Scleroderma

In the name of God the merciful the compassionate

Rheumatologist, Internist Iraj Salehi-Abari Rheumatologist, Internist salehiabari@sina.tums.ac.ir

Classification of Scleroderma: Salehi I. Classification of Scleroderma: Localized Scleroderma No visceral involvement No Typical hand involvement No Raynaud’s ph. No Auto-Antibody positivity Only sclerosis of one or more skin area Systemic Scleroderma (SSc) Scleroderma

Localized Scleroderma: Salehi I. Localized Scleroderma: Morphea: Plaque morphea Guttate morphea Generalized morphea Bullous morphea Deep morphea Linear Scleroderma Scleroderma

Plaque morphea: Local sclerosis in < 2 anatomic sites Salehi I. Scleroderma

Plaque morphea: Local sclerosis in < 2 anatomic sites Salehi I. Scleroderma

Generalized morphea: Skin sclerosis in > 3 anatomic sites Salehi I. Scleroderma

Linear Scleroderma: Children Salehi I. Linear Scleroderma: Children Growth impairment of the involved extremity Dermatomal distribution En coup de sabre Scleroderma

Salehi I. Scleroderma

Salehi I. Scleroderma

Salehi I. Scleroderma

Salehi I. Scleroderma

Systemic Sclerosis (SSc) Salehi I. Systemic Sclerosis (SSc) Definition: Multisystem, Chronic, Autoimmune Overproduction of collagen fibers Thickened & sclerotic skin Raynaud’s phenomenon Visceral organ involvement (fibrosis) Scleroderma

Epidemiology: Annual incidence in USA: 1-2 / 100,000 Salehi I. Epidemiology: Annual incidence in USA: 1-2 / 100,000 Peak onset age: 30-50 y/o 100 RA, 10 SLE, 1 Scl F/M ratio: 3/1 Black > other race Rare in children Rare in men < 30 y/o Scleroderma

Clinical staging of SSc: Salehi I. Clinical staging of SSc: Inflammatory stage: Early, Edematous phase Arthralgia, Soft tissue swelling Mistake for RA & other CTD Indurative stage: Intermediate fibrotic phase Hardness & thickness of skin Typical clinical features Atrophic stage: Late phase Very thin skin Scleroderma

Clinical classification of SSc: Salehi I. Clinical classification of SSc: Diffuse Cutaneous Scleroderma (dcSSc) Limited Cutaneous Scleroderma (lcSSc) Systemic Sclerosis sine Scleroderma Overlap syndrome Pre-Scleroderma or Early Scleroderma Scleroderma

Salehi I. Limited Cutaneous Scleroderma: Distal portion of extremities plus Head & neck Acrofacial Scleroderma

Salehi I. Diffuse Cutaneous Scleroderma: Distal + Proximal Head & Neck Trunk Trunkal Scleroderma

Intermediate Cutaneous Scl. Salehi I. Intermediate Cutaneous Scl. Scleroderma

Attention please: Almost all patients have skin involvement in the: Salehi I. Attention please: Almost all patients have skin involvement in the: Fingers: sclerodactyly Hands and Face Scleroderma

Pathogenesis: Unknown Genetic Background Salehi I. Pathogenesis: Unknown Genetic Background Environmental trigger factors (Ags) Vascular events: Raynaud’s ph. Endothelial injury Immunological events (autoimmunity) Cellular Humoral Activated fibrogenic fibroblast Scleroderma

Genetic considerations: Salehi I. Genetic considerations: Non-Mendelian pattern of inheritance Concordance rate of 4.7% in Monozygotic twins Positive family history of 1.6% in First degree relative Multiple Genetic loci Scleroderma

Multiple Genetic loci: Salehi I. Multiple Genetic loci: Genes encoding ACE Genes encoding endothelin-1 Genes encoding NOS Genes encoding CD19 Genes encoding monocyte chemoattractant protein-1 Genes encoding STAT4, IRF5, CTGF, SPARC Scleroderma

Environmental Antigenic triggers: Salehi I. Environmental Antigenic triggers: Viruses: Human CMV, and Parvovirus B19 Antitopoisomerase-I (Scl-70) recognize antigenic epitopes of the hCMV: Molecular mimicry Silica: The incidence of SSc is increased among miners exposed to silica Scleroderma

Environmental Antigenic triggers: Salehi I. Environmental Antigenic triggers: Polyvinyl chloride, Epoxy resins, Aromatic hydrocarbons (toluene,…) Cu, Fe: Treatment with D-penicillamine Drugs: Bleomycin, Pentazocine & Cocaine Scleroderma

