International Journal of Rheumatic Diseases 2013; 16: 754–761
ORIGINAL ARTICLE
Rapid control of disease activity by tocilizumab in 10 ‘difficult-to-treat’ cases of Takayasu arteritis Ruchika GOEL,1 Debashish DANDA,1 Sathish KUMAR2 and George JOSEPH3 Departments of 1Clinical Immunology and Rheumatology, CMC, 2Child Health, CMC, and 3Cardiology, CMC, Vellore, Tamil Nadu, India
Abstract Aim: To assess outcome of 10 ‘difficult to treat’ patients with Takayasu arteritis (TA) treated with tocilizumab. Methods: Records of 10 patients with TA who received at least six infusions of tocilizumab were studied and data related to demography, medications, investigations, angiography and outcome were analyzed. Results: Median age, disease duration and Indian Takayasu Arteritis Score (ITAS) of 10 patients were 24.5 (13– 53) years, 25.5 (1.5–60) months and 4.5 (0–13), respectively. All patients had active disease with ITAS of ≥ 1 and/or they were angiographically active in spite of treatment with steroids and second line agents for a median duration of 27 (15–60) months. Tocilizumab led to a clinical response with ITAS of 0 and reduction in acute phase reactants (APR) in 100% of patients by the fourth infusion. Six patients (60%) maintained clinical response with radiologically stable disease and normal APR up to the sixth infusion. Two out of three patients (66%) with normal APR at baseline achieved and maintained stable disease state up to the last infusion, in contrast to 49.2% (4/7) responders in those with baseline high APR. Tocilizumab facilitated rapid reduction in steroid dose from 24 15 to 5.4 4.9 mg/day (P = 0.003). However, following discontinuation of toclizumab therapy after six infusions, only two patients maintained stable disease state and the majority of them needed rescue therapy. There was no major adverse event or fatality. Conclusion: Tocilizumab may be an effective steroid-sparing option for rapid control of refractory disease activity in patients of TA. However, the benefit is not sustained after its withdrawal. Key words: Indian Takayasu Arteritis Score, India, Takayasu Arteritis, Tocilizumab, Vasculitides.
SIGNIFICANCE AND INNOVATION
INTRODUCTION
Interleukin-6 is a key cytokine in Takayasu arteritis This is the largest series on efficacy of tocilizumab in Takayasu artertitis, using an objective clinical tool and follow-up angiographic data Tocilizumab may be an effective, steroid-sparing and short-term option for rapid control of refractory disease activity in patients with Takayasu arteritis
Takayasu arteritis (TA) is a primary granulomatous large vessel vasculitis characterized by inflammation followed by stenosis of the aorta and its main branches.1 Glucocorticoids have been the mainstay of therapy in TA, but a good number of patients relapse upon tapering of steroids. Long-term continuation of steroids, on the other hand, is limited by its toxicity. Various steroid-sparing immunosuppressants such as methotrexate, azathioprine, mycophenolate mofetil and cylcophosphamide have been used in conjunction with tapering doses of steroids during induction and maintenance of remission in TA.2,3 Successful use of biological agents like infliximab and even rituximab in refractory cases have been reported.4,5
Correspondence: Professor Debashish Danda, Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore 632004, Tamil Nadu, India. Emails: [email protected]; [email protected]
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Tocilizumab in 10 cases of Takayasu arteritis
Interleukin 6 (IL-6) has emerged as a key cytokine in the pathogenesis of TA and its serum levels have been shown to correlate well with disease activity.6 Recently tocilizumab, a monoclonal antibody (mAb) blocking soluble IL-6 receptor (IL-R) has been shown to be an effective option in inducing and maintaining remission in both treatment-na€ıve as well as refractory cases of giant cell arteritis and TA.7–9 However, these series had smaller numbers of patients and therefore needed further reproducibility in a larger cohort. The aim of this observational study was to assess the outcome of 10 patients with TA treated with at least six doses of tocilizumab at the largest tertiary care teaching hospital in southern India.
METHODS Case records of 10 patients with TA, who had received at least six doses of monthly tocilizumab infusions, were studied. TA was diagnosed according to 1990 modified American College of Rheumatology (ACR) criteria.9 Details of demography, angiographic type,10 laboratory markers, clinical disease activity, medications used, treatment outcome and adverse events related to tocilizumab were noted at each visit. Clinically active disease was defined as an Indian Takayasu Arteritis activity Score (ITAS)11 of ≥ 1 with or without raised inflammatory markers. Briefly, ITAS is a weighted score derived from the Birmingham Vasculitis Score and comprises of 44 items from six organ-based systems. Special importance is given to 33 items of cardiovascular systems, for example, new loss of pulse, bruit, claudication and so on. Any new appearance of items in the preceding 3 months is given a score of 1; however, a cardiovascular item is given an additional weighted score. Absence of new symptoms or signs mentioned in the scoring sheet is assigned a value of 0. The final score is the sum of all individual scores. Raised acute phase reactants (APR) was defined as an erythrocyte sedimentation rate (ESR) > 20 mm in the first hour by Westergren method and C-reactive protein (CRP) > 5 mg/L. Evidence of new areas of vessel involvement or more than 70% in-stent re-stenosis (ISR) on conventional angiography was considered as angiographically active disease.
Indications for tocilizumab Disease activity by clinical evidence, APR or angiography as defined above were indications for tocilizumab. Toxicity of steroids in presence of refractory, active or relapsing disease requiring rapid control of disease in
International Journal of Rheumatic Diseases 2013; 16: 754–761
willing patients were additional prerequisites to recruit patients for tocilizumab infusion. Response to therapy was defined as attainment of ITAS of 0 during follow-up visits, with normalization of inflammatory markers and stable disease on conventional angiography or other imaging modalities, such as color Doppler or 18fluorodeoxyglucose-uptake study (positron emission tomography [PET]-computed tomography [CT] angiogram). In addition to attainment of ITAS of 0, reduction in dosage of steroids second line immunosuppresants to maintain stable disease was also considered as clinical response to tocilizumab therapy. All the patients had consented to receive tocilizumab after having understood about the cost, efficacy and possible adverse events of the drug. This study was approved by our Institutional Review Board (IRB) which encompasses ethics and research committees.
