News at the horizon Concepts of clinical behaviour in the ILDs Athol Wells Royal Brompton Hospital

AUW has received consultancy or lecturing fees from Actelion, Bayer, Boehringer Ingelheim, Gilead, Intermune/Roche

CHP, our most difficult disease The importance of observed or anticipated disease behaviour

Patterns of disease behaviour Depending upon definitions and triggers, we have over 1000 individual ILDs However, this does individualise separate HP and drug triggers. In reality, we have perhaps 50 ILDs But with regard to disease behaviour, logical treatment goals and monitoring, we have only five disorders

HP versus CHP CLINICAL BEHAVIOR TREATMENT GOAL 02/09/12 HP versus CHP CLINICAL BEHAVIOR TREATMENT GOAL MONITORING STRATEGY Reversible & self-limited Remove possible cause Short term (3-6 month) observation to confirm disease regression Reversible disease with risk of progression Initial response & then rationalize longer term therapy Short term observation to confirm treatment response. Long term observation to ensure that gains are preserved Stable with residual disease Maintain status Long term observation to assess disease course Progressive, irreversible disease with potential for stabilization To prevent progression Long term observation to assess disease course Progressive, irreversible disease despite therapy To slow progression Long-term observation to assess disease course, need for transplantation and effective palliation Travis WD et al. Am J Respir Crit Care Med 2013; 188:733-48

Can we rely on the evidence base to treat CHP with confidence? In current cohorts, disease behaviour is not taken into account in management

Treated total, n=93 Prednisolone, n=41 Pred + Aza, n=24 Pred + MMF, n=28

Caveats Neither these data nor any other evaluate treatment versus no treatment in a robust fashion Those receiving therapy had disease that was much more severe than those untreated and had worse outcome. The worthwhile data in this study relate to Adverse events in the shorter term, compared between regimens in the primary cohort: high dose prednisolone regimens strikingly more adverse events Differences in long term outcome (FVC change, mortality) across five cohorts: zilch!!!

Total, n=70 MMF, n=51 Aza, n=19 Pred 12mg daily

Why the evidence base does not mirror the real world….. These cohorts are reported as a “one size fits all” treatment approach In reality, we make a disease behaviour judgement whether a major response is plausible and if so, it is important not to miss an opportunity If disease is irreversible, why persist with high dose steroid therapy? We should be finding a civilised long term approach which, we hope, will prevent or retard disease progression.

CLINICAL BEHAVIOR TREATMENT GOAL MONITORING STRATEGY Reversible & self-limited Remove possible cause Short term (3-6 month) observation to confirm disease regression Reversible disease with risk of progression Initial response & then rationalize longer term therapy Short term observation to confirm Rx response. Long term observation to ensure that gains are preserved Stable with residual disease Maintain status Long term observation to assess disease course Progressive, irreversible disease with potential for stabilization To prevent progression Progressive, irreversible disease despite therapy To slow progression Long-term observation to assess disease course, need for transplant or effective palliation

This is where we are now positioned. News on the horizon: The future shape of IPF pathogenesis: precision medicine versus the progressive fibrotic phenotype The use of disease behaviour to modify diagnosis The future development of the disease behaviour classification

Where lies the future of “IPF” Will pathogenetic thinking be driven by “splitters”, who define IPF sub-groups from observed differences, in the hope of precision medicine? Will it be driven by “lumpers” (who search for a big picture over and above diagnostic nuance)? Will the amalgamation of IPF patients and non-IPF patients with IPF-like disease behaviour be more fruitful? To argue for the primacy of either assumes a level of knowledge that we do not yet possess

These are not mutually exclusive We need smarter splitting and smarter lumping. IPF should 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, we will see the dawn of classification across ILD by disease behaviour

The “progressive fibrotic phenotype” is here to stay

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?

Study of outcome in RA-ILD 157 patients with RA-ILD (Edinborough, London) 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: work in progress

HRCT patterns Appearances typical of IPF Peripheral honeycombing, distribution atypical for IPF Probable UIP Probable UIP, distribution atypical for IPF Inconsistent with UIP

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: work in progress

The clinical need for staging Decisions are dichotomous: treat or not, enrol in treatment trial or not We need definition of high and low risk disease We need to STAGE lung disease in CTD-ILD

Staging by severity: what is needed Simple, user-friendly system Accurate depiction of high and low risk in moderately experienced hands Conceptually easy

Disease extent determines mortality 100 80 60 40 20 120 Limited Duration of follow-up (months) Extensive Survival (%) Goh NS et al. Am J Respir Crit Care Med. 2008; 177:1248-54

