9/12/21 1 Management of Systemic Sclerosis Dinesh Khanna, M.D., M.S. Frederick G. L Huetwell Professor of Rheumatology Professor of Medicine University of Michigan [email protected] Twitter: @sclerodermaUM 1 Disclosures ¨ Grant support: Bayer, BMS, Pfizer, NIH/NIAID, NIH/NIAMS ¨ Consultant for clinical trial design or funding of an investigator-initiated trial: ¨ Stocks – Eicos Sciences, Inc. ¨ No promotional talk – Actelion – Bayer – BMS – Boehringer-Ingelheim – Chemomab – CSL Behring – Genentech/Roche – Horizon – Pfizer – Prometheus 2
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2021_Management_Scleroderma_OARManagement of Systemic Sclerosis
Dinesh Khanna, M.D., M.S. Frederick G. L Huetwell Professor of Rheumatology
Professor of Medicine University of Michigan [email protected]
Twitter: @sclerodermaUM
¨ Grant support: Bayer, BMS, Pfizer, NIH/NIAID, NIH/NIAMS ¨ Consultant for clinical trial design or funding of an investigator-initiated trial:
¨ Stocks – Eicos Sciences, Inc.
– CSL Behring – Genentech/Roche – Horizon – Pfizer – Prometheus
2
mailto:[email protected]
9/12/21
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• Young A, Khanna D. Systemic sclerosis: commonly asked questions by rheumatologists. J Clin Rheumatol 2015.
• Denton CP, Khanna D. Systemic sclerosis. Lancet 2017. • Roofeh D, Khanna D. Management of systemic sclerosis-
the first five years. Curr Opin Rheumatol 2020.
3
Criteria Domain Sub-Criteria Weight
Puffy fingers
2
Digital tip ulcers
Telangiectasia 2
Raynaud’s phenomenon 3
3
TOTAL SCORE of 9 or more as classified as SSc
Van den Hoogen F, Khanna D. Arth Rheum. 2013;65(11):2737-47.
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• Sclerodactyly 95% • Raynaud’s phenomenon 90% • +ANA by IIF 95%
If absent, think of scleroderma-like skin disorder
Clements P. Baillieres Best Pract Res Clin Rheumatol. 2000. Mar;14(1):1-16.
5
Limited Diffuse
Clements PJ, Furst DE. Systemic sclerosis. Philadelphia, PA: Lippincott Williams &Wilkins; 2004.
~55% ~35%
Anti-t opoisomerase I
Anti- Scl-70 = pulmonary fibrosis Anti-Centromere = PAH Anti-RNA pol III = renal crisis and malignancy Anti-PM-Scl = SSc-myositis overlap Anti-U3RNP and Anti-Th (nucleolar staining on ANA)=ILD and PAH
Clements PJ, Furst DE. Systemic Sclerosis; Lippincott, Williams & Wilkins, Baltimore, 2004.
50-60% have 3 common Ab Anti-centromere, anti-SCL70,
Anti-RNA pol III
Once the Diagnosis is Made…… Baseline Tests
• ANA by IIF • SSc antibodies – Anti-centromere – Anti-SCL-70 – Anti RNA Polymerase III
• Echocardiogram with Doppler • Electrocardiogram • PFT with DLCO • HRCT of lungs (non-contrast)
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Provided by Thomas Medsger2-5 years after first non RP symptom/sign
Usual Timing of Problems in Systemic Sclerosis
Limited
Diffuse
9
pulmonary hypertension
Provided by Thomas Medsger 2-5 years after first non RP symptom/sign
myocardial involvement interstitial lung disease
Skin in Systemic Sclerosis Who do you treat?
Associated with pain, stiffness, hand contractures, and disability
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§ 15 mg/week oral for a year1
§ 15 mg/week subcutaneous for 24 weeks2
– MMF-Supported by case series and post hoc analysis from the SLS-II § Mycophenolate mofetil at 3 grams/day3
– Pulse CYC at 500 mg on monthly basis4
• IVIG5
• Abatacept S/Q week6
• Tocilizumab S/Q week7 1. Pope J et al A&R. 2001 Jun;44(6):1351-1358. 2. Van den Hoogen et al. Br J Rheumatol. 1996 Apr;35(4):364-72. 3. Namas R et al. Arthritis Care Res (Hoboken). 2018 Mar;70(3):439-444. 4. Valentini et al. Scand J Rheumatol. 2006 Jul;35:1,35-38. 5. Poelman et al. J Rheumatol. 2015 Feb;42(2):236-42. 6. Khanna D, et al. Arthritis Rheumatol. 2020 Jan;72(1):125-136. 7. Khanna D, et al Lancet. 2017 Oct;390(10103):1685-1699.
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Treat with immunosuppressive
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SSc New Rising Renal patient + onset BP + creatinine = crisis
BP is very resistant to treatment ACE-inhibitors are the drugs of choice
Acute rise in BP defined as any of the following:
SBP > 140 mmHg DBP > 90mmHg A rise in SBP > 30 mmHg A rise in DBP > 20 mmHg
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Features Predictive of Renal Crisis
• 20% diffuse SSc have SRC • 90% SRC occur in diffuse SSc • <1% in classic limited SSc • Early disease - 80% with < 4 years symptoms • Rapidly progressive skin thickening • New cardiac events
CHF Pericardial effusion - before and during SRC
• Autoantibodies - anti-RNA polymerase III - 24-33% SRC (also severe skin), anti-topo predicts diffuse SSc but not SRC
Provided by Virginia Steen
Major Clinical Features of Renal Crisis
• Blood pressure - Severely increased, > 180/130 • Very resistant BP and difficult to control on outpatient basis • Renal function
Creatinine increases daily, even after BP controlled New onset proteinuria or hematuria
• Hematologic Microangiopathic hemolytic anemia Thrombocytopenia in 40%
• Cardiac Congestive heart failure Pericardial effusions
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• Admit to the hospital in a monitored bed • Begin ACE-inhibitor:
-Captopril 25 mg every 6-8 hours -Push dose to 50-100 mg every 6-8 hours.
-Lisinopril 5-10 mg every 12 hours -Push dose to 20-40 mg daily.
