Thomas A. Medsger, Jr., MD University of Pittsburgh School of Medicine Disclosures: None
1. idiopathic interstitial pneumonitis (IIP) - 30% of all ILD - most common form is idiopathic pulmonary fibrosis (IPF) or usual interstitial pneumonitis (UIP); can be confirmed either radiographically or pathologically - varying rate of progression but overall poor prognosis - an other form is non- specific interstitial pneumonitis (NSIP), which can be fibrotic or non- fibrotic NSIP 2. connective tissue disease (CTD- ILD) or undifferentiated CTD (UCTD) associated - 15% of all ILD - 40% of SSc patients; 30-80% of PM/DM patients; less frequent in RA, SLE, Sjogren syndrome - better prognosis
1. radiographic: bibasilar increase in interstitial markings on chest radiograph or high resolution CT scan (HRCT) without contrast - new lower radiation exposure CT scan protocol proposed 2. physiologic: restrictive lung disease with no evidence of obstructive lung disease (FVC <80% predicted with FEV1/FVC >70% predicted)
SSc ILD
IPF UCTD or AILD CTD- ILD ILD
1. retrospective study: 50 patients referred to Pulmonary Medicine for IPF, also evaluated by a rheumatologist 2. final diagnosis: 25 (50%) CTD- ILD 3. treatment changes resulted in 80% of patients with CTD- ILD and 30% of patients with IPF Castelino et al., Rheumatology 2010; 50: 483-493
National Jewish Medical Center (Denver) Cohort 97 (29%) positive ANA 25 (9%) ANA with nucleolar staining 13 anti- Th/To antibody positive 9 met criteria for ssssc Fischer et al. J Rheumatol 2006; 33: 1600-1605
Kinder et al., Am J Respir Crit Care Med 2010; 176: 691 697.
Park et al., Am J Respir Crit Care Med 2007; 175: 705-11
1. CTD features in ILD patients may be subtle Scleroderma PM/DM Sjogren Syndrome - puffy fingers - inflammatory polyarthralgias/it is - low C4 complement - Raynaud phenomenon - DM rash - hypergammaglobulinemia - abnormal nailfold capillaries - heartburn, dysphagia - positive ANA - proximal muscle weakness - elevated CPK - renal tubular acidosis (high Cl, low K, low Co2) 2. ILD may precede other CTD findings by months/years 3. In acute/severe ILD, few physicians look for extra- pulmonary manifestations
Gottron Papules
1. scleroderma sine scleroderma or ssssc (no scleroderma skin changes) 2. amyopathic DM (rash only, no muscle weakness) 3. anti- synthetase antibody syndrome without muscle weakness or rash 4. Sjogren syndrome with minimal or no sicca symptoms 5. undifferentiated CTD
definition: Raynaud, one typical SSc internal organ involvement, positive ANA, no other classifiable CTD - lc (limited cutaneous) SSc = 1794/3392 (53%) - of the 1794 lcssc, 107 (4%) had ssssc - of the 107 ssssc, 42 (39%) had ILD Aggarwal et al., Arthritis Rheum 2010; 62: Suppl 10: 463
6 5 4 3 2 1 0 Aggarwal et al., Arthritis Rheum 2010; 62: Suppl 10: 463 First Pittsburgh visit Raynaud Joint Lung Esophagus -30-25 -20-15 -10-5 0 5 10 15 20 25 30 Years before Diagnosis Time of diagnosis Years after Diagnosis Diagnosis delay (first SSc symptom to diagnosis) = 8.8 ±9.9 years
1. clinical features: myositis, polyarthritis, Raynaud, fever, mechanic s hands, ILD 2. autoantibodies: anti- Jo1 and 7 other non- Jo1 anti- synthetases (directed against aminoacyl- trna synthetase enzymes); 50% ANA negative 3. ILD present in 164 (81%) of 202 anti- synthetase patients in the Pittsburgh cohort 4. mean delay in diagnosis after pulmonary symptoms = 2.1 years
Homogeneous, diffuse cytoplasmic staining on IIF