The UKRSA staging system HRCT extent >20% <20% Indeterminate FVC >70% FVC <70% Extensive Disease Mild Disease

IPF (n=284) blue Extensive RAILD (n=68) green Limited RAILD (n=88) yellow Jacob J et al: work in progress

Separate UIP outcome subsets Non-RA-UIP, n = 18 Idio. NSIP, n = 66 CTD-NSIP, n=57 RA-UIP, n=19 IPF-UIP, n=203 Park JH et al. Am J Respir Crit Care Med 2007; 175:705-711

Can the PFF 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 Latsi PI et al. Am J Respir Crit Care Med 2003; 168:531-7 Jegal Y et al. Am J Respir Crit 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. Eur Respir J 2016; 477:588-96 Jacob J et al. Respir Med 2017; 130:43-51

Disease behaviour in differential diagnosis The difficult differentials with regard to management (anti-fibrotic therapy versus immunomodulation): IPF versus fibrotic NSIP IPF versus CHP

How likely is IPF: PE probabilities… Definite (95 - 100%) Probable (70 - 90%) Indeterminate (35 - 65%) - management???? Possible (10 - 30%) Unlikely (0 – 5%)

A highly reliable stress test: are you in need of a holiday A highly reliable stress test: are you in need of a holiday? Examine the next slide closely……..

For management purposes, a diagnosis can be….. Established >90% Provisional - high confidence 70-90% - low confidence 50-70% Unclassifiable <50% Ryerson CJ et al. Am J Respir Crit Care Med 2017: 196:1249-54.

“If you don’t know where you are going, any road will get you there”

Multidisciplinary diagnosis is very like the Cheshire cat Consider proposed categories for confidence of diagnosis

An established diagnosis

A provisional diagnosis

Unclassifiable disease

If the likelihood of IPF and fibrotic NSIP are both roughly 50% and you treat as for NSIP, how strongly should the treated course influence diagnostic likelihood? How likely is IPF if disease progresses despite treatment over one year? We can model indeterminate disease (likelihood 35% - 65%)

Longitudinal behaviour in fibrotic IIP Biopsy-proven IPF (n=84) or idiopathic fibrotic NSIP (n=72) Treated with corticosteroids or combined steroid/ immunosuppressive drugs At 12 months, FVC decline (5% or greater): IPF 55% NSIP 24% Zappala CZ et al. Eur Respir J 2010; 35:830-6

If IPF likelihood at baseline = 65% If disease progresses, IPF:NSIP = 55%:24% This likelihood of IPF is computed by multiplying the baseline likelihood (LR = 65/35) by the progression likelihood (LR = 55/24) …….. LR of IPF now 117/28 = 117/145 = 81% This shifts the IPF diagnosis from “provisional low confidence” to “provisional with high confidence”

If IPF likelihood at baseline = 35% If disease progresses, likelihood of IPF = 55%. This provides a provisional multidisciplinary diagnosis of IPF and opens the door for anti-fibrotic therapy If disease is stable, in the indeterminate 35%-65% range, likelihood of NSIP is 48-75% At 50/50 likelihood at baseline, 70% likelihood of IPF if disease progresses, 63% likelihood of NSIP if disease is stable When diagnostic likelihoods at baseline are a close call, the treated course provides a provisional multidisciplinary diagnosis

The disease behaviour classification should be developed across ILD and not confined to unclassifiable disease Future thinking in IPF (the progressive fibrotic phenotype) and the use of disease behaviour to refine MD diagnosis justify this initiative And there are other advantages……..

We need this approach in order to communicate

CTD-ILD: a poll (n=350). With regard to clinical utility, the IIP classification is: Intuitive, user friendly and readily understood by patients Is somewhat helpful to clinicians and patients although not always straightforward Difficult to grasp, arduous to apply but worthwhile Opaque, poorly understood by patients and of little clinical value

CTD-ILD: a poll (n=350). With regard to clinical utility, the IIP classification is: Intuitive, user friendly and readily understood by patients Is somewhat helpful to clinicians and patients although not always straightforward Difficult to grasp, arduous to apply but worthwhile Opaque, poorly understood by patients and of little clinical value 9% 17% 30% 43%

If correct in principle, this approach should apply generally 02/09/12 If correct in principle, this approach should apply generally NSIP HP CTD-ILD Sarcoidosis Drug-induced lung disease

Summary: key concepts We are entering an era in which ILD classification will become more dynamic In suspected IPF, the concept of the progressive fibrotic phenotype will increasingly inform pathogenetic thinking and management Studies of disease behaviour will allow greater precision in multidisciplinary diagnosis The disease behaviour classification might usefully be applied across ILD