Annual Rheumatology & Therapeutics Review for Organizations & Societies

Annual Rheumatology & Therapeutics Review for Organizations & Societies

A Rheumatologist s Approach to Interstitial Lung Disease

Outline ILD classification and patterns in CTD The clinical landscape and evaluation Management of CTD-ILD

Why Focus on ILD? Occurs commonly across the entire spectrum of CTD A multidisciplinary approach has been demonstrated to be useful Potentially the most devastating of pulmonary manifestations A driver of significant morbidity / mortality in CTD Often poses the most significant challenges to the practicing clinician

CTD-ILD is Not a Single Disease CTD ILD RA SLE SjS PM/DM SSc MCTD UCTD CTD ILD UIP NSIP OP LIP AIP

Usual Interstitial Pneumonia (UIP) Idiopathic UIP = IPF Honeycombing, fibrosis Likely the most common pattern in RA 2nd most common pattern in SSc Can see with HP, sarcoid, drug toxicity Least responsive to immunomodulatory therapy Poor prognosis Am. J. Respir. Crit. Care Med. 2002;165:277-304

Non-Specific Interstitial Pneumonia (NSIP) Cellular vs. fibrotic vs. mixed Ground glass Minimal honeycombing Strong suspicions for CTD Also seen with HP, infections, drug toxicity Survival in idiopathic interstitial pneumonia: C-NSIP > F-NSIP > UIP Am. J. Respir. Crit. Care Med. 2002;165:277-304

Lymphocytic Interstitial Pneumonia (LIP) Cystic lung disease Seen with Sjögren's RA SLE Differential Dx: Primarily LAM (Lymphangioleiomyomatosis) Other rare diseases

Other Patterns Acute interstitial pneumonia / diffuse alveolar damage infections CTDs Respiratory bronchiolitis-ild Smoking related lung disease Not CTD-associated Desquamative interstitial pneumonia Smoker s mostly Rarely with CTD

Prevalence Rates? Published estimates vary: SSc: 25-90% PM/DM: 5-70% RA: 2-63% SjS: 8-57% SLE: 3-38% Subclinical ILD in ~ 50%? Frankel & Brown Clinical Pulmonary Medicine 2006 Doyle et al AJRCCM 2012

Outline ILD classification and patterns in CTD The clinical landscape and evaluation Management of CTD-ILD

The Clinical Landscape Established CTD Determine whether ILD is CTD-associated Idiopathic ILD: Identifying occult CTD Idiopathic ILD: Suggestive forms of CTD-ILD

55-year-old man with RA, former smoker, develops exertional dyspnea and cough 10-year history of RF / CCP positive, erosive RA arthritis well controlled adalimumab, methotrexate, NSAID resting pox = 91% crackles at B/L bases chronic RA deformities without synovitis FVC 74%, FEV-1 73%, DLCO 64% Normal CBC, CMP, ESR 15

RA patients can have birds too A thorough evaluation is needed Exclude INFECTION Exclude drug toxicity (MTX) Consider alternative etiologies Concluding ILD is CTDassociated is a process of elimination

Role of Bronchoscopy? Infiltrates in immunocompromised host = infection until proven otherwise BAL is often needed to assess for: infection alveolar hemorrhage Recent data argue against use of BAL to predict outcome in SSc-ILD BAL neutrophilia, eosinophilia is associated with more severe disease Kowal-Bielecka et al Semin Arthritis Rheum 2010

Role of Surgical Lung Biopsy? Clinical realities: The biopsy finding may not impact on treatment decisions CTD-ILD patients tend to be treated with immunosuppressive therapies for ILD and the extra-thoracic disease irrespective of ILD pattern

Percentage survival Histopathology Matters for Idiopathic Interstitial Pneumonia 100 DIP/RBILD/Cellular NSIP Cellularity 75 50 25 Fibrotic NSIP UIP 0.0 0 20 40 60 80 100 Fibrosis Time (months) Nicholson et al. Am J Respir Crit Care Med 2000;162:2213-2217

Percent Survival Histopathology in CTD-ILD Did NOT Impact Survival 100 80 60 40 20 UIP CVD-UIP I-NSIP CVD-NSIP SSc: 37 RA: 28 SjS: 11 PM/DM: 8 MCTD: 5 Other: 4 0 Park et al, AJRCCM 2007 0 24 48 72 96 120 144 168 192 Follow up period (months)

Prognostic Factors for the Survival of Patients with Interstitial Pneumonia Associated with Collagen Vascular Disease Using a Univariate Cox Model n Hazard Ratio 95% Cl p Value Age, yr 93 1.059 1.015-1.105 0.008 Male Sex 93 1.250 0.477-3.273 NS Smokers vs. nonsmokers 93 1.066 0.386-2.941 NS Dyspnea score 83 1.578 1.099-2.265 0.013 CVD-UIP vs. CVD-NSIP 93 1.288 0.524-3.164 NS RA vs. other CVDs 93 1.840 0.750-4.515 NS Scleroderma vs. other CVDs 93 0.457 0.166-1.262 NS FVC, %, predicted 93 0.964 0.935-0.993 0.017 Dl co, %, predicted 89 0.982 0.954-1.011 NS TLC, %, predicted 80 0.983 0.945-1.022 NS PA 02 /Fi 02 ratio, mm Hg 87 0.999 0.991-1.007 NS Park et al, AJRCCM 2007

