Systemic Sclerosis (SSc) Alexandra Balbir-Gurman Systemic Sclerosis (SSc)

Systemic Sclerosis (SSc) Alexandra Balbir-Gurman

Systemic Sclerosis (SSc) Chronic disease Progressive course Skin thickening – scleroderma Multi-organ involvement Early and late SSc are different Subsets of SSc are different

Scleroderma-Systemic sclerosis Fibrosis: Skin Blood vessels Visceral organs Lung Heart GIT Kidney

Epidemiology Incidence: 1-2 to 100000 people Age: 35-55 y Gender: F:M = 8:1 African Americans have more severe disease

Division SSc Limited cutaneous SSc (CREST) (66%)- Lc SSc Distal extremities Face Diffuse cutaneous SSc (33%) – Dc SSc Distal extremities Face Proximal extremities Trunk Sine scleroderma (1%) Overlap syndrome (+RA, +PM,+SjS, +SLE)

CREST - LcSSc Calcinosis Raynaud’s phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia

Contributory factors Genetic 4.7% among twins 1.6% of SSc pts have a first-degree relative with SSc and even mor with CTD High incidence in Chostaw Indians Gene polymorphism in incoding of ACE, Endothelin-1, Nitric oxide synthetase, IL-1, IL-4, TNF, TGF Environmental CMV Parvovirus 19 Toxic oil syndrome (rapesses oils) Eosinophilia-myalgia syndrome (L-tryptophan) Silica miners Polyvinilchloride, epoxy resins, toluine, trichlorethylene. Drugs: bleomycin, pentazocine, cocain, appetite suppressor ???? Breast silicon implants????

Pathogenesis of SSc Vasculopathy Cellular and humoral immunity Progressive visceral and vascular fibrosis Animal models Tigh skin mouse Bleomycin induced in mice Chicken GVHD

Pathogenesis: Cellular and humoral autoimmunity T-cell, monocytes, macrophages cell activation T cells- CD4+ have elevated level of receptors to cytokines and adhesion molecules T cells, monocytes, macropheges show Th-2 response Cytokine production Excess of Th-2 cytokines IL-2, IL-4, IL-6, IL-13, Transforming Growth factor (TGF-), CTGF Deficit of Th-1 cytokines INF- B-cells activation Ab production T-cells and fibroblasts activation Fibroblast activation Collagen type I and III Collagen type VII (abnormal)

Pathogenesis: humoral immune abnormalities ANA (~100%) – correlate with SSc activity and severity Anti-topoisomerase (SCL-70) Anti-centromere Anti RNA-polymerase Ab against surface cell-surface Ag, secreted proteins: to fibroblasts, to EC, to PDGF receptors, to Fibrillin-1, to MMPe Other non specific Ab: RF+ SS-A, SS-B Anti-mitochondrial Ab (Primary Billiary Cirrhosis- PBC)

Pathogenesis: vascular damage Endothelial cell (EC) injury Endothelin 1(ET-1) excess Nitric oxide (NO) impaired production Prostacycline (PgI) impaired production Von Willebrand factor (vWF) activation Adhesion molecules activation (ICAM-1) PLT activation (thromboxane, PDGF) VEGF Dysfunction of autonomic and peripheral nervous system Reduced number of endothelial progenitor cells Obliterative vasculopathy

Pathogenesis Fibroblast activation Myofibroblasts transformation Overexpression of genes related to fibrosis: collagen, fibronectin, fibrillins Overproduction and accumulation of collagen - Small vessels damage Raynaud’s phenomenon GIT damage Heart Renal ischemia Lung – pulmonary hypertension Tissue collagen accumulation

Pathology - SSc Obliterative vasculopathy Early phase – perivascular inflammatory cells accumulation CD4+(skin) CD8+ (lungs) Fibrosis

Raynaud’s phenomenon (100%) Vaso-spastic phenomenon

Raynaud’s phenomenon (RP) Capillarosopy Distorted capillaries Wide loops Irregularity “dropout”

Ischemic ulcers

Pitting scars (criteria!!)

Skin changes Rodnan’s Score Mauskopf appearance Lips thinning Reduced oral aperture

Diffuse cutaneous SSc (criteria!!) Edema Thickening Dys-pigmentation Skin sclerosis Dryness

Sclerodactyly (criteria!!)