-Goal is to normalize blood pressure within 72 hours -Risk not the same with long standing hypertension
-Expect Cr to continue to -don’t stop ACE, even on dialysis
-Only contraindication- Resistant K+
• If inadequate result: -Add calcium-channel blocker, i/v furosemide, i/v nitroprusside and
other therapies -Role of continuous low dose I/V prostanoids -Dialyze as needed
Acute rise in BP defined as any of the following:
SBP > 140 mmHg DBP > 90mmHg A rise in SBP > 30 mmHg A rise in DBP > 20 mmHg
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Longer Term Therapy
• Transition to long acting ACE inhibitors • Example: enalapril or ramipril • Life long use
• If on dialysis, use lower dose on day of dialysis or on days not on dialysis due to lowering of BP
• Limit nephrotoxic agents • Await 18 months before considering renal transplant.
Penn et al. QJM. 2013 Sep; 106(9):839-48.
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Diffuse SSc
Early disease
-Check BP three times a week -Advice the patient on what
to do if abnormal BP or symptoms
RNA Poly 3++ SAME for other autoantibodies
Discussion that complication exists
but no clear recs
Early disease Late disease
Limited SSc
Association with SRC Use of prednisone > 15 mg /day in early SSc
Early dcSSc RNA Poly 3 +
Tendon friction rubs Pericardial effusion
Who to Screen?
♦ Systemic sclerosis-associated interstitial lung disease (SSc-ILD) affects approximately 70% of patients
♦ 25% to 30% have progressive ILD
♦ Significant morbidity and leading causes of mortality in SSc
♦ Disease is largely irreversible and goal is stabilization
♦ Current treatment approach includes immunosuppressive along with anti-fibrotic therapy
Denton C, Khanna D. Lancet 2017. Wallace B, et al. Curr Opin Rheumatol. 2016.
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Prediction of ILD Based on SSc Associated Antinuclear Antibody (ANA)
L = limited cutaneous SSc
D = diffuse cutaneous SSc
Provided by Chris Denton
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Annual exposure of airline crews on long-haul flights 2–3 [
Khanna D. Journal of Scleroderma related disorder 2021
Effective radiation dose for environmental exposure and chest imaging
Effective dose (mSv) Chest radiograph 0.02
Low dose lung cancer screening CT 1–2 Routine diagnostic chest CT 5–7
Chest HRCT Effective dose (mSv)
Standard protocol 2–4
9-slice protocol 0.08
How to screen?
– Complete PFT with DLCO lacks sensitivity to diagnose early ILD. False negative rate=27% 1
– HRCT with prone images
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applewebdata://91BBBF80-4840-4EEC-98CA-F50C75BCCE54/
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1. Moderate to Severe ILD on HRCT
2. FVC or DLCO <LLN or significant decline in FVC and DLCO
3. Desaturation on 02 saturation 4. +/ ++ symptoms
ILD on HRCT?
Close f/u with PFT every 6 months during 3 years
Subclinical (50%)
Treat
1. Mild ILD on HRCT 2. FVC and DLCO >LLN and no
significant decline in FVC and DLCO [if more than 1 value available]
3. No symptoms
High risk 1. dcSSc +SCL70 2. dcSSc +CRP
Low risk Phenotype
Progressive ILD
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§ Up to 3 grams/day in divided doses1
– Oral of monthly pulse intravenous cyclophosphamide § Daily oral cyclophosphamide = up to 2 mg/kg/day2
§ Monthly intravenous cyclophosphamide = 500-750 mg/kg3
followed by MMF or azathioprine – Rescue therapy
§ Rituximab therapy4
– Severe progressive ILD or not responsive disease § Autologous hematopoietic stem cell transplant5
§ Lung transplant6
51 year-old male--Will you treat him?
• New onset RP • +Scl-70 ab • Minimal bibasilar reticulations • CRP 2 mg/dL (ULN 0.8 mg/dl) • No SOB • FVC 82% • DLCO 80%
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focuSSced Is a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Tocilizumab—Should we treat EARLY ILD?
Screening (40 days)
Baseline
n=210
Week 48: Primary end point • CFB in mRSS Key secondary end points • CFB in %pFVC • Time to treatment
failure • PROs
PBO SC QW n=105
TCZ 162 mg SC QW
CFB, change from baseline; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; PROs, patient-reported outcomes; QW, weekly; SC, subcutaneous.
Escape therapy from week 16 (for FVC) or from week 24 (for mRSS or other significant SSc complications)
Key inclusion/exclusion criteria • SSc per ACR/EULAR criteria and ≤60 months
from first non-Raynaud’s symptom • mRSS 10-35 units • Active disease • At least one of these: CRP ≥6 mg/L;
ESR ≥28 mm/h; platelet count ≥330×109/L • No other rheumatic autoimmune disease • Other background immunomodulatory
therapies not allowed
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All Patients N=136
PBO n=68
TCZ n=68
Females, % 79 81 78 Age, years 48.1 (12.9) 47.6 (12.5) 48.7 (13.3) Duration of SSc, months 22.8 (16.8) 22.6 (16.6) 23.0 (17.2) Total mRSS 20.8 (7.0) 20.7 (6.8) 20.3 (7.2) %pFVC 79.6 (14.5) 81.5 (14.8) 77.7 (13.9) %pDLCO 70.4 (16.9) 72.1 (17.0) 68.7 (16.8)
ANA positive, n/N (%) 96.9 95.2 98.5 Anti-topoisomerase positive, (%)
68.7 68.8 68.7
14.5 9.4 19.4
Anti-centromere positive, n/N (%)
1.5 1.6 1.5
ANA, anti-nuclear antibody; QLF-LM, quantitative lung fibrosis of the most affected lobe; QLF-WL, quantitative lung fibrosis in whole lung; SD, standard deviation.
All data are mean (SD) and calculated based on n=106 for PBO and n=104 for TCZ unless stated otherwise.