RESULTS Ten patients with TA had completed six doses of monthly tocilizumab infusions (8 mg/kg/day with maximum of 600 mg/infusion) at the time of writing this manuscript. Nine out of 10 patients were female with median age of 24.5 (range 13–53) years. Median disease duration was 25.5 (range 1.5–60) months. All patients satisfied 1990 ACR classification criteria9 and had undergone conventional angiography for diagnosis of TA. Eight of these 10 patients with angiographically active disease also had overtly clinical disease activity with either high ITAS or raised inflammatory markers.
Descriptive details of disease activity and angiography in TA patients on tocilizumab therapy All 10 patients had angiographically active disease (Table 1). One of these 10 patients with short disease duration of 1.5 months and high ITAS had normalized inflammatory markers due to prior steroids and methotrexate treatment. She had opted for tocilizumab in order to rapidly reduce her dose of steroids. The remaining nine patients were refractory to treatment with steroids and mycophenolate or azathioprine for a median period of 27 (range 5–60) months. Eight of these 10 with angiographically active disease had overt clinically active disease with either high ITAS or raised inflammatory markers. Notably, one out of these eight patients had only clinically active disease (patient no. 7). The remaining two in this cohort of 10 patients (patients no. 3 and 5) had only angiographic activity. To be
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Table 1 Demography and indications of tocilizumab therapy Patient No.
Sex/ age (years)
Type†
Disease duration (months)
Prior immunosuppressant
1
F/26
I
12
MMf
2
F/48
Ic
27
MMf
3
F/53
Ic
27
MMf
4
M/25
V
57
5 6
F/26 F/20
V V
60 27
7
F/23
V
8
F/21
V
9
F/13
10
F/15
Baseline steroid dose (mg/day)
Inflammatory markers‡
5
R
2
R
27.5
0
WNL
Aza ? MMf
20
6
R
Aza MMf
2.5 40
0 1
WNL R
Mtx
30
5
WNL
24
MMf
20
13
R
V
5
MMf
25
4
R
V
10
MMf
50
4
R
1.5
25
Baseline ITAS
Stopped
Indication for TCZ
Active disease with raised inflammatory markers ISR with raised inflammatory markers ISR, steroid-induced diabetes and glaucoma, needing steroid rescue Clinically active, ISR with raised inflammatory markers Repeated ISR within 1 year ISR with raised inflammatory markers Clinically and angiographic active, patient opted Clinically active (2 years of adequate treatment) ISR with raised inflammatory markers ISR with raised inflammatory markers
†Angiographic type, ISR, in-stent restenosis; MMf, mycophenolate mofetil; Mtx, methotrexate; AZA, azathioprine. ‡Erythrocyte sedimentation rate or C-reactive protein; R, raised; WNL, within normal limits.
specific, these two patients did not have raised ITAS or inflammatory markers, but had angiographic progression of disease with repeated in-stent re-stenosis requiring repeated procedures on the same vessels. Both these patients had undergone a careful search for presence of dyslipidemia as well as anti-phospholipid antibodies, namely anti-cardiolipin antibodies, lupus anticoagulant and anti-beta-2 glycoprotein-1 antibodies as risk factors for in stent re-stenosis. Patient no. 3 had > 90% re-stenosis of successfully recanalized and stented subclavian arteries within 13 months of these interventions, inspite of dual anti-platelet agents and high-dose steroids following an uncomplicated, immediate postprocedural period. This patient had steroid-induced diabetes and glaucoma warranting rapid reduction in steroid dose and therefore she was given tocilizumab as an alternative to steroids. Patient no. 5 also had recurrent in-stent re-stenosis of > 80% in the left subclavian and celiac arteries (three and two times, respectively, in a span of 3 years) with abdominal angina without any evidence of thrombosis. As this patient was already grossly cushingoid, steroids was not to be escalated further and instead tocilizumab was initiated for her. All the patients had been screened for active or latent tuberculosis by high-resolution CT (HRCT) scan and
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interferon gamma-based assay (IGRA) prior to tocilizumab therapy. Two patients had tested positive for IGRA; however, they had normal HRCT chest scans. They were given isoniazid prophylaxis for 6 months. None had evidence of active infection, dyslipidemia or liver function abnormality prior to initiation of tocilizumab therapy. Follow-up conventional angiography was performed for nine out of 10 patients, while one patient with type 1 disease by baseline angiography underwent color Doppler study of involved vessels to determine disease status at the sixth infusion. This patient with type 1c+ (type 1 with coronary artery involvement) disease did not undergo follow-up angiography in view of persistently stable disease by ITAS along with normal APR throughout the follow-up period. Additional PET-CT angiogram was performed in two patients and it was abandoned for any other patients in view of poor correlation with clinical activity, APR, as well as conventional angiography findings, in addition to prohibitive costs.
Response to tocilizumab All 10 patients (100%) had achieved an initial clinical response with an ITAS of 0 and normalization of
International Journal of Rheumatic Diseases 2013; 16: 754–761
Tocilizumab in 10 cases of Takayasu arteritis
inflammatory markers by the fourth infusion (Table 1, Figs 1,2). Three out of 10 patients (30%) with initial clinical response by the fourth infusion relapsed both clinically and angiographically at last infusion. Seven out of 10 patients (70%) sustained clinical response until the last infusion. Follow-up imaging study (conventional angiography in nine patients and color Doppler study in one patient) during the last infusion confirmed stable disease in six of these seven patients (60% of the whole cohort), while one patient had angiographic evidence of disease progression at last infusion. The single patient with clinically stable disease and angiographically active disease at last infusion was a young man with persistently raised inflammatory markers.
Angiographic findings in the same patient included progression of re-stenosis (ISR) in the left subclavian artery endovascular stent from 70% (pre-tocilizumab) to complete occlusion by the sixth dose, although a PET-CT angiogram done at the fourth infusion in this patient did not show any uptake. In summary, clinically stable state with ITAS of 0 was observed in 70% of patients at the time of the sixth infusion, whereas absolute stable disease state by all three parameters, namely clinical assessment (ITAS), laboratory parameters (ESR, CRP) and angiography, was sustained in 60% of patients at their last infusion. Mean ESR dropped from 36.7 17.9 to 6.9 10.8 mm in the first hour (P = 0.002) and CRP levels
Figure 1 Flow chart of response to tocilizumab until last infusion. ITAS, Indian Takayasu Assessment Score; APR, acute phase reactants.
