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Clinical Approach: Evaluating CTD-ILD for the pulmonologist

Aryeh Fischer, MDAssociate Professor of Medicine

Division of RheumatologyDivision of Pulmonary Sciences and Critical Care Medicine

University of Colorado School of Medicine

Disclosures

• Industry relationships:

Actelion, aTyr Pharma, Boehringer-Ingelheim, Genentech-Roche, Gilead

ILD in CTD• Occurs commonly across the entire spectrum of CTD

• A multidisciplinary approach can be be useful

• Potentially the most devastating of pulmonary manifestations

• Poses significant challenges to the practicing clinician

“connective tissue disease”or

“collagen vascular disease” • spectrum of systemic

autoimmune diseases characterized by:– circulating autoantibodies– immune-mediated organ

damage– significant clinical

heterogeneity

The CTDs

• Rheumatoid arthritis• Systemic lupus erythematosus• Sjögren’s syndrome• Poly-/Dermatomyositis• Systemic sclerosis

(scleroderma)• Mixed CTD• Undifferentiated CTD

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ILDCTD

CTD-ILD represents a spectrum of diseases

CTDs

RASLESjSPM/DMSScMCTDUCTD

ILDs

NSIPUIPOPLIPDAD

Estimated prevalence rates of ILD in the various CTDs??

Adapted from Castelino and Varga Arthritis Res and Therapy 2010

CTD Estimated frequency of ILDSystemic sclerosis 45% (clinically significant)Rheumatoid arthritis 20 – 30% PM/DM 20 – 50%MCTD 20 – 60%Sjögren's syndrome Up to 25%SLE 2 to 8 %

Interstitial lung disease in scleroderma

• The majority of SSc patients have ILD

• F-NSIP is the most common pattern – UIP far less common– Rare to see the other patterns

• Clinically progressive in ~30%

• The leading cause of death

Solomon et al. Eur Resp Reviews 2013

ILD in poly-/dermatomyositis• ILD is the most common lung

manifestation of PM/DM

• Chief cause of mortality

• NSIP and NSIP/OP are the most common patterns– Can also see LIP, DAD, UIP

• Varied presentation

• Anti-synthetase syndrome

Miller et al. Rheum Dis Clinics NA 2015

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Interstitial lung disease in RA• ILD is the most common lung

manifestation of RA

• Varied presentation

• UIP is the most common pattern– Can also see NSIP, OP, LIP, DAD

• Accounts for 7% of all RA-associated deaths

• Risk of death is 3x higher than for RA without ILD

K Brown Proc Am Thor Soc 2007, Doyle CHEST 2013, Olson AJRCCM 2011

familial

CTD-ILD

medications

idiopathic

environmental occupational

smoking

infection?

??

?

?

?

?

?

the clinical landscape

Park et al. AJRCCM 2007;175:705-711

why assess for CTD?

A CTD-ILD diagnosis may impact:

• Treatment

• Prognosis

• Extra-thoracic disease– clinical context– surveillance for other features

CTD-ILD

IIP

Current approach to treatment

Idiopathic UIP(IPF)

CTD-ILD(ANY pattern) Idiopathic non-UIP

Clinical trialsLung transplantation Immunosuppression Immunosuppression

PirfenidoneNintedanib

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Other common – and potentially important –reasons to assess for CTD

Patient perspective:

• emotional

• sense of belonging

• frustrations with being labeled as “idiopathic”

Physician perspective:

• “if it’s CTD, I can do something about it”

• “the last thing I want to tell my patients is that it's idiopathic”

ILD in established CTD:

Determine whether ILD is CTD-associated

““““Idiopathic”””” ILD:

Identifyingoccult CTD

““““Idiopathic”””” ILD:

Is it really CTD?

the clinical landscape

55-year-old man former smoker, develops exertional dyspnea and cough…

• 10-year history of RF / CCP positive, erosive RA

• arthritis well controlled on MTX and an anti-TNF agent

• crackles at B/L bases

• chronic RA deformities without synovitis

• FVC 74%, FEV-1 73%, DLCO 64%

• ESR 15 Is this CTD-ILD?