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Clinically Meaningful Difference in Change From Baseline in %pFVC at Week 48
%pFVC PBO n=63
LSM change from baseline at week 48
-6.5 -0.1 6.4 (3.3, 9.4) p<0.0001
Absolute change in FVC, mL
-257 -20 238 (119, 357)
p=0.0001
3
Worsening (decrease in %pFVC) No Decline (increase in %pFVC)
80 75.5%
0 10 20
Nominal p=0.003 (Van Elteren])
24.5%
51.7%
Physiological decline ~25-30 ml every year in FVC after age of 25 years [Eur Respir J 2012]
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Tocilizumab is now FDA approved for SSc-ILD Indication: Slowing the Rate of Decline in
Pulmonary Function in Adults With Systemic Sclerosis-Associated Interstitial Lung Disease
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vTreatment with immunosuppressive therapy has modest effect1
vOne year of oral daily CYC did not improve time to death or organ failure vs. placebo in the SLS-I and II2
vNo published data to support the duration of therapy
vMy plan is long term therapy (at least 5 years) and then very slow taper
vDetailed discussion of flare of disease in a 20-30% with ILD and skin
1. Denton and Khanna. Lancet 2017 2. Volkmann E. ACR [abstract] 2017
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Nintedanib is a tyrosine kinase inhibitor that targets, amongst others, receptors specific for PDGF, FGF and VEGF.
1. Wollin L, et al. J Pharmacol Exp Ther. 2014;349:209-220. 2. Wollin L, et al. Eur Respir J. 2015;45:1434-1445.
3. Thannickal VJ, et al. J Biol Chem. 2003;278:12384-12389.
Nintedanib
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Trial Design
• Patients remained on blinded treatment until the last patient had reached week 52 but forno longer than 100 weeks
Randomized patients were stratified by anti-topoisomerase antibody (ATA) status (positive or negative). Dose reductions from 150 mg bid to 100 mg bid and treatment interruptions were permitted to manage adverse events. bid, twice daily; R, randomization.
Distler O, et al NEJM 2019
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Key Eligibility Criteria
Key Inclusion Criteria • SSc1 with first non-Raynaud symptom <7 years from
screening • ≥10% fibrosis of the lungs, confirmed by central
assessment of an HRCT scan performed ≤12 months before screening
• FVC ≥40% predicted • DLco 30–89% predicted
Permitted – Prednisone ≤10 mg/day or equivalent – Stable mycophenolate or methotrexate for ≥6 months prior
to randomization *Defined as previous clinical or echocardiographic evidence of significant right heart failure, history of right heart catheterization showing a cardiac index ≤2 l/min/m², or pulmonary hypertension requiring parenteral therapy with epoprostenol/treprostinil.
1. van den Hoogen F, et al. Arthritis Rheum 2013;65:2737–47.
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Female, n (%) 221 (76.7) 212 (73.6)
BMI, kg/m2, mean (SD) 25.9 (4.8) 25.8 (5.1)
Race, n (%)
Type of SSc, n (%)
Years since onset of first non-Raynaud symptom, median (minimum, maximum)
3.4 (0.3, 7.1) 3.5 (0.4, 7.2)
Anti-topoisomerase I antibody positive,n (%) 173 (60.1) 177 (61.5)
Taking mycophenolate, n (%) 139 (48.3) 140 (48.6)
Baseline Characteristics
36.8 (21.8) 35.2 (20.7)
FVC, mL, mean (SD) 2459 (736) 2541 (816) FVC, % predicted, mean (SD) 72.4 (16.8) 72.7 (16.6) DLco, % predicted, mean (SD)*
52.9 (15.1) 53.2 (15.1)
*Corrected for hemoglobin.
Nintedanib 288 283 281 273 Placebo 288 283 281 280
278 283
265 280
262 268
241 257
-120 -140
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week
No. of patients
M ea
n (S
E) a
bs ol
ut e
ch an
ge fro
m ba
se lin
e in
F VC
(m L)
yr )
Difference: 41.0 mL/yr (95% CI: 2.9, 79.0); p=0.04 Relative reduction: 44%
Primary endpoint analyzed using random coefficient regression model (with random slopes and intercepts) including ATA status, age, height, gender and baseline FVC (mL) as covariates
Annual rate of decline in FVC (mL/yr) Change from baseline in FVC (mL) over 52 weeks (primary endpoint)
Physiological decline ~25-30 ml every year in FVC after age of 25 years [Eur Respir J 2012]
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Rate of Decline in FVC (mL/yr) over 52 Weeks by Mycophenolate Use at Baseline
-40.2 -63.9-66.5
Relative reduction: 40%
Relative reduction: 46%Ad ju
st ed
ra te
(S E)
o fd
ec lin
e in
F VC
(m L/
Nintedanib (n=138)
Placebo (n=140)
Nintedanib (n=149)
Placebo (n=148)
Most Frequent Adverse Events
Adverse events reported over 52 weeks plus 28-day post-treatment period in >10% of patients in either treatment group. Data are n (%) of patients with ≥1 such adverse event coded based on MedDRA preferred terms.
Nintedanib (n=288) Placebo (n=288)
Diarrhea 218 (75.7) 91 (31.6) Nausea 91 (31.6) 39 (13.5) Vomiting 71 (24.7) 30 (10.4) Skin ulcer 53 (18.4) 50 (17.4) Cough 34 (11.8) 52 (18.1) Nasopharyngitis 36 (12.5) 49 (17.0) Upper respiratory tract infection 33 (11.5) 35 (12.2) Abdominal pain 33 (11.5) 21 (7.3) Fatigue 31 (10.8) 20 (6.9) Weight decreased 34 (11.8) 12 (4.2)
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• Add Tocilizumab • Add Rituximab • Stem cell
Transplant • Lung transplant
& Anti-SCL 70
• MMF 2-3 grams/day • ?CYC up to 2 mg/kg/ day or
500-750 mg/mg m2 *Initial preference MMF= Mycophenolate mofetil upto 3 grams/day CYC= Cyclophosphamide oral upto 2 mg/kg/day or monthly pulse
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Demographics
Age, years (mean) 44.9 46.9
Female, % 52.8 74.4
MRSS, mean (SD) 28.5 (8.7) 30.8 (10.5)
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Abbreviations: EFS, Event-free Survival; PP, Per Protocol (Treated) Population
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• Hemodynamic observation and should lead to identify underlying cause
• Pulmonary arterial hypertension (PAH) results from restricted flow through pulmonary arterial circulation – Leads to pulmonary vascular resistance (PVR), ultimate right heart
failure – Predominant cause - loss of vascular luminal volume from vascular
remodeling, excessive cell proliferation, ↓ apoptosis
What is Pulmonary Hypertension?
