Autoimmune Lung Disease

RICHARD MEEHAN, M.D.Professor of Medicine

Rheumatology National Jewish Health

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Disclosures

Other: Expert witness for RA-related bronchiolitis case

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Pulmonary Manifestations of Connective Tissue Disease

Spectrum of Clinical presentations of patients with suspected pulmonary manifestations of CTD

Diagnostic evaluation of patients with suspected CTD

Radiographic and histological variationsof Autoimmune lung disease

Treatment goals, therapeutic options, and monitoring of disease progression

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Common CTD with pulmonary manifestations

Systemic Sclerosis: Diffuse or limited “Scleroderma” (dcSSc, lcSSC) or Systemic sclerosis sine scleroderma

ANCA + vasculitis: Granulomatosis with polyangiitis(GPA, formerly Wegener’s granulomatosis)

Rheumatoid Arthritis: + Anti CCP Abs may precede synovitis by > 10 years and lung involvement may be first manifestation of RA

Inflammatory myopathies: Polymyositis, Dermatomyositis and antisynthetase syndrome.

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CTD with pulmonary manifestations

Eosinophilic Granulomatosis with Polyangitits(EGPA) ,formerly Churg-Strauss Syndrome

Sjogren’s Syndrome (SS) Primary or secondary Systemic Lupus Erythematosis (SLE) and or

primary antiphospholipid Antibody syndrome Undifferentiated (UCTD) or overlap syndromes Rare: Vasculitis, Relapsing Polychondritis

(RPC), Inflammatory Bowel associated airway disease, Ankylosing Spondylitis (AS)

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Thoracic manifestations of CTD

Airways:

Large (RP, limited ANCA+ vasculitis)

small- cellular and constrictive bronchiolitis (RA, SLE, SS, SSC), peri-bronchial inflammation (SS) R/O sarcoid, HP or Inflammatory bowel disease

Vascular - PAH (SSC),Vasculitis (SLE, UCTD), Anticardiolipin Antibodies (Primary APL AB syndrome or SLE), Pulmonary Hemorrhage (SLE, ACL Ab syndrome)

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Thoracic Manifestations of Connective Tissue Diseases

Serositis: pleural and pericardial (SLE, RA) Diffuse Lung disease/ILD: Non Specific Interstitial Pneumonitis (NSIP) seen with

most systemic CTDs), Usual Interstitial Pneumonitis (UIP) seen with SSc, RA, lymphocytic Interstitial Pneumonitis (LIP) seen in SS and SLE

Ground glass opacification Crytogenic Organizing Pheumonia (COP), Diffuse Alveolar Damage (DAD) due : SLE, RA, Vasculitis, PM/DM, r/o aspiration

Consolidation PM/DM, r/o infection Nodules/Cysts large nodules (RA), thin wall cysts (SS), large

cysts & nodules – (ANCA + Vasculitis), r/o infectious abscess especially non tuberculous mycobacterial disease

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Common Symptoms of CTD Related Lung Disease

Pulmonary symptoms of CTD- ILD are usually progressive exertional breathlessness and non-productive cough.

Pleurisy is common in CTD and commonly seen on VATS bx as pleural inflammation.

Other symptoms : Unintentional weight loss, fevers, and glucocorticoid responsiveness of joint pain, weakness, myalgias and fatigue.

Pulmonary manifestation may precede the onset of CTD and immunosuppressive therapy can mask CTD manifestations. (Ref)

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SSC: Recent onset Raynauds in pts > 40, sclerodactyly, digital ulcers, dysphagia or refractory GERD

PM/DM: Painless proximal muscle weakness, Rash, “mechanics hands.”

SS: Progressive oral or ocular sicca symptoms unrelated to medications, accelerated dental caries, parotid or lymph node enlargements, refractory sinusitis, dysphagia relieved with increased fluid ingestion, bronchiectasis and or nontuberculous mycobacterium disease.

RA: symmetrical small joint swelling and synovitis on examination

EGPA: Adult onset progressively severe and refractory Asthma , mononeuritis multiplex and/or small vessel vasculitis on cutaneous biopsy.

