1

Dr Debashish Danda

Department of Rheumatology

Christian Medical College, Vellore

Immunosuppression in Takayasu arteritis –

when and how

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New Mantra in Rheumatology Early Diagnosis & “Treat to Target”

• Key to better quality of life and possibly survival

• Applicable to all autoimmune rheumatic diseases

• Achieved by better disease marker and more effective agents

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Challenges in TA management

• Immune mechanisms not fully understood

• Does it ever burn out?

• Challenges in diagnosis and assessment of disease

• Paucity of Clinical trials/ Gold standard

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Predicting disease activity & outcome is difficult

Discordance between

– Clinical activity & histo-pathology : 38% (10/26 biopsies)

– APR response & MR progression : 46%

– Raised APR and angiographic progression : κ= 0.28 - 0.34

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009Schmidt J et al. Mayo Clin Proc. 2013;nn(n):1-9

Goel R, Kumar TS, Danda D, Joseph G, Bacon P, Jayaseelan V [unpublished data]

Clinically inactive disease vs gold standard

• Clinically inactive disease

• New angiographic changes detected in 60%4

• Ongoing vascular inflammation in aortic biopsy specimens: 44%5

4. Kerr GS etal. Ann Intern Med 1994;120:919–295. Lagneau P et al. Ann Surg 1987;205:157–66

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Histopathology of large vessel vasculitis

(a) photomicrographs of a normal aorta (b) giant cell arteritis and (c) Takayasu arteritis with corresponding sections stained with Movat pentachrome (d, e, and f).

The images are all taken at the same low magnification: (a) The intima and adventitial layers of a normal aorta arevery thin (d) The media shows multiple orderly layers of elastic lamellae stained black with Movat

A case of giant cell aortitis shows medial necrosis surrounded by mononuclear inflammatory cells and multinucleatedgiant cells (inset) (e) The elastic lamellae are disrupted in areas of inflammation but remain visible in the area of medial necrosis;

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(c) A case of Takayasu arteritis shows

inflammation in themedia and adventitia with

predominantly mononuclear cells and

occasional multinucleated giant

cells (inset)

(f) The media shows disruption and collapse of the elastic layer. Note that the intima in both aortitis cases is thicker than the media due to reactive hyperplasia and fibrosis. (e and f) The intimal hyperplasia appears blue green on Movat due to increased ground substance. Theadventitia shows fibrous thickening which becomes progressively more prominent in Takayasu arteritis. (e and f) The dense adventitial fibrosis is delineated by the yellow staining of collagen on Movat

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Immune mechanisms- recent understandings

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Newer Biomarkers

Biomarkers during follow up

Pentraxin-3 – a potential biomarker

13Lorenzo Dagna etal. Ann Intern Med. 2011;155(7):425-433

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Serum Amyloid A As A Marker of Disease Activity And Treatment Response In Takayasu Arteritis

• 197 TA patients screened b/w June 2014- Feb 2016• 99 TA patients (26 index visit) and 40 healthy controls • Active disease = 43 patients • Grumbling disease = 8• Stable disease= 48

0

100

200

300

400

500

Disease activity at baseline

Seru

m A

myl

oid

A (n

g/m

l)

Nair A, Goel R, Mohan H, Kabeerdoss J, Jayaseelan V, Danda D. Under review

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Follow up SAA levels were measured for 9 responders and 12 non-responders

• SAA levels decreased only in responders

[189.9 ng/ml to 119.0 ng/ml, p= 0.008]

• Levels did not change significantly in non- responders

[146.9 ng/ml to 148.5 ng/ml at follow up, p=0.695]

Other Newer Biomarkers

• MMP-2, -3

• IL-6

• RANTES (regulated upon activation and normal T expressed and secreted)

• VCAMs- Vascular cell adhesion molecules

• Unacylated and acylated ghrelin levels

The leptin/ghrelin ratio was significantly higher in TA patients than controls and had a positive correlation with disease activity

Matsuyama A, Sakai N, Ishigami M, et al. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation. 2003;108:1469-73.

Yilmaz H, Gerdan V, Kozaci D, et al. Ghrelin and adipokines as circulating markers of disease

activity in patients with Takayasu arteritis. Arthritis Res Ther. 2012;14:R272.

Biomarkers • No diagnostic markers• Raised ESR and CRP in active phase• For follow up

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Newer imaging

Recent progress in noninvasive imaging modalities

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A: MR angiography showing the occlusion of left subclavian and common carotid arteries.

