Disease Modifying Therapy in Scleroderma

Dr Shefali K SharmaAssociate Professor

Dept of Internal MedicinePGIMER

Chandigarh

Skin sclerosis

Inflammation

Vasculopathy

Clinical manifestations of systemic sclerosis

Shown with permission

EmotionalFinancialSocialPain

Digital ulceration

Macrovascular disease

Exocrine

Gastrointestinal

Renal

Musculoskeletal

Lung fibrosis

Cardiac

Pulmonary arterial hypertension

SSc

Localized

Morphea Linear

Systemic

Limited/ diffuse

CLASSIFICATION

Diffuse vs limited Distinguishing featuresDiffuse Limited

ILD ( severe in 15%) ILD severe

Heart (10%) Minimal Heart

Pulmonary Hypertension( 5%-10%) Pulmonary arterial Hypertension(10-15%)

Kidney( Severe10-15%) Minimal kidney

Large joint contractures Primary biliary cirrhosis

Worse survival overall

Best pract Res Clin Rheumatol;24(3):387-400

PATHOGENESIS

Pathogenesis

• SSc is not one clearly defined disease but a syndrome encompassing various phenotypes

• High frequency of AI ds in families of SSc pts• Strong evidence of linkage with HLA Class II• Environmental challenges e.g viruses, drugs, vinyl

chloride and silica induce clinical phenotypes similar to SSc

HLA Linkage in SSc: PGI Data

Early Vascular Changes

• Vascular injury precedes fibrosis inv. small vs.• Large gaps in endothelial cells, loss of integrity• Vacuolization of endothelial cell cytoplasm• Perivascular infiltrates with MN immune cells• Obliterative microvascular lesions• Rarefication of capillaries Pericytes and Smooth Muscle Cells• Pericytes have the potential to differentiate to vascular

smooth muscle cells, fibroblasts and myofibroblasts• Pericytes overexpress several cytokine receptors including

PDGFR

Fibroblasts

Fibroblasts Myofibroblasts Cytokines

Orchestra the production, deposition, remodeling of collagen & other extra cellular matrix components

Activation of Fibroblasts in Systemic Sclerosis

Early Vascular Changes ( Contd.)

Angiogenic

Angiostatic

Progressive Loss of Blood Vessels leads to HypoxiaHigh Plasma levels of Vascular Endothelial Growth Factor

How to treat Systemic SSc?Ds Specific/ Stage Specific Targeted therapies

• Targeted inhibition of signaling pathways by• Tyrosine kinase inhibitors

– PDGFR– TGF-βR– RAS

• Autoantibodies of functional relevance• Identification of biomarkers of disease severity

• Transcription patterns• Cellular reactive oxygen species• DNA damage signatures

Concept of targeted therapy in SSc

Concept of targeted therapy in SSc

SKIN DISEASE

Treatment Recommendations For Skin/MSK

• MTX effective in early dcSSc (supported by 2 RCT)• MMF is effective for skin, lacks RCT• CYC may be considered for severe skin involvement• Low dose prednisolone for tendon friction rub• Biologics used for inflammatory arthritis

Current Management of Digital Vasculopathy in SSc

Korn JH, et al. Arthritis Rheum 2004; 50:3985-93;

RAPIDS-1 placebo bosentan p value

All patients 43 78

Number of new ulcers 2.7 1.4 -48% 0.008**

Patients with baseline DU 24 52

Number of new ulcers 3.6 1.8 -50% 0.008**

RAPIDS-2placebo bosentan p value

All patients 89 95

Number of new ulcers 2.7 1.9 -30% 0.035*

*Poisson regression analysis **Pitman permutation analysis

Endothelin receptor blockade prevents new ischaemic digital ulcers in SSc

Matucci-Cerenic et al Ann Rheum Dis 2011, 70:32-8.

