Disclosures Clinical Approach: Evaluating Industry relationships: - PowerPoint PPT Presentation

11/5/2016 Disclosures Clinical Approach: Evaluating • Industry relationships: CTD-ILD for the pulmonologist Actelion, aTyr Pharma, Boehringer-Ingelheim, Genentech- Roche, Gilead Aryeh Fischer, MD Associate Professor of Medicine Division of Rheumatology Division of Pulmonary Sciences and Critical Care Medicine University of Colorado School of Medicine “ connective tissue disease” “ collagen vascular disease” ILD in CTD or • Occurs commonly across the entire spectrum of CTD • spectrum of systemic autoimmune diseases • A multidisciplinary approach can be be useful The CTDs characterized by: • Rheumatoid arthritis – circulating autoantibodies • Systemic lupus erythematosus • Potentially the most devastating of pulmonary – immune-mediated organ • Sjögren’s syndrome damage • manifestations – significant clinical Poly-/Dermatomyositis • Systemic sclerosis heterogeneity (scleroderma) • Poses significant challenges to the practicing clinician • Mixed CTD • Undifferentiated CTD 1

11/5/2016 CTD-ILD represents Estimated prevalence rates of ILD in the various CTDs?? a spectrum of diseases CTD Estimated frequency of ILD Systemic sclerosis 45% (clinically significant) Rheumatoid arthritis 20 – 30% CTD ILD PM/DM 20 – 50% CTDs ILDs MCTD 20 – 60% NSIP RA UIP SLE Sjögren's syndrome Up to 25% OP SjS LIP SLE 2 to 8 % PM/DM SSc DAD MCTD UCTD Adapted from Castelino and Varga Arthritis Res and Therapy 2010 Interstitial lung disease in scleroderma ILD in poly-/dermatomyositis • ILD is the most common lung • The majority of SSc patients have ILD manifestation of PM/DM • • F-NSIP is the most common pattern Chief cause of mortality – UIP far less common • – Rare to see the other patterns NSIP and NSIP/OP are the most common patterns – Can also see LIP, DAD, UIP • Clinically progressive in ~30% • • Varied presentation The leading cause of death • Anti-synthetase syndrome Miller et al. Rheum Dis Clinics NA 2015 Solomon et al. Eur Resp Reviews 2013 2

11/5/2016 the clinical landscape Interstitial lung disease in RA environmental occupational ? ? • ILD is the most common lung medications familial smoking ? manifestation of RA ? ? infection ? • Varied presentation • UIP is the most common pattern – Can also see NSIP, OP, LIP, DAD • Accounts for 7% of all RA-associated deaths ? ? • Risk of death is 3x higher than for RA without ILD idiopathic CTD-ILD K Brown Proc Am Thor Soc 2007, Doyle CHEST 2013, Olson AJRCCM 2011 Current approach to treatment why assess for CTD? CTD-ILD Idiopathic UIP A CTD-ILD diagnosis may impact: Idiopathic non-UIP (ANY pattern) (IPF) • Treatment CTD-ILD • Prognosis • Extra-thoracic disease IIP Clinical trials Immunosuppression – clinical context Immunosuppression Lung transplantation – surveillance for other features Pirfenidone Nintedanib Park et al. AJRCCM 2007;175:705-711 3

11/5/2016 Other common – and potentially important – the clinical landscape reasons to assess for CTD Patient perspective: Physician perspective: • “ if it ’ s CTD, I can do something about it ” • emotional • “ the last thing I want to tell • sense of belonging “ Idiopathic ” “ “ “ ” ” ILD: ” “ “ Idiopathic ” “ “ ” ” ILD: ” idiopathic ” labeled as “ idiopathic ” my patients is that it ' s ILD in established CTD: • frustrations with being Determine whether Is it really CTD? Identifying ILD is CTD-associated occult CTD 55-year-old man former smoker, develops exertional ILD in established CTD: checklist dyspnea and cough… 1. Confirm the CTD • 10-year history of RF / CCP positive, erosive RA 2. Consider alternative etiologies • arthritis well controlled on MTX and an anti-TNF agent • 3. Determine whether the ILD pattern “fits” crackles at B/L bases • chronic RA deformities without synovitis 4. BAL to exclude infection Concluding ILD is “ CTD- associated ” • FVC 74%, FEV-1 73%, DLCO 64% Is this CTD-ILD? 5. Biopsy the atypicals • ESR 15 is a process of elimination 4