ILD in established CTD: checklist1. Confirm the CTD

2. Consider alternative etiologies

3. Determine whether the ILD pattern “fits”

4. BAL to exclude infection

5. Biopsy the atypicalsConcluding ILD is “CTD-associated”

is a process of elimination

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DIAGNOSTIC EVALUATION OF ILD IN CTD

SYMPTOMS

PHYSICAL EXAM

RISK FACTORS

CTD PHENOTYPIC ASPECTS

PULMONARY PHYSIOLOGY

DIAGNOSTIC IMAGING

BRONCHOSCOPY

BIOPSY Symptoms• Dyspnea may be due to

any number of causes– MSK impact / extra-thoracic

disease– Sedentary patients /

deconditioning – Cardiac– Anemia (e.g., GAVE)– Depression

• Unreliable reporting• Unreliable assessment

• Assess impact of dyspnea on ADLs, other activities

• Pace / progression

• Cough more likely to be due to GERD

• Absence of dyspnea does not mean absence of ILD

Physical exam

• Audible bibasilar crackles strongly predictive of ILD

• Absence of crackles does not mean absence of ILD

• Skin informs about skin. Not the lungs.– Same can be said re: joints in RA and muscles in myositis

High risk of missing significant SSc-ILD when relying solely on PFTs

64/102 (63.0%) with significant ILD on HRCT

27/102 (26.0%) had an FVC

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High resolution CT imaging• Modality of choice for detecting

CTD-ILD

• Easy method to determine disease extent– i.e., disease severity

• Multi-compartment disease• Esophageal findings

• May suggest pulmonary vascular disease: PA diameter, pericardial abnormalities

Role of surgical lung biopsy?Clinical realities:

• May not impact treatment

– Immunosuppression may be needed – for ILD and the extra-thoracic disease – irrespective of ILD pattern

• Risks associated with the surgery

Park et al, AJRCCM 2007

Staging system – not histopathology – predicts prognosis in SSc-ILD

215 consecutive SSc patients evaluated at the Royal BromptonHospital between 1990 and 1999

Goh et al. AJRCCM 2008

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When do I recommend a surgical lung biopsy?

• pre-existing CTD and concerns for an alternative etiology

• “atypical” HRCT

• idiopathic ILD – and thinking it may be CTD

• ultimately, the decision is individualized 35 year old limited SSc and positive Scl-70

ILD in established CTD:

Determine whether ILD is CTD-associated

““““Idiopathic”””” ILD:

Identifyingoccult CTD

““““Idiopathic”””” ILD:

Is it really CTD?

the clinical landscape

identifying new CTD in those presenting with ILD is common

114 consecutive patients evaluated in an ILD referral center

34 (30%) with well-defined CTD

17 (15%) with well established CTD prior to ILD

17 (15%) diagnosed with new CTD

Mittoo S et al. Resp Med 2009. 103:1152

Identifying occult CTD: what’s helpful?• demographics

– 40 year old women don’t get IPF

• extrathoracic manifestations

• serologies

• HRCT findings

• histopathology

which ones?

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Quantifiable, specific extra-thoracic features suggesting CTD

• Sclerodactyly• Mechanic hands• Gottron’s papules• Digital edema• Raynaud’s

– capillary microscopy • inflammatory arthritis of

bilateral wrists or MCPs• KCS sicca?• Esophageal dilation /

hypomotility

tortuosity

dilatation dropout

Useful autoantibodies for CTD-ILD (?)Most common CTD association

High-titer ANA (>1:320) Many

RF (>60 IU/mL) Many / RA

Anti-centromere SSc

Nucleolar-ANA SSc

Anti-CCP RA

Anti-Scl-70 SSc

Anti-Ro (SS-A) Many

Anti-tRNA synthetase (Jo-1, PL-7, PL-12, others) PM / DM

Anti-PM-Scl SSc / PM overlap

Anti-La (SS-B) Sjögren's ’’’’s, SLE

Anti-dsDNA SLE

Anti-RNP MCTD, SLE / SSc

Anti-Smith SLE

Anti-MDA-5 CADM

HRCT clues for CTD-ILD

• multi-compartment involvement

• dilated esophagus

• pericardial thickening or effusion

• NSIP, LIP, NSIP/OP, OP, (UIP)

Fischer et al Resp Med 2009Hwang et al J Comput Assist Tomogr 33, 410-5

Histopathology features of CTD-ILD

• secondary histopathologic features:– dense perivascular

collagen– extensive pleuritis– lymphoid aggregates

with germinal center formation

– prominent plasmacytic infiltration

– inflammatory airways• follicular bronchiolitis

• “multi-compartment”involvement– parenchyma, airways,

vascular, pleura

• Primary patterns– NSIP, OP, LIP– UIP– DAD

Leslie et al Semin Respir Crit Care Med 2007;28(4):369

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Two “common” spectra worth highlighting…