Common CTD Specific Manifestations

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Physical Examination HEENT: Nasal Septal perforation (SLE,

Wegner’s), parotid or submandibular enlargement and adenopathy (SS), scleritis, (SLE, RA, AS, IBD, RPC) decreased tear production Schirmer’s (SS)

CR: Elevated JVP/ fixed slit P2 (PAH), Rubs (SLE), dry crackles bases (ILD), expiratory wheezes (EGPA, Bronchiolitis), neck stridor (RP, WG).

GI: splenomegaly (SLE, SS).

MSK: synovitis, contractures, tapered digits, ulcers, nodules, deformities, proximal muscle weakness.

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Skin: SSC: telangiectasias, sclerodactaly, calcinosis,

digital ulcers and abnormal NCM SLE: malar rash, alopecia, levido, nasal septal

perforation, oral ulcers, retinal changes, hand rash,

Nodules: SLE, SarcoidPM/DM: Heliotrope rash and Gottron’s

papules, “mechanics hands”.EGPA: E nodosum, palpable purpura, foot

or wrist drop

Physical Examination

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Laboratory Evaluation Is there evidence of systemic inflammation?↑CRP, ↑ ESR, ↓ albumin, SPEP (polyclonal gammapathy), anemia (normochromicnormocytic) , ↑ Plt count, and ↓ WBC, ↑CPK and/or aldolase (myositis)

Hep B S Ag, C Ab and HIV screen in all patients.UA: proteinuria/hematuria (nephritis)Antiphospholipid Abs, anti-Beta 2 Glycoprotein

1 Abs, lupus anticoagulants (RVVT or prolonged PT which fails to correct), false positive RPR increases risk for PE/DVT

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Serologic Studies

Most serologic studies are neither adequate, nor sufficient to diagnose or exclude CTDs due to poor specificity and sensitivity.

ANA and ANA Profile: Ds-DNA, and Sm are very specific for SLE, SSA and SSB can be positive in ANA negative SS pts,

Anti-nucleolar pattern common in dcSScAnti-centromere staining pattern is seen often

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Serologic Studies continued

Scl 70 (anti-DNA topoisomerase I)- correlates with diffuse scleroderma related ILD and is rarely a false positive

Jo-1 (aminoacyl-tRNA synthestase) seen in Polymyositis and dermatomyositis associated ILD. There are many other anti-synthetase Abs, full myositis Ab panel may need to be ordered

Anti neutrophic cytoplasmic antibodies c-ANCA, and anti PR3 Abs (proteinase 3, in granulomatosis with

polyangitis) p-ANCA and anti MPO Abs, (myeloperoxidase) seen in EGPA,

microscopic polyangitis and inflammatory bowel diseaseProp

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Physiology Studies

Complete PFTS, 6 MWT needed as baseline prior to therapy and q 3-6 months.

If low DLCO is out of proportion to ILD disease severity on HRCT suspect PAH, PEs or cardiac shunt

Very high RV with progressive decline in air flow rates with a negative bronchodilator response or negative methacholine challenge is suspious for constrictive bronchioloitis.

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Thoracic Imaging Findings HRCT Chest: Valuable at documenting pathologic

processes, severity and irreversibility and may guide decisions as to whether additional invasive diagnostic studies are indicated.

UIP-Honeycombing, mild GGO, bilateral, basal predominance, traction bronchiectasis, ( RA, SSC)

NSIP- rare honeycombing, predominant GGO (may be confluent), basal predominance, traction bronchiectasis (SSC, PM/DM, RA)

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Imaging Studies

OP (Organizing Pneumonia)- multifocal consolidation, GGO, subpleural or peribronchovascular (PM/DM,RA)

LIP (Lymphocytic Interstitial Pneumonitis)-multiple thin walled cysts,peribronchovascular, GGO (SS, RA)

Bronchiolitis- bronchiectasis, mosaic air trapping on expiration (RA, SS, IBD)

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Invasive Procedures VATS BX: Most Definitive IPF (idiopathic pulmonary

fibrosis) versus HP (hypersensitivity pneumonitis) versus UIP (fibroblastic foci) versus NSIP (homogeneous inflammation and fibrosis). Connective Tissue Disease more likely to contain lymphoid hyperplasia, pleuritis and perivascular collagen deposition.

