Follow along to Dr. Strek's presentation on monitoring your lung health for patients with scleroderma.

1. Mary E. Strek MD, FCCP, ATSF
Professor of Medicine, Clinical Pharmacology & Pharmacogenomics
Director, Pulmonary Medicine Consult Service
Director, Interstitial Lung Disease Program
Scleroderma Lung Disease:
Best Practices for Monitoring and Treatment

2. Pulmonary Manifestations of Connective Tissue Disease
• Common and under-recognized
• May not track with rheumatologic symptoms
• Impairs quality of life
• May masquerade as idiopathic lung disease
• Incomplete or atypical presentation
• Presenting manifestation
• Lung dominant or limited
• TREATABLE!

3. CTD Antibody Test Interstitial Lung Disease
(ILD)
Pulmonary
Hypertension
Pleural
Disease
Scleroderma ANA, Scl-70
Centromere
Non-specific interstitial
pneumonia (NSIP)
Usual Interstitial Pneumonia
Primary
Secondary to ILD
Uncommon
Rheumatoid
arthritis
Rheumatoid factor,
CCP
UIP
NSIP
Secondary to ILD Common
SLE ANA, dsDNA, Smith Uncommon Primary Common
MCTD ANA, RNP NSIP Primary
Secondary to ILD
Uncommon
Autoimmune
Myositis
ANA, SS-A, Jo-1
Myositis associated
OP, NSIP, UIP Secondary to ILD Uncommon
Sjogren’s
Syndrome
ANA, SS-A, SS-B NSIP, UIP, LIP Secondary to ILD Uncommon
Pulmonary Complications of Connective Tissue Disease (CTD)

4. Scleroderma: Pulmonary Manifestations
• Aspiration/esophageal dysmotility
• Interstitial Lung Disease in > 50% cases
• Pulmonary hypertension in 8-12%
• Pleuritis: Pleuroparenchymal fibroelastosis
• Pulmonary scar carcinoma

5. Objectives: Best Practices for Scleroderma Lung Disease
• Interstitial Lung Disease (ILD)
• Diagnosis
• Effective Therapies
• Monitoring
• Pulmonary Hypertension (PH)
• Diagnosis
• Therapies
• Monitoring

6. Systemic Sclerosis (SSc): Diagnostic Criteria

7. Genetics
Exposure
risk
Immune
response
Determinants
of disease
course
Injury
Repair
Factors Determining Clinical Presentation

8. Scleroderma: An inhalational injury?
• Occupations associated with
Scleroderma
• Sand blasting
• Stone fabrication
• Metal industry/steel mill
• Brick layers
• Paint and electronic
manufacturers
Susceptible
host
Exposures and
Inflammation
• Silica
• Solvents
• Welding
fumes
Autoantibody
formation
• ANA
• Centromere
• Scl-70
• RNA
polymerase III
SSc +
ILD

9. Scleroderma: Occupational Exposures
• Case control study
• 100 subjects with Scleroderma
• 300 age/sex/cigarette matched controls
• Increased risk of scleroderma: crystalline
silica, paint thinner, aromatic solvents,
chlorinated solvents, ketones and welding
fumes
• Exposures differed by gender
• Occupations: sand blasting, granite cutting,
brick laying, cement work, metal industry, sheet
metal workers, paint and electronic
manufacturers
Marie, Autoimmunity Rev 2014;13:151-156
• 40 cases PULMONARY silicosis
• 9 (23%) had autoimmune disease;
7 fold increase vs population
• 6/9 had mediastinal adenopathy
• 3 Scleroderma, 2 Rheumatoid arthritis,
2 MCTD, 1 Antisynthetase syndrome
Schtraichman, Occupational Med 2015;65:444-450

10. Emerging Occupations: Stone Fabrication
• Association between inhaled silica and
Connective Tissue Disease and ILD
• Scleroderma > Rheumatoid arthritis
• Men
• HRCT: Silicosis, upper lobe fibrosis,
mediastinal adenopathy
• Progressive with increased mortality
Rose, MMWR 2019; 68:813-818
Turner, AJRCCM 2019; epub
PREVENTABLE!

