Disclosures. Scleroderma: Early Diagnosis How early is early? 10/28/2013. Difficult Scleroderma: How do I Approach this Patient?

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1 Disclosures Financial support: None Difficult Scleroderma: How do I Approach this Patient? Francesco Boin, MD Assistant Professor of Medicine Director, Translational Research Johns Hopkins Scleroderma Center Investigational medications and/or off label uses discussed in this presentation include: mofetil mycophenolate, cyclophosphamide, prostacyclin, endothelin receptor inhibitors Scleroderma: Early Diagnosis How early is early? Case Study #1 31 years old Caucasian woman presenting with: 2 year history of Raynaud s phenomenon. No digital ulceration Arthralgias and occasional cough over the past 6 months Positive anti-nuclear antibodies (ANA 1: 320) with centromere pattern, anti-rnp, RF and anti-ccp antibodies Pulmonary function tests and chest x-ray are normal Physical examination No skin fibrosis, no joint swelling or effusion Nailfold capillary visualization shows several dilated capillary loops Does this patient have scleroderma? Yes No Maybe Scleroderma: Classification and Clinical Subsets? Type I Type II Type II Early SSc Pre-SSc LIMITED DIFFUSE SSc sine-ssc or Undifferentiated Connective Tissue Disease (UCTD).. Establishing diagnosis of scleroderma 1980 ACR Criteria Must have (a) or two of (b), (c), or (d) CREST Criteria Must have 3 of the 5 features Early SSc Criteria Must have all 3 a. Proximal SSc (proximal to MCPs/MTPs) b. Digital Pits c. Sclerodactyly d. Pulmonary Fibrosis (CXR; HRCT) Calcinosis Raynaud s Phenomenon Esophageal dysmotility Sclerodactyly Telangiectasias a. Definite Raynaud s Phenomenon b. Abnormal Capillary Loops c. Specific Scleroderma Autoantibody Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980 LeRoy EC, Medsger TA Jr. J Rheumatol

2 2013 Classification Criteria for Systemic Sclerosis Skin thickening proximal to MCP joints (sufficient criterion) Skin thickening of the fingers (only count the higher score) Fingertip lesions (only count the higher score) 9 Puffy fingers Sclerodactyly Digital tip ulcers Fingertip pitting scars Telangiectasia 2 Abnormal nailfold capillaries 2 Pulmonary arterial hypertension and/or Interstitial lung disease Raynaud's phenomenon 3 SSc-related autoantibodies (maximum score is 3) Anti centromere Anti topoisomerase I Anti RNA polymerase III 3 Patients with score 9 are classified as having definite Systemic Sclerosis EARLY SSc LeRoy Medsger CLINICAL CASE #1 8 8 Case Study #1 31 years old Caucasian woman presenting with: 2 year history of Raynaud s phenomenon. No digital ulceration Arthralgias and occasional cough over the past 6 months Positive anti-nuclear antibodies (ANA 1: 320) with centromere pattern, anti-rnp, RF and anti-ccp antibodies Pulmonary function tests and chest x-ray are normal Physical examination No skin fibrosis, no joint swelling or effusion Nailfold capillary visualization shows several dilated capillary loops Does this patient have scleroderma? Yes No Maybe Case Study #1 Early-SSc or Pre-SSc What is the best predictor of progression towards definite Scleroderma? Anti-centromere antibodies Nailfold capillary abnormalities New onset of cough History of Raynaud s phenomenon Prevalence of Raynaud s Phenomenon USA 3-5% Spain 3-5% Japan 3% Netherlands 2.9% Italy 2.1% Women > Men Young > Old 15% in young teenager women after menarche When a Connective Tissue Disorder should be suspected? Late age of onset Male gender Asymmetry Severe Raynaud s with ulcerations Positive autoantibodies Nailfold capillary abnormalities 10-15% of patients with Raynaud s may develop a Connective Tissue Disorder Raynaud s Phenomenon Progression to CTD or SSC Follow-up median, years Progression Nailfold capillaries HR=14.4 Nailfold capillaries OR=14.6 Nailfold capillaries OR=21.8 2

