Disclosures. Clinical Approach: Evaluating CTD-ILD for the pulmonologist. ILD in CTD. connective tissue disease or collagen vascular disease

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1 Disclosures Clinical Approach: Evaluating CTD-ILD for the pulmonologist Industry relationships: 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 ILD in CTD Occurs commonly across the entire spectrum of CTD A multidisciplinary approach can be be useful Potentially the most devastating of pulmonary manifestations Poses significant challenges to the practicing clinician spectrum of systemic autoimmune diseases characterized by: connective tissue disease or collagen vascular disease circulating autoantibodies immune-mediated organ damage significant clinical heterogeneity The CTDs Rheumatoid arthritis Systemic lupus erythematosus Sjögren s syndrome Poly-/Dermatomyositis Systemic sclerosis (scleroderma) Mixed CTD Undifferentiated CTD 1

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

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

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

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

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

7 When do I recommend a surgical lung biopsy the clinical landscape pre-existing CTD and concerns for an alternative etiology atypical HRCT idiopathic ILD and thinking it may be CTD ILD in established CTD: Idiopathic ILD: Idiopathic ILD: ultimately, the decision is individualized 35 year old limited SSc and positive Scl-70 Determine whether ILD is CTD-associated Identifying occult CTD Is it really CTD identifying new CTD in those presenting with ILD is common 114 consecutive patients evaluated in an ILD referral center Identifying occult CTD: what s helpful demographics 40 year old women don t get IPF 34 (30%) with well-defined CTD extrathoracic manifestations serologies 17 (15%) with well established CTD prior to ILD 17 (15%) diagnosed with new CTD HRCT findings histopathology which ones Mittoo S et al. Resp Med :1152 7

8 Quantifiable, specific extra-thoracic features suggesting CTD Sclerodactyly Mechanic hands Gottron s papules Digital edema Raynaud s capillary microscopy inflammatory arthritis of bilateral wrists or MCPs KCS sicca Esophageal dilation / hypomotility tortuosity dilatation dropout Useful autoantibodies for CTD-ILD () Most common CTD association High-titer ANA (>1:320) Many RF (>60 IU/mL) Many / RA Anti-centromere SSc Nucleolar-ANA SSc Anti-CCP RA Anti-Scl-70 SSc Anti-Ro (SS-A) Many Anti-tRNA synthetase (Jo-1, PL-7, PL-12, others) PM / DM Anti-PM-Scl SSc / PM overlap Anti-La (SS-B) Sjögren's s, SLE Anti-dsDNA SLE Anti-RNP MCTD, SLE / SSc Anti-Smith SLE Anti-MDA-5 CADM HRCT clues for CTD-ILD multi-compartment involvement dilated esophagus pericardial thickening or effusion NSIP, LIP, NSIP/OP, OP, (UIP) Histopathology features of CTD-ILD secondary histopathologic features: dense perivascular collagen extensive pleuritis lymphoid aggregates with germinal center formation prominent plasmacytic infiltration inflammatory airways follicular bronchiolitis multi-compartment involvement parenchyma, airways, vascular, pleura Primary patterns NSIP, OP, LIP UIP DAD Fischer et al Resp Med 2009 Hwang et al J Comput Assist Tomogr33, Leslie et al Semin Respir Crit Care Med 2007;28(4):369 8

9 Two common spectra worth highlighting systemic sclerosis (SSc) Subtle scleroderma spectrum Subtle myositis spectrum limited cutaneous SSc SSc sine scleroderma diffuse cutaneous SSc Diffuse easier to diagnose; present to rheumatologists Limited / Sine more subtle may only come to attention due to lung disease anti-synthetase syndrome screening for CTD-ILD with an ANA, ANA profile, RF, CCP, and Scl- 70, misses the anti-synthetase syndrome Classic presentation: Jo-1 positive ILD Myositis Raynaud s phenomenon 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

10 the clinical landscape 67 year-old woman with exertional dyspnea CTD-ILD ILD in established CTD: Determine whether ILD is CTD-associated Idiopathic ILD: Identifying occult CTD Idiopathic ILD: Is it really CTD long-standing Raynaud s phenomenon ANA negative Isolated Ro-52 positive HRCT: possible UIP VATS: UIP with lymphoid aggregates CTD-ILD CTD-ILD 40 year-old woman with nothing extrathoracic ANA positive 1:320 speckled biopsy-proven NSIP overlapping features: organizing pneumonia lymphoid follicles with germinal centers 60 year-old man Recent onset Raynaud s phenomenon HRCT with fibrosing interstitial pneumonia ANA 1:640 speckled 10

11 55 year old woman No arthritis or other CTD features HRCT = UIP High titer RF positive High titer CCP positive CTD-ILD Statement of the problem Many patients with IIP have subtle features suggestive of an autoimmune etiology Current strategies for identifying and classifying these patients are controversial and inadequate Proposed terminology: UCTD, lung-dominant CTD, and auto-immune featured ILD Each have their own set of proposed criteria None have been validated Multi-centered prospective studies are needed to answer important questions about the natural history of this ILD subgroup Existing criteria only partly overlap Patients with interstitial pneumonia with features of autoimmune disease have improved survival compared to patients that do not Autoimmune features Autoimmune features 119 patients with chronic fibrosing interstitial pneumonia 4 different set of criteria for interstitial pneumonia with features of autoimmunity P=0.03 P=0.06 These data support the efforts to standardize the definition Autoimmune features Autoimmune features P=0.07 P=0.10 Assayag D et al, Respir Med 2015 Assayag D et al, Respir Med

12 Interstitial Pneumonia with Autoimmune Features (IPAF) Interstitial Pneumonia with Autoimmune Features (IPAF) 1. Presence of an interstitial pneumonia (by HRCT or surgical lung biopsy) and, 2. Exclusion of alternative etiologies and, 3. Does not meet criteria of a defined CTD and, 4. At least one feature from at least two of these domains: A B Clinical domain Serologic domain 67 year-old woman Raynaud s phenomenon High titer Ro-52 / SS-A VATS: UIP with extensive lymphoid aggregates Morphologic domain C Courtesy of Prof V Cottin Fischer et al ERJ July 2015 The IPAF intersect Do those with IPAF behave like CTD- ILD or IIP CTD-ILD IPAF Idiopathic Interstitial Pneumonia (IPF, insip) IPAF Park et al. AJRCCM 2007;175:

13 Summary ILD in pre-existing CTD: Exclude alternative etiologies Biopsy the atypical HRCT / atypical scenario CTD-ILD = diagnosis of exclusion ILD as the first manifestation of CTD: Multidisciplinary evaluations are useful Remember the scleroderma and myositis spectrum disorders Consider demographics, serologies, clinical features, radiology, pathology Challenges of suggestive forms of CTD-ILD: Consider interstitial pneumonia with autoimmune features Needs to be studied 13