Vascular events: Upon Raynaud’s phenomenon Salehi I. Vascular events: Upon Raynaud’s phenomenon Viruses, superoxide radicals, auto-antibodies,…(Ags) Endothelial injury Endothelial injury  endothelium-derived vasoconstrictor (Endothelin-1) increases and endothelium-derived vasodilators (NO, Prostacyclin) decrease Scleroderma

Salehi I. Vascular events: Vascular injury  Increased expression of ICAM-1 and other AMs Vascular injury  Platelet aggregation  release of Serotonin, Thromboxane, and PDGF Defective fibrinolysis Microvessels show enhanced permeability and leukocyte diapedesis Scleroderma

Salehi I. Vascular events: Ischemia-reperfusion  Reactive oxygen species (ROS)  further damage the endothelium Defective revascularization despite elevated levels of Vascular endothelial growth factor (VEGF) and other angiogenic factors Scleroderma

Salehi I. Vascular events: The number of endothelial progenitor cells is reduced in circulation, and their differentiation into mature endothelial cells is impaired  Wide spread capillary malformation and loss, obliterative vasculopathy of small and medium-sized arteries, and failure to repair damaged vessels are hallmarks of SSc Scleroderma

Salehi I. Vascular events: Myointimal cells proliferate, Basement membrane is thickened and fibrosis of the adventitial layers develops Occlusive vasculopathy affects capillaries arterioles and even large vessels in many organs  reduced blood flow, tissue ischemia  generation of profibrotic factors. Scleroderma

Vascular events: Vascular injury  Leukocyte Recruitment Salehi I. Vascular events: Vascular injury  Leukocyte Recruitment Leukocyte Recruitment  Th2 cytokines Th2 cytokines  Fibroblast activation Leukocyte Recruitment  Auto-Antibodies Auto-Antibodies  Vascular injury Auto-Antibodies  Fibroblast activation Scleroderma

Salehi I. Vascular events: Initial vascular injury in a genetically susceptible individual leads to functional and structural vascular alterations, inflammation and autoimmunity Inflammatory and immune responses initiate and sustain fibroblast activation and differentiation, resulting in pathologic fibrogenesis and irreversible tissue damage Scleroderma

Vascular events: Progressive luminal occlusion Salehi I. Vascular events: Progressive luminal occlusion Persistent endothelial cell damage Adventitial fibrosis Establish a vicious cycle Scleroderma

Fibrosis events: Fibroblast activation & Tissue hypoxia  Salehi I. Fibrosis events: Fibroblast activation & Tissue hypoxia  Collagen accumulation Extracellular matrix reorganization Impaired matrix degradation  Tissue fibrosis Scleroderma

Fibrosis events: Fibrogenic phenotype fibroblasts: Salehi I. Fibrosis events: Fibrogenic phenotype fibroblasts: “Scleroderma phenotype” Uncontrolable production of collagen Scleroderma

Autoimmunity: Auto-antibodies Animal models Salehi I. Autoimmunity: Auto-antibodies Animal models Lymphocytes & AECA  Apoptosis of endothelial cells Scleroderma

Host susceptibility for SSc: Salehi I. Host susceptibility for SSc: Compatible Genetic background Basal Vasculopathy: Basal Immunologic abnormalities and Autoimmunity: Cellular, Humoral “Scleroderma phenotype” of fibroblasts Scleroderma

Salehi I. Host susceptibility: Basal Vasculopathy: Raynaud’s ph.: highly sensitive alpha-2 adrenergic receptors on vascular smooth-muscle cells Vascular endothelium has potential of easy injury and dysregulation  platelet aggregation Endothelium-derived vasoconstrictors increases and vasodilators decrease  luminal occlusion Endothelial cells overexpress ICAM-1 and other AMs  facilitate leukocyte diapedesis Reduced Endothelial progenitor cells with impaired differentiation  defective revascularization Scleroderma

Basal Cellular Autoimmunity: Salehi I. Host susceptibility: Basal Cellular Autoimmunity: CD4(+) T cells have elevated levels of alpha-1 Integrin AMs  enhanced ability to bind to endothelium & to fibroblasts Activated Macrophages & T cells show Th2 immune response & secrete IL-4 & IL-13 Th2 cytokines  production of TGF-B  collagen synthesis TGF-B stimulates its own synthesis, as well as that of CTGF. SoTGF-B establishes an autocrine/paracrine stimulatory loop that sustains activation of fibroblasts Defective immunosuppressive function of Regulatory T cells (Tregs)  loss of immune Tolerance B cells  TGF-B & Autoantibadies Scleroderma

