Immunosuppressives and Connective

Tissue Disease associated ILD

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