Lung Dominant CTD

Dr. Pravin HissariaMD, DM, FRCPA, FRACP (Australia)Clinical Immunologist and ImmunopathologistSenior Staff SpecialistRoyal Adelaide Hospital / SA PathologyAdelaide South Australia

Adelaide Immunology Allergy and Arthritis Centre

Ahmedabad

Criteria-based clinical diagnostics

Clinical symptom 1

Clinical symptom 2

Clinical symptom 3

Serologic result: Diagnosis

Specific serologic result: Prognosis

Criteria = rigorously defined items

What about Interstitial lung diseases in Rheumatological practice?

• ILD can be a manifestation of any or all CTDs

• But…….• It’s included in diagnostic criteria in only

one disease (PSS)…

Illustrative Case

• 56 yr old female with dyspnoea, dry cough and moderate restrictive lung disease

• Raynaud’s phenomenon, telengiectasias

• HRCT Thorax – NSIP, esophageal dilatation

• ANA – 1:1280 Hom ENA-Ro60• ??? Diagnosis

UCTD criteria

• Signs and symptoms of CTD• Not fulfilling criteria for a defined

connective tissue disease• Disease duration of at least 3 years

J Rheumatol 2005, 2005

What about ILD in respiratory practices?

• 1990s Long term cohort studies in ILD• 15-20% were eventually classified as

CTD-ILD– These patients had better prognosis

• ANA and RF recommended in several consensus guidelines

• 1994 – NSIP was first recognised (Katzenstein et al, 1994)

Respiration 1995, Eur resp J 2006; Am J Resp Crit Care 1996

Respiratory literature - 1990s

• Confirmed that 15-20% of ILD patients progressed to CTD – ILD during follow up.

• However, ANA and RF were not useful• Rheumatology referral not useful• Diagnostic criteria not met• UCTD was proposed as a diagnostic

criterion• Autoantibody positive ILD ….

J Bras Pneumol 2013

Epidemiology studies through 2000s

• About 18-25% of ILD were being confirmed to have CTDs

• About 20% had some other autoimmune symptoms

• ANA – 56%, RF-31%, Anti Ro 15%• Inflammatory Myositis were present in

significant proportion• IPF (UIP) had worst prognosis with

Immunosuppressive therapy

Seminal papers

• Takahashi et al (Respirology 2007)• Anti PL-12 positivity in IPF• Only a subgroup of pts had auto-

antibodies to alanyl t-RNA synthetase • Distinct from CTD-ILD (no myositis)• ANA is not a single test !!!!!!!!!!!!!!!!!

Story of NSIP

• International experts in ILD met under ATS

• All submitted cases of idiopathic NSIP• 43% ANA+ve, 23% RF +ve

Raynaud’s 8% and Arthritis 5%• Better prognosis• Multi-discplinary approach

recommended

Am J Respi Crit Care Med 2008

Multiple entities were created

• Undifferentiated CTD (UCTD) – ILD • Lung Dominant CTDs• Early CTD• formes frustes of CTD• Occult CTD• Overlap CTD• Autoimmune featured CTD

Proposed criteria for UCTD

Concept of UCTD (Respiratory physician persepective)

• Kinder et al (Ohio)• UCTD diagnosis in 62% in previously

IIP• Majority of NSIP (71%) met the criteria• Demographic differences – Younger

women• No mention of overall prognosis

Am J resp Crit Care Med 2007

Alternative view points

Vij et al, Chest 2007

Autoimmune featured ILD were somewhere intermediate between IPF

and CTD-ILD

Lung Dominant CTD

Further studies

• Still very heterogeneous group• Conflicting results • Few cohorts reported no difference in

long term survival with identification of LD-CTD

• However – further sub-group analysis showed that High titre ANA, inflammatory pattern and demographics were still associated with favorable outcome

What does this mean for Rheumatologist?

• CTD – ILD : ILD in setting of well established Autoimmune disease

• UCTD – ILD : ILD in setting of other symptoms/signs with a rheumatological flavour

• ILD – Occult CTD : ILD with positive auto-antibodies and/or radiology and/or histopathology s/o autoimmunity

What does this mean for Rheumatologist?

• ILD with few autoimmune features – Do thorough examination and further tests

• Never completely rely on chest physicians• ILD may precede CTD esp. IIM (50%), Not common in SSc or

RA. Sjogren’s• Acute onset – IIM likely (anti MDA-5)• Rare auto-antibodies – Anti PL7 and PL12• Subtle extra-pulmonary manifestations

Clinical evaluation in LD-CTD

• Skin – Scleordactyly, digital ulcers, telengiectasia, Gottron’s, Heliotrope, Other dermatomyositis specific rashes, mechanics hands, periungual erythema, hyperkeratosis

• Muscles – myalgias, proximal muscle weakness

• Sicca symptoms• Raynaud’s phenomenon

HRCT Features

HRCT Thorax – Few important points to remember• Acceptable sensitivity for differentiating

between NSIP and UIP• CTD-ILD – predominant patterns are NSIP, OP

and LIP• Overlap patterns are more important• NSIP with OP – Inflammatory Myositis• UIP with nodules – RA• Extra-Pulmonary features

– Esophageal dilatation – SSc– Serositis – SLE– Emphysema/ILD – RA– Pulmonary trunk dilatation - PAH

ILD with auto-antibody positivity

• ANA and RF are only screening tests• Non-classical ANA patterns more

important– Nucelolar pattern – Cytoplasmic pattern– ANA negative

• RF is a very non-specific test• Order more extensive serology

Further Auto-antibody testing

• Rheumatoid serology – RF and Anti CCP• Myositis specific antibodies – Anti-synthetase

antibodies (Jo1, PL7, PL12), MDA-5• Scleroderma specific antibodies –

Centromere, Tho/Th, Scl-70, PM-Scl, U1 RNP• Sjogren’s syndrome : SSA/Ro 52/60

antibodies, SSB (La) antibody• Other ancillary tests – Total CK, Aldolase,

APR, complements

Impact on management and

prognosis

Histopathological pattern

• Lung biopsy not absolutely essential – CTD-ILD histological pattern less important prognostically than Idiopathic ILD

• However prognosis in UCTD-ILD group differs eg. UCTD–NSIP vs UCTD-UIP

• But NSIP or OP might tilt clinical decision towards intervention

• Rules out infection and other differential diagnosis

Few histopathological features consistent with CTD-ILD

• Rheumatoid granulomatous inflammation is diagnostic

• Secondary lymphoid structures – aggregates with germinal centres

• Pleural based inflammation• Prominent Plasmacytic infiltration• Dense peri-vascular collagen• Perivascular inflammation

Management

• No definitive guidelines available• Most are retrospective studies• Most important – IPF has worst

prognosis with immunosuppressive treatment

• Treat as per usual indications for the suspected CTD

Conclusion

• It is a new and evolving entity• Diagnostic criteria have been established• Important to distinguish in clinic as it has

important treatment and prognostic implications

• Newer auto-antibody testing is important – Are available in India now.

• Multi-disciplinary clinics are the future• Classical example of the need for accurately

phenotyping the disease