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1.1 Idiopathic PAH 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 PAH associated with:
1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis
1.5 PAH long-term responders to CCBs 1.6 PAH with overt features of venous/ capillaries involvement 1.7 Persistent PH of the newborn syndrome
2.1 PH due to HF with preserved LVEF 2.2 PH due to HF with reduced LVEF 2.3 Valvular heart disease 2.4 Congenital/acquired cardiovascular conditions
leading to post-capillary PH
1. Pulmonary Arterial Hypertension
3. PH Due to Lung Diseases and/or Hypoxia
4. PH Due to Pulmonary Artery Obstructions
5. PH With Unclear and/or Multifactorial Mechanisms
3.1 Obstructive lung disease 3.2 Restrictive lung disease 3.3 Other lung disease with mixed restrictive/ obstructive pattern 3.4 Hypoxia without lung disease 3.5 Developmental lung disorders
4.1 Chronic thromboembolic PH 4.2 Other pulmonary artery obstructions
5.1 Hematological disorders 5.2 Systemic and metabolic disorders 5.3 Others 5.4 Complex congenital heart disease
6th World Symposium Classification of PH
Simonneau G, et al. Eur Resp J. 2019;53:1801913
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Badesch D et al. J Am Coll Cardiol. 2009;54(1 Suppl):S55-66. Galiè et al. Eur Respir J. 2019;53(1):1802148.
New Hemodynamic Definition of PH/PAH
PH
PCWP/LVEDP ≤15 mm Hg
>20
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Recommendations Resting echocardiography is recommended as a screening test in asymptomatic patients with SSc, followed by annual screening with echocardiography, DLCO and biomarkers
*The DETECT algorithm is not yet validated in patients with DLCO > 60%
DLCO: diffusing capacity of the lung for carbon monoxide; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; SSc: systemic sclerosis. aClass of recommendation bLevel of evidence.
1. Khanna D, et al. Arthritis Rheum. 2013 Dec;65(12):3194-201. 2. Hoeper M, et al. J Am Coll Cardiol. 2013 Dec;62(25 Suppl):D42-D50. 3. Frost A, et al Eur Respir J. 2019 Jan;53(1):1801904. 4. Galiè N, et al. Eur Respir J 2015 Oct;46(4):903-75. 5. Galiè N, et al. Eur Heart J 2016 Aug;48(2):311-4.
Recommendations from 5th and 6th WSPH2,3:
Annual screening for PAH is recommended in (cardiopulmonary) asymptomatic patients with the SSc spectrum of diseases
Recommendations from 2015 ESC/ERS guidelines4,5:
Recommendations for Screening and Detection of PAH-CTD1:
Every patient with SSc should be screened annually for PAH due to the high prevalence of PAH in SSc
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Echo TR jet normal/ abnormal Right ventricular dysfunction
RHC
Current Paradigm to Refer for RHC
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Screening
Echo
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• DETECT v2.0 was released in January 2019
STEP 1
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Risk of a Clinical Event by Drug Treatment and PAH Etiology
Five randomized controlled trials (N=3172; n=941 with CTD-PAH [30%]) reported HRs for a morbidity or mortality event by drug treatment and PAH etiology. Clinical event definitions varied between trials but generally included death, worsening of PAH, hospitalization due to PAH, and treatment escalation. Khanna D, et al. Arthritis Rheumatol. 2021 [Epub ahead of print].
Overall PAH population 36% reduction in risk of a clinical event HR=0.64 (95% CI, 0.54–0.75; P<0.001):
CTD-PAH population 36% reduction in risk of a clinical event HR=0.64 (95% CI, 0.51–0.81; P<0.001)
Study name Active arm (n)
Control arm (n)
COMPASS-2 159 175 0.83 (0.61-1.14)
SERAPHIN 242 250 0.55 (0.41-0.74)
GRIPHON 574 582 0.60 (0.49-0.73)
FREEDOM-EV 346 344 0.74 (0.56-0.97)
AMBITION 253 247 0.50 (0.35-0.72)
Overall 0.64 (0.54-0.75)
Active arm better
Control arm better
Control arm (n)
Overall 0.64 (0.51-0.81)
Active arm better
Control arm better
Prostacyclin Analogs Prostacyclin Agonists
Sildenafil (PO) FDA Approved: June 2005
Epoprostenol (IV ) Flolan FDA Approved: September 1995 Veletri FDA Approved: June 2008
Selexipag (PO) FDA Approved: December 2015
Ambrisentan (PO) FDA Approved: June 2007
Tadalafil (PO) FDA Approved: May 2009
Treprostinil (IV, SC, PO, and inhaled) First (SC formulation) FDA Approved: July 2002
Macitentan (PO) FDA Approved: October 2013
Riociguat (PO) FDA Approved: October 2013
Iloprost (inhaled) FDA Approved: December 2004
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed April 1, 2016.
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Raynaud’s Phenomenon in SSc1
• 95% of patients with SSc • Part of the 2013 ACR EULAR Classification criteria2
• Mainly affects digits; can affect ears, nose, etc. • Triphasic color change
- Pallor– cold-induced digital artery vasospasm and venous spasm - Cyanosis— Vasodilation of venous system - Rubor– dilatation of Atrial Venous Anastomosis with influx of oxygenated
blood
• Clinical diagnosis - Ask the following screening questions1:
§ Are your fingers unusually sensitive to cold? § Do your fingers change color when exposed to cold temperatures? § Do they turn white, blue, or both?
1. Wigley and Flavahan. N Engl J Med 2016;375(6):556-565. 2. Van den Hoogen, et al. Arthritis Rheum 2013 Nov;65(11):2737-47.