Bronchoscopy: BX may identify granulomas (sarcoidosis or Hypersensitivity pneumonitis) or Cancer. Cultures needed to exclude atypical mycobacterium disease, differential cell counts.

Sublabial BX: Positive Focus score of lymphocyte aggregates and fibrosis typical of an autoimmune exocrineopathy. 34% of 38 pts suspected of SS related ILD had a positive + thus reducing need for VATS Bx (Fischer et al CHEST 2009)

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Other Studies Cardiac Echo: evaluate for PAH (Pulmonary Artery

Hypertension) suspected if an asymptomatic pericardial-effusion identified in Scleroderma patients cardiomyopathy (Fischer et al Chest 131:988, 2007)

Full Exercise study: if confusing physiology and co-exisitingcardiac dysfunction

Hand xray: erosions, cartilage loss and periarticularosteopenia (RA) but Ultrasound and especially MRI are more sensitive for documenting synovitis than physical exam, distal tuft resorption and calcinosis are seen in SSC

Selected: R heart cath, CT angio, Tailored barium swallow evaluate for aspiration risk, DEXA all patients at risk for low bone mass. Nailfold capillary microscopy (SSC)

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Germinal center

Lymphoid Hyperplasia

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Minor Salivary Gland Biopsy From Normal And Patient With SS

Normal Abnormal

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Primary SS

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LIP

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NSIP, Cyst, Bronchiectasis

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RA Pleural effusion

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Post tx of COP with AZA 3 years

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56 yo male Fibrotic NSIP (VATS) preclinical RA

2013 pre treatment 2014 post treatment

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BO in RA Expiration images hrCT

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Constrictive bronchiolitisProp

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Environmental Induced BO/HP in Iraq

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59 yo SLE patient fibrotic NSIP

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Systemic Sclerosis

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65 yo SSC PAH and ILD

2014 2004

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Polymyositis ILD

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Therapeutic Approach and Management

Immune suppressive drugs. Must balance the risk of irreversible loss of lung function vs increased risk of drug toxicity in particular patient.

Determine rate of deterioration based upon prior PFTs, SaO2 and or hrCT imaging especially fibrosis

Determine responsiveness of prior immunosuppressive regiments as this also affects prognosis.

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Therapeutic Approach and Management

General guidelines: Achieve and document maximum improvement in physiology before tapering immunosuppressive agents (12 months). Then try to maintain the clinical response with less toxic or lower doses of immune suppressive agents.

Be vigilant of extra-pulmonary manifestations of disease or drugs; GERD (risk of aspiration), steroid myopathy, digit necrosis, disabling arthritis or osteoporosis.

Clinical respiratory deterioration could be the result of drug toxicity, infection or AIP (disease flare during taper of drugs)

Future multicenter SSC treatment trials for ILD are ongoing at NJH, Aryeh Fisher as PI now enrolling for SLS II trial (Cytoxan vs MMF) and SCOT trial (hi dose immunosuppressive with Autologous stem Cell transplantation) shouldallow us to better define optimum therapy in selected patient populations.

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Treatment OptionsPrednisone: 40-60mg daily or pulse solumedrol 1 gm daily

times 3 may be used initially to achieve a more rapid response until prednisone sparing agent is efficacious which may take 4-6 weeks.

Azathioprine (AZA): Azathioprine may be used for serositis, or mild disease which is slowly progressive or in patients unlikely to tolerate CYC or MMF (due to expenses).

Cyclophosphamide (Cytoxan, CYC): Probable most effective against CTD-ILD, daily oral route carries greater toxicity than monthly iv (500-1,000mg/M2).