Basal Humoral Autoimmunity: Salehi I. Host susceptibility: Basal Humoral Autoimmunity: Antinuclear antibodies (ANA) in virtualy all patients: Anti-topoisomerase-I (Scl-70) Anti-centromere antibody (ACA) Anti RNA polymerases antibody Anti-fibroblasts Ab (Scl-70 ?), AECA, Anti-PDGF receptor Ab, Anti-fibrillin & Anti MMP Ab Proteolytic cleavage, increased expression, and altered localization of cellular proteins in SSc  proteins are recognized as neoepitopes by B cells Scleroderma

“Scleroderma phenotype” of fibroblasts: Salehi I. Host susceptibility: “Scleroderma phenotype” of fibroblasts: In SSc in addition to resident fibroblasts, epithelial cells and endothelial cells can differentiate into myofibroblasts In SSc circulating mesanchymal progenitor cells of bone marrow origin contribute to fibrosis Fibroblasts of SSc are “Scleroderma phenotype”: Enhanced secretion of collagen, cytokines & growth factors Expression of chemokine receptors and cell surface AMs Resistance to apoptosis Autocrine TGF-B signaling Scleroderma

Senario of pathophysiology: Salehi I. Senario of pathophysiology: In a susceptible individual, Complex interplay between basal vasculopathy and autoimmunity affects on fibrogenic fibroblasts and initiate and amplify the fibrotic process Scleroderma

Vascular involvement: Salehi I. Vascular involvement: Early stage: Reversible vasospasm in arterioles Transient Raynaud ph. Intermediate stage: Vasospasm + mild to moderate fixed stenosis Prolonged RP and digital ischemia and ulceration Late stage: Severe fixed stenosis Digital infarction and auto-amputation Scleroderma

Classic case of SSc: A middle age woman with: Raynaud’s ph Salehi I. Classic case of SSc: A middle age woman with: Raynaud’s ph Skin hardness, hyper-hypopigmentation Masked face, telangiectasia, Micro-ostia Sclerodactyly, Pitting ulcer Dysphagia, Pyrosis, Diarrhea Dyspnea on exersion, dry cough Arthralgia, myalgia Scleroderma

General manifestations: Salehi I. General manifestations: Most frequent: Fatigue, Stiff joints Loss of strength, Pain Sleep difficulties Skin discoloration Less frequent: Breathlessness, depression, sore eyes Upset stomach, nausea, weight loss Scleroderma

Raynaud phenomenon (RP): Salehi I. Raynaud phenomenon (RP): Definition: Sequential color changes in the digits due to arterial vasoconstriction, precipitated by cold, stress, a decrease in temperature and vibration. Epidemiology: 3-5% of general population More frequent in women Scleroderma

Raynaud phenomenon (RP): Salehi I. Raynaud phenomenon (RP): Triphasic color changes: Pallority = ‘’White’’ 2 p. Cyanosis = ‘’Blue’’ 1 p. Redness = ‘’Red’’ 1 p. Scleroderma

Active Raynaud’s phenomenon Salehi I. Active Raynaud’s phenomenon Scleroderma

Raynaud phenomenon (RP): Salehi I. Raynaud phenomenon (RP): Diagnosis is only made by History Definite RP: repeated episodes of biphasic color changes upon exposure to cold Possible RP: Uniphasic color changes + numbness or paresthesia No RP: No color changes upon exposure to cold Scleroderma

Raynaud phenomenon (RP): Salehi I. Raynaud phenomenon (RP): Primary (idiopathic, isolated): Without a definable underling cause An exaggeration of normal vasoconstriction to cold exposure Secondary (pathologic): With an underling disease or cause Raynaud syndrome Scleroderma

Secondary Raynaud ph: Systemic Sclerosis SLE, other CTD Salehi I. Secondary Raynaud ph: Systemic Sclerosis SLE, other CTD Occlusive vascular disease Drugs/toxins Hematologic abnormalities Use of vibrating tools & vascular trauma Frostbite Scleroderma

Secondary Raynaud ph: Other Connective tissue diseases: MCTD Salehi I. Secondary Raynaud ph: Other Connective tissue diseases: MCTD Overlap syndrome PM/DM RA Sjogres’s syndrome UCTD Vasculitis Scleroderma

Secondary Raynaud ph: Occlusive vascular disease: Hypothyroidism Salehi I. Secondary Raynaud ph: Occlusive vascular disease: Arteriosclerosis Atheroemboli Thromboangiitis obliterans Hypothyroidism Scleroderma

Drugs/toxins cause RP Amphetamines Beta blockers, Clonidine Interferon-alpha Bleomycin, Cisplatin, Vinblastine Cocaine, Nicotine Cyclosporine Ergot, Methysergide Vinyl chloride Salehi I. Scleroderma

Secondary Raynaud ph: Hematologic disease: Cold agglutinin disease Salehi I. Secondary Raynaud ph: Hematologic disease: Cold agglutinin disease Cryofibrinogenemia Cryoglobulinemia Paraproteinemia Polycythemia Scleroderma

