Mary E. Strek, MDProfessor of Medicine

University of Chicago Medicine

Scleroderma: State of the Art Management

April 16, 2016

Pulmonary Complications of Scleroderma

Common and under recognized May not track with other manifestations Impair quality of life May masquerade as “idiopathic” disease

- Forme fruste (incomplete or atypical form)

- Presenting manifestation

- Lung dominant or limited

MAY BE TREATABLE!

Pulmonary Complications in CTDDisease Antibody Airway ILD Vascular Pleural

RA RF, aCCP Bronchiolitis, Bronchiectasis

UIP Secondary Effusions

SLE ANA, dsDNA, Smith Bronchiolitis Not common

PrimaryAlveolar Hemorrhage

Effusions

Scleroderma ANA, Scl-70Anticentromere (PAH)

Rare fNSIPUIP

SecondaryPrimary

Rare

MCTD ANA, RNP Notcommon

fNSIP PrimarySecondary

Notcommon

DM/PM ANA, SS-A, Jo-1Myositis panel

Rare OPNSIPUIPDAD

Secondary Rare

Sjogren’s ANA, SS-A, SS-B Bronchiectasis NSIPLIPUIP

Secondary Notcommon

Systemic Sclerosis (SS): Classification Criteria

- Definite SS ≥ 9

Van den Hoogen, Ann Rheum Dis 2013;72:1747

Systemic Sclerosis Sine Scleroderma

Originally described 40 years ago Uncommon variant of limited scleroderma

- No sclerodactyly but skin thickening/digital edema

- Interstitial lung disease in > 80%

Positive ANA > 93% Non-specific interstitial pneumonia (NSIP)

Puffy digits

6

Systemic Sclerosis Sine Scleroderma

Fischer, CHEST 2006;130:976

Systemic Sclerosis Sine Scleroderma

Scleroderma: Pulmonary Manifestations

Interstitial lung disease (ILD) is very common Esophageal dysfunction and aspiration Pulmonary HTN alone and with ILD Airway disease

- Obstructive lung disease (follicular bronchiolitis)

Pleuritis Pulmonary “scar” carcinoma Restriction of chest wall or respiratory muscle weakness

Scleroderma: Phenotypes

Solomon Eur Resp Rev 2013;22:6-19Wigley, Mayo Clin Proc 2013; 88:377-393

Interstitial Lung Disease Pulmonary Hypertension

Pathogenesis Activation of lung fibroblasts pulmonary fibrosis

Injury to vascular endothelium arterial fibrosis

Prevalence 40-75% PFTs90% CT

13-35% ECHO7-13% RHC

Associated with Antitopoisomerase I (SCL-70) Anticentromere

Cause of death in SSc 35% 30%

Compared to idiopathic ILD SSc-ILD improved survival SSc-PH worse survival

Scleroderma Associated ILD Physical exam/labs

- Clubbing uncommon/Raynaud’s phenomenon frequent- anti-Scl-70 antibody correlates with ILD (seen 1/3rd)

Pulmonary function abnormalities- Decreased TLC in 32 – 67% patients- Decreased FVC in up to 77% patients- Decreased DLCO in 90%

Major histopathologic patterns- NSIP most common (56% vs 72% vs 76%)- Most cases fibrotic (vs cellular) NSIP- UIP pattern (honeycombing on HRCT)

Scleroderma: Fibrotic NSIP

Scleroderma: Fibrotic NSIP

Cellular NSIP

Cellular NSIP

Slide courtesy of Aliya Husain, MD.

Cellular NSIP

Scleroderma ILD: Prognosis Progresses to severe ILD in 15% May be rapidly progressive in 1st 2 years

- HRCT with ground-glass opacities

- PFT’s show decline in FVC or diffusing capacity

Gradual decline in lung function or stable disease in others ILD may affect survival

- PFT’s predictive

- Prognosis may be better if NSIP noted on biopsy

Scleroderma ILD: Whom to Treat?

Solomon Eur Resp Rev 2013;22:6-19

Scleroderma ILD: Whom to Treat?

Goh AJRCCM 2008;177:1248

Scleroderma: Mild Disease

1999 2003

Scleroderma: Extensive ILD

Scleroderma ILD: Treatment

Vij, CHEST 2013;143:1-11

Cyclophosphamide (Cytoxan)

Potent but toxicity limits long-term use Nitrogen mustard like alkylating agent Progressive reduction in B and T lymphocytes 500 to 750 mg/m2 BSA IV then monthly bolus May increase dose up to 1 g/m2 BSA Decrease dose renal insufficiency

Marder, Semin Respir Crit Care Med 2007; 28:398-417

Cyclophosphamide MAJOR TOXICITY: Bone marrow, hemorrhagic cystitis

(can be fatal) Hydration! Urine output > 100 mL/h In ICU may need catheter drainage and bladder irrigation OTHER TOXICITIES: Infection, infertility, pulmonary,

Cancers (bladder, cervix, skin, leukemia) MONITOR: CBC, renal function and UA weekly then every