B: MR angiography showing late gadolinium enhancement of the walls of the aorta and neck arteries.

C: 3D CT angiography showing occlusion of bilateral subclavian arteries and increased collateral arteries.

D: Contrast CT showing increased thickness of aortic and pulmonary arteries and their branches.

E and F: FDG-PET/CT showing increased uptake in aortic arch, brachiocephalic artery,and common carotid artery.

G: Sonography of the neck artery showing narrowing of the common carotid artery.

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PET-CT variable results

Mandal SK, Gupta N, Goel R….. Danda D et al. Imaging in Takayasu arteritis, Indian J Rheumatol. (2015)

Delayed contrast enhance MRI – especially for arterial wall inflammation

Comparison of various modalities in diagnosis and disease assessment in TA

Investigation Sensitivity Specificity

ESR* 72% 56%

hs CRP* 71.4% 100%

FDG-PET* 92% 100%

MRA* ̴� 100% ̴� 100%

CTA* 95% 100%

PTX-3** 82.1-89% 87-94.1%

*in diagnosing TA **in differentiating active and inactive TA

Kerr GS etal . Takayasu arteritis. Ann Intern Med. 1994 Jun 1;120(11):919–29. Ishihara T etal. Diagnosis and assessment of Takayasu arteritis by multiple biomarkers. Circ J. 2013;77(2):477–83. Dagna Letal. Pentraxin-3 as a marker of disease activity in Takayasu arteritis. Ann Intern Med. 2011 Oct 4;155(7):425–33. Webb M, et al. The role of 18F-FDG PET in characterising disease activity in Takayasu arteritis. Eur J Nucl Med Mol Imaging. 2004 May;31(5):627–34. Yamada I etal. Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three-dimensional MR angiography. J Magn Reson Imaging. 2000 May;11(5):481–7. Yamada I etal. Takayasu arteritis: evaluation of the thoracic aorta with CT angiography. Radiology. 1998 Oct;209(1):103–9.

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Assessing disease

Kerr’s criteria (NIH criteria)

• Fever or arthralgia

• Raised ESR (>20 mm/h)

• Features of vascular ischaemia or inflammation

• Typical angiographic features

Not widely validated and is limited in scope

Kerr GS etal. Ann Intern Med 1994;120:919–2924

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Newer Assessment Tools

DIE.TAK : an objective assessment of disease extent in TA

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ITAS-2010 and ITAS-A in disease monitoring

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ITAS-2010 and ITAS-A : a validated tool in Indian patients with TA

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Course of the Disease

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Normal ESR/ CRP

High ESR/CRP

Normal ESR/ CRP

High ESR/ CRP

Normal ESR/ CRP

Early diagnosis and treatment–better outcome

Ishikawa K, Maetani S. Long-term outcome for 120 Japanese patients with Takayasu’s disease: clinical and statistical analyses of related prognostic factors. Circulation 1994; 90:1855–1860

Early TA (systemic disease) Usually presents with raised markers

Mostly goes clinically undetected

5 yr Survival And Event Free Survival rate

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Monophasic subset or Burnt out disease is rare

In an Italian cohort, 13% patients with clinically active

disease throughout did not require immunosuppression at all

Kerr GS, Hallahan CW, Giordano J. Ann Surg 1987; 205: 157–166Vanoli etal. Arthritis and rheumatism 2005; 53: 100-7 (104 Italian pts)

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How to predict subsets with good outcome ?

• Predictors of sustained inactive disease:

– Low ESR values at baseline visit,

– Low CRP values at baseline visit

– Low DEI.Tak scores

– Type 4 disease

• Prediction model: Sensitivity -70% ; Specificity - 61% Goel R, Danda D, Joseph G, Nair A, Ravindran R, TS Kumar, Jayaseelan L, Jayaseelan V, Paul Bacon. Unpublished data

Relapses in biological course of disease

Takayasu arteritis is a chronic, relapsing, autoimmune, large vessel vasculitis

Schmidt J et al. Mayo Clin Proc. 2013;nn(n):1-9

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No of relapses correlates with likelihood of disability (p< 0.0001)

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 (Cleveland Clinics)

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Relapses cause disability, treatment prevents

• N= 75 ; 30 followed up 3 yrs (4 months-10 years)

• All patients who followed up were treated with steroids

• 73% required adjunctive immunosuppressive agents

Remission 93% (28/30)

