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Explore the evolution of ILD classification & the importance of personalized treatments for better outcomes. Learn how ILD treatment is changing in the 21st century.
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Is it time to change ILD classification? Pneumotrieste 2019: April 2nd Athol Wells Royal Brompton Hospital, London, UK
AUW has received consultancy or lecturing fees from Actelion, Bayer, BoehringerIngelheim, Gilead, Intermune/Roche
ILD in 2013 ILD in 2015
The idiopathic interstitial pneumonias (2013) Major Idiopathic Interstitial Pneumonias Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Rare Idiopathic Interstitial Pneumonias Idiopathic lymphoid interstitial pneumonia Idiopathic pleuropulmonary fibroelastosis Unclassifiable idiopathic interstitial pneumonias Histological patterns with no defining clinical entity Acute fibrinoid organizing pneumonia Airway centred interstitial fibrosis Travis W et al, Am J RespCrit Care Med 2013;188:733
Every way of classifying a thing is but a way of handling it for some particular purpose William James Our conception of ILD has changed greatly in recent decades History is there to be learned from. ILD in 2030 will not be the same disease as it is today
Purpose of a classification • “Old classifications never die: only the people that use them do” • Every classification has a particular purpose: aetiologic, imaging, histopathologic etc • A classification must have utility – providing either pathogenetic insights or direct clinical utility. Most classifications cannot do both – especially the IIP classification….. Anon
IIP classification • IIPs are not all idiopathic, not all interstitial and not pneumonias…… • But the acronym does serve to indicate a group of apparently idiopathic disorders with a common presentation • The utility of the classification is the distinction between individual disorders in the natural history and treated course, best exemplified by the distinction between IPF and idiopathic NSIP….
Chronic renal disease circa 2000 • Complex histological terms • Overlap between disorders • Entities not understood except by super-specialists • Prognosis not well tied to individual entities Major disenchantment led to a radically simplified classification
Chronic kidney disease (KDOQI) classification 2002 • Essentially a prognostic classification • Simple categories based on three variables: degree of structural damage, degree of functional impairment (GFR), change in the next six months • Fine histological distinctions discarded
A key added disadvantage of both the IIP and the pre-2002 classification…… • Both are formulated at a single point in time • In neither is disease behavior taken into account • But it is disease behaviour that we treat • Histospecific diagnosis is really a “middle man” • It provides us with average outcomes Sometimes average outcomes are meaningless mean statements ……
74 patients with IPF (“UIP”) or fibrotic NSIP, treated for one year Survival patterns based on longitudinal behaviour Some NSIP patients have an IPF-like survival pattern Latsi PI et al. Am J Respir Crit Care Med 2003; 168:531-7
As long as the IIP classification provided separate disease-specific treatment algorithms, overlap in outcomes did not matter But then came the first chink in the armour of the existing IIP classification…
The elephant in the room: patients who do not fit into a classification
We needed a different question in unclassifiable disease In classifiable disease, the primary question had been “what is the diagnosis”? In unclassifiable disease, the primary question is “what are you going to do about it”?
Broadly speaking, there are only limited possible approaches in chronic disease • A disease can be left alone (if it is self limited and will a) regress; or b) persist as a “footprint” of a previous “hit” • If not self-limited, perhaps it can be wholly or partially removed with treatment • If not, perhaps it cannot be prevented from worsening • If not, perhaps progression can at least be retarded
Why it is that in 2019 the disease behaviour classification is an idea whose time has come….
ILD treatment 21st century “It is better to predict dramatic things that don´t happen than boring things that do” Nathan Myhrvold
With regard to the future of ILD treatment, we have reached a fork in the road Do we lump or do we split?
Splitting…….. Our recommendation is that future clinical trials attempt to utilize biomarkers found in circulation or tissue samples to identify aberrant fibrotic pathways that are unique to that particular patientOnce this personalized approach …is taken, it is likely that ….many drugs….will provide patient specific benefit Loomis-King H et al. Curr Op Pharmacol 2013; 13:377-85
Personalised medicine is a beautiful idea Beautiful ideas are dangerous
Personalised/precision medicine • Pro: a beautiful idea. Precedents, especially in malignant disease • Con: has not been convincingly demonstrated in ILD. The malignant precedent might be misleading: primitive clonal cells may be more vulnerable to single pathway manipulation • Successes in CF and asthma should encourage us
What is lacking for ILD precision medicine • Evidence of specific endotypes (e.g. in IPF) that benefit from specific treatments • Current validated biomarkers that identify such sub-types or are robust in predicting IPF progression. However, promise in several areas. • Current biomarkers fit for use as end-points (i.e. fit for use as serial change markers in clinical trials) • This is the menu of what is needed
Splitting celebrates the IIP classification • Splitting gave us NSIP • Further splitting may give us new IPF entities based on specific responses to therapies • It is fair to say that our current scientific hierarchy is strongly biased towards spltting • My thesis is that the value placed on splitting is over-valued
However, the key dilemma remains… • The future of IPF may be driven either by “splitters” (who draw distinctions from observed detail) or “lumpers” (who search for a big picture over and above diagnostic nuance). • Will unique treatment outcomes be recognised in distinct patient sub-groups? • Or will the recognition of a clinically progressive fibrotic phenotype, with the amalgamation of IPF and non-IPF patients with IPF-like behaviour, be more fruitful?