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Figure 2 Acute phase reactant response to tocilizumab and representative follow-up angiography. ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
declined from 14.9 18.4 to 8.0 20.3 (P = 0.442) (Fig. 2). Infusion of tocilizumab also facilitated rapid reduction in steroid dose from 24 15 to 5.4 4.9 mg/day (P = 0.003).
Response in patients with raised baseline APR versus those with normal APR Among the 10 patients studied, seven (70%) patients had raised APR and three (30%) had APR within normal limits at baseline. Four out of these seven (49.2%) patients with raised APR at baseline achieved a stable disease state by all three parameters and sustained this benefit until the last infusion.
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Of the three patients with normal APR at baseline, one (patient no. 7) had high ITAS score at baseline and this patient continued to do well on tocilizumab until the sixth infusion, only to relapse again at the fifth month after withdrawl of tocilizumab as indicated by increased ITAS and rising APR. One other patient in this subset (patient no. 5) did not maintain angiographically stable disease at last infusion, in-spite of showing an initial clinical response by the fourth infusion. The remaining patient of these three (patient no. 3) showed patent subclavian artery with good flow through the stent by color Doppler at the sixth infusion. However, a repeat angiography performed at 5 months post-toc-
International Journal of Rheumatic Diseases 2013; 16: 754–761
Tocilizumab in 10 cases of Takayasu arteritis
ilizumab withdrawal again showed in-stent re-stenosis of the same vessel in this patient. Tapering of steroid dose was dictated by attainment of ITAS of 0 and normalization of inflammatory markers, with the intention of attaining a dose equivalent to or less than 7.5 mg/day of prednisolone. Steroid dosage was reduced from mean baseline 24 15.1 mg/day to 5.4 4.9 mg/day at the sixth dose. Second line immunosuppressant was discontinued prior to the first infusion of tocilizumab in five patients and an additional two patients were taken off these agents by the second infusion. Only three patients continued mycophenolate until the sixth infusion. None of the patients had serious adverse events. One patient each had transient skin rash, transient transaminitis, uncomplicated urinary tract infection and upper respiratory tract infection. One other patient had bleeding per rectum before the third dose, which was later found to be due to hemorrhoids and was unrelated to tocilizumab.
Extended follow up after withdrawal of tocilizumab Data was available for nine out of 10 patients with median follow-up of 8 months (range 3–14 months) after discontinuation of tocilizumab with one patient being lost to follow-up. Among them, stable disease state was maintained in only two patients up to their last recorded post-tocilizumab follow-up visit; three had relapsed after a period of good response and four patients had persistently active disease after cessation of tocilizumab (Table 2). This necessitated escalation of steroid dose in three patients and re-introduction of additional infusions of tocilizumab in three others. However, second line agents (mycophenolate mofetil or azathioprine) were restarted in all patients after withdrawal of tocilizumab infusion; six of them were restarted on these agents within 2 months of discontinuing tocilizumab and the remaining two were on these agents by the fifth and sixth month respectively after discontinuation of the infusion. With these measures, 60% (n = 6) of patients had regained stable disease state, while 30% (n = 3) continued to have active or grumbling disease at the last posttocilizumab follow-up visits.
DISCUSSION At present, there is paucity of an ideal steroid sparing agent for TA. Published literature6 as well as our previous work (R. Goel, D. Danda, S. Natarajan, J. Mathew,
International Journal of Rheumatic Diseases 2013; 16: 754–761
V. Balaji, G. Joseph, unpubl. observ.), suggest IL-6 to be a key cytokine-mediating inflammation in TA. This biological basis and concurrent results of our present series, similar to successful case reports from the literature, indicate that tocilizumab therapy may be a safe and effective, steroid-sparing option for refractory cases of TA.7–9,12 Two recently reported case series with two TA patients in each have shown efficacy of tocilizumab, mainly in refractory cases.8,9,12 One of these reports had shown modest benefit,8 while the one by Salvarani et al.9 showed reduction in inflammation by PET-CT studies. The latest retrospective study by Stone and colleagues. reconfirmed the efficacy of tocilizumab for large vessel vasculitis as a group.12 In the present study too, we have demonstrated a good clinical response, defined as ITAS of 0 or reduction in dosage of steroids and/or other immunosupressants in 100% of patients by the fourth infusion and in 70% at the sixth infusion. Notably, 60% of patients had maintained an unequivocally stable disease state at the sixth infusion by all three criteria, namely clinical, radiological and APRs. However, we note with caution the return of disease activity after discontinuation of the drug in three out of these six patients who had attained complete remission on tocilizumab. Earlier reports from the literature showed presence of subclinical inflammation in TA as evidenced by angiographic progression in 60% and presence of histologically active disease in 44% of patients inspite of normal APRs.1 The pathogenesis of stent re-stenosis is an interplay of thrombus formation and/or acute and chronic inflammation. Infact, persistence of chronic inflammation beyond 90 days is shown to be associated with increased intimal thickness and restenosis.13 This may be more so in the setting of an already existing inflammatory condition such as TA. Moreover, biological inflammation has been shown to increase the odds of procedural complications like in-stent re-stenosis in TA by up to seven times.14 A careful search excluded thrombus formation at the stent placement site to be the cause of re-stenosis in our patients. Thus, we were justified in initiating tocilizumab for the subset of patients (n = 3) with normal APR and angiographically progressive disease at baseline. A recent report on tocilizumab in lupus has shown successful reduction in number of activated T cells and B cells with tocilizumab therapy in a subset of patients with raised numbers of these cells at baseline irrespective of their APR status.15 Tocilizumab, therefore, appears to be a promising alternative to high-dose steroids and an effective stop-gap
759
760
27.5
20
3
4
30
20
25
50
7
8
9
10
3
10
5
5
5
1
10
0
0
15
Steroid dose (mg/day)
6
6
3
8
Lost to follow up
8
9
5
14
12
Duration† (months)
0
0
7.5
30
–
7.5
10
1
0
7.5
Steroid dose (mg/day)
†Duration calculated from the time tocilizumab was discontinued; Angio, conventional angiography. ¶Erythrocyte sedimentation rate or C-reactive protein; R, raised; WNL, within normal limits; ND, not done. §Angio: A, active; S, stable; G, grumbling; Re, relapse. MMf, mycophenolate mofetil; AZA, azathioprine; TCZ,tocilizumab; PDN, prednisolone equivalent.