Percentage survival In SSc-ILD, Physiology Drives Mortality 100 75 80 subjects with biopsied SSc-ILD: 78% NSIP, 15% UIP DLco + DLco -/+ 50 25 DLco - DLco -/+ Bouros et al. AJCCRM 2002 0 0 24 48 72 96 Time (months)

Survival (%) SSc-ILD: Disease Extent, Severity Impact Prognosis (ie, NOT pathologic pattern) HRCT extent 100 10% Indeterminate > 30% 75 Limited FVC 70% FVC < 70% Limited Disease Extensive Disease 50 25 0 0 Extensive HR=3.46; p<0.0005 20 40 60 80 100 120 Duration of follow-up (months) Goh et al. AJRCCM 2008; 177:1248 1254

Indications for Surgical Lung Biopsy? pre-existing CTD and concerns for an alternative etiology atypical HRCT idiopathic ILD and thinking it may be CTD poorly defined CTD ultimately, the decision is individualized

The Clinical Landscape Established CTD Determine whether ILD is CTD-associated Idiopathic ILD: Identifying occult CTD Idiopathic ILD: Suggestive forms of CTD-ILD

49 year old woman with acute onset of exertional dyspnea and cough No medications Never smoker No occupational or environmental exposures Rheumatologic ROS: Raynaud s phenomenon Exam: Puffy hands / wrists, bi-basilar crackles

CBC normal ESR 27 CPK 189 Negative: ANA SS-B, Smith, RNP, dsdna RF, CCP ANCA panel SS-A moderately positive TLC 62% FVC 45% DLco 25% Walk-Ox: 6 L O 2 VATS: NSIP Overlapping OP Increased perivascular collagen

environmental occupational medications infection??? familial??? smoking?? CTD-ILD idiopathic

Percent Survival Why Assess for CTD? A diagnosis of CTD-ILD may impact: 100 Treatment Prognosis 80 60 40 Extra-thoracic disease clinical context surveillance for other features 20 0 0 p<0.001 IIP CVD-IP 24 48 72 96 120 144 168 192 Follow up period (months) Park et al. AJRCCM 2007;175:705-711

Other common and potentially important reasons to assess for CTD Patient perspective: Physician perspective: emotional sense of belonging frustrations with being labeled as idiopathic 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 as the Presenting Manifestation of CTD multi-disciplinary collaboration helps ILD may be the first - or ONLY - manifestation of underlying CTD extrathoracic manifestations of underlying CTD may be subtle

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

What s Helpful? demographics 40 year old women don t get IPF extrathoracic manifestations serologies HRCT findings which ones? histopathology

Quantifiable, Specific Extra-thoracic Features Suggesting CTD sclerodactyly Raynaud s phenomenon capillary microscopy keratoconjuctivitis sicca Mechanic hands Digital edema Gottron s papules inflammatory arthritis of bilateral wrists or MCPs esophageal dilation / hypomotility tortuosity dilatation dropout

Useful Autoantibodies for CTD-ILD Most common CTD association High-titer ANA (>1:320) RF (>60 IU/mL) Anti-centromere Nucleolar-ANA Anti-CCP Anti-Scl-70 Anti-Ro Anti-La Anti-dsDNA Anti-RNP Anti-Smith Anti-tRNA synthetase (Jo-1, PL-7, PL-12, others) Anti-PM-Scl Many Many / RA SSc SSc RA SSc Many Sjögren's s, SLE SLE MCTD, SLE / SSc SLE PM / DM SSc / PM overlap

HRCT Clues for CTD-ILD multi-compartment involvement dilated esophagus pericardial thickening or effusion bilateral, bibasilar, and peripheral-predominant NSIP Hwang 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 Multi-compartment involvement parenchyma, airways, vascular, pleura NSIP, UIP, OP, LIP, AIP/DAD Leslie et al Semin Respir Crit Care Med 2007;28(4):369

This is What CTD-ILD Looks Like

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.

The Clinical Landscape Established CTD Determine whether ILD is CTD-associated Idiopathic ILD: Identifying occult CTD Idiopathic ILD: Suggestive forms of CTD-ILD

CTD-ILD? 40 year-old woman with nothing extrathoracic ANA positive 1:320 speckled biopsy-proven NSIP overlapping features: organizing pneumonia lymphoid follicles with germinal centers

55 year old man with UIP: RF and CCP Both High-positive; No Arthritis RA-ILD? IPF?

