Connective Tissue Disorder- Associated Interstitial Lung Disease (CTD-ILD) and Updates Maria Elena Vega, M.D Assistant Professor of Medicine Lewis Katz School of Medicine at Temple University Nothing to disclose Disclosures
Objectives Describe the magnitude of ILD in CTD. Define CTD-ILD. Appraise the utility of PFT, 6-minute walk test and high resolution chest CT in diagnosing CTD-ILD. Review updates and treatment of CTD-ILD. Pulmonary involvement in CTD The lung is a common site of complication of systemic CTD. Can involve: The respiratory muscles, the pleura, the conducting airways, the lung parenchyma and the pulmonary vessels.
Lung Involvement in CTD Lung Involvement SS RA Sjogren s Syndrome MCTD PM/DM SLE ILD Likely Common Possible Common Likely Unusual Pulmonary Hypertension Airways Disease Likely Unusual Unusual Likely Unusual Unusual Unusual Common Common Possible Unusual Possible Pleural Unusual Common Possible Possible Unusual Likely Diffuse Alveolar Hemorrhage Unusual Unusual Unusual Unusual Unusual Common ILD in CTD IDL is one of the most common and clinically important manifestations of CTD. It can also be the first and only manifestation of previously unrecognized CTD. ILD can also occur as a complication of treatment for CTD.
Definition of CTD-ILD The ILDs are a group of diffuse parenchymal lung disorders that are classified according to specific clinical, radiological and histopathological features. ILD has no identifiable cause = Idiopathic Associated with an underlying CTD. Incident Cases of ILD Coultas AJRCCM 1994;150: 967-72
Epidemiology The overall incidence of CTD-ILD is estimated at 15%. Radiographic prevalence on high resolution computerized tomography (HRCT): RA 19% PM/DM 23-38% SLE 30% MCTD 52-85% SS 75% SSc 70-90 % Epidemiology ILD is the leading cause of morbidity and mortality in CTD. CTD-ILD is associated with a more favorable prognosis than is idiopathic interstitial pneumonia of equivalent severity.
Histopathology NSIP (Non-Specific Interstitial Pneumonia) - most Cellular Fibrotic - Scleroderma / Systemic Sclerosis, PM /DM UIP (Usual Interstitial Pneumonia) RA LIP (Lymphocytic Interstitial Pneumonia) Sjogren s Syndrome OP (Organizing Pneumonia) RA, PM/DM Diagnosis PFT and 6 min walk Pulmonary Function Test Spirometry decreased FVC Lung volumes decreased TLC Diffusion capacity reduced Six minute walk test Evaluate for resting or exertional hypoxemia
Diagnosis - HRCT High-resolution computed tomography (HRCT) of the lung provides detailed visualization of the lung parenchyma. More sensitive than chest X ray and PFT. The technique of HRCT involves use of 1-2-mmthick collimation scans with a high spatial frequency algorithm. NSIP pattern The predominant finding is ground glass opacity (GGO). NSIP is by far the most common ILD in patients with connective tissue disease.
UIP pattern Honeycombing consisting of multilayered thick-walled cysts. Architectural distortion with traction bronchiectasis due to fibrosis. Predominance in basal and subpleural region. Organizing Pneumonia Bilateral peripheral consolidations, sharply demarcated. Consolidations may be migratory.
Lymphocytic Interstitial Pneumonia CT findings are nonspecific but include mixed alveolar interstitial infiltrates and thin-walled cysts. Treatment Decisions to treat depend on spirometry data and symptom decline. Debate over treating patients if they have radiographic pattern of UIP. Treatment if obvious GGOs. Vary by underlying CTD.