40
6
2.5
0
2
5
25
Disease activity: ITAS, Lab¶, Angio§ ITAS = 5, Lab R, Angio A ITAS = 2, Lab R, Angio A ITAS = 0, Lab WNL, Angio A ITAS = 6, Lab R, Angio A ITAS = 0, Lab WNL, Angio A ITAS = 1, Lab R, Angio A ITAS = 5, Lab WNL, Angio A ITAS = 13, Lab R, Angio A ITAS = 4, Lab R, Angio A ITAS = 4, Lab R, Angio A
At last dose Disease activity: ITAS, Lab¶, Angio§ ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio ND ITAS = 0, Lab R, Angio A ITAS = 2, Lab WNL, Angio A ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio S ITAS = 4, Lab WNL, Angio A ITAS = 0, Lab WNL, Angio S ITAS = 4, Lab WNL, Angio A
During TCZ infusion
At baseline visit
Steroid dose (mg/day)
1
Patient no.
Table 2 Response to tocilizumab and extended follow-up after withdrawal of tocilizumab
MMf 2 gm/ day + TCZ 10th dose
MMf 2 gm/day
MMf 2 gm/day
MMf 2 gm/day
–
AZA 100 mg/day
S
S
G
S
–
S
A
A
Rescue TCZ + MMf 2 gm/day MMf 2 gm/day
S
S
Disease activity
MMf 2 gm/day
MMf 2 gm/ day + TCZ 12th dose
Second line immunosuppressant
Last visit
Post-TCZ withdrawal†
Active at 3 months
Stable throughout
Persistently grumbling acitvity
Relapsed at 5 months
–
Active at 2 months
Persistently active
Persistently active
Stable throughout
Relapsed at 6 months
Disease course
R. Goel et al.
International Journal of Rheumatic Diseases 2013; 16: 754–761
Tocilizumab in 10 cases of Takayasu arteritis
measure to attain rapid control of disease in refractory or relapsing cases of TA. However, its role in those with clinically active disease with normal APR needs further studies as its beneficial effect on arresting in-stent re-stenosis was short-lasting in our series. Long-term follow-up studies with large randomized controlled trials are needed to establish efficacy of tocilizumab in TA. It is also not clear whether angiographic evidence of activity reflects a true biological inflammation as a part of the disease process, or is it due to thrombosis and/or fibrosis as a part of disease sequelae or mechanical trauma incited by stents? It is possible that the patients with normal APR with angiographic progression could represent a totally different disease subset of patients. Ours is the largest series examining tocilizumab therapy in TA. To the best of our knowledge, this is also the first report of use of this drug in Asian patients with TA with follow-up imaging data in all patients to define true response, apart from clinical response by ITAS score, reduction in steroid and/or immunosuppressant dosage and normalization of APR. In our setting, PET-CT peformed for two patients did not correlate well with clinical and angiographic assessment of disease, nor did they correlate with inflammatory markers, similar to a few reports in literature.16 Patients, therefore, were not subjected to this expensive imaging option for evaluation.
CONCLUSION Tocilizumab may be an effective, steroid-sparing stopgap measure in refractory and relapsing patients with TA for rapid control of disease activity. While it can be an alternative to steroids in TA, second line agents like mycophenolate may have to be initiated and continued along with tocilizumab to sustain its steroid-sparing benefit even after withdrawl of tocilizumab.
DISCLOSURES None.
REFERENCES 1 Kerr GS, Hallahan CW, Giordano J et al. (1994) Takayasu arteritis. Ann Intern Med 120, 919–29. 2 Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS (1994) Treatment of glucocorticoid-resistant or relapsing Takayasu’s arteritis with methotrexate. Arthritis Rheum 37, 578–82.
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3 Goel R, Danda D, Mathew J, Edwin N (2010) Mycophenolatemofetil in Takayasu’s arteritis. Clin Rheumatol 29, 329–32. 4 Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P (2004) Anti-tumor necrosis factor therapy in patients with difficult-to-treat Takayasu arteritis. Arthritis Rheum 50, 2296–304. 5 Hoyer BF, Mumtaz IM, Loddenkemper K et al. (2012) Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 71, 75–9. 6 Park MC, Lee SW, Park YB, Lee SK (2006) Serum cytokine profiles and their correlations with disease activity in Takayasu’s arteritis. Rheumatology 45, 545–8. 7 Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T (2008) Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum 58, 1197–200. 8 Seitz M, Reichenbacha S, Bonel HM, Adler S, Wermelinger F, Villiger PM (2011) Rapid induction of remission in large vessel vasculitis by IL-6 blockade. Swiss Med Wkly 141, w13156. 9 Salvarani C, Magnani L, Catanoso M et al. (2012) Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology 51, 151–6. 10 Moriwaki R, Noda M, Yajima M, Sharma BK, Numano F (1997) Clinical manifestations of Takayasu arteritis in India and Japan – new classification of angiographic findings. Angiology 48(5), 369–79. 11 Mishra R, Danda D, Jayaseelan L, Sivakumar R, Lawrence A, Bacon PA (2008) ITAS & DEI.TAK—scores for clinical disease activity and damage extent in Takayasu’s aortoarteritis (TA). Rheumatology 47(Suppl 2), 101. 12 Unizony S, Arias-Urdaneta L, Miloslavsky E et al. (2012) Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res 64, 1720–9. 13 Farb A, Kolodgie FD, Hwang J-Y et al. (2004) Extracellular matrix changes in stented human coronary arteritis. Circulation 110, 940–7. 14 Saadoun D, Lambert M, Miraul T et al. (2012) Retrospective analysis of surgery versus endovascular intervention in Takayasu arteritis. Circulation 125, 813–9. 15 Shirota Y, Yarboro C, Fischer R, Pham TH, Lipsky P, Illei GG (2013) Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis 72(1), 118– 28. 16 Arnaud L, Haroche J, Malek Z et al. (2009) Is (18)Ffluorodeoxyglucose positron emission tomography scanning a reliable way to assess disease activity in Takayasu arteritis? Arthritis Rheum 60, 1193–200.