11. Scleroderma: Diagnosis of Clinical Types
Solomon, Eur Resp Rev 2013;22:6-19
Wigley, Mayo Clin Proc 2013; 88:377-393
Interstitial Lung Disease Pulmonary Hypertension
Pathways Activation of lung fibroblasts 
pulmonary fibrosis
Injury to vascular endothelium 
arterial fibrosis
How common 40-75% Pulmonary Function
90% CT Chest
13-35% Echocardiogram
7-13% Right Heart catheterization
Antibodies Scl-70
RNA polymerase III
Anticentromere
% of scleroderma deaths 35% 30%
Compared to idiopathic
disease
SSc-ILD improved survival SSc-PH worse survival

12. Scleroderma-ILD
• ILD noted in majority of patients
• Progressive ILD in 15-20% of patients
• Scl-70 antibody, Black, older age, male, early decline FVC/DLCO
• Affects survival
• Lower lung function associated with worse outcome
• Nonspecific interstitial pneumonia > Usual interstitial pneumonia
1999 2003
EXUBERANT HONEYCOMBING ASSOCIATED WITH CTD

13. Non-specific interstitial pneumonia: Inflammatory ILD

14. Non-specific interstitial pneumonia (NSIP): Fibrotic

15. Scleroderma ILD: Treatment Options
Drug Mechanism of Action Level of Evidence
Cyclophosphamide Alkylating agent Randomized controlled trials
Scleroderma Lung Study I and II
Mycophenolate mofetil Inhibits purine synthesis Randomized controlled trial
Scleroderma Lung Study II
Azathioprine Purine antagonist Placebo controlled trial
Ritiximab Binds to CD-20 on B lymphocytes Randomized controlled trial vs
cyclophosphamide
Stem cell transplant Ablates immune system Randomized controlled trial vs
cyclophosphamide
Tocilizumab IL-6 receptor antibody Randomized placebo controlled trial
Nintedanib Tyrosine kinase inhibitor Randomized placebo controlled
trial; Mycophenolate allowed

16. Mycophenolate Mofetil (CellCept)
 Potent and well tolerated
 Inhibits critical enzyme in purine synthesis in activated lymphocytes
 Starting dose 500 mg twice daily, target dose 1500 mg twice daily
 Side effects: Diarrhea, Infections, skin cancer
 Lower rate side effects: hospitalizations, GI, infections
 If GI side effect: decrease dose, more frequent intervals (TID), Myfortic
 MONITOR: Blood count, Metabolic panel every 3 months
 TERATOGENIC/AVOID DURING PREGNANCY
Marder, Semin Respir Crit Care Med 2007; 28:398-417

17. Scleroderma Lung Study II: CYC vs Mycophenolate
• Randomized, double-blind, parallel
group trial 14 US centers
• Cyclophosphamide (CYC) x 12 mos vs
mycophenolate mofetil 1500 mg twice
daily x 24 mos
• Study Design:
• Scleroderma < 7yrs
• Dyspnea grade ≥ 2
• Restriction on PFT’s (FVC 45-85% and
DLCO >30% predicted)
• HRCT must show ground glass opacity
• Primary end-point change FVC as %
predicted normal x 24 mos
Tashkin, Lancet Respir Med 2016; 4:708-719

18. Scleroderma Lung Study II: Results
CYCLOPHOSPHAMIDE MYCOPHENOLATE MOFETIL
Number Enrolled N=73 N=69
Number Analyzed N=53 N=53
Number Stopped N=36 N=20
Target Dose 2.0 mg/kg/day 1500 mg BID
Change % Predicted FVC +2.88% (95%CI 1.19-4.58) +2.19% (95%CI 0.53-3.84)
DLCO Declined No change
Adverse Effects Leucopenia n=30
Thrombocytopenia n=4
n=4
n=0
Tashkin, Lancet Respir Med 2016; 4:708-719
Patients who continued on therapy did better!