• Subtle scleroderma spectrum

• Subtle myositis spectrum

systemic sclerosis (SSc)

limited cutaneous SScdiffuse cutaneous SSc

SSc sine sclerodermaDiffuse

“easier” to diagnose;present to rheumatologists

Limited / Sinemore subtlemay only come to attention due to lung disease

• Classic presentation:– Jo-1 positive– ILD – Myositis– Raynaud’s phenomenon– “mechanic hands”– Inflammatory arthritis– Often ANA negative

• Other tRNA synthetase antibodies have been identified but not routinely checked

anti-synthetase syndrome

““““mechanic hands ””””

screening for CTD-ILD with an ANA, ANA profile, RF, CCP, and Scl-70, misses the anti-synthetase syndrome

and many of these patients do NOT have myositis

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ILD in established CTD:

Determine whether ILD is CTD-associated

““““Idiopathic”””” ILD:

Identifyingoccult CTD

““““Idiopathic”””” ILD:

Is it really CTD?

the clinical landscape CTD-ILD?• 67 year-old woman

with exertional dyspnea

• long-standing Raynaud’s phenomenon

• ANA negative• Isolated Ro-52 positive• HRCT: possible UIP• VATS: UIP with lymphoid

aggregates

CTD-ILD?• 40 year-old woman

with nothing extra-thoracic

• ANA positive 1:320 speckled

• biopsy-proven NSIP • overlapping features:

• organizing pneumonia• lymphoid follicles with

germinal centers

CTD-ILD?• 60 year-old man

• Recent onset Raynaud’s phenomenon

• HRCT with fibrosing interstitial pneumonia

• ANA 1:640 speckled

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CTD-ILD?• 55 year old woman

• No arthritis or other CTD features

• HRCT = UIP

• High titer RF positive• High titer CCP positive

Statement of the problem• Many patients with IIP have subtle features suggestive of an

autoimmune etiology

• Current strategies for identifying and classifying these patients are controversial and inadequate

• Proposed terminology:– “UCTD”, “lung-dominant CTD”, and “auto-immune featured ILD”

• Each have their own set of proposed criteria • None have been validated

• Multi-centered prospective studies are needed to answer important questions about the natural history of this ILD subgroup

Existing criteria only partly overlap

Assayag D et al, Respir Med 2015

• 119 patients with chronic fibrosing interstitial pneumonia

• 4 different set of criteria for interstitial pneumonia with features of autoimmunity

Patients with interstitial pneumonia with features of autoimmune disease have improved survival compared to patients that do not

P=0.03 P=0.06

P=0.07 P=0.10

Assayag D et al, Respir Med 2015

These data support the efforts to standardize the definition

Autoimmune featuresAutoimmune features

Autoimmune featuresAutoimmune features

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“Interstitial Pneumonia with Autoimmune Features” (IPAF)

Courtesy of Prof V CottinFischer et al ERJ July 2015

Interstitial Pneumonia with Autoimmune Features (IPAF)1. Presence of an interstitial pneumonia (by HRCT or surgical lung biopsy) and,2. Exclusion of alternative etiologies and,3. Does not meet criteria of a defined CTD and, 4. At least one feature from at least two of these domains:

A

B

C

67 year-old woman• Raynaud’s phenomenon• High titer Ro-52 / SS-A• VATS: UIP with extensive

lymphoid aggregates

Clinical domain

Serologic domain

Morphologic domain

The IPAF “intersect”

CTD-ILD

Idiopathic Interstitial

Pneumonia(IPF, iNSIP)

IPAF

Park et al. AJRCCM 2007;175:705-711

Do those with “IPAF” behave like CTD-ILD or IIP?

IPAF

?

?

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Summary• ILD in pre-existing CTD:

– Exclude alternative etiologies– Biopsy the atypical HRCT / atypical scenario– CTD-ILD = diagnosis of exclusion

• ILD as the first manifestation of CTD:– Multidisciplinary evaluations are useful– Remember the scleroderma and myositis spectrum disorders– Consider demographics, serologies, clinical features, radiology, pathology

• Challenges of suggestive forms of CTD-ILD:– Consider “interstitial pneumonia with autoimmune features”– Needs to be studied