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ORIGINAL ARTICLE
Rapid control of disease activity by tocilizumab in 10 ‘difficult-to-treat’ cases of Takayasu arteritis Ruchika GOEL,1 Debashish DANDA,1 Sathish KUMAR2 and George JOSEPH3 Departments of 1Clinical Immunology and Rheumatology, CMC, 2Child Health, CMC, and 3Cardiology, CMC, Vellore, Tamil Nadu, India
Abstract Aim: To assess outcome of 10 ‘difficult to treat’ patients with Takayasu arteritis (TA) treated with tocilizumab. Methods: Records of 10 patients with TA who received at least six infusions of tocilizumab were studied and data related to demography, medications, investigations, angiography and outcome were analyzed. Results: Median age, disease duration and Indian Takayasu Arteritis Score (ITAS) of 10 patients were 24.5 (13– 53) years, 25.5 (1.5–60) months and 4.5 (0–13), respectively. All patients had active disease with ITAS of ≥ 1 and/or they were angiographically active in spite of treatment with steroids and second line agents for a median duration of 27 (15–60) months. Tocilizumab led to a clinical response with ITAS of 0 and reduction in acute phase reactants (APR) in 100% of patients by the fourth infusion. Six patients (60%) maintained clinical response with radiologically stable disease and normal APR up to the sixth infusion. Two out of three patients (66%) with normal APR at baseline achieved and maintained stable disease state up to the last infusion, in contrast to 49.2% (4/7) responders in those with baseline high APR. Tocilizumab facilitated rapid reduction in steroid dose from 24 15 to 5.4 4.9 mg/day (P = 0.003). However, following discontinuation of toclizumab therapy after six infusions, only two patients maintained stable disease state and the majority of them needed rescue therapy. There was no major adverse event or fatality. Conclusion: Tocilizumab may be an effective steroid-sparing option for rapid control of refractory disease activity in patients of TA. However, the benefit is not sustained after its withdrawal. Key words: Indian Takayasu Arteritis Score, India, Takayasu Arteritis, Tocilizumab, Vasculitides.
SIGNIFICANCE AND INNOVATION
INTRODUCTION
Interleukin-6 is a key cytokine in Takayasu arteritis This is the largest series on efficacy of tocilizumab in Takayasu artertitis, using an objective clinical tool and follow-up angiographic data Tocilizumab may be an effective, steroid-sparing and short-term option for rapid control of refractory disease activity in patients with Takayasu arteritis
Takayasu arteritis (TA) is a primary granulomatous large vessel vasculitis characterized by inflammation followed by stenosis of the aorta and its main branches.1 Glucocorticoids have been the mainstay of therapy in TA, but a good number of patients relapse upon tapering of steroids. Long-term continuation of steroids, on the other hand, is limited by its toxicity. Various steroid-sparing immunosuppressants such as methotrexate, azathioprine, mycophenolate mofetil and cylcophosphamide have been used in conjunction with tapering doses of steroids during induction and maintenance of remission in TA.2,3 Successful use of biological agents like infliximab and even rituximab in refractory cases have been reported.4,5
Correspondence: Professor Debashish Danda, Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore 632004, Tamil Nadu, India. Emails: [email protected]; [email protected]
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Tocilizumab in 10 cases of Takayasu arteritis
Interleukin 6 (IL-6) has emerged as a key cytokine in the pathogenesis of TA and its serum levels have been shown to correlate well with disease activity.6 Recently tocilizumab, a monoclonal antibody (mAb) blocking soluble IL-6 receptor (IL-R) has been shown to be an effective option in inducing and maintaining remission in both treatment-na€ıve as well as refractory cases of giant cell arteritis and TA.7–9 However, these series had smaller numbers of patients and therefore needed further reproducibility in a larger cohort. The aim of this observational study was to assess the outcome of 10 patients with TA treated with at least six doses of tocilizumab at the largest tertiary care teaching hospital in southern India.
METHODS Case records of 10 patients with TA, who had received at least six doses of monthly tocilizumab infusions, were studied. TA was diagnosed according to 1990 modified American College of Rheumatology (ACR) criteria.9 Details of demography, angiographic type,10 laboratory markers, clinical disease activity, medications used, treatment outcome and adverse events related to tocilizumab were noted at each visit. Clinically active disease was defined as an Indian Takayasu Arteritis activity Score (ITAS)11 of ≥ 1 with or without raised inflammatory markers. Briefly, ITAS is a weighted score derived from the Birmingham Vasculitis Score and comprises of 44 items from six organ-based systems. Special importance is given to 33 items of cardiovascular systems, for example, new loss of pulse, bruit, claudication and so on. Any new appearance of items in the preceding 3 months is given a score of 1; however, a cardiovascular item is given an additional weighted score. Absence of new symptoms or signs mentioned in the scoring sheet is assigned a value of 0. The final score is the sum of all individual scores. Raised acute phase reactants (APR) was defined as an erythrocyte sedimentation rate (ESR) > 20 mm in the first hour by Westergren method and C-reactive protein (CRP) > 5 mg/L. Evidence of new areas of vessel involvement or more than 70% in-stent re-stenosis (ISR) on conventional angiography was considered as angiographically active disease.
Indications for tocilizumab Disease activity by clinical evidence, APR or angiography as defined above were indications for tocilizumab. Toxicity of steroids in presence of refractory, active or relapsing disease requiring rapid control of disease in
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willing patients were additional prerequisites to recruit patients for tocilizumab infusion. Response to therapy was defined as attainment of ITAS of 0 during follow-up visits, with normalization of inflammatory markers and stable disease on conventional angiography or other imaging modalities, such as color Doppler or 18fluorodeoxyglucose-uptake study (positron emission tomography [PET]-computed tomography [CT] angiogram). In addition to attainment of ITAS of 0, reduction in dosage of steroids second line immunosuppresants to maintain stable disease was also considered as clinical response to tocilizumab therapy. All the patients had consented to receive tocilizumab after having understood about the cost, efficacy and possible adverse events of the drug. This study was approved by our Institutional Review Board (IRB) which encompasses ethics and research committees.