Mycophenolate Mofetil (MMF): less toxic than cytoxanand usually better tolerated than AZA and appears superior to AZA in treating SSC, PM and UCTD related CTD, expensive (Swigris, et al. Chest 2006).

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Other Treatment Options

Cyclosporine: May be effective in patients with intolerance to above agents due to cytopenias or infections.

Tacrolimus: Similar to cyclosporine but more expensive yet better tolerated (author’s experience)

Combinations: Infliximab 5mg/kg and MMF or AZA may be helpful in RA associated Bronchiolitis whereas sever BO may need CYC (author’s experience).

Rituximab: May be of benefit in LIP (RA, SS or SLE) or ANCA + lung disease.

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Bibliography

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2. Sakamoto O, Saita N, Ando M, Kohrogi H, Suga M, Ando M. Two cases of Sjogren's syndrome with multiple bullae. Intern Med 2002;41(2):124-8.

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5. Medications with pulmonary toxicity www.pneumotox.com6. Fathi M, Lundberg IE. Interstitial lung disease in polymyositis and dermatomyositis. Curr

Opin Rheumatol 2005;17(6):701-6.7. Lee HK, Kim DS, Yoo B, et al. Histopathological pattern and clinical features of

rheumatoid arthritis-associated interstitial lung disease. Chest 2005;127(6):2019-27.8. Kocheril SV, Appleton BE, Somers EC, et al. Comparison of disease progression and

mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia. Arthritis Rheum 2005;53(4):549-57.

9. King, TE, Kim EJ, Kinder BW. Chapter 26 Connective Tissue Diseases in Interstitial Lung Disease, 5th Edition, Schwarz ML and King TE (eds), 2011. Peoples Medical Publishing House Shelton, CT-USA.

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Bibliography10. Swigris, JJ, Olson, AL, Fischer, et al. Mycophenolate mofetil is safe, well-tolerated,

and preserves lung function in patients with connective tissue diseases-related interstitial lung disease. Chest 2006;130:30-36.

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14. Swigris JJ, Fischer A, Gillis, Meehan RT, and Brown K. Pulmonary and thrombotic Manifestations of Systemic Lupus Erythematosus. Chest 2008; 133: 271-280.

15. Frankel SK, Brown KK. Collagen Vascular Diseases of the Lung. Clinical Pulmonary Medicine 2006; 13:25-35.

16. Bongartz T, Nannini C, Medina-Velasquez YF et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis a population-based study. Arthritis & Rheumatism 2010; 62: 1583-1591.

17. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging 2009; 24: 299-309.

18. Swigris JJ, Brown KK, Flaherty KR. The idiopathic interstitial pneumonias and connective tissue disease-associated interstitial lung disease. Current Rheumatology Reviews 2010; 6: 91-98

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Bibliography: Lung involvement in preclinical RA

19. Reynisdottir G, Karimi R, Joshua V, Olsen H et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheum 2014:66: 31-39.

20. Willis VC, Demoruelle MK, Derber LA, Chartier-Logan CJ et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum 2013; 65L 2545-2555.

21. Demoruelle MK, Weisman MH, Simonian PL, Lunch DA et al. Airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating sire of autoimmunity? Arthritis Rheum. 2012; 64: 1756-1761.

22. Majka DS, Deane KD, Parrish LA, Lazar AA et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Ann Rheum Dis 2008; 67: 801-807.

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Pulmonary Manifestations Associated with Various Connective Tissue Diseases

Diseases Serositis Fibrotic ILD COP PAH Hemorrhage Airway

RA ++ ++ ++ + Rare +

Systemic Sclerosis + +++ + +++ Rare +

Polymyositis/Dermatomyositis

+ +++ ++ + Rare +

Systemic lupus erthematosus

+++ + ++ ++ ++ Rare

Sjogren’s syndrome + ++ + Rare Rare ++

Ankylosing spondylitis Rare + Rare Rare Rare +

Relapsing polychondritis Rare Rare Rare Rare Rare +++

Wegener’s granulomatosis Rare ++ ++ Rare ++ +

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