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Management of Raynaud’s Phenomenon Establish diagnosis and identify any underlying cause
amenable to treatment
Treat underlying cause
General/lifestyle measures: Patient education • Avoid cold, keep warm • Stop smoking (Complementary therapies)
Drug therapy: first time CCB, PDE5 inhibitor, ARB, SSRI, alpha blocker, ACE inhibitor, Topical nitrate ±
Antiplatelet and/or statin therapy Effective
Ineffective
Effective
Ineffective
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Funded by NIH/NIAID Clinical ACE and NIH/NIAMS R01, R21 and K24
65
Dinesh Khanna, M.D., M.S. Frederick G. L Huetwell Professor of Rheumatology
Professor of Medicine University of Michigan [email protected]
Twitter: @sclerodermaUM
¨ Grant support: Bayer, BMS, Pfizer, NIH/NIAID, NIH/NIAMS ¨ Consultant for clinical trial design or funding of an investigator-initiated trial:
¨ Stocks – Eicos Sciences, Inc.
– CSL Behring – Genentech/Roche – Horizon – Pfizer – Prometheus
2
mailto:[email protected]
9/12/21
2
• Young A, Khanna D. Systemic sclerosis: commonly asked questions by rheumatologists. J Clin Rheumatol 2015.
• Denton CP, Khanna D. Systemic sclerosis. Lancet 2017. • Roofeh D, Khanna D. Management of systemic sclerosis-
the first five years. Curr Opin Rheumatol 2020.
3
Criteria Domain Sub-Criteria Weight
Puffy fingers
2
Digital tip ulcers
Telangiectasia 2
Raynaud’s phenomenon 3
3
TOTAL SCORE of 9 or more as classified as SSc
Van den Hoogen F, Khanna D. Arth Rheum. 2013;65(11):2737-47.
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• Sclerodactyly 95% • Raynaud’s phenomenon 90% • +ANA by IIF 95%
If absent, think of scleroderma-like skin disorder
Clements P. Baillieres Best Pract Res Clin Rheumatol. 2000. Mar;14(1):1-16.
5
Limited Diffuse
Clements PJ, Furst DE. Systemic sclerosis. Philadelphia, PA: Lippincott Williams &Wilkins; 2004.
~55% ~35%
Anti-t opoisomerase I
Anti- Scl-70 = pulmonary fibrosis Anti-Centromere = PAH Anti-RNA pol III = renal crisis and malignancy Anti-PM-Scl = SSc-myositis overlap Anti-U3RNP and Anti-Th (nucleolar staining on ANA)=ILD and PAH
Clements PJ, Furst DE. Systemic Sclerosis; Lippincott, Williams & Wilkins, Baltimore, 2004.
50-60% have 3 common Ab Anti-centromere, anti-SCL70,
Anti-RNA pol III
Once the Diagnosis is Made…… Baseline Tests
• ANA by IIF • SSc antibodies – Anti-centromere – Anti-SCL-70 – Anti RNA Polymerase III
• Echocardiogram with Doppler • Electrocardiogram • PFT with DLCO • HRCT of lungs (non-contrast)
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Provided by Thomas Medsger2-5 years after first non RP symptom/sign
Usual Timing of Problems in Systemic Sclerosis
Limited
Diffuse
9
pulmonary hypertension
Provided by Thomas Medsger 2-5 years after first non RP symptom/sign
myocardial involvement interstitial lung disease
Skin in Systemic Sclerosis Who do you treat?
Associated with pain, stiffness, hand contractures, and disability
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§ 15 mg/week oral for a year1
§ 15 mg/week subcutaneous for 24 weeks2
– MMF-Supported by case series and post hoc analysis from the SLS-II § Mycophenolate mofetil at 3 grams/day3
– Pulse CYC at 500 mg on monthly basis4
• IVIG5
• Abatacept S/Q week6
• Tocilizumab S/Q week7 1. Pope J et al A&R. 2001 Jun;44(6):1351-1358. 2. Van den Hoogen et al. Br J Rheumatol. 1996 Apr;35(4):364-72. 3. Namas R et al. Arthritis Care Res (Hoboken). 2018 Mar;70(3):439-444. 4. Valentini et al. Scand J Rheumatol. 2006 Jul;35:1,35-38. 5. Poelman et al. J Rheumatol. 2015 Feb;42(2):236-42. 6. Khanna D, et al. Arthritis Rheumatol. 2020 Jan;72(1):125-136. 7. Khanna D, et al Lancet. 2017 Oct;390(10103):1685-1699.
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Treat with immunosuppressive
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SSc New Rising Renal patient + onset BP + creatinine = crisis
BP is very resistant to treatment ACE-inhibitors are the drugs of choice
Acute rise in BP defined as any of the following:
SBP > 140 mmHg DBP > 90mmHg A rise in SBP > 30 mmHg A rise in DBP > 20 mmHg
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Features Predictive of Renal Crisis
• 20% diffuse SSc have SRC • 90% SRC occur in diffuse SSc • <1% in classic limited SSc • Early disease - 80% with < 4 years symptoms • Rapidly progressive skin thickening • New cardiac events
CHF Pericardial effusion - before and during SRC
• Autoantibodies - anti-RNA polymerase III - 24-33% SRC (also severe skin), anti-topo predicts diffuse SSc but not SRC
Provided by Virginia Steen
Major Clinical Features of Renal Crisis
• Blood pressure - Severely increased, > 180/130 • Very resistant BP and difficult to control on outpatient basis • Renal function
Creatinine increases daily, even after BP controlled New onset proteinuria or hematuria
• Hematologic Microangiopathic hemolytic anemia Thrombocytopenia in 40%
• Cardiac Congestive heart failure Pericardial effusions
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• Admit to the hospital in a monitored bed • Begin ACE-inhibitor:
-Captopril 25 mg every 6-8 hours -Push dose to 50-100 mg every 6-8 hours.
-Lisinopril 5-10 mg every 12 hours -Push dose to 20-40 mg daily.