RESULTS Ten patients with TA had completed six doses of monthly tocilizumab infusions (8 mg/kg/day with maximum of 600 mg/infusion) at the time of writing this manuscript. Nine out of 10 patients were female with median age of 24.5 (range 13–53) years. Median disease duration was 25.5 (range 1.5–60) months. All patients satisfied 1990 ACR classification criteria9 and had undergone conventional angiography for diagnosis of TA. Eight of these 10 patients with angiographically active disease also had overtly clinical disease activity with either high ITAS or raised inflammatory markers.
Descriptive details of disease activity and angiography in TA patients on tocilizumab therapy All 10 patients had angiographically active disease (Table 1). One of these 10 patients with short disease duration of 1.5 months and high ITAS had normalized inflammatory markers due to prior steroids and methotrexate treatment. She had opted for tocilizumab in order to rapidly reduce her dose of steroids. The remaining nine patients were refractory to treatment with steroids and mycophenolate or azathioprine for a median period of 27 (range 5–60) months. Eight of these 10 with angiographically active disease had overt clinically active disease with either high ITAS or raised inflammatory markers. Notably, one out of these eight patients had only clinically active disease (patient no. 7). The remaining two in this cohort of 10 patients (patients no. 3 and 5) had only angiographic activity. To be
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Table 1 Demography and indications of tocilizumab therapy Patient No.
Sex/ age (years)
Type†
Disease duration (months)
Prior immunosuppressant
1
F/26
I
12
MMf
2
F/48
Ic
27
MMf
3
F/53
Ic
27
MMf
4
M/25
V
57
5 6
F/26 F/20
V V
60 27
7
F/23
V
8
F/21
V
9
F/13
10
F/15
Baseline steroid dose (mg/day)
Inflammatory markers‡
5
R
2
R
27.5
0
WNL
Aza ? MMf
20
6
R
Aza MMf
2.5 40
0 1
WNL R
Mtx
30
5
WNL
24
MMf
20
13
R
V
5
MMf
25
4
R
V
10
MMf
50
4
R
1.5
25
Baseline ITAS
Stopped
Indication for TCZ
Active disease with raised inflammatory markers ISR with raised inflammatory markers ISR, steroid-induced diabetes and glaucoma, needing steroid rescue Clinically active, ISR with raised inflammatory markers Repeated ISR within 1 year ISR with raised inflammatory markers Clinically and angiographic active, patient opted Clinically active (2 years of adequate treatment) ISR with raised inflammatory markers ISR with raised inflammatory markers
†Angiographic type, ISR, in-stent restenosis; MMf, mycophenolate mofetil; Mtx, methotrexate; AZA, azathioprine. ‡Erythrocyte sedimentation rate or C-reactive protein; R, raised; WNL, within normal limits.
specific, these two patients did not have raised ITAS or inflammatory markers, but had angiographic progression of disease with repeated in-stent re-stenosis requiring repeated procedures on the same vessels. Both these patients had undergone a careful search for presence of dyslipidemia as well as anti-phospholipid antibodies, namely anti-cardiolipin antibodies, lupus anticoagulant and anti-beta-2 glycoprotein-1 antibodies as risk factors for in stent re-stenosis. Patient no. 3 had > 90% re-stenosis of successfully recanalized and stented subclavian arteries within 13 months of these interventions, inspite of dual anti-platelet agents and high-dose steroids following an uncomplicated, immediate postprocedural period. This patient had steroid-induced diabetes and glaucoma warranting rapid reduction in steroid dose and therefore she was given tocilizumab as an alternative to steroids. Patient no. 5 also had recurrent in-stent re-stenosis of > 80% in the left subclavian and celiac arteries (three and two times, respectively, in a span of 3 years) with abdominal angina without any evidence of thrombosis. As this patient was already grossly cushingoid, steroids was not to be escalated further and instead tocilizumab was initiated for her. All the patients had been screened for active or latent tuberculosis by high-resolution CT (HRCT) scan and
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interferon gamma-based assay (IGRA) prior to tocilizumab therapy. Two patients had tested positive for IGRA; however, they had normal HRCT chest scans. They were given isoniazid prophylaxis for 6 months. None had evidence of active infection, dyslipidemia or liver function abnormality prior to initiation of tocilizumab therapy. Follow-up conventional angiography was performed for nine out of 10 patients, while one patient with type 1 disease by baseline angiography underwent color Doppler study of involved vessels to determine disease status at the sixth infusion. This patient with type 1c+ (type 1 with coronary artery involvement) disease did not undergo follow-up angiography in view of persistently stable disease by ITAS along with normal APR throughout the follow-up period. Additional PET-CT angiogram was performed in two patients and it was abandoned for any other patients in view of poor correlation with clinical activity, APR, as well as conventional angiography findings, in addition to prohibitive costs.
Response to tocilizumab All 10 patients (100%) had achieved an initial clinical response with an ITAS of 0 and normalization of
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Tocilizumab in 10 cases of Takayasu arteritis
inflammatory markers by the fourth infusion (Table 1, Figs 1,2). Three out of 10 patients (30%) with initial clinical response by the fourth infusion relapsed both clinically and angiographically at last infusion. Seven out of 10 patients (70%) sustained clinical response until the last infusion. Follow-up imaging study (conventional angiography in nine patients and color Doppler study in one patient) during the last infusion confirmed stable disease in six of these seven patients (60% of the whole cohort), while one patient had angiographic evidence of disease progression at last infusion. The single patient with clinically stable disease and angiographically active disease at last infusion was a young man with persistently raised inflammatory markers.
Angiographic findings in the same patient included progression of re-stenosis (ISR) in the left subclavian artery endovascular stent from 70% (pre-tocilizumab) to complete occlusion by the sixth dose, although a PET-CT angiogram done at the fourth infusion in this patient did not show any uptake. In summary, clinically stable state with ITAS of 0 was observed in 70% of patients at the time of the sixth infusion, whereas absolute stable disease state by all three parameters, namely clinical assessment (ITAS), laboratory parameters (ESR, CRP) and angiography, was sustained in 60% of patients at their last infusion. Mean ESR dropped from 36.7 17.9 to 6.9 10.8 mm in the first hour (P = 0.002) and CRP levels
Figure 1 Flow chart of response to tocilizumab until last infusion. ITAS, Indian Takayasu Assessment Score; APR, acute phase reactants.