Remission with steroid monotherapy 20 % (6/30)

Sustained remission (≥6 months on <10mg/kg)

28% (8/28)

Sustained remission till last follow up 18% (5/28)

Persistent active disease 2

No. of relapses correlated with likelihood of disability (p< 0.0001)

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 (Cleveland Clinics)

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Persistent active disease associated with progression of damage

Persistently stable (any steroid dose)

Partial response

Relapsing Delayed response

Persistently active

p1* p2*

No. of patients with ∆TADS calculated

112 41 54 7 28

Median ∆TADS 0 (0-1, range 0-9)

1 (0-2, range: 0-8)

1 (0-3, range 0-9)

2 (0=3, range 0-3)

2 (0.25-3, range 0-10)

0.000 0.000

Increment in TADS score (∆TADS) in patients with different disease course

p1 - persistently stable vs persistently active group p2 – persistently stable vs relapsing disease

Goel R, Danda D, Joseph G, Nair A, Ravindran R, TS Kumar, Jayaseelan L, Jayaseelan V, Paul Bacon. Unpublished data

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Immunosuppression improves QoL

• SVDRC effort

• N= 150 patients

• Improvement in QoL- 51%

• No change in QoL- 37%

• Worsening of QoL – 12%

• II line agents- 19%

– Response was good in 29%, fair in 33% & ineffective in 29%

Ito I. Medical treatment of Takayasu arteritis: Heart Vessels Suppl 1992; 7: 133–137

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We need to treat TA

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When to treat

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Stages of TA

Normal ESR/ CRP

High ESR/CRP

Normal ESR/ CRP

High ESR/ CRP

Normal ESR/ CRP

Which group would benefit from Immunosuppression

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Biological inflammation at the time of vascular procedure independently associated with procedure

Saadoun D et al. Circulation 2012;125:813-819Copyright © American Heart Association

166 Vascular Procedures in 79 Patients With TA

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HOW TO TREAT

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Radial pulse became palpable in 5 patients with steroids

N= 84 Korean patients

Nakao etal. Circulation 1967; 35: 1141-1155

Steroids works in 62% of TA

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Independent predictor for remission in TA

– Low ESR at diagnosis

– &

– Treatment with glucocorticoids

Park MC etal. Scand J Rheumatol. 2005 Jul-Aug;34(4):284-92

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Steroids in pediatric TA

• N= 40; follow up = 34 pts for 21.5 (IQR 8.7- 37.2)

• Relapse in 15 children at a median duration of 16.5 (9.5- 47 months)

• Median steroid dose at relapse – 5 (IQR -0-15)mg/day

Steroids with 2nd line agents 34 (85%)

Remission 30/ 34

Sustained remission till last follow up 15/ 34

Persistent active disease 4

Goel R, Kumar TS, Danda D, Joseph G, Bacon P, Jayaseelan V [unpublished data]

Higher disease progression was observed in patients with persistent active/ relapsing disease

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How much steroid is adequate

• N= 556 • Initial steroid dose – 20-40mg/d• Effective • Reduce side effect • Improve compliance in patients

Our series (503 patients) – steroid 0.5 mg/kg/day was as good as 1mg/kg/day

Yang, et al: TA in China. J Rheumatol 2014;41:2439–46

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How fast to taper N= 106 patients (Japan)

Relapse- free rate significantly higher with mean dose reduction rate of prednisolone <1.2 mg/month (59.1% vs. 0%, P=0.0001)

Ohigashi H etal. Circ J 2012; 76: 1004 – 1011

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Treatment of Glucocorticoid-resistant or relapsing Takayasu Arteritis with Methotrexate Gary S. Hoffman etal. Arthritis & Rheumatism 1994;37(4) : 578-582

Methotrexate : sustained remission for 18 months in 50% patients

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Mtx/ MMF used sustained remission improvement0

5

10

15

20

25

30

35

40

45 43

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CCF cohort (MTX based)

MTx used sustained response for 6 months

No.

of p

atien

ts (

%)

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009

Methotrexate

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Steroids with Azathioprine : arrested disease progression in 100%

• N= 65 new patients (1996 -2001)

• 15 had active disease, treated with azathioprine + prednisolone

• At 3 months :

– Clinical improvement : 100%

• At 1 year:

– Clinical Improvement sustained

– Angiogram showed no progression / new lesions in any patient

Valsakumar AK, Valappil UC, Jorapur V, Garg N, Nityanand S, Sinha N . J Rheumatol. 2003;30(8):1793-8