Treatment - Cyclophosphamide There are few adequately powered randomized controlled trials in patients with CTD ILD. Utility of cyclophosphamide in the treatment of scleroderma associated ILD. Scleroderma Lung Study I: oral cyclophosphamide vs placebo for 1 year improvement in FVC N Engl J Med 2006; 354:2655-2666 Treatment - Cyclophosphamide Initial combination therapy with low dose steroids and cyclophosphamide IV every month for 6 months followed by maintenance with Azathioprine vs placebo Non significant trend towards improvement in FVC. Suggests that the effect wanes over time. Arthritis Rheum. 2006;54(12):3962-70
Mycophenolate Mofetil (MMF) Has been studied in various CTD-ILD populations with generally favorable results. Case series of 125 patients Scleroderma (n=44), PM/DM (n=32), RA (n=19) Sustained improvement in FVC and reduced steroid requirement J Rheumatol 2013; 40:640-6 Mycophenolate Mofetil Scleroderma Lung Study II: Randomized, double-blind, parallel group trial. MMF for 24 months or oral cyclophosphamide for 12 months followed by placebo for 12 months. MMF was better tolerated and associated with less toxicity FVC did not differ significantly between the two treatment groups Lancet Respir Med. 2016;4(9):708-719
Scleroderma Lung Study III Combining Pirfenidone With Mycophenolate (SLSIII) Double-blind, randomized and placebocontrolled. Scleroderma-related Interstitial Lung Disease. Oral MMF and a placebo or combination of oral MMF and oral pirfenidone. Antifibrotic Agents Agents that had been shown to have efficacy in the treatment of idiopathic pulmonary fibrosis (IPF): Pirfenidone: antifibrotic agent that inhibits transforming growth factor beta (TGF-b)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation in vitro. Nintedanib: a receptor blocker for multiple tyrosine kinases
Nintedanib (Ofev) The main benefits are a reduction in the rate of decline in lung function and a longer time to first exacerbation. Side effects: diarrhea (62 %), nausea (24%), vomiting (12%), and elevation in LFT. N Engl J Med. 2014;370(22):2071 / N Engl J Med. 2011;365(12):1079 Pirfenidone (Esbriet) Significant reduction in the one-year rate of decline in FVC compared to placebo. Pirfenidone reduced the decline in the 6 MWD, improved progression-free survival. Side effects: rash, photosensitivity, nausea, diarrhea, abdominal discomfort, anorexia and fatigue. N Engl J Med. 2014;370(22):2083
Biologic agents RA Rituximab refractory scleroderma (case series) stability or inc in FVC at 6-12 months. Rituximab Versus Cyclophosphamide in Connective Tissue Disease-ILD (RECITAL) Scleroderma, IIM, MCTD Calcineurin Inhibitors Case studies and case series in patients with DM/PM ILD and IIM ILD Retrospective studies PM/DM and IIM ILD Tacrolimus 1-3 mg / day Cyclosporine 2-5 mg /kg/ day
Lung transplantation Lung transplantation may be an option for carefully selected patients with CTD-ILD that are not responsive to pharmacologic interventions Bob 70 year old former smoker man Seronegative RA, GERD, CAD, carotid stenting. 6/2016 RA saturation 86%, ambulated 304 meters, required 4 L. 7/2017 RA saturation 96%, ambulated 270 meters, did not require oxygen.
Initial HRCT Chest After treatment
Iona 70 year old woman with a past 35 pack-year smoking history, undifferentiated connective tissue disease, ILD and emphysema. On MMF since 2013. FVC TLC DLCO Room air saturation Distance (meters) Oxygen with ambulation 2014 63% 62% 50% 97% 305 none 2015 65% 66% 52% 98% 361 none 2016 59% 74% 48% 96% 335 none 2017 59% 54% 46% 98% 305 none 2018 62% 63% 47% 98% 290 none 2017 2013
Lydia ILD diagnosed by a lung biopsy in Puerto Rico in 2010 (biopsy most consistent with UIP) Anti Synthetase Syndrome FVC TLC DLCO Room air saturation 2013 67% 37% Distance (meters) Oxygen with ambulation 2014 62% 58% 32% 98% 342 none 2018 42% 43% 21% 84% 360 6 liters 2013 2018
Interstitial Pneumonia with Autoinmmune Features Patients with idiopathic interstitial pneumonia (IIP) with clinical features that suggest an underlying autoimmune process. Do not meet established criteria for connective tissue disease. The European Respiratory Society/American thoracic Society Task Force on undifferentiated forms of connective tissue disease associated interstitial lung disease (May 2015). Interstitial pneumonia with autoimmune features (IPAF) Classification Clinical domain Specific extrathoracic features Serologic domain Specific circulating autoantibodies Morphologic domain Specific chest imaging features, histopathologic features or pulmonary physiologic features
IPAF Prospective studies are needed to determine the natural history and clinical implications of this classification and to allow for an evidence-based approach to the management of this cohort of patients.
Multidisciplinary discussion The multidisciplinary approach is to goal standard for diagnosing and treating patients with CTD-ILD. Pulmonologists, Rheumatologists, Radiologists, and Pathologists. Conclusions Patients with CDT-ILD should be followed regularly with a six minute walk test, PFT and HRCT of the chest. Multidisciplinary approach is to goal standard for diagnosing and treating patients with CTD-ILD. Immunosuppression is the mainstay of treatment for ILD. Clinical trials of novel therapies are needed to inform best treatment strategies.
References Tashkin DP at al. Cyclophosphamide versus Placebo in Scleroderma Lung Disease. N Engl J Med 2006; 354:2655-2666. Hoyles RK at al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54(12):3962-70. Fisher A at al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013; 40:640-6. Tashkin DP at al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-719. References Richeldi L at al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071. Richeldi L at al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079. King TE Jr. at al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083. Fisher at al. An official European Respiratory Society/ American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015; 46: 976-987.