MANAGEMENT OF ILD

Pulmonary Involvement

LUNGILD

ILD

Clinical features: Lungs60% of patients affected

• Leading cause of mortality and morbidity in later stage of SSc

Complains• Dry cough,

breathlessness

Investigations

1. Routine2. HRCT Chest3. PFT

1Hoyles et al Arthritis Rheum 2006; 54:3962-70

Cyclophosphamide for lung fibrosis in SSc• Fibrosing alveolitis in scleroderma trial (FAST)1 monthly intravenous

cyclophosphamide 600mg/m2 for 6 months followed by (po) azathioprine, or placebo in 45 patients

– Over 12 months FVC change favoured active treatment (p=0.04, BMI corrected – uncorrected p=0.08)

FAST primary outcome: FVC

p=0.08

2.442.462.482.502.522.542.562.582.602.622.64

baseline 3 months 6 months 9 months 12months

Months from baseline

Abs

olut

e FV

C (m

ean

at e

ach

time

poin

t)

ACTIVE PLACEBO

– Magnitude of difference 5.5% (4.8% adjusted) • active arm improved (+2.5 % predicted) • placebo arm worsened (-3.0 % predicted)

Treatment Protocol Followed

CYC + High Dose steroids

Induction: CYC + Low dose steroids Maintainence :AZA

MMF

Nihtyanova et al, Rheumatology 2007, 46:442-5

Prob

a bilit

y

543210

1.0

0.9

0.8

0.7

0.6

Time to development of significant lung fibrosis*

MMF n = 109

Control* n = 63

Years from commencement of treatment

Prop

ortio

n w

ithou

t sig

nific

ant

lung

invo

lvem

ent

P=0.037

*FVC <55% predicted or D15%

Mycophenolate mofetil may prevent progression of clinically significant lung fibrosis in diffuse SSc

Note: SLS-II data presented as abstract EULAR 2015 – 12 months of oral cyclophosphamide versus 24 months MMF – confirms benefit of MMF (see - www.sls.med.ucla.edu)

Rituximab in connective tissue disease associated lung fibrosis

Eur Respir J. 2012 Jan 26. [Epup]Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy.Keir GJ, Maher TM, Hansell DM, Denton CP, Ong VH, Singh S, Wells AU, Renzoni EA.

Treatment of lung fibrosis in systemic sclerosis•Early detection

− Serology, subset, PFT, HRCT, clinical features

•Staging− UK-RSA Staging system* applied Immunosuppression− iv cyclophosphamide (600mg/m2)− Oral MMF (2g/d) or azathioprine (150mg/d)− Prednisolone 10mg daily− Consider rituximab for refractory or progressive lung disease

•Rigorous anti-reflux therapy − PPI, H2 antagonist, prokinetic

•Other interventions− N-acetyl cysteine po 600mg tds− Oxygen – intermittent or long term low flow− Identification and treatment of pulmonary hypertension

Detection

Staging(≥20% lung threshold)*

Medical management

* Goh NS et al. Am J Resp Crit Care Med. 2008, 177:1248-54.

Demographic & Clinical Characteristics

Total Number of SSc Patients 530SSc with ILD 177SSc with ILD & PAH 70No of Females: Males 458:72ANA Positivity (IIF) 520

Demographic & Clinical Characteristics of ILD Patients

Total No of ILD pts 177ILD treated with CYC 74ILD not treated with CYC (FVC>70%) 82Incomplete data 17Mortality 4

Demographic & Clinical Characteristics of ILD Patients received CYC

Total No of Patients 74

Mean Age of Presentation 41

Male: Female 7:67

Limited : Diffuse 31:43

Mean FVC at Baseline 61.88%

Mortality 2

Year N Improved (%) Stabilized(%) Worsened (%)

1 73 6 (8.2) 52 (71.2) 15 (20.5)

2 61 8 (13.1) 43 (70.5) 10 (16.4)

3 47 12 (25.5) 32 (68.1) 3 (6.4)

4 34 11 (32.4) 16 (47.1) 7 (20.6)

5 22 6 (18.7) 11 (50) 5 (22.7)

6 16 3 (27.3) 8 (50) 5 (31.3)