11/5/2016 Symptoms BIOPSY SYMPTOMS BRONCHOSCOPY • Dyspnea may be due to • Assess impact of dyspnea PHYSICAL EXAM any number of causes on ADLs, other activities – MSK impact / extra-thoracic disease • Pace / progression – Sedentary patients / DIAGNOSTIC deconditioning EVALUATION – Cardiac OF ILD IN CTD DIAGNOSTIC • Cough more likely to be – Anemia (e.g., GAVE) IMAGING – Depression due to GERD RISK FACTORS • Unreliable reporting • Absence of dyspnea does • Unreliable assessment CTD PHENOTYPIC PULMONARY not mean absence of ILD ASPECTS PHYSIOLOGY High risk of missing significant SSc-ILD when Physical exam relying solely on PFTs 102 consecutive SSc patients enrolled • Audible bibasilar crackles strongly predictive of ILD 64/102 (63.0%) with significant ILD on HRCT 27/102 (26.0%) had an FVC<80% • Absence of crackles does not mean absence of ILD 40/64 (62.5%) had significant ILD on HRCT and a normal FVC • Skin informs about skin. Not the lungs. – Same can be said re: joints in RA and muscles in myositis 5/40 (6.0%) with normal FVC had severe lung fibrosis Suliman et al Arthritis Rheum 2015 5

11/5/2016 High resolution CT imaging Role of surgical lung biopsy? Clinical realities: • Modality of choice for detecting CTD-ILD • May not impact treatment • Easy method to determine disease extent – i.e., disease severity – Immunosuppression may be needed – for ILD and the • Multi-compartment disease extra-thoracic disease – irrespective of ILD pattern • Esophageal findings • Risks associated with the surgery • May suggest pulmonary vascular disease: PA diameter, pericardial abnormalities Staging system – not histopathology – predicts prognosis in SSc-ILD 215 consecutive SSc patients evaluated at the Royal Brompton Hospital between 1990 and 1999 Goh et al. AJRCCM 2008 Park et al, AJRCCM 2007 6

11/5/2016 the clinical landscape When do I recommend a surgical lung biopsy? • pre-existing CTD and concerns for an • “ atypical ” HRCT alternative etiology “ Idiopathic ” “ “ “ ” ILD: ” ” • idiopathic ILD – and “ “ Idiopathic ” “ “ ” ” ” ILD: thinking it may be CTD ILD in established CTD: • ultimately, the decision is Determine whether Is it really CTD? Identifying ILD is CTD-associated 35 year old limited SSc and positive Scl-70 occult CTD individualized identifying new CTD in those presenting Identifying occult CTD: what’s helpful? with ILD is common • demographics 114 consecutive patients – 40 year old women don’t get IPF evaluated in an ILD referral center • extrathoracic manifestations 34 (30%) with well-defined CTD • serologies which ones? • HRCT findings 17 (15%) with well established 17 (15%) diagnosed CTD prior to ILD with new CTD • histopathology Mittoo S et al. Resp Med 2009. 103:1152 7

11/5/2016 Useful autoantibodies for CTD-ILD (?) Quantifiable, specific extra-thoracic Most common CTD association features suggesting CTD High-titer ANA (>1:320) Many RF (>60 IU/mL) Many / RA • Sclerodactyly Anti-centromere SSc • Mechanic hands Nucleolar-ANA SSc • Gottron’s papules Anti-CCP RA • Digital edema Anti-Scl-70 SSc • Raynaud’s Anti-Ro (SS-A) Many – capillary microscopy Anti-tRNA synthetase (Jo-1, PL-7, PL-12, others) PM / DM Sjögren's ’ ’ ’ s, SLE ’ tortuosity Anti-PM-Scl SSc / PM overlap • inflammatory arthritis of dropout Anti-La (SS-B) dilatation bilateral wrists or MCPs Anti-dsDNA SLE • KCS sicca? Anti-RNP MCTD, SLE / SSc • Esophageal dilation / Anti-Smith SLE hypomotility Anti-MDA-5 CADM HRCT clues for Histopathology features of CTD-ILD • “ multi-compartment ” CTD-ILD • secondary histopathologic • multi-compartment features: involvement – dense perivascular involvement – parenchyma, airways, collagen vascular, pleura • dilated esophagus – extensive pleuritis – lymphoid aggregates • pericardial thickening or • Primary patterns with germinal center effusion – NSIP, OP, LIP formation – UIP – prominent plasmacytic • NSIP, LIP, NSIP/OP, OP, (UIP) – DAD infiltration – inflammatory airways • follicular bronchiolitis Fischer et al Resp Med 2009 Leslie et al Semin Respir Crit Care Med 2007;28(4):369 Hwang et al J Comput Assist Tomogr 33 , 410-5 8

11/5/2016 Two “common” spectra worth highlighting… systemic sclerosis (SSc) diffuse cutaneous SSc limited cutaneous SSc • Subtle scleroderma spectrum SSc sine scleroderma “ easier ” to diagnose; • Subtle myositis spectrum Diffuse present to rheumatologists Limited / Sine more subtle may only come to attention due to lung disease screening for CTD-ILD with an ANA, ANA profile, RF, CCP, and Scl- anti-synthetase syndrome 70, misses the anti-synthetase syndrome • Classic presentation: – Jo-1 positive – ILD – Raynaud ’ s phenomenon – Myositis – “ mechanic hands ” – Inflammatory arthritis – Often ANA negative • Other tRNA synthetase antibodies have been identified but not routinely checked and many of these patients do NOT have myositis “ mechanic hands ” “ “ “ ” ” ” 9