10.3899/jrheum. 161467.

Please cite this article as: Barra L, et al, Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.019