Sclerodactyly (criteria!!) Acro-osteolysis

Telangietasia

Calcinosis

Calcinosis

Musculoskeletal features Arthritis Carpal tunnel syndrome Tendinitis Tendon friction rub Acro-osteolysis Myositis

GIT involvement (50-90%) Xerostomia, periodontitis Esophageal dysmotility and reflux – GERD Heartburn Regurgitation Dysphagia Esophagitis Stricture Barret’s esophagus Hoarsness Aspiration pneumonitis

GIT involvement Gastroparesis Watermelon stomach - GAVE (GIT bleeding) Bacterial overgrowth Malabsorption Diarrhea Malnutrition Weight loss Pseudoileus - obstruction Fecal incontinence Rectal prolapse Pneumatosis cystoides intestinalis Primary billiary cirrhosis (PBC)

Pulmonary involvement Pleuritis Interstitial lung disease Pulmonary hypertension Both Leading cause of death

Pulmonary fibrosis (PF) (criteria!!) Cough Effort dyspnea Rest dyspnea Hypoxemia Secondary PAH Right CHF Right ventricular arrhythmias (VF) Death

Lung fibrosis – bibasilar (16-43%) Nonspecific interstitial pneumonia (biopsy) Risk factors: male gender, African Americans, DcSSc, SCL70++, low FVC, low DLCO HRCT Ground glass Mediatinal lymphadenopathy Pulmonary nodules Honey combing BAL LFT Reduced FVC Reduced DLCO Elevated serum KL-6 marker of type II and alveolar macrophages activation

Effort dyspnea Fatigue Syncope Rest dyspnea Hypoxemia Right CHF Right ventricular arrhythmias (VF) Death Pulmonary hypertension (PAH-primary)

Pulmonary hypertension (12-25%) Risk factors: Lc SSc, late age onset, severe RP, ACA, U1-RNP, U3-RNP Ab. HRCT Almost normal Lung function tests Normal FVC Reduced DLCO ECHO PAP>25 mmHg (rest) BNP and N-terminal BNP elevation Right heart catheter Elevated PAP Normal wedge pressure

Heart disease Pericarditis, tamponade Arrhythmias Conduction defects Diastolic dysfunction Relatively rare IHD Myocarditis CHF Left (hypertension) Right (lung disease, PAH) Myocardiopathy

Renal disease (crisis) Early disease Precipitating factors Dehydration, hypotension Pregnancy DcSSc, male gender, anti RNA polymerase III Ab High doses of Cs Renal crisis Hypertension Headache Blurred vision Chest pain Dyspnea Renal failure Microangiopathic hemolytic anemia, thrombocytopenia Left CHF Encephalopthy Mild proteinuria

Others +SSc PBC in Limited SSc Sicca syndrome Impotence Hypothyroidism Celiac disease B12 deficiency Neuropathy Depression Pregnancy problems:

Diagnostic criteria SSc Major Diffuse cutaneous SSc Minor Pitting scars Sclerodactyly Pulmonary fibrosis

Laboratory tests Anemia Iron deficiency B12, FA deficiency Microangiopathic hemolytic anemia ESR elevation not prominent Hupoalbuminemia CK elevation ANA, SCL70, ACA, anti RNAIII polymerase, KL-6, AMA, Gliadin Ab etc

DD in SSc Scleredema Scleromyxedema Nephrogenic systemic fibrosis GVHD Eosinophilic fasceitis

Treatment SSc: medicamentous, education RP Keep worm, wax CCB AIIRB Prostacyclin (Ilomedin) ET-1 RB PDE Statins Local nitrate Sympathectomy Ulcers/calcinosis Antibiotics Debridement

Treatment SSc GIT Supportive PPI inhibitors (H2-blockers) Laser coagulation for GAVE Broad spectrum antibiotics for overgrowth Hyperalimentation parenteral Octreotide for severe hypomotility Surgery occasionally

Treatment SSc Skin Small doses of steroids Cytotoxic drugs (cyclophosphamide, MTX) Joints Small doses of steroids DMARD’s (MTX, Mycophenolate Mofetil - MMF) Physiotherapy Myositis Steroids DMARD’s (MTX), IVIG

