clinical science session : progressive systemic sclerosis - disease modifying therapy in scleroderma...
TRANSCRIPT
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Disease Modifying Therapy in Scleroderma
Dr Shefali K SharmaAssociate Professor
Dept of Internal MedicinePGIMER
Chandigarh
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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
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SSc
Localized
Morphea Linear
Systemic
Limited/ diffuse
CLASSIFICATION
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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
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PATHOGENESIS
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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
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HLA Linkage in SSc: PGI Data
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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
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Fibroblasts
Fibroblasts Myofibroblasts Cytokines
Orchestra the production, deposition, remodeling of collagen & other extra cellular matrix components
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Activation of Fibroblasts in Systemic Sclerosis
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Early Vascular Changes ( Contd.)
Angiogenic
Angiostatic
Progressive Loss of Blood Vessels leads to HypoxiaHigh Plasma levels of Vascular Endothelial Growth Factor
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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
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Concept of targeted therapy in SSc
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Concept of targeted therapy in SSc
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SKIN DISEASE
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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
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Current Management of Digital Vasculopathy in SSc
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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.
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MANAGEMENT OF ILD
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Pulmonary Involvement
LUNGILD
ILD
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Clinical features: Lungs60% of patients affected
• Leading cause of mortality and morbidity in later stage of SSc
Complains• Dry cough,
breathlessness
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Investigations
1. Routine2. HRCT Chest3. PFT
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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)
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Treatment Protocol Followed
CYC + High Dose steroids
Induction: CYC + Low dose steroids Maintainence :AZA
MMF
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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)
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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.
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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.
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Demographic & Clinical Characteristics
Total Number of SSc Patients 530SSc with ILD 177SSc with ILD & PAH 70No of Females: Males 458:72ANA Positivity (IIF) 520
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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
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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
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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
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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
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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
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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
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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
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Poster at APLAR
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TREATMENT GI SYMPTOMS IN SSC
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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.
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Pulmonary arterial hypertension
Scleroderma renal crisis
Systemic sclerosis as a vascular disease
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MANAGEMENT OF PAH
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PAH :Definition • PH resting mPAP ≥ 25mmHg at rest• Prevalence is 10-15%• Primary or secondary
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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
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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
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SCLERODERMA RENAL CRISIS
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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
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CARDIAC INVOLVEMENT IN SSC
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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
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Rheumatology Clinic, PGIMER Data SSc : 550 patients
Pts No
Cardiac 10
Pericardial 6
Myocardial 2
Arrythmias 2
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• 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
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Potential Immunomodulatory strategies
Methotrexate Cyclophosphamide Azathioprine Mycophenolate mofetil Stem cell transplant (autologous/allogeneic Tacrolimus, rapamycin Biological agents (rituximab, abatacept)
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EMERGING STRATEGIES FOR SSC
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Potential Novel Therapies in SSc
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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
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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)
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Oral Paper at APLAR
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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
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Anti fibrotic therapies target TGFβ
TGFβ
Metelimumab
Resolimumab
Riociguat
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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)
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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
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Tyrosine Kinase Signaling Pathways
• Imatinib• Nilotinib• Dasatinib• Nintedanib
• Perfenidone
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Peroxisome proliferator activated receptor
• PPAR-ϒ activation inhibits TGFβ induced fibrosis• Pan-PPAR-ϒ agonist IVA337 : Phase II trial in dc SSc
(NCT02503644)
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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.
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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
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Autologous haemopoietic stem cell transplantation
Mobilisation4-6g cyclophosphamide
Conditioning8-16g cyclophosphamide
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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
?
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Work published this year
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Oral Paper at APLAR
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Poster at APLAR
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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
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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.
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Thank You