Primary Raynaud phenomenon: Salehi I. Primary Raynaud phenomenon: Age of onset: 15-30 years More common in female Occur in multiple family members Spontaneous remission may occur May be aggravated by: HTN, CVD, atheroslerosis, and diabetes mellitus Scleroderma

Diagnostic criteria of Primary RP: Salehi I. Diagnostic criteria of Primary RP: Symmetric episodic attacks No evidence of peripheral vascular disease No tissue gangrene, tissue injury, or digital pitting Negative nailfold capillary examination Negative ANA and normal ESR Scleroderma

Normal nailfold Capillaroscopy Salehi I. Normal nailfold Capillaroscopy Scleroderma

Clinical clues to suggest secondary RP: Salehi I. Clinical clues to suggest secondary RP: Later age of onset (>30-40 years) Male gender Painful RP RP with digital ulceration and gangrene Asymmetric attacks RP associated with other signs or symptoms Abnormal lab. data: CBC, ESR, auto-antibodies,… Scleroderma

Salehi I. Scleroderma

Nailfold capillary microscopy: Salehi I. Nailfold capillary microscopy: Enlarged capillary loops or Distorted capillary loops and Relative paucity of loops Suggest an underlying CTD Enlargement associated with loss of capillaries More suggestion of SSc Scleroderma

‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Salehi I. ‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Scleroderma

Salehi I. ‘’Active’’ phase nailfold capillaries in dcSSc: Capillary dilatation and avascular areas Scleroderma

Salehi I. Scleroderma

Approach to Raynaud phenomenon: Salehi I. Approach to Raynaud phenomenon: Step I: History and physical examination by GP Step II: Nailfold capillary microscopy by GP If they are normal, then Primary RP is made by a GP, and no need for laboratory tests. But if there are any abnormality or nailfold capillary microscopy cannot perform Step III: Hx., Ph. Exam. and Nailfold capillary microscopy by Rheumatologist Step IV: Laboratory tests Scleroderma

Skin involvement: Universal feature of SSc Characterized by: Salehi I. Skin involvement: Universal feature of SSc Characterized by: Skin thickening, hardness, and fixation The fingers, hands and face are at first Prominent skin manifestation: . Pruritus and edema in the early stages . Sclerodactyly . Digital ulcers & pitting of fingertips . Telangiectasia . Calcinosis cutis Scleroderma

Skin involvement: Diffuse tanning in the absence of sun exposure Salehi I. Skin involvement: Diffuse tanning in the absence of sun exposure Vitiligo-like hypopigmentation “Salt-and-pepper” appearance: In scalp, upper back, chest Pigment loss spares the perifollicular areas Dry skin, hair loss: Collagen accumulation causes oblitration of hair follicles, sweat & sebaceous glands Scleroderma

The assessment of skin involvement: Salehi I. The assessment of skin involvement: Estimation of: Skin thickness Pliability (hardness) Fixation to underling structures (tethering) The modified Rodnan skin score: In 17 distinct areas of the body Score from 0 (nl) to 3 (most severe) Gold standard is skin palpation by Rheumatologist Ultrasonography & Durometer ? Scleroderma

Salehi I. Scleroderma

Face: “Mauskopf” face Microstomia (fish mouth) Salehi I. Face: “Mauskopf” face Shiny taut skin Masklike & expressionless Decreased skin folds Microstomia (fish mouth) Perioral radial furrowing “Beak-like” nose Small sharp nose: Omega sign Matlike telangiectases Scleroderma

Hand involvement:

Salehi I. Scleroderma

‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Salehi I. ‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Scleroderma

Hand involvement: Sclerodactyly : Tapered fingers Salehi I. Hand involvement: Sclerodactyly : Thickening of finger skin Fibrosis of tendons Tapered fingers Transverse creases on the dorsum of the fingers disappear Scleroderma

Hand involvement: Digital ulcerations “Digital pits” = Pitting ulcers Salehi I. Hand involvement: Digital ulcerations Superinfection Osteomyelitis “Digital pits” = Pitting ulcers Healing of ischemic fingertip ulcerations Scleroderma

Hand involvement: Dissolution of terminal phalanges Salehi I. Hand involvement: Dissolution of terminal phalanges Loss of volar pads of the fingertips  Resorption of the terminal phalangs: Acro-osteolysis Periungual telangiectasia Scleroderma

Hand involvement:

Salehi I. Scleroderma

‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Salehi I. ‘’Slow’’ phase nailfold capillaries in lcSSc: Capillary dilatation Scleroderma

