Scleroderma: State of the Art Management
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Mary E. Strek, M.D. of the University of Chicago offers information regarding the effects of Scleroderma and possible medications that can be used.
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Scleroderma: State of the Art Management
- 1. Mary E. Strek, MD Professor of Medicine University of Chicago Medicine Scleroderma: State of the Art Management April 16, 2016
- 2. 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!
- 3. Pulmonary Complications in CTD Disease Antibody Airway ILD Vascular Pleural RA RF, aCCP Bronchiolitis, Bronchiectasis UIP Secondary Effusions SLE ANA, dsDNA, Smith Bronchiolitis Not common Primary Alveolar Hemorrhage Effusions Scleroderma ANA, Scl-70 Anticentromere (PAH) Rare fNSIP UIP Secondary Primary Rare MCTD ANA, RNP Not common fNSIP Primary Secondary Not common DM/PM ANA, SS-A, Jo-1 Myositis panel Rare OP NSIP UIP DAD Secondary Rare Sjogren’s ANA, SS-A, SS-B Bronchiectasis NSIP LIP UIP Secondary Not common
- 4. Systemic Sclerosis (SS): Classification Criteria - Definite SS 9≥ Van den Hoogen, Ann Rheum Dis 2013;72:1747
- 5. 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)
- 7. Systemic Sclerosis Sine Scleroderma Fischer, CHEST 2006;130:976
- 8. Systemic Sclerosis Sine Scleroderma
- 9. 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
- 10. Scleroderma: Phenotypes Solomon Eur Resp Rev 2013;22:6-19 Wigley, 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% PFTs 90% CT 13-35% ECHO 7-13% 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
- 11. 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)
- 14. Cellular NSIP
- 15. Cellular NSIP
- 16. Slide courtesy of Aliya Husain, MD. Cellular NSIP
- 17. 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
- 18. Scleroderma ILD: Whom to Treat? Solomon Eur Resp Rev 2013;22:6-19
- 19. Scleroderma ILD: Whom to Treat? Goh AJRCCM 2008;177:1248
- 20. Scleroderma: Mild Disease 1999 2003
- 22. Scleroderma ILD: Treatment Vij, CHEST 2013;143:1-11
- 23. 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
- 24. 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
- 25. 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
- 26. 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)
- 28. 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
- 29. Mycophenolate in Scleroderma Fischer, J Rheumatol 2013; 40:640-646
- 30. Mycophenolate in Scleroderma Fischer, J Rheumatol 2013; 40:640-646
- 31. 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
- 32. • 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
- 33. Efficacy Data: Nintedanib in IPF NEJM 2014;370:2071-82
- 34. Adverse EffectsDRUG ADVERSE EFFECT DOSE MODIFICATION ADDITIONAL MEASURES NINTEDANIB 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
- 35. 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
- 36. GERD: Its Role Lee, Am J Med 2010;123:304-311
- 37. 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
- 39. 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
- 40. And Don’t Forget! Infection Pulmonary Embolism Medication toxicity Cigarette smoking related complications Environmental and occupational exposures
Editor's Notes
- Acid reflux is common in IPF May be clinically silent Evidence of increased acid exposure in IPF vs ILD Hiatal hernia more common (39%) in IPF vs COPD 13.3% or asthma (16.67%) Microaspiration may play a role in pathogenesis Could this contribute to acute exacerbations?