3 Case Study #1 Early-SSc or Pre-SSc What is the best predictor of progression towards definite Scleroderma? Digital Capillary Microscopy in Scleroderma Capillary dilatation Anti-centromere antibodies Nailfold capillary abnormalities New onset of cough Capillary loss Hemorrhages Neoangiogenesis History of Raynaud s phenomenon Nailfold Capillary Microscopy Bedside procedure: A drop of immersion oil is placed at the fingernail base; nail fold capillaries are magnified and examined using an ophthalmoscope set at 10 to 40 diopters. Abnormal Nailfold Capillaries UCTD Window of Opportunity Very Early SSc Early SSc Raynaud s Phenomenon Established SSc ANA (95%) Scleroderma-specific autoantibodies (ACA, SCL70, RNAP3) Abnormal Nailfold Capillaries Puffy fingers Scleroderma: Lung Disease Doc, I am getting short of breath! Sclerodactyly SSc Organ involvement Monitoring/Therapy Monitoring/Therapy Adapted from Mattucci-Cerinic et al. Ann Rheum Dis

4 Clinical Case 45 years old Caucasian female presenting on October 2009 with: Raynaud s phenomenon for the past 2 years with digital ulcers Acid reflux (GERD) Fatigue, weight loss Progressive breathlessness Positive ANA 1:320 in speckled pattern Physical Exam Sclerodactyly Bibasilar fine crackles at chest auscultation Pulmonary Function Tests Year FVC DLCO % 71% SSc-dyspnea What would you do next to establish the etiology of this SSc patient s breathlessness? Echocardiogram Repeat PFTs High Resolution Computed Tomography (HRCT) Laboratory testing Right Heart Catheterization Breathlessness (Dyspnea) in Scleroderma Interstitial lung disease Pulmonary Vascular disease Cardiac disease Anemia (GAVE) Myopathy Deconditioning Initial work-up Pulmonary Function Tests HRCT scan ECHO & EKG Basic Labs Special lab tests Pro-BNP CPK Troponin I SSc-dyspnea What would you do next to establish the origin of this SSc patient s breathlessness? Echocardiogram Repeat PFTs High Resolution Computed Tomography (HRCT) Laboratory testing Right Heart Catheterization SSc-ILD SSc-ILD: Facts to Remember ILD occurs in both limited and diffuse skin disease: 70-80% diffuse patients; 15-25% limited patients (SLS data) Not all ILD is bad: had mild or no ILD; 27% had moderate and 13% had severe disease (Steen Arthritis Rheum 1994) 4

5 PERCENT CUMULATIVE SURVIVAL FVC 10/28/2013 Not all ILD is bad YEARS FROM DISEASE ONSET Lowest FVC at any time during course of SSc MINIMAL PULMONARY FIBROSIS N=467 FVC > 75% MODERATE PULMONARY FIBROSIS N=213 FVC 75% and 50% SEVERE PULMONARY FIBROSIS N=116 FVC <50% SSc-ILD: Facts to Remember ILD occurs in both limited and diffuse skin disease: 70-80% diffuse patients; 15-25% limited patients (SLS data) Not all ILD is bad: had mild or no ILD; 27% had moderate and 13% had severe disease (Steen V Arthritis Rheum 1994) While ILD is an early manifestation, late onset and progression occurs Steen VM. Arthritis Rheum 1994 SSc-ILD Loss of Function Course of Lung Disease in SSc Greatest FVC loss within 2-4 years from diagnosis 100% 50% Greater 10% (FVC L) change in 4-6 mo interval is consistent with progressive ILD secondary to scleroderma Steen VM. J Clin Rheumatol 2005;11:40-6 Time (years) SSc-ILD Which of the following DOES NOT predict lung disease progression and outcome? Anti-SCL70 positivity Low baseline FVC Fibrosis on chest High Resolution CT Mean PAP >25 mmhg (RHC) Abnormal Bronchoalveolar lavage (BAL) SSc-ILD: Facts to Remember Non-white ethnicity and anti-topoisomerase (Scl70) and anti-u3-rnp positive patients have worse lung disease (Gelber Ann Rheum Dis 2013) Baseline FVC may predict lung function decline and survival (Plastiras A&R 2006; Goh Am J Respir Crit Care Med 2008) 5