Calcinosis cutis: Most common in patients with lcSSc & positive ACA Salehi I. Skin involvement: Calcinosis cutis: Most common in patients with lcSSc & positive ACA CPPD deposition Visualized on plain X-Rays Typical locations: finger pads, palms, extensor surfaces of the forearms, olecranon & prepatellar bursae Persistent firm, nontender subcutaneous lumps If ulcerate  drainage of chalky white material Scleroderma

Neck sign

Barnett’s sign: Vertical striations in the skin with neck extension Salehi I. Barnett’s sign: Vertical striations in the skin with neck extension Scleroderma

Organ involvement: Gastrointestinal Pulmonary Renal Cardiac Salehi I. Organ involvement: Gastrointestinal Pulmonary Renal Cardiac Musculoskeletal Ophthalmic Others Scleroderma

Gastrointestinal involvement: Salehi I. Gastrointestinal involvement: In 90% of cases Any part of GI About 50% symptomatic Esophageal: most common Pathology: . Smooth muscle atrophy . Gut wall fibrosis Scleroderma

Oral involvement: Micro-ostia (fish mouth) Salehi I. Oral involvement: Micro-ostia (fish mouth) Rigidity of tongue with short frenulum Rigidity & tenderness of oral mucosa Malalignment of teeth Oropharyngeal dysphagia: 25% Oropharyngeal incoordination: 25% Sjogren’s syndrome Impaired mastication & deglutition Scleroderma

Esophageal involvement (90%): Salehi I. Esophageal involvement (90%): Lower two-thirds of Esophagus: Reduced or No peristalsis Dilated lumen Decreased LES tone GERD: pyrosis Dysmotility: dysphagia Hiatal hernia Scleroderma

Esophageal involvement (90%): Salehi I. Esophageal involvement (90%): In past: Manometry, Barium swallow Nowadays: Esophagoscopy if: Complications are suspected Persistent symptoms after PPI therapy Esophagoscopy: Reflux esophagitis, candidiasis Barrett’s esophagus, LE stricture Scleroderma

Gastric involvement: Gastric emptying: delayed Mucosal telangiectasia: Salehi I. Gastric involvement: Gastric emptying: delayed Mucosal telangiectasia: Watermelon stomach Upper GI bleeding Gastric antral venous ectasia (GAVE): Unexplained IDA Gastroparesis: rare Scleroderma

Salehi I. Watermelon stomach Scleroderma

Small bowel involvement: Salehi I. Small bowel involvement: Reduced peristalsis Abdominal distension Bacterial overgrowth Intermittent diarrhea-constipation Malabsorption Pseudo-obstruction & Perforation Pneumatosis cystoides intestinalis Volvulus Pseudo-obstruction Pneumatosis intestinalis Rectal prolaps, incontinence Scleroderma

Colonic disease: Anorectum: most common Wide-mouthed diverticuli Salehi I. Colonic disease: Anorectum: most common Fecal incontinence Rectal prolapse Gastrocolic reflex: absent Wide-mouthed diverticuli Constipation Colonic perforation Colonic infarction Scleroderma

Pulmonary involvement: Salehi I. Pulmonary involvement: In most patients with SSc: 70% Leading cause of death Two main types: Interstitial Lung Disease (ILD) Pulmonary Arterial Hypertension (PAH) Scleroderma

Pulmonary involvement: Salehi I. Pulmonary involvement: Less common types: Aspiration pneumonia Pulmonary hemorrhage Obliterative Bronchiolitis Extraparenchymal restrictive lung disease Spontaneous pneumothorax Drug induced lung disease Lung cancer (Bronchoalveolar Carcinoma) Scleroderma

Pulmonary involvement: Salehi I. Pulmonary involvement: Common presentations: DOE: most common Chronic dry cough: common Reduced exercise tolerance, fatigue Chest pain: uncommon Hemoptysis: Rare Asymptomatic: 1/3 Basal “Velcro” crackles Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: Up to 90% in autopsy Up to 85% in HRCT Up to 43% clinically: “Velcro” crackles CXR-PA: Lower lobes reticular pattern Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: HRCT: one or combination of below patterns Reticular linear opacities Nodular opacities Honey comb cystic changes Ground glass opacification Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: FEV-1: Unaffected FVC: Decreased FEV-1/FVC: Normal or increased DLCO: Decreased Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: Risk factors for ILD: Male gender African-American race Diffuse cutaneous SSc Severe GERD Presence of anti-topoisomerase-I Low FVC or DLCO at initial presentation Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: Rapid progressive ILD Within the first 3 years of disease Significant DOE Extensive “Velcro” crackles Extensive pattern in HRCT The FVC can decline by 30%/year Scleroderma