2 weeks, periodic LFT’s Urine cytology and PAP smears annually

Scleroderma Lung Study Double-blind, randomized placebo controlled trial

Effect of oral cyclophosphamide (CYC) vs placebo

Study design:

- Scleroderma and dyspnea

- Restriction on PFT’s (FVC 45-85%/DLCO >30% predicted)

- Inflammatory ILD on BAL or ground-glass on HRCT

- CYC 2mg/kg/day (average dose 100mg) or placebo for 1 year

- 2nd year follow-up OFF therapy

- Primary end-point FVC at 12 months

Conducted by NIH at 13 centers

Tashkin, NEJM 2006; 354:2655

Scleroderma Lung Study Results:

- Screened 267 pts, 158 randomized

- Baseline characteristics matched; disability score lower placebo

- 54 pts in CYC and 55 in placebo completed study

Mean adjusted absolute difference in FVC at 12 months 2.53% (95% CI, 0.28 to 4.79%) favoring CYC (P<0.03)

Adverse events greater in CYC group (hematuria, leukopenia, anemia, pneumonia) and 3 malignancies (bladder, vulvar, angiosarcoma scalp)

Scleroderma Lung Study

Mycophenolate Mofetil (CellCept)

Potent and well tolerated Inhibits critical enzyme in purine synthesis in activated lymphocytes Starting dose 500 mg BID, target dose 1000 mg BID Great variability serum levels in patients on same dose TOXICITIES: GI, Infections, Leukopenia less common Lower rate side effects: hospitalizations, GI, infections, amenorrhea If GI toxicity: decrease dose, more freq intervals (TID) MONITOR: CBC after dose change then monthly EXPENSIVE so insurance may not cover TERATOGENIC/PREGNANCY CATEGORY X

Marder, Semin Respir Crit Care Med 2007; 28:398-417

Mycophenolate in Scleroderma

Fischer, J Rheumatol 2013; 40:640-646

Mycophenolate in Scleroderma

Fischer, J Rheumatol 2013; 40:640-646

Azathioprine (Imuran)

Less potent and slower onset of action cyclophosphamide Metabolized to purine antagonist 6-mercatopurine Inhibits both cellular and humoral immunity Starting dose 50 mg daily,1.5-2 mg/kg (maximum 200 mg)

daily Low thiopurine methotransferase level increase risk BM

toxicity TOXICITIES: Bone marrow, liver, infection, cancer? MONITOR: CBC, LFTs after dose change then monthly

Marder, Semin Respir Crit Care Med 2007; 28:398-417

• Nintedanib– Tyrosine kinase inhibitor– DOSE 150 mg BID, can reduce to 100 mg BID– MONITOR Liver function monthly x 3 mos then Q 3 mos

• Pirfenidone– Antifibrotic effects– DOSE 267 mg TID x 2 weeks, then 534 mg TID x 2 weeks,

then 801 mg TID– MONITOR Liver function monthly x 6 mos then Q 3 mos

Overview FDA approved IPF Meds

Efficacy Data: Nintedanib in IPF

NEJM 2014;370:2071-82

Adverse EffectsDRUG ADVERSE EFFECT DOSE MODIFICATION ADDITIONAL

MEASURESNINTEDANIB Diarrhea Reduce dose Imodium

N/abdominal pain Reduce dose/food PPI, H2 blocker

Arterial thrombosis Caution in high risk cardiovascular disease

Monitor for cardiac events

Elevated LFTs Reduce or interrupt dose Monitor LFTs

DRUG INTERACTIONS

Ketoconazole, Emycin, carbamazepine, phenytoin, rifampin

Avoid with anticoagulants?

PIRFENIDONE N/V/anorexia Reduce dose/food PPI, H2 blocker

Rash HOLD drug Avoid sunlight

Elevated LFTs Reduce or interrupt dose Monitor LFTs

Agranulocytosis STOP DRUG Monitor CBC?

DRUG INTERACTIONS

Fluvoxamine Avoid Ciprofloxacin

Scleroderma Associated Pulm HTN Often unrelated to ILD Risk factors- Raynaud’s, limited scleroderma,

anticentromere Ab PFT’s

- FVC 80% predicted- DLCO 40%predicted

Often severe- HFpEF common- High frequency pericardial disease- Echo may not correlate- Treatment responsive

GERD: Its Role

Lee, Am J Med 2010;123:304-311

GERD: Management Weight loss if obese

Elevate head of bed

Avoid eating 2-3 hrs before lying down

Eliminate foods (caffeine, ETOH etc) that trigger reflux

Proton pump inhibitor 30-60 min before first meal day

Prokinetic agent

Nissan fundoplication often not an option due to dysmotility

Katz, Am J Gastroenterol 2013; 108:308-328

Monitoring

INFECTION, INFECTION, INFECTION!

Scleroderma Chronic multisystem autoimmune disease

Variable clinical course

Includes mild and subtle disease

Minority have significant interstitial lung disease

Treat BEFORE irreversible organ damage occurs

Wigley, Mayo Clin Proc 2013; 88:377-393

And Don’t Forget!

Infection

Pulmonary Embolism

Medication toxicity

Cigarette smoking related complications

Environmental and occupational exposures