Treatment SSc Pulmonary fibrosis Steroids?? Cyclophosphamide MMF Oxygen Pulmonary hypertension ET-1 receptor inhibitors (Tracleer) Sildenafil Synthetic prostacyclins (Flolan, Ilomedin, Treprostenil) Oxygen Diuretics, oral anticoagulants, digoxin Lung transplantation

Treatment SSc Renal To avoid NSAID, Cs, B-blockers ACE inhibitors AIIRB Dialysis Late transplantation Heart Pacemaker Symptomatic

Prognosis SSc Diffuse 10-year 55% SCL-70 Anti RNA polymerase Pulmonary fibrosis Renal crisis Heart damage Limited 10-year 75% PAH Heart damage

Multidisciplinary approach

Mixed Connective Tissue Disease - MCTD Alexandra Balbir-Gurman

MCTD Coexisting SLE SSc - limited Polymyositis RA Antibodies to U1-RNP

MCTD- clinical features RP, puffy hands, myalgia Sclerodactyly, calcinosis, telangiectasias, esophageal dysmotility Malar rash, photosensitivity Heliotropic rash, nephritis Erosive arthritis Sicca syndrome (Sjogren’s syndrome)

MCTD – life threatening conditions Pneumonitis and pulmonary fibrosis PAH Pericarditis Nephrotic syndrome – membranous nephritis

MCTD – Laboratory data High inflammatory markers ESR CRP Hyperglobulinemia ANA, U1-RNP

MCTD- treatment Cs high doses DMARD’s CYC Prognosis – better then SSc

Eosinophilic fasciitis Scleroderma-like skin disease Cobblestone “peau d’orange”skin Fingers are spared No internal organ involvement Transient eosinophilia High ESR, CRP No antibodies Deep skin biopsy with fascia: inflammatory infiltrate with eosinophils Treatment: Cs +/- DMARD’s

Incidence: 1-8/1 000 000 Age: 10-15 years 45-60 years Gender: F:M = 2:1 (IBM F:M = 1:2) Secondary myopathy: statins rabdomyolysis INFLAMMATORY MYOPATHY EPIDEMIOLOGY

Classification Polymyositis Dermatomyositis Childhood dermatomyositis Myositis associated with Collagen diseases Myositis associated with malignancy Inclusion body myositis

Polymyositis Progressive course Proxymal muscles weakness** Dysphagia Dyspnea Chest muscles weakness Lung fibrosis Cardiomyopathy Weight loss, low grade fever, fatigue

Dermatomyositis Skin changes Heliotrope rash (eyes, neck, fingers) Proxymal muscles weakness Dysphagia Dyspnea Chest muscles weakness Lung fibrosis Cardiomyopathy Raynaud’s phenomenon Calcinosis Weight loss, fever, fatigue

Dermatomyositis

Heliotrope rash- Gottron’s signs

Heliotrope rash

PM/DM with malignancy Age >60 years Breast Ovary Rectal Lung Lymphomas

Myositis and CVD Overlap Systemic sclerosis SLE RA MCTD Sjogren’s syndrome Crohn’s disease

Diagnosis - criteria Symmetric muscle weakness (+/-dysphagia, +/-respiratory weakness) Elevation of muscle enzymes (AST, ALT, CK, LDH, aldolase) EMG changes (polyphasic motor units, fibrillation) Biopsy (necrosis, atrophy, cell infiltration) Rash (Dermatomyositis)

Myositis – additional laboratory tests Elevated ESR Elevated CRP Antinuclear antibodies 30% Anti synthetase- anti Jo-1 Pulmonary fibrosis Differential diagnosis HIV related HCV related Drug related (statins, bezafibrate)

Pathology Muscle, skin

Treatment Steroids DMARD’s Methotrexate Imurane MMF IV gamma-globulins-high doses Pulmonary fibrosis, myocarditis Cyclophosphamide GIT PPI Prokinetic drugs RP CCB, Ilomedin

Prognosis 5-year survival – 75% Severe muscle wasting Muscle contractures Pulmonary fibrosis CHF Malignancy +/- 3 years