Retrospective Analysis: ILD Patients Post Cyclophosphamide

FVC at 1 and 2 year after IV CYC

Improved Stabilzed Worsened0

1020304050607080

8.22

71.23

20.55

1 year

Improved Stabilzed Worsened0

10

20

30

40

50

60

70

80

13.12

70.49

16.39

2 years

N=73

N=61

FVC at 3 and 4 years after IV CYC

Improved Stabilzed Worsened0

10

20

30

40

50

60

70

80

25.53

68.09

6.38

3 years

Improved Stabilzed Worsened05

101520253035404550

32.35

47.06

20.59

4 years

N=47

N=34

FVC at 5 and 6 years after IV CYC

Improved Stabilzed Worsened0

10

20

30

40

50

60

27.27

50

22.73

5 years

Improved Stabilzed Worsened0

10

20

30

40

50

60

18.75

50

31.25

6 years

N=22

N=16

Comparison with previous studies

Author Number of patients Treatment Baseline FVC % predicted

Follow up duration Outcome

Tashkin (SLS1) 2006 145 Oral CYC or placebo for 12 months

68.1±1.0 2 years Stabilization

Hoyles (FAST) 2006 45 IV CYC +CS f/b AZA or placebo

80.1±10.3 1 year Stabilization

Espinosa 2011

37 IV CYC for 24 months 64.9±17.4 2 years Stabilization

Mittoo2006

38 Oral CYC for atleast 6 months

63.3±12.4 5.1 years 45% had decline in FVC

Our data 74 IV CYC for 6 months f/b AZA

61.88±16.1 5 years 31% had decline in FVC

Poster at APLAR

TREATMENT GI SYMPTOMS IN SSC

80-90%

40%10-50%

50-70%

Systemic sclerosis GI complications

Incontinence

Abdominal pain/Distension

Gastro-oesophageal

Diarrhoea

Weight loss/Nutritional Issues

Constipation

oesophagus

stomach

pancreas

Small intestine

rectum

colon

Liver

Clin Exp Rheumatol 2014; 32: S214-S221.

Pulmonary arterial hypertension

Scleroderma renal crisis

Systemic sclerosis as a vascular disease

MANAGEMENT OF PAH

PAH :Definition • PH resting mPAP ≥ 25mmHg at rest• Prevalence is 10-15%• Primary or secondary

Licensed targeted therapies for PAH in systemic sclerosis

Endothelin receptor antagonists

Selective phosphodiesterase inhibitors

Prostacyclin analogues

Bosentan* (approved 2001)AmbrisentanSitaxentan (withdrawn)Macitentan (approved 2013)

Sildenafil (approved 2005)TadalafilRiociguat – guanylate cyclase agonist (approved 2013)

EpoprostenolTreprostinilIloprost

ET1NOcGMP PGI2Mechanism

p.o. p.o.

i.v., s.c., inh.

*licensed for SSc digital ulcers 2007

Rationale for combination therapy• Three mechanistic pathways for PAH :

• The endothelin, • Nitric oxide • Prostacyclin (PGI2) pathways

• Combinations leads to • enhanced efficacy • permit individual agents to be used in lower dosages thereby minimizing toxicity.

• Possible that combination therapy could result in drug interactions

SCLERODERMA RENAL CRISIS

Scleroderma Renal Crisis

• GC can precipitate SRC,• Keep dose less than 10mg/day• ACEi initial choice for SRC• No evidence to support prophylactic use of ACEi

CARDIAC INVOLVEMENT IN SSC

Cardiac ManifestationCardiac Manifestations

Pericardial Acute pericarditis, chronic pericarditis, pericardial fibrosis,pericardial effusion,tamponade

Myocardial Myocardial fibrosis,ventricular dysfunction, myocarditis

Conduction Defects Autonomic dysfunction, heart block, supraventricular dysrhythmia,ventricular dysrhythmia

Vascular Mural fibrosis, intimal proliferation, platelet fibrin clotting

Rheum Dis Clin N Am: 2014, 87-102

Rheumatology Clinic, PGIMER Data SSc : 550 patients

Pts No

Cardiac 10

Pericardial 6

Myocardial 2

Arrythmias 2

• 36 year old male with diffuse cutaneous systemic sclerosis

• Developed exertional dyspnoea, angina and palpitations, cardiac enzymes elevated

• Cardiac MRI showed LVEF of 39% with abnormal subendocardial enhancement

• Treated with monthly IV CYC / IV MP and oral steroids• Repeat echocardigraphy after 5 pulses had LVEF of 50%

with symptomatic improvement of patient

Scand J Rheumatol 2010; 39: 349-50

Potential Immunomodulatory strategies

Methotrexate Cyclophosphamide Azathioprine Mycophenolate mofetil Stem cell transplant (autologous/allogeneic Tacrolimus, rapamycin Biological agents (rituximab, abatacept)

EMERGING STRATEGIES FOR SSC

Potential Novel Therapies in SSc

Rituximab

• EUSTAR cohort pts receiving R had greater percentage decline in mRSS compared with matched controls

• Also pts on R had less decline in FVC vs controls Ann Rheum dis.2015;74(6):1188-1194