-Goal is to normalize blood pressure within 72 hours -Risk not the same with long standing hypertension
-Expect Cr to continue to -don’t stop ACE, even on dialysis
-Only contraindication- Resistant K+
• If inadequate result: -Add calcium-channel blocker, i/v furosemide, i/v nitroprusside and
other therapies -Role of continuous low dose I/V prostanoids -Dialyze as needed
Acute rise in BP defined as any of the following:
SBP > 140 mmHg DBP > 90mmHg A rise in SBP > 30 mmHg A rise in DBP > 20 mmHg
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Longer Term Therapy
• Transition to long acting ACE inhibitors • Example: enalapril or ramipril • Life long use
• If on dialysis, use lower dose on day of dialysis or on days not on dialysis due to lowering of BP
• Limit nephrotoxic agents • Await 18 months before considering renal transplant.
Penn et al. QJM. 2013 Sep; 106(9):839-48.
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Diffuse SSc
Early disease
-Check BP three times a week -Advice the patient on what
to do if abnormal BP or symptoms
RNA Poly 3++ SAME for other autoantibodies
Discussion that complication exists
but no clear recs
Early disease Late disease
Limited SSc
Association with SRC Use of prednisone > 15 mg /day in early SSc
Early dcSSc RNA Poly 3 +
Tendon friction rubs Pericardial effusion
Who to Screen?
♦ Systemic sclerosis-associated interstitial lung disease (SSc-ILD) affects approximately 70% of patients
♦ 25% to 30% have progressive ILD
♦ Significant morbidity and leading causes of mortality in SSc
♦ Disease is largely irreversible and goal is stabilization
♦ Current treatment approach includes immunosuppressive along with anti-fibrotic therapy
Denton C, Khanna D. Lancet 2017. Wallace B, et al. Curr Opin Rheumatol. 2016.
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Prediction of ILD Based on SSc Associated Antinuclear Antibody (ANA)
L = limited cutaneous SSc
D = diffuse cutaneous SSc
Provided by Chris Denton
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Annual exposure of airline crews on long-haul flights 2–3 [
Khanna D. Journal of Scleroderma related disorder 2021
Effective radiation dose for environmental exposure and chest imaging
Effective dose (mSv) Chest radiograph 0.02
Low dose lung cancer screening CT 1–2 Routine diagnostic chest CT 5–7
Chest HRCT Effective dose (mSv)
Standard protocol 2–4
9-slice protocol 0.08
How to screen?
– Complete PFT with DLCO lacks sensitivity to diagnose early ILD. False negative rate=27% 1
– HRCT with prone images
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applewebdata://91BBBF80-4840-4EEC-98CA-F50C75BCCE54/
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1. Moderate to Severe ILD on HRCT
2. FVC or DLCO <LLN or significant decline in FVC and DLCO
3. Desaturation on 02 saturation 4. +/ ++ symptoms
ILD on HRCT?
Close f/u with PFT every 6 months during 3 years
Subclinical (50%)
Treat
1. Mild ILD on HRCT 2. FVC and DLCO >LLN and no
significant decline in FVC and DLCO [if more than 1 value available]
3. No symptoms
High risk 1. dcSSc +SCL70 2. dcSSc +CRP
Low risk Phenotype
Progressive ILD
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§ Up to 3 grams/day in divided doses1
– Oral of monthly pulse intravenous cyclophosphamide § Daily oral cyclophosphamide = up to 2 mg/kg/day2
§ Monthly intravenous cyclophosphamide = 500-750 mg/kg3
followed by MMF or azathioprine – Rescue therapy
§ Rituximab therapy4
– Severe progressive ILD or not responsive disease § Autologous hematopoietic stem cell transplant5
§ Lung transplant6
51 year-old male--Will you treat him?
• New onset RP • +Scl-70 ab • Minimal bibasilar reticulations • CRP 2 mg/dL (ULN 0.8 mg/dl) • No SOB • FVC 82% • DLCO 80%
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focuSSced Is a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Tocilizumab—Should we treat EARLY ILD?
Screening (40 days)
Baseline
n=210
Week 48: Primary end point • CFB in mRSS Key secondary end points • CFB in %pFVC • Time to treatment
failure • PROs
PBO SC QW n=105
TCZ 162 mg SC QW
CFB, change from baseline; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; PROs, patient-reported outcomes; QW, weekly; SC, subcutaneous.
Escape therapy from week 16 (for FVC) or from week 24 (for mRSS or other significant SSc complications)
Key inclusion/exclusion criteria • SSc per ACR/EULAR criteria and ≤60 months
from first non-Raynaud’s symptom • mRSS 10-35 units • Active disease • At least one of these: CRP ≥6 mg/L;
ESR ≥28 mm/h; platelet count ≥330×109/L • No other rheumatic autoimmune disease • Other background immunomodulatory
therapies not allowed
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All Patients N=136
PBO n=68
TCZ n=68
Females, % 79 81 78 Age, years 48.1 (12.9) 47.6 (12.5) 48.7 (13.3) Duration of SSc, months 22.8 (16.8) 22.6 (16.6) 23.0 (17.2) Total mRSS 20.8 (7.0) 20.7 (6.8) 20.3 (7.2) %pFVC 79.6 (14.5) 81.5 (14.8) 77.7 (13.9) %pDLCO 70.4 (16.9) 72.1 (17.0) 68.7 (16.8)
ANA positive, n/N (%) 96.9 95.2 98.5 Anti-topoisomerase positive, (%)
68.7 68.8 68.7
14.5 9.4 19.4
Anti-centromere positive, n/N (%)
1.5 1.6 1.5
ANA, anti-nuclear antibody; QLF-LM, quantitative lung fibrosis of the most affected lobe; QLF-WL, quantitative lung fibrosis in whole lung; SD, standard deviation.
All data are mean (SD) and calculated based on n=106 for PBO and n=104 for TCZ unless stated otherwise.