Interstitial lung disease: Salehi I. Interstitial lung disease: Bronchoalveolar lavage (BAL): PMN > 2% &/or Eosinophils > 3% is correlated with more extensive ILD in HRCT Serum level of KL-6: Measurement of KL-6, a glycoprotein found in type II pneumocytes and alveolar macrophages is a biomarker for the detection and serial monitoring of ILD in SSc Scleroderma

Salehi I. Scleroderma

Salehi I. Scleroderma

Pulmonary arterial hypertension (PAH): Salehi I. Pulmonary arterial hypertension (PAH): Definition: Mean Pulmonary arterial pressure > 25 mmHg Pulmonary capillary wedge pressure < 15 mmHg In 10-15% of patients with SSc Development of RHF DOE, Angina, Exertional near-syncope With significant mortality Scleroderma

Pulmonary arterial hypertension (PAH): Salehi I. Pulmonary arterial hypertension (PAH): Risk factors of PAH: Limited cuteneous SSc Positive ACA Late age at disease onset Severe Raynaud’s ph. Anti U1-RNP, U3-RNP (Fibrillarin) and B23 Scleroderma

Pulmonary arterial hypertension (PAH): Salehi I. Pulmonary arterial hypertension (PAH): Doppler Echocardiography: Used as screening PA systolic pressure > 40 mmHg at rest suggest PAH Serum level of brain natriuretic peptide (BNP): Used as screening and monitoring of PAH Scleroderma

Renal involvement: 50% clinical involvement 60-80% in autopsy Salehi I. Renal involvement: 50% clinical involvement 60-80% in autopsy Sclerodermal Renal Crisis (SRC) The most dreaded complication of SSc Almost always within first 4 years of disease Scleroderma

Sclerodermal Renal Crisis: In 10-20% of dcSSc ARF with NL U/A Salehi I. Sclerodermal Renal Crisis: In 10-20% of dcSSc ARF with NL U/A New & a few Pr or RBC or granular casts in U/A Abrupt onset of Marked HTN (10% NL HTN): Headache, blurred vision, chest pain Pericarditis, CHF Microangiopathic hemolytic anemia Activated RAA system + nephrosclerosis Scleroderma

Risk factors of SRC: Diffuse, advanced skin involvement Male gender Salehi I. Risk factors of SRC: Diffuse, advanced skin involvement Male gender African American race Glucocorticoid use (MDS-HDS) Anti RNA polymeras I & III Cyclosporine Scleroderma

Screening for SRC: In high risk pt.: Daily home BP measurement Salehi I. Screening for SRC: In high risk pt.: Daily home BP measurement In other pt.: Biweekly BP measurement In all pt.: Plasma Cr & Urine Pr Checking every 3-6 months Scleroderma

Palpable tendon friction rubs Pericardial effusion Salehi I. Alarm signs of impending SRC: Palpable tendon friction rubs Pericardial effusion Pericardial friction rub New unexplained anemia New unexplained thrombocytopenia Scleroderma

Salehi I. Outcome of SRC: Oliguria or Cr > 3 mg/dl at presentation predicts poor outcome, with permanent hemodialysis and high mortality Using short-acting ACE inhibitors to achieve adequate BP control before the onset of renal failure results in improved prognosis Scleroderma

Lung Cancer The risk is increased similarly in both lcSSc & dcSSc Salehi I. Lung Cancer The risk is increased similarly in both lcSSc & dcSSc The risk is 5 x nl population 1/3 of cancer in SSc Scleroderma

Other Cancers Tongue Breast Esophagus ( Barrett’s  Adenocarcinoma) Salehi I. Other Cancers Tongue Breast Esophagus ( Barrett’s  Adenocarcinoma) Scleroderma

Cardiac involvement: In dcSSc more than lcSSc Salehi I. Cardiac involvement: In dcSSc more than lcSSc Within 3 years of the onset of skin thickening Often clinically silent All layers of heart may be involved Scleroderma

Cardiac involvement: Secondary to systemic HTN or PAH: Salehi I. Cardiac involvement: Secondary to systemic HTN or PAH: most common LVH, RVH, and CHF Pericarditis + effusion: PE alarm sign of SRC Myocardial fibrosis, Myocarditis Valvular regurgitation Scleroderma

Cardiac involvement: Angina pectoris Conduction disturbances Salehi I. Cardiac involvement: Angina pectoris Conduction disturbances Arrhythmias: Atrial & Ventricular tachycardias Tissue Doppler Echo (TDE) & Cardiac MRI Thallium perfusion studies Serum level of NT-Pro-BNP as a marker of primary cardiac involvement Scleroderma

Musculoskeletal disease: Salehi I. Musculoskeletal disease: In early stage of disease: CTS: common & may be presenting feature Edema & swelling of hands Generalized arthralgia-myalgia Hand joints: most common Scleroderma