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Mtx/ MMF used sustained remission improvement0

10

20

30

40

50

60

70

80

90

100

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2823

100 100

Methotrexate basedAzathioprine based

patie

nts

(%)

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009Valsakumar AK etal. J Rheumatol. 2003;30(8):1793-8

Azathioprine appears better than Methotrexate

Mycophenolate mofetil in Takayasu’s arteritis

Retrospective study of 21 TA patients on mycophenolate mofetil January 2005 to August 2008 Disease duration: 35.5±28.4 months

mean duration of follow-up - 9.6 (±6.4) months

Goel R, Danda D,Mathew J, Edwin N. Clin Rheumatol (2010) 29:329–332

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Mtx/Aza/ MMf used sustained remission improvement0

10

20

30

40

50

60

70

80

90

100

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2823

100 100

5650

10096

methotrexate based*

azathioprine based ** (n= 15/65) at 1yr follow up

mycophenolate based$ (n=19/40)

Adult TA (MMf)% (n=21/21)

patie

nts

(%)

Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009Valsakumar AK etal. J Rheumatol. 2003;30(8):1793-8

Goel R, Kumar TS, Danda D, Joseph G, Jayaseelan V. J Rheum 2014 Goel R, Danda D, Mathew J, Edwin N. Clin Rheumatol (2010) 29:329–332

Mycophenolate & Azathioprine probably better than Methotrexate

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Mycophenolate probably better than Methotrexate

• In CCF cohort

– MTX was used in majority (43%)

– Sustained remission in only 28%

– 50% relapses (17/34) occurred while on MTX

• In our study (pediatric TA)

– MMf was used in 19/34 (56%)

– Sustained remission in 50% (pediatric TA)

– Improvement in 96% of adult TA Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009

Goel R, Danda D, Mathew J, Edwin N. Clin Rheumatol (2010) 29:329–332

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Mycophenolate in TA

• N= 503 patients

• Immunosuppression ≈ 95% ;MMF in 320 patients

• 251 patients- follow up 42 (IQR: 24-81) months

• Follow up of patients on MMF – 160 • Sustained inactive disease (ITAS 2010 CRP = 0)– 36.9%

• Adverse reaction – 1 (Rash) Goel R, Danda D, Joseph G, Nair A, Ravindran R, TS Kumar, Jayaseelan L, Jayaseelan V, Paul Bacon. Unpublished data

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Cyclophosphamide

Indications:

retinal vasculitis, P + disease with or without aneurysm, severe aortic regurgitation, myocarditis

Myocardial Involvement in TA7 patients( resistant to steroids)- Steroids +2 mg/kg/ day oral CYC

27.5 months(mean)

No clinical or radiological progression

Hemorrhagic cystitis-2Oligomenorrhoea - 7

Shelhamer JH, Volkman DJ, Parrillo JE et al.Takayasu’s arteritis and its therapy. Ann Intern Med

1985;103:1216.

8 patients- Steroids +2 mg/kg/ day oral CYC

No clinical or morphological progression

Talwar KK, Chopra P, Narula J et al. Myocardialinvolvement and its response to immunosuppressive

therapy in nonspecific aortoarteritis (Takayasu’s disease)—a study by endomyocardial biopsy. Int J Cardiol

1988;21:32334.

100% improvement in aorto-arteritis associated myocarditis with immunosuppression

N= 13 non-specific aortoarteritis and myocarditis in EM biopsy

on prednisolone & CYC At 12, 24, 52 weeks

Clinical Improvement 100%

ESR drop 48 +/- 12 mm/1st h to 31 +/- 12 mm/1st h, p < 0.05

Resolution of EM biopsy changes 100%

Arterial lesions static, no new lesions

Talwar KK etal. Int J Cardiol. 1993 Apr;39(1):79-8461

Open surgery Endovascular procedure

Revascularisation /aneurysm repair

Sequential therapy

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Sequential therapy

EULAR recommendations for the management oflarge vessel vasculitis

Recommendation Level of evidence Median Strength of Recommendation

Thorough clinical and imaging assessment of the arterial tree when adiagnosis of Takayasu arteritis is suspected

3 C

Early initiation of high-dose glucocorticoid therapy for induction ofremission in large vessel vasculitis

3 C

Immunosuppressive agent should be considered for use in largevessel vasculitis as adjunctive therapy