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Clinically Meaningful Difference in Change From Baseline in %pFVC at Week 48
%pFVC PBO n=63
LSM change from baseline at week 48
-6.5 -0.1 6.4 (3.3, 9.4) p<0.0001
Absolute change in FVC, mL
-257 -20 238 (119, 357)
p=0.0001
3
Worsening (decrease in %pFVC) No Decline (increase in %pFVC)
80 75.5%
0 10 20
Nominal p=0.003 (Van Elteren])
24.5%
51.7%
Physiological decline ~25-30 ml every year in FVC after age of 25 years [Eur Respir J 2012]
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Tocilizumab is now FDA approved for SSc-ILD Indication: Slowing the Rate of Decline in
Pulmonary Function in Adults With Systemic Sclerosis-Associated Interstitial Lung Disease
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vTreatment with immunosuppressive therapy has modest effect1
vOne year of oral daily CYC did not improve time to death or organ failure vs. placebo in the SLS-I and II2
vNo published data to support the duration of therapy
vMy plan is long term therapy (at least 5 years) and then very slow taper
vDetailed discussion of flare of disease in a 20-30% with ILD and skin
1. Denton and Khanna. Lancet 2017 2. Volkmann E. ACR [abstract] 2017
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Nintedanib is a tyrosine kinase inhibitor that targets, amongst others, receptors specific for PDGF, FGF and VEGF.
1. Wollin L, et al. J Pharmacol Exp Ther. 2014;349:209-220. 2. Wollin L, et al. Eur Respir J. 2015;45:1434-1445.
3. Thannickal VJ, et al. J Biol Chem. 2003;278:12384-12389.
Nintedanib
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Trial Design
• Patients remained on blinded treatment until the last patient had reached week 52 but forno longer than 100 weeks
Randomized patients were stratified by anti-topoisomerase antibody (ATA) status (positive or negative). Dose reductions from 150 mg bid to 100 mg bid and treatment interruptions were permitted to manage adverse events. bid, twice daily; R, randomization.
Distler O, et al NEJM 2019
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Key Eligibility Criteria
Key Inclusion Criteria • SSc1 with first non-Raynaud symptom <7 years from
screening • ≥10% fibrosis of the lungs, confirmed by central
assessment of an HRCT scan performed ≤12 months before screening
• FVC ≥40% predicted • DLco 30–89% predicted
Permitted – Prednisone ≤10 mg/day or equivalent – Stable mycophenolate or methotrexate for ≥6 months prior
to randomization *Defined as previous clinical or echocardiographic evidence of significant right heart failure, history of right heart catheterization showing a cardiac index ≤2 l/min/m², or pulmonary hypertension requiring parenteral therapy with epoprostenol/treprostinil.
1. van den Hoogen F, et al. Arthritis Rheum 2013;65:2737–47.
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Female, n (%) 221 (76.7) 212 (73.6)
BMI, kg/m2, mean (SD) 25.9 (4.8) 25.8 (5.1)
Race, n (%)
Type of SSc, n (%)
Years since onset of first non-Raynaud symptom, median (minimum, maximum)
3.4 (0.3, 7.1) 3.5 (0.4, 7.2)
Anti-topoisomerase I antibody positive,n (%) 173 (60.1) 177 (61.5)
Taking mycophenolate, n (%) 139 (48.3) 140 (48.6)
Baseline Characteristics
36.8 (21.8) 35.2 (20.7)
FVC, mL, mean (SD) 2459 (736) 2541 (816) FVC, % predicted, mean (SD) 72.4 (16.8) 72.7 (16.6) DLco, % predicted, mean (SD)*
52.9 (15.1) 53.2 (15.1)
*Corrected for hemoglobin.
Nintedanib 288 283 281 273 Placebo 288 283 281 280
278 283
265 280
262 268
241 257
-120 -140
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week
No. of patients
M ea
n (S
E) a
bs ol
ut e
ch an
ge fro
m ba
se lin
e in
F VC
(m L)
yr )
Difference: 41.0 mL/yr (95% CI: 2.9, 79.0); p=0.04 Relative reduction: 44%
Primary endpoint analyzed using random coefficient regression model (with random slopes and intercepts) including ATA status, age, height, gender and baseline FVC (mL) as covariates
Annual rate of decline in FVC (mL/yr) Change from baseline in FVC (mL) over 52 weeks (primary endpoint)
Physiological decline ~25-30 ml every year in FVC after age of 25 years [Eur Respir J 2012]
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Rate of Decline in FVC (mL/yr) over 52 Weeks by Mycophenolate Use at Baseline
-40.2 -63.9-66.5
Relative reduction: 40%
Relative reduction: 46%Ad ju
st ed
ra te
(S E)
o fd
ec lin
e in
F VC
(m L/
Nintedanib (n=138)
Placebo (n=140)
Nintedanib (n=149)
Placebo (n=148)
Most Frequent Adverse Events
Adverse events reported over 52 weeks plus 28-day post-treatment period in >10% of patients in either treatment group. Data are n (%) of patients with ≥1 such adverse event coded based on MedDRA preferred terms.
Nintedanib (n=288) Placebo (n=288)
Diarrhea 218 (75.7) 91 (31.6) Nausea 91 (31.6) 39 (13.5) Vomiting 71 (24.7) 30 (10.4) Skin ulcer 53 (18.4) 50 (17.4) Cough 34 (11.8) 52 (18.1) Nasopharyngitis 36 (12.5) 49 (17.0) Upper respiratory tract infection 33 (11.5) 35 (12.2) Abdominal pain 33 (11.5) 21 (7.3) Fatigue 31 (10.8) 20 (6.9) Weight decreased 34 (11.8) 12 (4.2)
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• Add Tocilizumab • Add Rituximab • Stem cell
Transplant • Lung transplant
& Anti-SCL 70
• MMF 2-3 grams/day • ?CYC up to 2 mg/kg/ day or
500-750 mg/mg m2 *Initial preference MMF= Mycophenolate mofetil upto 3 grams/day CYC= Cyclophosphamide oral upto 2 mg/kg/day or monthly pulse
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Demographics
Age, years (mean) 44.9 46.9
Female, % 52.8 74.4
MRSS, mean (SD) 28.5 (8.7) 30.8 (10.5)
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Abbreviations: EFS, Event-free Survival; PP, Per Protocol (Treated) Population
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• Hemodynamic observation and should lead to identify underlying cause
• Pulmonary arterial hypertension (PAH) results from restricted flow through pulmonary arterial circulation – Leads to pulmonary vascular resistance (PVR), ultimate right heart
failure – Predominant cause - loss of vascular luminal volume from vascular
remodeling, excessive cell proliferation, ↓ apoptosis
What is Pulmonary Hypertension?
