Systemic Sclerosis Interstitial Lung Disease: Best Practice Approaches to Clinical

Management

Rebecca Keith MD

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Systemic Sclerosis ILD: Best Practice Approaches to Clinical Management

• Identify clinical features and risk factors for SSc-ILD• Review Current and emerging therapies to select the

best treatment approach for patients with SSc-ILD• Evaluate best practice approaches to communicating

and educating the patient with SSc-ILD

Learning Objectives

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Interstitial Lung Diseases

• Diverse group of disorders (>150) that resultinflammation/scarring of the pulmonary parenchyma

• Similar presentation– Progressive dyspnea and dry cough– Abnormal pulmonary physiology– Abnormal CXR and/or HRCT

• Multiple Etiologies– Idiopathic– Systemic diseases (connective tissue disorders)– Drug, environmental, or occupational exposures– Genetic

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The Interstitium

The loose-binding connective tissue (peribronchovascular sheaths, interlobular septa, subpleura)

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Interstitial Lung Disease

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Systemic Sclerosis

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> 9 systemic sclerosis

van den Hoogen F, et al. Arthritis Rheum 2013; 65:2737.

ILD can develop in limited cutaneous SSc and diffuse skin disease

Cottin. Respiratory Research 2019: 20 :13Prop

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Clinical approach when your diagnosis is a mystery

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Raghu AJRCCM 2018Prop

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Clinical Case

• 47 year-old male • 2 years of progressive respiratory symptoms, including

dyspnea and dry cough• Underwent a CXR which demonstrated abnormalities

concerning for interstitial lung disease• Referred to pulmonary clinic for further evaluationProp

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What should be your first step in evaluating this

patient’s interstitial lung disease further?

1. High resolution CT of chest, interstitial lung diseases protocol

2. Surgical lung biopsy3. A detailed history and physical examination4. Cryobiopsy involving two or more lobes5. Bronchoscopy and bronchoalveolar lavage

ARS Question

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Investigate

History• Systemic diseases• Occupational &

Environmental History• Drug & Medication History• Family HistoryReview of Systems• Extra-pulmonary

manifestations

Examination• Pulmonary exam• Extra-pulmonary signsLaboratories• Extra-pulmonary organ

dysfunction• Auto-immune serologiesProp

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Additional history• Endorses hand stiffness and skin tightening over his digits• Raynaud’s • No muscle weakness

• Lifelong non-smoker• Aircraft mechanic – exposure to jet fumes• No identifiable environmental exposures identified by detailed questionnaire.

Specifically no household birds, water damaged wood or carpeting, visible mold, or down products

• No family history of ILD or CTD

• Physical Exam confirmed skin tightening involving whole digits. • Pulmonary Function Tests: FVC 77% predicted, DLCO 62% predicted

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CT Chest

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CT chest

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HRCT Features

• Basilar predominant• Peribronchovascular• Subpleural sparing• Ground glass opacities• Reticulation• Traction bronchiectasis • No honeycombing

NSIP Pattern

Cryptogenic Organizing Pneumonia

UIP PatternNSIP Pattern

(Significant Fibrosis)

NSIP Pattern (Cellular with limited fibrosis)

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What would be the next best diagnostic step?

1. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy

2. Laboratory serologic studies to evaluate for a connective tissue disease

3. Cryobiopsy4. Surgical lung biopsy5. None of the above, proceed to treatment

ARS Question

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Results, Rheumatologic Studies

• ANA 1:80• Rheumatoid factor negative• Anti-CCP negative• Anti-dsDNA negative• Anti-Ro/SSa negative• Anti-La/SSb negative• Anti-Sm negative• Anti-RNP negative• Anti-Scl70 negative• Anti-Centromere negative• RNA polymerase III positive• Myositis panel and aldolase negative

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What is your working diagnosis?

1. Unclassifiable interstitial lung disease2. Idiopathic pulmonary fibrosis3. Scleroderma associated interstitial lung

disease4. Hypersensitivity pneumonitis

ARS Question

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ACR/EULAR criteria for the classification of Systemic sclerosis

13

van den Hoogen F, et al. Arthritis Rheum 2013; 65:2737.Prop

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What is the best initial therapy for his lung disease?

1. Prednisone 1 mg/kg with slow taper2. Mycophenolate 3. Cyclophosphamide4. Pirfenidone or Nintedanib5. Mycophenolate and Nintedanib

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Scleroderma Lung Study II• 142 patients randomized to MMF for 2 years or

cyclophosphamide for one year• Inclusion criteria:

– FVC 45-80%; FEV/FVC > 65%– DLCO >40%– any extent of ground glass opacities on HRCT

with or without reticulation– Disease onset within 7 years

• Primary Outcome: Change in FVC % pred– MMF 2.19% improvement– Cyclophosphamide 2.88% improvement

• Both treatments improved dyspnea, skin• Mycophenolate better tolerated

– Similar rates of adverse effects– CYC discontinued more frequently

Lancet Resp Med 2016; 708-19Prop

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Nintedanib in Systemic SclerosisSENSCIS Trial• 576 patients with SSc randomized to nintedanib or

placebo for one year• HRCT with fibrosis >10% lungs• Disease onset within 7 years• FVC >40%• DLCO 30-89%

• Background therapy with MMF (48%), MTX (6.6%), or prednisone 10mg or less

• Primary outcome: Annual rate of decline of FVC (mL/year)

• No differences in symptoms or other clinical signs of SSc.