Musculoskeletal disease: Salehi I. Musculoskeletal disease: Stiff joints in dcSSc: Elbow, Shoulder, Knee Large joint contractures Tendon friction rubs Fingers, wrist, elbow, knee and ankle True arthritis uncommon Erosive polyarthritis of hands: may be Scleroderma

Musculoskeletal disease: Salehi I. Musculoskeletal disease: Muscle weakness: common Disuse atrophy Malnutrition Overlap with polymyositis Myopathies Scleroderma

Musculoskeletal disease: Salehi I. Musculoskeletal disease: Erosive polyarthritis with positive RF: overlap of RA & Scl HA arthropathy OA of DIP & CMC1 Acro-osteolysis, resorption of mandibular condyles, osteolysis of ribs and distal clavicles Scleroderma

Neurologic involvement: Salehi I. Neurologic involvement: Neuropathies Cranial, Peripheral, Autonomic Entrapment, Cutaneous Trigeminal neuralgia CNS: uncommon to rare Headache, Seizures, Stroke, Vascular disease Radiculopathy, myelopathy Scleroderma

Genitourinary involvement: Salehi I. Genitourinary involvement: In men: Erectile dysfunction: 80% Male impotence In women: Sexual dysfunction Vaginal dryness Constriction of the vaginal introitus Dyspareunia: > 1/2 Scleroderma

Difficult pregnancy: dcSSc Salehi I. Sjogren’s syndrome Hypothyroidism PBC: lcSSc Difficult pregnancy: dcSSc Scleroderma

CREST syndrome : Calcinosis Raynaud’s ph. Esophageal dysmotility Salehi I. CREST syndrome : Calcinosis Raynaud’s ph. Esophageal dysmotility Sclerodactyly Telangiectasia Scleroderma

Lab. Data: CBC: Anemia ESR Renal FT, Liver FT FANA: 95%, speckled CXR Salehi I. Lab. Data: CBC: Anemia ESR Renal FT, Liver FT FANA: 95%, speckled Scl-70 ACA CXR Scleroderma

Lab. Data: AOCD; mild, most common IDA: GAVE, chronic esophagitis Salehi I. Lab. Data: AOCD; mild, most common IDA: GAVE, chronic esophagitis Macrocytic anemia: B12, Folate deficiency Drugs: MTX Microangiopathic hemolytic anemia: SRC Scleroderma

Lab. Data: Pancytopenia: Elevated ESR: Drugs SRC Malignancy Myositis Salehi I. Lab. Data: Pancytopenia: Drugs SRC Malignancy Elevated ESR: Myositis Scleroderma

Lab. Data: Antitopoisomerase I (Scl-70) Highly specific for SSc High risk of ILD Associated with dcSSc Anti-centromere antibodies (ACA) Associated with lcSSc Salehi I. Lab. Data: Scleroderma

Lab. Data: AntiU3-RNP (Fibrillarin): SSc + PAH Salehi I. AntiPM-Scl: PM + Scl AntiU3-RNP (Fibrillarin): SSc + PAH Anti RNA polymerase I & III: only in SSc Anti RNA polymerase II: in SLE or SSc RF: 25% Lab. Data: Scleroderma

Attention please: Scl-70 & ACA & Salehi I. Attention please: Scl-70 & ACA & Anti-RNA polymerase III antibody tests are highly specific (> 99.5%) but only moderately sensitive (20-50%) Over 95% of SSc patients have at least one autoantibodies Scleroderma

Lab. Data: GI Endoscopy Doppler Echocardiography HRCT of lung Salehi I. Lab. Data: GI Endoscopy Doppler Echocardiography HRCT of lung Hand X-Ray Manometry, Dlco Spirometry, Pletismography Thyroid FT Skin biopsy Scleroderma

Skin biopsy: Not necessary for diagnosis of SSc Salehi I. Skin biopsy: Not necessary for diagnosis of SSc Only done in doubtful cases For DD with Scleroderma-like disorders May be necessary for localized Scleroderma Should include subcutaneous tissue, fascia, and muscle Scleroderma

Scleroderma-like disorders: Salehi I. Scleroderma-like disorders: Scleredema Scleromyxedema Diabetes Mellitus Hypothyroidism Nephrogenic systemic fibrosis Amyloidosis Eosinophilic fasciitis Chronic GVHD Scleroderma

Limited Cutaneous SSc (lcSSc): Salehi I. Limited Cutaneous SSc (lcSSc): Raynaud’s ph. For years Acro-facial skin sclerosis Dilated nailfold capillary loops( no drop-out ) Accompanied by CREST syndrome Pulmonary Artery Hypertension( PAH ) ILD lately & SRC rarely occurs ACA: 70 - 80% Scleroderma

