immunosuppressives & connective tissue disease associated ild

8/10/2019 Immunosuppressives & Connective Tissue Disease associated ILD

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Overview

Definitions

Drugs

Natural History

Treatment of ILD Can drugs cause ILD

Role of newer agents


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Connective Tissue Disease

Rheumatoid Disease Connective-Tissue disease

Joints Synovitis Synovitis less common

Subtypes SeropositiveSeronegative

Systemic SclerosisIdiopathic 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


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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


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Am J Respir Crit Care Med2008


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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)


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Pulsed IV cyclo

152 patients screened, 107 excluded

22 active treatment, 23 placebo 4.19% improvement in FVC (p=0.08)


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Meta analysis of 17 studies

Cyclophosphamide (IV or oral) prevents decline of FVC but

not DLco at 12/12

Size of effect marginal (


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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


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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


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ImmunosuppressivesHydroxychloroquine 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


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Lancet 2002

Mortality: Mtx vs not

Mtx in context of other DMARDS

1240 pts enrolledbetween 1981-1999

Weighted Coxs PH

model to examine risk

of death by use of

MTx


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Retrospective data suggest prevalance

of 3.5-7.6%

Prospective study of patients startedon 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


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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


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Death due to

lung disease

RR 1.53

(0.46-5.01)

Pneumonitis

RR 8.81

(1.79-34.72)


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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


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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


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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


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Fibrosis (IPF) vs Inflammation (NSIP/CTD)

Pirfenidone/Nintedanib for CVD-assoc disease?

Pirfenidone/Nintedanib parallel to Mtx

29 May 2014


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Questions

immunosuppressives & connective tissue disease associated ild

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