• Nintedanib discontinued 16% vs 8.7%• Adverse effects included diarrhea (76% vs 32%)

and LFT elevations (4.9 vs 0.7%); NEJM 2019; 2518-28

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Nintedanib in Systemic Sclerosis

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Nintedanib in Systemic Sclerosis

Nintedanib Placebo

All patients -52.4 mL -93.3 mL 41mL (95% CI 3-79mL)

Background MMF -40.2 mL -66.5 mL

No MMF therapy -63.9 mL -119.3 mL

• Effective therapies to treat interstitial lung disease in SSC (CYC, MMF)

• 48% received background therapy with MMF

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Nintedanib in Systemic SclerosisINBUILD trial• 663 patients with progressive fibrosing lung disease (PF-ILD)

other than IPF randomized to nintedanib or placebo• FVC >45%• DLCO 30-80%• HRCT with fibrosis >10% lungs; stratified by UIP pattern• Progression with past 2 years• Primary outcome: Annual rate of decline of FVC (mL/year)• No background therapy allowed initially—could be added if

further progression at 6 months• 25.6% had CTD-ILD; (52% had RA; 23% SSc)

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NEJM Med 2019; 138:1718-1727Prop

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Patient remains on mycophenolate mofetil at 1500 mg BID. He returns to

your clinic after 18 months noting gradually worsening shortness of breath.

FVC 4.09 (77% pred)DLCO 20.99 (62% pred)

FVC 2.68 (52% pred)DLCO 11.56 (40% pred)D

A high-resolution chest CT is obtained. Prop

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CT Chest

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NSIP Pattern ProgressionInitial Current

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What would be the next best treatment?

1. Prednisone 1mg/kg with slow taper, continue mycophenolate2. Rituximab, continue mycophenolate3. Change to Cyclophosphamide4. Nintedanib BID, continue mycophenolate5. Pirfenidone TID, continue mycophenolate

ARS Question

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Progressive Fibrosis in Scleroderma

Considerations:• Treat inflammation in lungs?• Slow development of fibrosis with antifibrotic?• Treat extrapulmonary manifestations?

• Tolerability• Transplant eligibility

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Pirfenidone in Scleroderma-ILD

• LOTUSS Trial• Multicenter, randomized, open-

label, phase 2 tolerability study• Confirmed SSc by ACR criteria (less

than 7 years from first non-Raynaud symptom)

• HRCT with ILD within past 2 yrs• FVC ≥ 50%, DLCO ≥ 40%• Randomized 1:1 PFD 2403 mg/d (2-

or 4-wk titration) for 16 weeks• 1° endpt: Treatment-emergent AEs• 2° endpt: Exploratory disease

outcomes

Khanna D, et al. J Rheumatol 2016;43:1672-79.

• TEAEs consistent with 3 prior phase 3 RCTs in IPF (n=1247)• Severe TEAE, TE SAE, TEAE leading to d/c more common in2-wk rather than 4-wk titration

r phase 3 RCTs in IPF (n

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Pirfenidone in Systemic Sclerosis: Future Studies

• Scleroderma Lung Study (SLS) III– Phase 2 RCT, PFD + MMF vs. PBO + MMF; goal n = 150 patients– Primary endpoint: Change in FVC %predicted over 18 months– Secondary endpoints: Change in mRSS, extent/total fibrosis on

HRCT, etc.– PI: Roth (UCLA), collab: Genentech (NCT03221257)

• Phase 3 RCT, 1° endpt: relative change in FVC % over 52 weeks– PI: Zhang (Beijing Continent Pharm Co.) (NCT03856853); goal n

= 144

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What patient’s need to know• Scleroderma disease education

• Disease can range from mild to severe• Disease course if variable• Can involve many organ systems

• Skin• Vascular system – Raynaud’s• Lungs - ILD• Kidneys – Renal impairment or Renal crisis• Heart – Pulmonary hypertension• Digestive system – GERD and esophageal dysmotility• Teeth – Decreased oral opening and Sicca • Sexual health – Erectile dysfunction, vaginal dryness and constriction

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What patient’s need to know• Care is provided by a multidisciplinary team

• Rheumatologist • Pulmonologist - ILD• Pulmonologist/Cardiologist – Pulmonary Hypertension• Gastroenterologist – GERD and esophageal dysmotility

• What to expect for disease monitoring• Pulmonary physiology• Oxygen titration• 6-minute walk distance• Echo/Right heart catheterization• CT imaging• Clinical exam

• Pulmonary rehabilitation can improve exercise capacity and HRQL

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• Lung transplant can be an option for some patients with lung limited disease

• Self care is important• Supportive care for the patient’s care giver

network is important• Support groups are a good way to network and

find support

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