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Figure 2 Acute phase reactant response to tocilizumab and representative follow-up angiography. ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
declined from 14.9 18.4 to 8.0 20.3 (P = 0.442) (Fig. 2). Infusion of tocilizumab also facilitated rapid reduction in steroid dose from 24 15 to 5.4 4.9 mg/day (P = 0.003).
Response in patients with raised baseline APR versus those with normal APR Among the 10 patients studied, seven (70%) patients had raised APR and three (30%) had APR within normal limits at baseline. Four out of these seven (49.2%) patients with raised APR at baseline achieved a stable disease state by all three parameters and sustained this benefit until the last infusion.
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Of the three patients with normal APR at baseline, one (patient no. 7) had high ITAS score at baseline and this patient continued to do well on tocilizumab until the sixth infusion, only to relapse again at the fifth month after withdrawl of tocilizumab as indicated by increased ITAS and rising APR. One other patient in this subset (patient no. 5) did not maintain angiographically stable disease at last infusion, in-spite of showing an initial clinical response by the fourth infusion. The remaining patient of these three (patient no. 3) showed patent subclavian artery with good flow through the stent by color Doppler at the sixth infusion. However, a repeat angiography performed at 5 months post-toc-
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Tocilizumab in 10 cases of Takayasu arteritis
ilizumab withdrawal again showed in-stent re-stenosis of the same vessel in this patient. Tapering of steroid dose was dictated by attainment of ITAS of 0 and normalization of inflammatory markers, with the intention of attaining a dose equivalent to or less than 7.5 mg/day of prednisolone. Steroid dosage was reduced from mean baseline 24 15.1 mg/day to 5.4 4.9 mg/day at the sixth dose. Second line immunosuppressant was discontinued prior to the first infusion of tocilizumab in five patients and an additional two patients were taken off these agents by the second infusion. Only three patients continued mycophenolate until the sixth infusion. None of the patients had serious adverse events. One patient each had transient skin rash, transient transaminitis, uncomplicated urinary tract infection and upper respiratory tract infection. One other patient had bleeding per rectum before the third dose, which was later found to be due to hemorrhoids and was unrelated to tocilizumab.
Extended follow up after withdrawal of tocilizumab Data was available for nine out of 10 patients with median follow-up of 8 months (range 3–14 months) after discontinuation of tocilizumab with one patient being lost to follow-up. Among them, stable disease state was maintained in only two patients up to their last recorded post-tocilizumab follow-up visit; three had relapsed after a period of good response and four patients had persistently active disease after cessation of tocilizumab (Table 2). This necessitated escalation of steroid dose in three patients and re-introduction of additional infusions of tocilizumab in three others. However, second line agents (mycophenolate mofetil or azathioprine) were restarted in all patients after withdrawal of tocilizumab infusion; six of them were restarted on these agents within 2 months of discontinuing tocilizumab and the remaining two were on these agents by the fifth and sixth month respectively after discontinuation of the infusion. With these measures, 60% (n = 6) of patients had regained stable disease state, while 30% (n = 3) continued to have active or grumbling disease at the last posttocilizumab follow-up visits.
DISCUSSION At present, there is paucity of an ideal steroid sparing agent for TA. Published literature6 as well as our previous work (R. Goel, D. Danda, S. Natarajan, J. Mathew,
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V. Balaji, G. Joseph, unpubl. observ.), suggest IL-6 to be a key cytokine-mediating inflammation in TA. This biological basis and concurrent results of our present series, similar to successful case reports from the literature, indicate that tocilizumab therapy may be a safe and effective, steroid-sparing option for refractory cases of TA.7–9,12 Two recently reported case series with two TA patients in each have shown efficacy of tocilizumab, mainly in refractory cases.8,9,12 One of these reports had shown modest benefit,8 while the one by Salvarani et al.9 showed reduction in inflammation by PET-CT studies. The latest retrospective study by Stone and colleagues. reconfirmed the efficacy of tocilizumab for large vessel vasculitis as a group.12 In the present study too, we have demonstrated a good clinical response, defined as ITAS of 0 or reduction in dosage of steroids and/or other immunosupressants in 100% of patients by the fourth infusion and in 70% at the sixth infusion. Notably, 60% of patients had maintained an unequivocally stable disease state at the sixth infusion by all three criteria, namely clinical, radiological and APRs. However, we note with caution the return of disease activity after discontinuation of the drug in three out of these six patients who had attained complete remission on tocilizumab. Earlier reports from the literature showed presence of subclinical inflammation in TA as evidenced by angiographic progression in 60% and presence of histologically active disease in 44% of patients inspite of normal APRs.1 The pathogenesis of stent re-stenosis is an interplay of thrombus formation and/or acute and chronic inflammation. Infact, persistence of chronic inflammation beyond 90 days is shown to be associated with increased intimal thickness and restenosis.13 This may be more so in the setting of an already existing inflammatory condition such as TA. Moreover, biological inflammation has been shown to increase the odds of procedural complications like in-stent re-stenosis in TA by up to seven times.14 A careful search excluded thrombus formation at the stent placement site to be the cause of re-stenosis in our patients. Thus, we were justified in initiating tocilizumab for the subset of patients (n = 3) with normal APR and angiographically progressive disease at baseline. A recent report on tocilizumab in lupus has shown successful reduction in number of activated T cells and B cells with tocilizumab therapy in a subset of patients with raised numbers of these cells at baseline irrespective of their APR status.15 Tocilizumab, therefore, appears to be a promising alternative to high-dose steroids and an effective stop-gap
759
760
27.5
20
3
4
30
20
25
50
7
8
9
10
3
10
5
5
5
1
10
0
0
15
Steroid dose (mg/day)
6
6
3
8
Lost to follow up
8
9
5
14
12
Duration† (months)
0
0
7.5
30
–
7.5
10
1
0
7.5
Steroid dose (mg/day)
†Duration calculated from the time tocilizumab was discontinued; Angio, conventional angiography. ¶Erythrocyte sedimentation rate or C-reactive protein; R, raised; WNL, within normal limits; ND, not done. §Angio: A, active; S, stable; G, grumbling; Re, relapse. MMf, mycophenolate mofetil; AZA, azathioprine; TCZ,tocilizumab; PDN, prednisolone equivalent.