• SSC associated polyarthritis (NCT01748084)• SSc associated PAH (NCT01086540)

Anti vasculopathicAnti fibroticImmune modulatory effects

Abatacept

• Improved SSc associated polyarthritis Ann Rheum dis.2013;72(7):1217-1220

• 5/7 pts in A group and 1/3 pts in placebo group had 30% improvement in mRSS

• Phase II trial A in dcSSc skin assessed by mRSS as primary end point (NCT02161406)

Oral Paper at APLAR

Fibrosis Transforming Growth Factor

• TGF β central fibrotic signaling in SSc• Binding of TGFβ to cell surface receptors activates

the SMAD signaling pathway leading to fibroblast activation

• Expression of pro fibrotic genes• Epithelial-mesenchymal transition

Anti fibrotic therapies target TGFβ

TGFβ

Metelimumab

Resolimumab

Riociguat

Interleukin-6

• Produced by B Cells, T cells & fibroblasts• Promotes inflammation & fibrosis

• Phase II RCT• Greater decline in mRSS score (p=0.06)• Lesser decline in FVC(p<0.05)

Lancet.2016;doi:10.1016/S0140-6736(16)00232-4

• Phase III trial currently recruiting (NCT02453256)

Targeting the IL-6 axis in diffuse systemic sclerosis

180120600

100

80

60

40

20

0

Disease duration (months)

Number at risk

HighLow

15 5 3 124 15 5 1

IL-6 serum level at presentation predicts survival

Surv

ival

%p=0.02, Log rank analysis

high

Low IL-6

Khan et al. Ann Rheum Dis. 2012;71:1235-42.

X200 vascular

Immunostaining IL-6 in dcSSc skin

X200 fibroblast

IL-6

(pg/

ml)

Controls

50

40

30

20

10

0dcSSc

High pltsdcSSc

Normal plts

lcSSc*

IL-6 serum level in SSc

50403020100

40

30

20

10

0

IL-6 (pg/ml)

MR

SS a

t 36

mon

ths

r=0.86p<0.01

IL-6 serum level at presentation predicts skin score at 36 months

A Phase II/III Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab Versus Placebo in Patients with Systemic Sclerosis (WA27788 faSScinate)

Sponsor: Genentech-RocheTarget: 86 patients

Tyrosine Kinase Signaling Pathways

• Imatinib• Nilotinib• Dasatinib• Nintedanib

• Perfenidone

Peroxisome proliferator activated receptor

• PPAR-ϒ activation inhibits TGFβ induced fibrosis• Pan-PPAR-ϒ agonist IVA337 : Phase II trial in dc SSc

(NCT02503644)

IVIG: Refractory active dcSSc

• mRSS score was compared at baseline, 6,12 months.• Changes in mRSS were compared with3 large RCTs

with other medications: D-pen,relaxin, type1 collagen, MMF.

• IVIG effective adjunctive therapy for active dcSSc.

Role of VEGF• Tissue hypoxia induces neoangiogenesis • SSc vascular repair and angiogenesis is disturbed • The key molecules in the induction of angiogenesis is VEGF • Single local administration of VEGF121-fibrin can achieve sufficient

revascularisation

Autologous haemopoietic stem cell transplantation

Mobilisation4-6g cyclophosphamide

Conditioning8-16g cyclophosphamide

Autologous haemopoietic stem cell transplantation

• American SSc Stem Cell vs Immune suppression trial (ASSIST)

• Autologous Stem Cell Transplantation International SSc Trial (ASTIS)

• HSCT pts showed significant in mRSS and in FVC• Higher treatment related mortality

?

Work published this year

Oral Paper at APLAR

Poster at APLAR

Conclusions• SSc has the highest case-specific mortality of any autoimmune

rheumatic disease– Survival is improving

– Organ-based therapies are available

– Vascular and immunosuppressive strategies emerging

• Better understanding of SSc biology – Pathogenesis

– Biomarkers

– Targeted therapeutics

• Current management should focus on morbidity as much as mortality– Stratified approach to treatment is required

– Effective anti-fibrotic treatments are needed

Question35years, FemaleDiffuse Systemic SclerosisSevere skin involvementHRCT Chest : Early ILDEcho: Not suggestive of PAHPFT: FVC = 40%

How will you Treat:1. Cyclophosphamide2. No treatment3. Steroids4. Follow up the patient with serial PFTs, mRSS.

Thank You