- underappreciated underlying CTD (most often myositis) - acute respiratory failure; ICU admission - clinical/pathologic picture: ARDS with diffuse alveolar damage (DAD) 73 Pittsburgh anti- Jo1 patients (14) (59) Richards et al., Arthritis Rheum 2009; 60: 2183-2192 Won Huh et al., Resp Med 2007; 101: 1613-1624
June 6
Steen et. al, Ann Rheum Dis 2007; 66:940-944
rapid loss in FVC in first 1-2 years FVC (% predicted) 80 70 60 50 40 30 20 10 0 0-1 n=31 1-2 n=21 2-4 n=36 slow loss of FVC in later years 4-5 n=32 5-8 n=22 8-10 n=14 > 10 n=9 Disease Duration (years) Steen et al., Arthritis Rheum 1984; 37:1290-6
Flow diagram of staging system for application in clinical practice Limited and extensive disease correlate with good and poor survival at 5 years, respectively good prognosis 75% 5 years poor prognosis 30% 5 years Goh et al., Am J Respir Care Med 2008: 177; 1248-1254
SSc-ASSOCIATED AUTOANTIBODIES FREQUENCY OF PF U11/U12 RNP 23/33 (70%) SIGNIFICANCE vs. U11/U12 Topoisomerase I 204/425 (48%) p < 0.02 Ku 6/14 (43%) NS PM-Scl 27/65 (42%) p < 0.009 Th/To 47/121 (39%) p < 0.002 U1 RNP 36/123 (29%) p < 0.0001 U3 RNP 16/84 (19%) p < 0.0001 RNA Polymerase III 63/343 (18%) p < 0.0001 Centromere 59/436 (14%) p < 0.0001 * Overlaps excluded; no patient had more than one SSc- associated antibody Denominator = total number of antibody positive patients Fertig et al., Arthritis Rheum 2009; 61:963.
multicenter, randomized, double- blind, placebo controlled trial 158 patients with SSc and ILD oral CY vs. placebo for one year Tashkin et al. N Engl J Med 2006; 354: 2655-2666
benefit gone after 2 years Tashkin et al., Am J Respir Crit Care Med 2007; 176: 1026-1034.
summary of 5 retrospective or open label studies published 2006-2012 69 SSc patients MMF 2-3 Gm/day, 8-24 months; 3 reports with prednisone mean changes in FVC compared with baseline: +2%, +11%, 0%, +3%, +4% mean changes in DLCO compared with baseline: +4%, +11%, - 4%, +14%
1. patients lose up to 40% of FVC in first year of disease 2. use Goh et al. guidelines to determine disease extent, prognosis 3. indications for treatment: falling FVC and increasing dyspnea; worsening HRCT; O2 desaturation with exercise 4. corticosteroids and IS drugs synergistic but concern re: renal crisis in SSc patients with diffuse cutaneous involvement, palpable tendon friction rubs, anti- RNA polymerase III antibody 5. start cyclophosphamide monthly IV x 3-6 months then convert to MMF 2-3 Gm/day for maintenance 6. other considerations for maintenance/salvage cyclosporin or tacrolimus; azathioprine; methotrexate
7. control acid reflux disease (aspiration) 8. limit predisone to less than 15 mg/day 9. pneumovax and annual flu vaccine 10. lung transplantation 11. don t overtreat end- stage lung disease 12. beware secondary pulmonary arterial hypertension (worsening dyspnea with unchanged FVC but falling DLCO)
1. pirfenidone - inhibits release of profibrotic factors from fibroblasts and macrophages - ILD < 2 years; moderate severity (FVC > 50%) - randomized, double- blind controlled 16 week trial - all patients receive active drug (two different drug titrations) 2. pomalidomide - inhibits many pro- inflammatory cytokines and chemokines - randomized, placebo- controlled, 52 weeks - FVC 45-70% predicted or FVC 70-80% predicted with fall in FVC > 5% in preceding 24 months - concomitant MMF or CY permitted 3. daily oral CY vs. daily oral MMF (SLS2) - - ranodmized; CY 1 year, MMF 2 years ILD mild to moderate (FVC < 80% predicted) 4. anti- IL13 and other monoclonal antibodies directed against small molecule targets in IPF, not yet in CTD- ILD