Limitations of Rheumatologic Classification Criteria Without extra-thoracic manifestations, rheumatologists are reluctant to label CTD even ILD with highly-specific autoantibodies ILD is not included in the classification criteria for any of the CTDs, except as a minor criterion for SSc

Interstitial Pneumonia with Autoimmune Features (IPAF)

Outline ILD classification and patterns in CTD The clinical landscape and evaluation Management of CTD-ILD

Management Aspects: CTD-ILD is not a Single Disease CTD ILD RA SLE SjS PM/DM SSc MCTD UCTD CTD ILD UIP NSIP OP LIP AIP

Consider Underlying Histologic Pattern? RA-OP Are these all treated the same? RA-LIP RA-C-NSIP RA-F-NSIP RA-UIP

Whom to Treat? Depends on: impairment (subjective and objective) pace of disease other factors (age, co-morbid conditions) Treat: clinically-significant, progressive disease

Determining impairment Subjective How to assess dyspnea? Standardized questionnaires? Objective PFTs Walk-oximetry 6MWT Disease extent by HRCT

RA-ILD: What s Driving Therapy? disease activity disease activity time disease activity disease activity time RA = ORANGE ILD = BLUE time time

Survival, % Cyclophosphamide in SSc-ILD Appears to Impact Physiology and Survival No CYC: FVC -7%, DLCO -9% CYC: FVC +4.3%, DLC0 +1.0% 100 80 34 23 20 13 10 CYC: better survival experience 60 40 14 7 3 20 0 0 6 12 18 24 30 36 42 48 54 60 Time, mo White et al Ann Int Med 2000;132:947-954

Change from Baseline in FVC Scleroderma Lung Study +15 +10 Cyclophosphamide 49.3% 49% had improvement improved Placebo 26.4% 26% had improvement improved +5-0 -5-10 -15 0 0 50.7% had worsening 73.6% had worsening 51% worsened 74% worsened Frequency (%) 25 20 15 10 5 5 10 15 20 25 Tashkin et al 2006 NEJM 354;2655-66

Fibrosing alveolitis in SSc Trial low-dose prednisone, IV CYC x 6 months followed by AZA vs. placebo BASELINE 1-YR FOLLOW-UP Rx (n=22) Placebo (n=23) Rx (n=19) Placebo (n=18) FVC 80 81 83 78 0.08 DLCO 53 55 50 52 0.64 TLC 82 77 80 74 0.61 P Hoyles et al. Arthritis Rheum 2006

MMF Improves Lung Function in CTD-ILD median daily prednisone dose: at MMF initiation = 20 mg Pred dose through time among subjects with SSc, PM/DM, RA or LD-CTD after 9-12 months on MMF = 5 mg (p<0.0001) Predicted Mean 30 28 Mean prednisone dose (mg) 26 24 22 20 18 16 14 12 10 8 6 4 2 0-250 -200-150 -100-50 0 50 100 150 200 250 weeks weeks before and after MMF initiation CTDdx1 1 2 3 4 Red line=ra, Black line=ssc, Blue line=pm/dm, Green line=lung dominant-ctd Fischer et al. J Rheumatol 2013

FVC% Change in FVC over time -156 to 0 weeks -104 to 0 weeks -52 to 0 weeks 0 to 52 weeks 0 to 104 weeks 0 to 156 weeks FVC% -2.3 ± 5.0 p=0.6-1.5 ± 3.3 p=0.6-0.8 ± 1.7 p=0.6 Figure 2A. Plot of mixed-effects model estimates for FVC% over time 4.9 ± 1.9 p=0.01 6.1 ± 1.8 p=0.0008 7.3 ± 2.6 0.004 weeks before and after MMF initiation Fischer et al. J Rheumatol 2013 MMF start Weeks before and after MMF initiation

MMF in CTD-ILD In a diverse and large cohort of CTD-ILD, we observed that MMF was well tolerated had a low rate of discontinuation was associated with effective corticosteroid tapering was associated with stabilization or improvement in FVC and/or DLco MMF warrants prospective study MMF may replace CYC as 1 st line therapy for CTD-ILD Fischer et al. J Rheumatol 2013

Other Options? Azathioprine well tolerated familiar FAST trial in SSc case series suggest role for variety of CTD-ILD Cyclosporine, Tacrolimus may be particularly effective in patients with myositis ILD Rituximab Refractory myositis-ild

Gauging Response Subjective symptoms tolerance FVC DLCO 6MWT HRCT best of 5 wins

Non-drug Therapy pulmonary rehab use O2 correctly PH assessments GERD N-acetylcysteine (NAC)? Pneumocystis prophylaxis vaccines mental health

Summary All of the IIP patterns are seen in CTD (except RB-ILD, DIP) NSIP is the most common pattern in CTD UIP is the most common pattern in RA ILD in pre-existing CTD Exclude alternative etiologies Biopsy the atypical HRCT / atypical scenario CTD-ILD = diagnosis of exclusion Predictors of mortality in SSc-ILD: physiology and extent of ILD ILD as the first manifestation of CTD Multidisciplinary evaluations are useful Consider demographics, serologies, clinical features, radiology, pathology Controversies surrounding suggestive forms of CTD-ILD

Summary Not every patient with CTD-ILD needs treatment Consider what s driving need for treatment Extra-thoracic vs. intra-thoracic disease activity Determine degree of impairment, pace of the disease Treat only those with clinically-significant, progressive ILD Management is not evidence-based Consider underlying CTD and ILD pattern MMF use is popular in Colorado warrants prospective study Desperate need for better therapies