Dr Felix Woodhead MRCP PhD Consultant Physician Leicester ILD unit Overview Definitions Drugs Natural History Treatment of ILD Can drugs cause ILD Role of newer agents
Connective Tissue Disease Rheumatoid Disease Connective-Tissue disease Joints Synovitis Synovitis less common Subtypes Seropositive Seronegative Systemic Sclerosis Idiopathic Inflammatory Myositis (PM/DM) Sjgrens, MCTD, SLE Immunology Rheumatoid Factor anti-CCP Antinuclear antibodies ENAs Extra-articular features Uncommon at diagnosis Common Lung: (CT/biopsy) UIP > NSIP > OP NSIP > OP > DAD. UIP uncommon Immunosuppressives Hydroxychloroquine CTD = RA Sulphasalazine RA Methotrexate RA > CTD Leflunomide RA Calcineurin inhibitors (cyclosporine/tacrolimus) RA = CTD (infrequent) Azathioprine CTD Mycophenolate Mofetil CTD > RA Cyclophosphamide CTD > RA anti-TNF RA > CTD anti-CD20 (rituximab) RA = CTD T-cell co-stim blocker (abatacept) RA IL6 blocker (tocilizumab) RA Cryptogenic Fibrosing Alveolitis Bibasal Crackles Restrictive Spirometry or isolated low TLco Basally-predominant fibrosis on CXR Absence of pneumoconiosis, EAA or known connective tissue disease
Am J Respir Crit Care Med 2008 Am J Respir Crit Care Med 2008 SSc patients with active alveolitis on BAL or ground-glass on HRCT 267 patients screened 79 oral cyclophosphamide 79 placebo 2.53% better FVC at 12/12 than placebo (p=0.03) Pulsed IV cyclo 152 patients screened, 107 excluded 22 active treatment, 23 placebo 4.19% improvement in FVC (p=0.08) Meta analysis of 17 studies Cyclophosphamide (IV or oral) prevents decline of FVC but not DLco at 12/12 Size of effect marginal (<10% FVC or DLco) Retrospective study 125 patients CTD (44 SSc, 32 PM/DM, 18 RA etc) Improvements in FVC and DLco at 1,2 and 3 years UIP subgroup stability NSIP subgroup improvement Case series of 8 patients with severe CTD-associated ILD All previously extensively treated 5 PM/DM, 2 undifferentiated CTD, 1 Scleroderma Physiological improvement in 7 patients 2 came of ventilator
Immunosuppressives Hydroxychloroquine CTD = RA Sulphasalazine RA Methotrexate RA > CTD Leflunomide RA Calcineurin inhibitors (cyclosporine/tacrolimus) RA = CTD (infrequent) Azathioprine CTD Mycophenolate Mofetil CTD > RA Cyclophosphamide CTD > RA anti-TNF RA > CTD anti-CD20 (rituximab) RA = CTD T-cell co-stim blocker (abatacept) RA IL6 blocker (tocilizumab) RA Lancet 2002 Mortality: Mtx vs not Mtx in context of other DMARDS 1240 pts enrolled between 1981-1999 Weighted Coxs PH model to examine risk of death by use of MTx
Methotrexate usually given to patients with more severe disease (confounding by indication) Multivariate analysis weighted by the propensity to receive the drug given other cofactors 5,626 RA pts followed prospectively for 25 years 666 (12%) died adjusted HR for death|methotrexate 0.30 (0.09-1.03) Retrospective data suggest prevalance of 3.5-7.6% Prospective study of patients started on low-dose Mtx 223 pts enrolled, fu for 2 years or till Mtx-P follow up: 223 to 6/12, 185 to 2 yrs Only 2 cases: 6/52 & 11/52 into Rx 1 case/192 patient-years 1460 patients with early arthritis 1986-1998 70% received sulphasalazine, 42% methotrexate, 0 biologics 12,586 person-years of data Median follow up 10 years RA-ILD diagnosed in 43 Death due to lung disease RR 1.53 (0.46-5.01) Pneumonitis RR 8.81 (1.79-34.72) Searched MEDLINE from 1990-2010 for biologics and ILD 93% anti-TNF (etanercept/infliximab), 5 (4%) rituximab Not all patients had full data: 15/52 with reported outcome (29%) died
British Society of Rheumatology Biologics Register (BSRBR) established 2001 10,649 anti-TNF vs 3,464 DMARD-only group RA-ILD: 299/10649 (2.8%) anti-TNF; 68/3464 (2.0%) DMARD All cause mortality similar for ILD in both RA-ILD groups, before and after adjustment for potential confounders RA-ILD cause of death in 15/70 (21%) anti-TNF vs 1/14 (7%) DMARD group
Ann Rheum Dis. 2010 Summary Variety of rheumatological conditions Best studied is SSc Methotrexate important in RA survival ?not causative in chronic fibrosis main issue is Mtx-P No good data on treatment of RA-ILD Fibrosis (IPF) vs Inflammation (NSIP/CTD) Pirfenidone/Nintedanib for CVD-assoc disease? Pirfenidone/Nintedanib parallel to Mtx 29 May 2014 Questions