SSc PAH
IPAH AIPAH CTD- PAH Rich et al. National Prospective Study of Primary PAH - Ann Intern Med 1987; 107: 216-223 - 32 centers, 187 patients; 19 (10%) Raynaud phenomenon and 54 (29%) positive ANA
Outcomes: poor survival before recent therapeutic advances (< 50% 2 year survival); worse than idiopathic PAH Prevalence: 8-12% At risk patients: lcssc, anti- centromere, anti- Th/To and anti- U3RNP antibodies; anti- Scl 70 protective Clinical features: rapidly progressive dyspnea on exertion; increased P2 sound; tricuspid insufficiency murmur; right sided heart failure; echocardiogram estimated PA systolic pressure > 45 mmhg; right- sided cardiac cath PA mean pressure > 25 mmhg with normal wedge pressure
Survival in Pittsburgh SSc- PAH Patients by Autoantibody Pol IIITopo topo U1RNP U3 ACACA ThTo Time from first confirmation of PAH (years)
1. Expert panel consensus statement: echocardiogram every year (overkill per Thomas A. Medsger, Jr.) 2. Do echo at first visit and, if normal, every 3 years thereafter - do earlier if unexplained increase in dyspnea, progressive fall in DLCO or increase in FVC: DLCO percent predicted ratio to 1.6:1 or greater 3. If suspect PAH and echo previously normal at rest, request exercise echo 4. If echo estimated peak PA systolic pressure > 45 mmhg, do right heart cath for clarification (many patients with echo PA >45mmHg have normal PA pressure on RHC)
Humbert et al., N Engl J Med 2004; 351:1427
1. vasodilators - endothelin antagonists (bosentan, ambrisentan) - phosphodiesterase V inhibitors (sildenafil) - prostacyclin derivatives (epoprostenol) 2. immunosuppressive drugs - evidence of autoimmunity in humans and animal models (perivascular mononuclear cell infiltrates including B cells) - case reports of responders to cyclophsophamide, particularly anti- U1RNP positive patients - ongoing trial of Rituxan vs. placebo in SSc- PAH
from studies of Holers et al. in RA, serum anti- CCP and RF present before clinical disease (many months/years) developed pre- RA cohort (asymptomatic first degree relatives of established RA patients with and without anti- CCP and RF) bronchial wall thickening on HRCT found in 76% of antibody positive vs. 33% of antibody negative pre- RA subjects anti- CCP antibodies found in BAL fluid but not in serum in antibody positive pre- RA subjects other microbiome consideration as source of antigens precipitating RA: oral mucosa, GI tract prevention trial of Rituxan in pre- RA cohort (Netherlands) Demourelle et al., Arthritis Rheum 2012; 64: 1757-61
Scleroderma Center - Gerald P. Rodnan, MD (deceased) - Virginia D. Steen, MD - Robyn T. Domsic, MD, MPH - Carol A. Feghali- Bostwick, PhD - Chester V. Oddis, MD - Rohit Aggarwal, MD - Kathryn Torok, MD - Masataka Kuwana, MD - Yutaka Okano, MD - Mary Lucas, RN, MPH - Dana Ivanco - Maureen Laffoon - Noreen Fertig, BS - Zengbiao Qi, PhD Funding - NIAMS - Scleroderma Foundation - ACR REF - Private Foundations - Generous Patients Immunology - Penelope Morel, MD - Patrizia Fuschiotti, PhD Cardiology - - William P. Follansbee, MD Michael Mathier, MD - Hunter Champion, MD Pulmonary - Gregory R. Owens, MD (deceased) - - Kevin F. Gibson, MD Kristen Veraldi, MD, PhD Gastroenterology - Klaus Bielefeldt, MD, PhD - Kenneth Fasanella, MD Renal - John P. Johnson, MD Dermatology - Vincent Falanga, MD Hand Surgery - Robert A. Kaufmann, MD - Matthew M. Tomaino, MD - Neil F. Jones, MD