Lumping and splitting are the yin and the yang of pathogenetic thinking • We need smarter splitting and smarter lumping. • IPF will continue to be sub-grouped. Biomarkers associated with IPF and with more progressive IPF should be explored in progressive non-IPF disorders • Examples of shared pathogenetic pathways between IPF and non-IPF fibrotic disease are now emerging • We are not permitted to use anti-fibrotic therapy in progressive fibrotic non-IPF disorders
A great deal now depends upon current anti-fibrotic trials in grouped non-IPF disorders If these studies are positive, there will be a major changes in the treatment of progressive fibrotic diseases and a sea change in ILD classification…
Can the progressive fibrotic phenotype be identified with confidence at baseline? • This would be ideal, especially if anti-fibrotic trials in non-IPF are positive • There are a number of studies in which biopsy or HRCT features (usually of UIP) are associated with a bad outcome in CHP, CTD-ILD, unclassifiable disease • But is baseline data really good enough? Disease severity in non-UIP? HRCT pattern of UIP?
100 Limited 80 60 Extensive Survival (%) 40 20 0 80 20 60 100 40 0 120 Duration of follow-up (months) Disease extent determines mortality in SSC Goh NS et al. Am J RespirCrit Care Med. 2008; 177:1248-54
The UKRSA staging system HRCT extent >20% <20% Indeterminate FVC >70% FVC <70% Extensive Disease Mild Disease
Is the presence of a UIP pattern in diseases other than IPF sufficiently predictive of a poor outcome?
Median survival n = 62, DLco 48% RA nonUIP: 6.6 yrs n = 20, DLco 50% RAUIP: 3.2 yrs n = 51, Dlco 41% IPF: 2.6 yrs Kim EJ et al. Eur Respir J 2010; 35:1322-8
Study of outcome in RA-ILD • 157 patients with RA-ILD (Edinborough, London), chosen because, IPF apart, RA-ILD may be the MOST progressive fibrotic phenotype • Examination of a priori variables against mortality • HRCT pattern (UIP, probable UIP, inconsistent with UIP) • Staging of disease severity using the Goh SSc-ILD criteria Jacob J et al: EurRespir J 2019; 53:pii1800869
HRCT patterns • Appearances typical of IPF • Peripheral honeycombing, distribution atypical for IPF • Probable UIP • Probable UIP, distribution atypical for IPF • Inconsistent with UIP Jacob J et al: EurRespir J 2019; 53:pii1800869
IPF (n=284) blue – mean survival 2.9 years RAILD definite UIP pattern (n=55) green - mean survival 3.5 years RAILD probable UIP pattern (n=56) yellow - mean survival 4.6 years RAILD inconsistent (n=46) violet – mean survival 5.3 years Jacob J et al: EurRespir J 2019; 53:pii1800869
(This also works in RA-ILD) IPF (n=284) blue Extensive RAILD (n=68) green Limited RAILD (n=88) yellow Jacob J et al: EurRespir J 2019; 53:pii1800869
Can the progressive fibrotic phenotype be identified with confidence at baseline? • Not yet!!! • Based on current data, the PFF may eventually be defined from baseline HRCT (with biopsy findings in some cases) and emerging molecular data • But for the moment, the PFF equates to progression despite treatment considered to be appropriate in individual ILDs
Disorders in which observed FVC (or HRCT) progression drives mortality • Idiopathic NSIP • SSc-ILD • CHP • RA-ILD • Unclassifiable lung disease (serial HRCT) Latsi PI et al. Am J RespirCrit Care Med 2003; 168:531-7 Jegal Y et al. Am J RespirCrit Care Med 2005; 171:639-44 Goh NS et al. Arthritis Rheumatol 2017; 69:1670-8 Gimenez A et al. Thorax 2017; epub ahead of print Solomon JJ et al. EurRespir J 2016; 477:588-96 Jacob J et al. Respir Med 2017; 130:43-51
If current studies of anti-fibrotic therapy are positive in progressive non-IPF pulmonary fibrosis, ILD classification will change radically • RELIEF: Pirfenidone in unclassifiable ILD • INBUILD: Nintedanib in progressive fibrotic non-IPF disorders, stratified by UIP-like disease on HRCT
The “progressive fibrotic phenotype” is here to stay EurRespir J 2018; 17: pii1800692
“Indolent/stable disease” • MICO: • Masterful Inactivity • with Cat-like Observation • The role of the doctor is to amuse the patient while nature takes its course • (Voltaire)