Diffuse Cutaneous SSc (dcSSc): Salehi I. Diffuse Cutaneous SSc (dcSSc): Raynaud’s ph. Followed, within one year, by puffy skin changes Trunkal & acro-facial skin sclerosis Tendon friction rubs Nailfold capillary dilatation (with drop-out) Early & significant incidence of SRC, ILD, GI & cardiac disease Anti-Scl-70: 30% Scleroderma

Pre-Scleroderma Subclinical Scleroderma Early Scleroderma Salehi I. Pre-Scleroderma Subclinical Scleroderma Early Scleroderma Scleroderma

Pre-Scleroderm Raynaud’s phenomenon plus Salehi I. Pre-Scleroderm Raynaud’s phenomenon plus Nailfold capillary changes &/or Autoantibodies: Scl-70 ACA Anti-RNA polymerase No skin involvement Scleroderma

Diagnosis of SSc: Clinical: Upon No skin biopsy: only for History & Salehi I. Diagnosis of SSc: Clinical: Upon History & Physical examination No skin biopsy: only for Localized Scl. DD with Scl. Like disorders Scleroderma

Diagnosis of SSc: Combination of skin induration plus > 1 of: Salehi I. Diagnosis of SSc: Combination of skin induration plus > 1 of: Heartburn &/or dysphagia of new onset Acute onset of HTN & renal failure DOE + ILD, or PAH Diarrhea with malabsorption Facial, lip, or hand telangiectasia Digital infarctions & or pitting ulcer Erectile dysfunction Scleroderma

Attention please: The presence of : Calcinosis cutis Salehi I. Attention please: The presence of : Calcinosis cutis Hyperpigmentation &/or Skin telangiectasia and Facial and Fingers features Can differentiate SSc from other DD Scleroderma

Prognosis & Mortality: Salehi I. Prognosis & Mortality: Mortality rate: in dcSSc # 5-8 fold higher than nl population In lcSSc # 2 fold The most common cause of death in dcSSc: Pulmonary fibrosis &/or PAH SRC Cardiac Scleroderma

Management: No cure, No remission Localized or Systemic Scl. Salehi I. Management: No cure, No remission Localized or Systemic Scl. Which type of systemic Scl. Nonpharmacologic therapy Pharmacologic Symptomatic therapy Systemic therapy: Vascular + Immunologic + Fibrotic Minor vs major Scleroderma

Salehi I. Attention please: Elucidation of the precise interplay between the Vascular, Immunologic and Fibrotic components of SSc is likely to be an important first step towards more effective therapy Scleroderma

Disease modifying therapy: Salehi I. Disease modifying therapy: Immunosuppressive therapy: Glucocorticoids (LDS) MTX Mycophenolate mofetil Cyclophosphamide Autologous stem cell transplantation Scleroderma

Disease modifying therapy: Salehi I. Disease modifying therapy: Anti-fibrotic therapy: D-penicillamine: Standard-dose: 750 mg/day Low-dose: 125 mg qod Scleroderma

Disease modifying therapy: Salehi I. Disease modifying therapy: Vascular therapy: Calcium channel blockers: Diltiazem Angiotensin II receptor blockers: Losartan Alpha-1 blocker: prazocin 5-phosphodiesterase inhibitors: Sildenafil SSRI: Fluoxetine Topical nitroglycerine IV prostaglandine: Iloprost Anti-platelet agent: low-dose Aspirin Endothein-1 receptor antagonist: Bosentan Scleroderma

Pulmonary therapy: Severe acute ILD: Cyclophosphamide plus Salehi I. Pulmonary therapy: Severe acute ILD: Cyclophosphamide plus Medium dose Glucocorticoids Symptomatic PAH: Bosentan Sildenafil Scleroderma

Gastrointestinal therapy: Salehi I. Gastrointestinal therapy: GERD: PPI Omeprazole, Pantozol Nexium (esomeprazole) GI bleeding: Watermelon, GAVE Laser photocoagulation Bacterial overgrowth: Metronidazole Erythromycin & Tetracycline Chronic hypomotility: Octreotide Scleroderma

Scleroderma Renal Crisis therapy: Salehi I. Scleroderma Renal Crisis therapy: ACE inhibitors: 90% of cases Hemodialysis: 2/3 of cases In ½ of cases: recovery In ½ of cases who are unable to D/C dialysis after 2 years: Renal transplantation Recurrency of SRC in transplanted kidney is rare Scleroderma

Symptomatic therapy: Pruritus Dry skin Dyspareunia Salehi I. Symptomatic therapy: Pruritus Dry skin Dyspareunia Facial telangiectasis DOE Scleroderma

Salehi I. Scleroderma