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1.1 Idiopathic PAH 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 PAH associated with:
1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis
1.5 PAH long-term responders to CCBs 1.6 PAH with overt features of venous/ capillaries involvement 1.7 Persistent PH of the newborn syndrome
2.1 PH due to HF with preserved LVEF 2.2 PH due to HF with reduced LVEF 2.3 Valvular heart disease 2.4 Congenital/acquired cardiovascular conditions
leading to post-capillary PH
1. Pulmonary Arterial Hypertension
3. PH Due to Lung Diseases and/or Hypoxia
4. PH Due to Pulmonary Artery Obstructions
5. PH With Unclear and/or Multifactorial Mechanisms
3.1 Obstructive lung disease 3.2 Restrictive lung disease 3.3 Other lung disease with mixed restrictive/ obstructive pattern 3.4 Hypoxia without lung disease 3.5 Developmental lung disorders
4.1 Chronic thromboembolic PH 4.2 Other pulmonary artery obstructions
5.1 Hematological disorders 5.2 Systemic and metabolic disorders 5.3 Others 5.4 Complex congenital heart disease
6th World Symposium Classification of PH
Simonneau G, et al. Eur Resp J. 2019;53:1801913
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Badesch D et al. J Am Coll Cardiol. 2009;54(1 Suppl):S55-66. Galiè et al. Eur Respir J. 2019;53(1):1802148.
New Hemodynamic Definition of PH/PAH
PH
PCWP/LVEDP ≤15 mm Hg
>20
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Recommendations Resting echocardiography is recommended as a screening test in asymptomatic patients with SSc, followed by annual screening with echocardiography, DLCO and biomarkers
*The DETECT algorithm is not yet validated in patients with DLCO > 60%
DLCO: diffusing capacity of the lung for carbon monoxide; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; SSc: systemic sclerosis. aClass of recommendation bLevel of evidence.
1. Khanna D, et al. Arthritis Rheum. 2013 Dec;65(12):3194-201. 2. Hoeper M, et al. J Am Coll Cardiol. 2013 Dec;62(25 Suppl):D42-D50. 3. Frost A, et al Eur Respir J. 2019 Jan;53(1):1801904. 4. Galiè N, et al. Eur Respir J 2015 Oct;46(4):903-75. 5. Galiè N, et al. Eur Heart J 2016 Aug;48(2):311-4.
Recommendations from 5th and 6th WSPH2,3:
Annual screening for PAH is recommended in (cardiopulmonary) asymptomatic patients with the SSc spectrum of diseases
Recommendations from 2015 ESC/ERS guidelines4,5:
Recommendations for Screening and Detection of PAH-CTD1:
Every patient with SSc should be screened annually for PAH due to the high prevalence of PAH in SSc
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Echo TR jet normal/ abnormal Right ventricular dysfunction
RHC
Current Paradigm to Refer for RHC
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58
Screening
Echo
58
• DETECT v2.0 was released in January 2019
STEP 1
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Risk of a Clinical Event by Drug Treatment and PAH Etiology
Five randomized controlled trials (N=3172; n=941 with CTD-PAH [30%]) reported HRs for a morbidity or mortality event by drug treatment and PAH etiology. Clinical event definitions varied between trials but generally included death, worsening of PAH, hospitalization due to PAH, and treatment escalation. Khanna D, et al. Arthritis Rheumatol. 2021 [Epub ahead of print].
Overall PAH population 36% reduction in risk of a clinical event HR=0.64 (95% CI, 0.54–0.75; P<0.001):
CTD-PAH population 36% reduction in risk of a clinical event HR=0.64 (95% CI, 0.51–0.81; P<0.001)
Study name Active arm (n)
Control arm (n)
COMPASS-2 159 175 0.83 (0.61-1.14)
SERAPHIN 242 250 0.55 (0.41-0.74)
GRIPHON 574 582 0.60 (0.49-0.73)
FREEDOM-EV 346 344 0.74 (0.56-0.97)
AMBITION 253 247 0.50 (0.35-0.72)
Overall 0.64 (0.54-0.75)
Active arm better
Control arm better
Control arm (n)
Overall 0.64 (0.51-0.81)
Active arm better
Control arm better
Prostacyclin Analogs Prostacyclin Agonists
Sildenafil (PO) FDA Approved: June 2005
Epoprostenol (IV ) Flolan FDA Approved: September 1995 Veletri FDA Approved: June 2008
Selexipag (PO) FDA Approved: December 2015
Ambrisentan (PO) FDA Approved: June 2007
Tadalafil (PO) FDA Approved: May 2009
Treprostinil (IV, SC, PO, and inhaled) First (SC formulation) FDA Approved: July 2002
Macitentan (PO) FDA Approved: October 2013
Riociguat (PO) FDA Approved: October 2013
Iloprost (inhaled) FDA Approved: December 2004
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed April 1, 2016.
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Raynaud’s Phenomenon in SSc1
• 95% of patients with SSc • Part of the 2013 ACR EULAR Classification criteria2
• Mainly affects digits; can affect ears, nose, etc. • Triphasic color change
- Pallor– cold-induced digital artery vasospasm and venous spasm - Cyanosis— Vasodilation of venous system - Rubor– dilatation of Atrial Venous Anastomosis with influx of oxygenated
blood
• Clinical diagnosis - Ask the following screening questions1:
§ Are your fingers unusually sensitive to cold? § Do your fingers change color when exposed to cold temperatures? § Do they turn white, blue, or both?
1. Wigley and Flavahan. N Engl J Med 2016;375(6):556-565. 2. Van den Hoogen, et al. Arthritis Rheum 2013 Nov;65(11):2737-47.
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Management of Raynaud’s Phenomenon Establish diagnosis and identify any underlying cause
amenable to treatment
Treat underlying cause
General/lifestyle measures: Patient education • Avoid cold, keep warm • Stop smoking (Complementary therapies)
Drug therapy: first time CCB, PDE5 inhibitor, ARB, SSRI, alpha blocker, ACE inhibitor, Topical nitrate ±
Antiplatelet and/or statin therapy Effective
Ineffective
Effective
Ineffective
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Funded by NIH/NIAID Clinical ACE and NIH/NIAMS R01, R21 and K24
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