40
6
2.5
0
2
5
25
Disease activity: ITAS, Lab¶, Angio§ ITAS = 5, Lab R, Angio A ITAS = 2, Lab R, Angio A ITAS = 0, Lab WNL, Angio A ITAS = 6, Lab R, Angio A ITAS = 0, Lab WNL, Angio A ITAS = 1, Lab R, Angio A ITAS = 5, Lab WNL, Angio A ITAS = 13, Lab R, Angio A ITAS = 4, Lab R, Angio A ITAS = 4, Lab R, Angio A
At last dose Disease activity: ITAS, Lab¶, Angio§ ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio ND ITAS = 0, Lab R, Angio A ITAS = 2, Lab WNL, Angio A ITAS = 0, Lab WNL, Angio S ITAS = 0, Lab WNL, Angio S ITAS = 4, Lab WNL, Angio A ITAS = 0, Lab WNL, Angio S ITAS = 4, Lab WNL, Angio A
During TCZ infusion
At baseline visit
Steroid dose (mg/day)
1
Patient no.
Table 2 Response to tocilizumab and extended follow-up after withdrawal of tocilizumab
MMf 2 gm/ day + TCZ 10th dose
MMf 2 gm/day
MMf 2 gm/day
MMf 2 gm/day
–
AZA 100 mg/day
S
S
G
S
–
S
A
A
Rescue TCZ + MMf 2 gm/day MMf 2 gm/day
S
S
Disease activity
MMf 2 gm/day
MMf 2 gm/ day + TCZ 12th dose
Second line immunosuppressant
Last visit
Post-TCZ withdrawal†
Active at 3 months
Stable throughout
Persistently grumbling acitvity
Relapsed at 5 months
–
Active at 2 months
Persistently active
Persistently active
Stable throughout
Relapsed at 6 months
Disease course
R. Goel et al.
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Tocilizumab in 10 cases of Takayasu arteritis
measure to attain rapid control of disease in refractory or relapsing cases of TA. However, its role in those with clinically active disease with normal APR needs further studies as its beneficial effect on arresting in-stent re-stenosis was short-lasting in our series. Long-term follow-up studies with large randomized controlled trials are needed to establish efficacy of tocilizumab in TA. It is also not clear whether angiographic evidence of activity reflects a true biological inflammation as a part of the disease process, or is it due to thrombosis and/or fibrosis as a part of disease sequelae or mechanical trauma incited by stents? It is possible that the patients with normal APR with angiographic progression could represent a totally different disease subset of patients. Ours is the largest series examining tocilizumab therapy in TA. To the best of our knowledge, this is also the first report of use of this drug in Asian patients with TA with follow-up imaging data in all patients to define true response, apart from clinical response by ITAS score, reduction in steroid and/or immunosuppressant dosage and normalization of APR. In our setting, PET-CT peformed for two patients did not correlate well with clinical and angiographic assessment of disease, nor did they correlate with inflammatory markers, similar to a few reports in literature.16 Patients, therefore, were not subjected to this expensive imaging option for evaluation.
CONCLUSION Tocilizumab may be an effective, steroid-sparing stopgap measure in refractory and relapsing patients with TA for rapid control of disease activity. While it can be an alternative to steroids in TA, second line agents like mycophenolate may have to be initiated and continued along with tocilizumab to sustain its steroid-sparing benefit even after withdrawl of tocilizumab.
DISCLOSURES None.
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3 Goel R, Danda D, Mathew J, Edwin N (2010) Mycophenolatemofetil in Takayasu’s arteritis. Clin Rheumatol 29, 329–32. 4 Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P (2004) Anti-tumor necrosis factor therapy in patients with difficult-to-treat Takayasu arteritis. Arthritis Rheum 50, 2296–304. 5 Hoyer BF, Mumtaz IM, Loddenkemper K et al. (2012) Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 71, 75–9. 6 Park MC, Lee SW, Park YB, Lee SK (2006) Serum cytokine profiles and their correlations with disease activity in Takayasu’s arteritis. Rheumatology 45, 545–8. 7 Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T (2008) Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum 58, 1197–200. 8 Seitz M, Reichenbacha S, Bonel HM, Adler S, Wermelinger F, Villiger PM (2011) Rapid induction of remission in large vessel vasculitis by IL-6 blockade. Swiss Med Wkly 141, w13156. 9 Salvarani C, Magnani L, Catanoso M et al. (2012) Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology 51, 151–6. 10 Moriwaki R, Noda M, Yajima M, Sharma BK, Numano F (1997) Clinical manifestations of Takayasu arteritis in India and Japan – new classification of angiographic findings. Angiology 48(5), 369–79. 11 Mishra R, Danda D, Jayaseelan L, Sivakumar R, Lawrence A, Bacon PA (2008) ITAS & DEI.TAK—scores for clinical disease activity and damage extent in Takayasu’s aortoarteritis (TA). Rheumatology 47(Suppl 2), 101. 12 Unizony S, Arias-Urdaneta L, Miloslavsky E et al. (2012) Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res 64, 1720–9. 13 Farb A, Kolodgie FD, Hwang J-Y et al. (2004) Extracellular matrix changes in stented human coronary arteritis. Circulation 110, 940–7. 14 Saadoun D, Lambert M, Miraul T et al. (2012) Retrospective analysis of surgery versus endovascular intervention in Takayasu arteritis. Circulation 125, 813–9. 15 Shirota Y, Yarboro C, Fischer R, Pham TH, Lipsky P, Illei GG (2013) Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis 72(1), 118– 28. 16 Arnaud L, Haroche J, Malek Z et al. (2009) Is (18)Ffluorodeoxyglucose positron emission tomography scanning a reliable way to assess disease activity in Takayasu arteritis? Arthritis Rheum 60, 1193–200.
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