6 Probability of NOT decreasing FVC % of predicted 10/28/2013 Baseline FVC predicts pulmonary function decline and survival FVC 80% FVC 80% Time from diagnosis (years) Plastiras A&R 2006 SSc-ILD: Facts to Remember Non-white and anti-topoisomerase (Scl70) and anti-u3-rnp positive patients have worse disease (Gelber Ann Rheum Dis 2013) Baseline FVC may predict lung function decline and survival (Plastiras A&R 2006; Goh Am J Respir Crit Care Med 2008) Fibrosis on HRCT predicts worse outcome (SLS study; Goh Am J Respir Crit Care Med 2008) Goh Am J Respir Crit Care Med 2008 SSc-ILD: Facts to Remember Non-white and anti-topoisomerase (Scl70) and anti-u3-rnp positive patients have worse disease (Gelber Ann Rheum Dis 2013) Baseline FVC may predict lung function decline and survival (Plastiras A&R 2006; Goh Am J Respir Crit Care Med 2008) Fibrosis on HRCT predicts worse outcome (SLS study; Goh Am J Respir Crit Care Med 2008) BAL analysis may help define disease but does not predict long-term outcome (Mitto et al A&R 2007) BAL alveolitis does not predict long-term outcome in SLS-ILD Scleroderma Lung Study (SLS) Placebo Arm 141 pts 101 BAL positive 40 BAL negative Positive BAL alveolitis >3.0% neutrophils and/or >2.0% eosinophils) Strange C. Am J Respir Crit Care Med 2008 SSc-dyspnea SSc-Interstitial Lung Disease Which of the following DOES NOT predict lung disease progression and outcome? Anti-SCL70 positivity Low baseline FVC Fibrosis on chest High Resolution CT Mean PAP >25 mmhg (RHC) Abnormal Bronchoalveolar lavage (BAL) 80% 75% 70% 65% 55% 50% 45% 40% 68% 62% MMF 1000bid MMF 500bid DLCO FVC How would you treat this patient? 6

7 % of predicted % of predicted 10/28/2013 Scleroderma - Interstitial Lung Disease Treatment Options Immunosuppression alone (non-selective or targeted) Cyclophosphamide (daily vs. IV monthly) Mycophenolate Mofetil Scleroderma Lung Study (SLS) II Autologous Hematopoietic stem cell transplantation (safety?) Rituximab (efficacy?) Anti-fibrotic therapy Anti-cytokines: IL-13, CTGF Tyrosine Kinase inhibitors: Imatinib, Dasatinib Endothelin Receptor Antagonist: Bosentan Anti-Thrombin Pirfenidone Scleroderma Lung Study (SLS) CYC vs. placebo FVC % pp Trial stop Combination therapy? Tashkin et al Am J Resp Ctir care Med 2007 Scleroderma - Interstitial Lung Disease Treatment Options Immunosuppression alone (non-selective or targeted) Cyclophosphamide (daily vs. IV monthly) Mycophenolate Mofetil Scleroderma Lung Study (SLS) II Autologous Hematopoietic stem cell transplantation (safety?) Rituximab (efficacy?) Anti-fibrotic therapy Anti-cytokines: IL-13, CTGF Tyrosine Kinase inhibitors: Imatinib, Dasatinib Endothelin Receptor Antagonist: Bosentan Anti-Thrombin Pirfenidone Combination therapy? 80% 75% 70% 65% 55% 50% 45% 40% 68% MMF 1500bid SSc-Interstitial Lung Disease 62% MMF 1000bid MMF 500bid DLCO FVC How would you treat this patient? MMF=mycophenolate mofetil Case Study #3 45 yo WF with limited SSc Progressive dyspnea Scleroderma Lung Disease Early Detection 100% 90% 87% 100% 80% 70% 71% 58% 58% 64% 64% 62% 62% Functional Status 50% 46% DLCO 40% FVC Aggressive Therapy 30% 20% 10% 0% MMF CYC CYC AZA Jan-13 Jul-13 50% 100% FVC% 7