19. focuSSced Study: Tocilizumab vs Placebo
• Randomized, double-blind, international
• Tocilizumab 162 mg injection vs placebo
x 48 wks
• Study Design
• Diffuse skin Scleroderma < 5 yrs
• Elevated ESR, CRP or platelet count
• Excluded FVC % pred < 55% or DLCO < 45%
• Primary endpoint: change skin score
• Secondary endpoint: % predicted FVC at 48
wks
• Primary skin fibrosis endpoint negative
• Infection 52% tocilizumab vs 50% placebo
Khanna, Lancet Respir Med 2020;8:963-74

20. Scleroderma SENSCIS Study: Nintedanib vs Placebo
• Randomized, double-blind, international trial
• Scleroderma < 7 yrs, Pulmonary fibrosis > 10% lung on CT
• Nintedanib x 12 mos vs placebo
• Mycophenolate mofetil allowed
• Study Results:
• N= 576 pts
• Adjusted annual rate change in nintedanib group -52.9 ml/yr vs -93.3 ml/yr in placebo
• No change in skin thickening
Distler et al. N Engl J Med 2019; epub

21. Scleroderma SENSCIS Study: Nintedanib vs Placebo
Distler, N Engl J Med 2019; 380:2518-28

22. Progressive Pulmonary Fibrosis INBUILD Study: Nintedanib
Flaherty, N Engl J Med 2019; 381:1718-27

23. Scleroderma: Pulmonary Hypertension
• Often unrelated to extent of interstitial lung disease
• Risk factors: Raynauds, limited skin scleroderma, anticentromere
• Pulmonary Function Tests
• Forced Vital Capacity (FVC) 80% predicted (Normal)
• Diffusing Capacity (DLCO) 40%predicted (Very reduced)
• May be severe
• Heart dysfunction common
• Echo may not correlate
• Treatment responsive with better outcomes if therapy started early

24. Scleroderma: Pulmonary Hypertension

25. Scleroderma: Pulmonary Hypertension

26. Pulmonary Hypertension: Treatment Options

27. Assessing Disease Severity/Progression
• Patient reported symptoms
• 6-minute walk testing
• Ambulatory oxygen saturation
• Pulmonary Function Testing
• Following signs/symptoms regularly
over time
• Stable
• Slowly progressive
• Rapidly progressive

28. CTD-ILD
Mild and non-
progressive
ILD
Follow
PFTs/6MWT
3-6 mos
Minimize risk
factors
(GERD, meds)
Moderate/severe
and/or progressive
TREAT
MEDS
O2, Rehab,
GERD
Chartrand, Rheum Dis Clin N Am 2015; 41:279-294
Scleroderma-ILD: Whom and When To Treat

29. Best Practices: Monitoring for ILD and Pulmonary Hypertension
General Parameter Specific Parameter Time Course
Lung Function Pulmonary Function Tests Every 4-6 months
Oxygen Levels Six-minute Walk Test Every 4-6 months
Chest Imaging ILD Protocol Chest CT Every 1-2 years, sooner if
change in symptoms
Heart Function Echocardiogram Yearly
Pulmonary Hypertension Right and Left Heart
Catheterization
If echocardiogram or other
cardiac tests abnormal
Vaccination Influenza
COVID-19
Yearly
Every 6 months?
Vaccination Pneumococcal PCV20
Shingrix
Once
Two doses

30. Conclusions: Best Practices Scleroderma Lung Disease
• Interstitial Lung Disease (ILD)
• Diagnosis: ILD Chest CT scan and Pulmonary Function Testing (PFTs)
• Effective Therapies: Mycophenolate, Tocilizumab, Nintedanib
• Monitoring: PFTs every 4-6 mos, CT every 1-2 yrs
• Pulmonary Hypertension (PH)
• Diagnosis: Echo and Catheterization
• Therapies: Vasodilators, Tyvaso
• Monitoring: Echo every 12 mos