3 C

Monitoring of therapy for large vessel vasculitis should be clinical and supported bymeasurement of inflammatory markers

3 C

Reconstructive surgery for Takayasu arteritis should be performed in the quiescentphase of disease and should be undertaken at expert centres

3 C

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Tocilizumab as a stop gap measure

• N= 10 active TA patients (disease duration 25.5 (1.5-60) months

• Indication for 9 patients was active disease with repeated instent

restenosis

Response No. of patients (n= 10)

Sustained remission (during 6 doses) 6

Reduction in steroids to <10mg/day 7

Sustained remission post TCZ withdrawal 2

Major adverse events 0

Mean steroid dose reduction : 24 ± 15 to 5.4 ± 4.9 mg/day

Goel R, Danda D, Kumar S, Joseph G. Int J Rheum Dis. 2013 Dec;16(6):754–61

Pre TCZ ESR

Post TCZ ESR Pre TCZ CRP

Post TCZ CRP

Pre TCZ ITAS

Post TCZ ITAS Pre TCZ steroid Post TCZ steroid

Median, range 34, 94 3, 36 11.6, 56.7 2.96, 61.95 4, 13 0, 4 25, 50 5, 15

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OUR TREATMENT MODEL

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• Initial High dose steroid

• If patient affords, Toccilizumab monthly x at least 3 doses & during flare / pre endovascular intervention

• If cant afford, slow tapering from 0.5mg/kg/day

• Rapid taper of steroid to 7.5 mg / day in a month of Toccilizumab

• Mycophenolate / Azathioprine (if not affording MMF) on longterm

• Refractory disease TNF blockers

• Assess ITAS

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Overall disease course

Persistent stable disease n= 116 (last steroid dose ≤ 5mg/d n= 87)

Relapsing- remitting disease n= 56

Persistent active disease (refractory disease) n= 27

Determining disease activity

• ITAS 2010 =0

Overall disease course N (%) (n= 251)

Remission 172 (69%)

Persistent stable disease 116 (46.2%)

Persistent stable disease with last steroid dose ≤ 5mg/d

87 (34.6%)

Relapsed disease 56 (22%)Refractory 27 (11%)3 yr cumulative relapse free survival 55%

Christian Medical College, Vellore (unpublished data)

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Outcome

Study Patients studied N follow up/ duration (yrs) Mtx/Aza/MMf

Kerr etal, NIH 60 45/5.5 Not specified/ very few

CCF, USA 75 30/3 43%/7%/7%

Mayo Clinic, USA 126 79/ 5.5 58% / 19% /18%

Japanese 106 35/ 0.5-5 50% , 35% CSA (very few on II line)

CMC Vellore 503 251/ 3.5 9%/19%/62%

Sustained remission (lasting for 6 months)- 71% (Mayo clinic)

72Goel R, Danda D, Joseph G, Nair A, Ravindran R, TS Kumar, Jayaseelan L, Jayaseelan V, Paul Bacon. Unpublished data

Biologicals in refractory cases

steorids

MMf/ aza/mtx

sustained inactive disease in 39.8% of patients

CMC Vellore- concurrent steroids and II line immunosuppression at induction

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“Treat to target” in TA – possible?

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Rituximab

Tocilizumab

TNF blockers

Th17 blocker

Therapy in Takayasu arteritis

Anti- TNF

Tocilizumab Ustekinumab

Rituximab

Corti

cost

eroi

dsM

Mf,

CYC,

MTx

, CSA

No Difference between anti- TNF and Tocilizumab

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Recent RCTs (ACR abstract)

TCZ / Abatacept on 26 patients –not powered to conclude

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Rituximab

N= 17 pts analyzed for B cell subsets 3 refractory cases treated with BCDT

Hoyer BF et al. Ann Rheum Dis 2012;71:75–79

• Upcoming therapies- ROCK inhibition• NOTCH inhibition

Ustekinumab

• N=3 with refractory TAK

• 40mg of ustekinumab at day 0 and day 28

• Treatment was well tolerated

• Inflammatory markers decreased,

• At 84 day repeat MRA: A reduction in vascular wall enhancement

was not observed

Terao C etal. Ann Rheum Dis 2015;74:1111-1112

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Summary

• Steroid + Mycophenolate is a good option

• Tocilizumab a good stopgap steroid sparing option

• ITAS monitoring helps

• TNF blockers in refractory cases

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Acknowledgement

• Dr Ruchika Goel

• Prof Paul Bacon

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Thank you