8 Scleroderma Renal Crisis How to ACE the diagnosis and management Case Study #4 58 years old Caucasian male March 2012 July 2012 August 2012 October 2012 New onset RP Scleroderma Renal Crisis Rapidly progressive skin fibrosis (UE/LE) Joint swelling and tendon friction rubs Diagnosis of diffuse Systemic Sclerosis Anti-RNA polymerase III positive Started on Prednisone 40 mg orally daily MTX 20 mg orally weekly Hypertensive urgency (210/120 mmhg) Headaches Dyspnea and chest pain Creatinine 3.4 mg/dl Anemia (Hemoglobin 9.8 g/l) Thrombocytopenia (55,000/mm 3 ) Case Study #4 Which features increase the risk for SRC in this patient? Gender Short disease course High creatinine Recent corticosteroid therapy Anti-RNA polymerase III positivity Thrombocytopenia Cardiac involvement : Facts to Remember Develops in 5-10% of SSc patients Can precede SSc diagnosis (20%) Risk factors Early diffuse skin disease (2-4 yrs from SSc onset, median 8 months) Use of corticosteroids (higher doses or low doses for prolonged time) Use of cyclosporine Anti-RNA polymerase III () Outcome Responsive to ACE inhibitors Reduction of mortality from 42% to 4 % after early 1970 s Overall 5-year mortality 30-50% Penn Q J Med 2007 Teixeira Ann Rheum Dis 2008 Steen Ann Rheum Dis 2007 Guillven L Rheumatology 2012 Case Study #4 Which features increase the risk for SRC in this patient? Gender Short disease course High creatinine Recent corticosteroid therapy Anti-RNA polymerase III positivity Thrombocytopenia Cardiac involvement : Clinical Presentation Abrupt onset of very high blood pressure (>150/90 mmhg) Sudden renal failure (raising serum creatinine, mild proteinuria) Features of malignant hypertension headache malaise retinopathy encephalopathy (lethargy, confusion, seizures) CHF/Pulmonary edema Anemia, thrombocytopenia 8

9 Which of the following features is NOT associated with SRC? Normal blood pressure Normal renal function Anti-U3-RNP positivity Reduced ADAMTS13 Pericardial effusion : Clinical Presentation SRC Typical Features Very high blood pressure (>150/90 mmhg) Sudden renal failure Malignant hypertension and CHF Hemolytic anemia and/or thrombocytopenia SRC Atypical Features Without renal failure (early) Without hypertension (10%) Asymptomatic pericardial effusion With or without renal failure or hypertension Which of the following clinical features is not associated with SRC? Normal blood pressure Normal renal function Anti-U3-RNP positivity ADAMTS13 positive test Pericardial effusion ADAMTS13 Markedly decreased (<10%) or absent in TTP patients, normal in SSc Renal Crisis Worse prognosis Males Creatinine >3 mg/dl at presentation Normotensive SRC Cardiac involvement Prior use ACE inhibitors Worse response to Rx Cardiac involvement Myocarditis, arrhythmias Denton C P et al. Rheumatology 2009 Presentation 25% Dialysis 75% Medical Therapy Early phase (< 24m) 75% 25% Medical Therapy Dialysis Management 30% of SRC patients do not respond adequately to ACE inhibitors Long term outcome (>24m) 40% Dialysis Medical Therapy Steen VD et al. Ann Intern Med 1990 Penn H et al. QJM 2007 Teixeira L et al. Ann Rheum Dis 2008 Batal I et al. Int J Rheumatol

10 Difficult to control or refractory SRC (30%) Management ACE inhibitors Calcium Channel Blockers Angiotensin Receptor Blockers (ARBs) ET receptor blockers initial therapy Combination, escalate dose Not effective alone Step-up therapy with ACEi Combination Small pilot, safety/rationale Prostacyclin IV infusion Anecdotal Plasma Exchange New drugs? If TTP present Untested for SRC Caskey Lancet 1997 Cheung Am J Kidney Dis 2005 Penn QJM 2013 Mouthon Hum Pathol 2011 Riociguat Guanylate cyclase stimulator Ghofraini N Engl J Med 2013 Direct renin inhibitors (i.e. aliskiren) Contraindication combo with ACE/ARBs in renal failure Staessen Lancet Start short-acting ACEi goal sys BP 20mmHg/24hr (avoid hypotension) Maximize ACEi dose Additional therapy: ARBs CCB ETA IV prostacyclin no response no response Accelerated hypertension >150/85 mmhg response no response Hospitalization Monitor renal function Renal Failure Hemodialysis Kidney transplant Progressive renal impairment Renal biopsy confirm diagnosis measure damage prognosis Assess for kidney function improvement up to 24 months after SRC Recovery Thanks 10