Systemic Sclerosis ANAS MUHANNAa MD,FACR AL-QUDS UNIVERSITY FACULTY OF MEDICINE

Sclero / derma Hard Skin Definition: Generalized disorder of connective tissue affecting the skin, internal organs and blood vessels. F:M = 3-9 :1 Peak onset : 30-50 years Prevalence 10-20 per 100,000

types I and III collagens (vinyl chloride, trichloroethylen) Pathophysiology pathogenic mechanisms Endothelial cell injury Fibroblast activation Cellular and humoral immunologic derangement ?? types I and III collagens glycosaminoglycans fibronectin Silica exposure Solvent exposure (vinyl chloride, trichloroethylen) Radiation

The nature of the vascular dysfunction in SSc

Severe alterations in small blood vessels of skin and internal organs, including fibrosis and perivascular cellular infiltration with activated T cells, are almost always present in systemic sclerosis.

Histologic Findings square morphology/ rigidity of the tissue biopsy specimen due to striking pan-dermal sclerosis. The number of adnexal structures is reduced, characteristic feature. A significant inflammatory cell infiltrate is not observed.

History of present illness …

Skin Diffuse pruritus Skin tightness and induration Skin pigmentary changes (hyperpigmentation or hypopigmentation;

Cutaneous and mucosal telangiectasis Vascular system Raynaud phenomenon Healed pitting ulcers in fingertips Cutaneous and mucosal telangiectasis

Raynaud phenomenon 70% present with this symptom 95% eventually develop it during the course of their disease

pitting ulcers in fingertips

Gastrointestinal system Gastroesophageal reflux (lead to hoarseness, aspiration pneumonia, and dysphagia) Dyspepsia, bloating, and early satiety Constipation alternating with diarrhea (may lead to malabsorption)

Destruction of enzymes Cont: Small int. wall fibrosis ↑ bacteria Destruction of enzymes & bile salts ↓ motility malabsorbtion

Musculoskeletal system generalized arthralgias and morning stiffness mimic other systemic autoimmune diseases Myalgia Loss in joint range of motion Symptoms of carpal tunnel syndrome Muscle weakness Respiratory system Progressive dyspnea Chest pain (precordial) due to pulmonary artery hypertension Dry persistent cough due to restrictive lung disease

Cardiovascular system Dyspnea due to pericardial effusion, congestive heart failure, or myocardial fibrosis Palpitations, irregular heart beats, and syncope due to conduction abnormalities Congestive heart failure Renal system Hypertension Renal crisis Chronic renal insufficiency

Ears, nose, and throat Sicca syndrome Poor dentition due to sicca syndrome Loosening of dentition due to alteration in the tooth suspensory ligament and thickening of the periodontal membrane Hoarseness due to acid reflux or vocal cord fibrosis

Neurologic Genitourinary system Endocrine system Constitutional Facial pain and hand paresthesias due to sensory peripheral entrapment neuropathy Headache and stroke during hypertensive renal crisis Genitourinary system Erectile dysfunction Dyspareunia (if introitus is affected) Endocrine system Hypothyroidism Constitutional Fatigue Weight loss

Lets do examination…

skin

Salt-pepper appearance Skin pigmentary changes Salt-pepper appearance Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.

Telangiectasias dilated vessels located just beneath the dermis on any skin area, but they are most obvious in the face (perioral area), hands, and anterior chest.

swollen Sclerodactyly indurated sclerotic stage

Calcinosis

Acrosclerosis/sclerodactyly.

microstomia

Eyes, ears, nose, and throat Salivary production may be decreased and spontaneous sublingual pooling of saliva may be absent. Xerostomia and xerophthalmia may be part of the examination findings. D/D primary Sjögren syndrome. Oropharyngeal and esophageal cancers are more common in persons with diffuse systemic sclerosis.

Cardiovascular system Pericardial effusion is usually asymptomatic (30%) Clinically significant pericarditis is rare. Cor pulmonale may develop secondary to long-standing pulmonary fibrosis or pulmonary artery hypertension. Conduction abnormalities, including complete A-V block, Infiltrative cardiomyopathy with replacement of cardiac muscle by fibrous tissue can lead to arrhythmias, heart failure, or both.

Neurologic system Trigeminal neuralgia (uncommon) and carpal tunnel symptoms result from peripheral entrapment neuropathies. rare, sensory neuropathies unrelated to entrapment may be present.

Renal system Renal crisis occurs in 10% of all patients. Renal crisis presents as accelerated hypertension, oliguria, headache, dyspnea, edema, and rapidly rising serum creatinine levels. 10% NO HTN. Renal crisis is observed within 4 years of diagnosis in about 75% men have a greater risk than women. IF not treated aggressively invariably leads to renal failure, requiring dialysis or renal transplantation, or even death. Preventing : Check blood pressure, monitor serum creatinine, and start (ACE) inhibitors early in at-risk patients. Avoid high doses of corticosteroids since this is a significant risk factor for renal crisis.

Reflux due to decreased lower esophageal sphincter pressure Gastrointestinal system Reflux due to decreased lower esophageal sphincter pressure Severe esophagitis Barrett metaplasia (can lead to cancer) Candida esophagitis Esophageal strictures Gastric vascular antral ectasia (dilated submucosal capillaries), also known as watermelon stomach Primary biliary cirrhosis (PBC) associated with antimitochondrial antibodies Wide-mouth colonic diverticula Malabsorption , constipation, pseudo-obstruction, gastroparesis Anal sphincter incompetence

Respiratory system Dry rales may be the only physical examination finding pulmonary artery hypertension. . active alveolitis interstitial fibrosis Patients are at risk for aspiration pneumonia due to lower esophageal sphincter incompetence.

Musculoskeletal system Clinically apparent synovitis is uncommon. Hand and joint function may decline over time because of skin tightening rather than arthropathy. Tendon friction rubs are found almost exclusively in diffuse systemic sclerosis and may be detected as the tendon is moved actively or passively. Myositis may cause weakness and muscle wasting. Levels of serum creatine kinase (CK) and aldolase are elevated. Acroosteolysis (ie, resorption or dissolution of the distal end of the phalanx) may occur. Flexion contractures of any affected joint may occur.

Vascular changes Raynaud phenomenon :may precede obvious systemic sclerosis features by months or even years. Infarction / dry gangrene may be due to severe vasospasm or to structural vascular occlusion. involves the digits , the lips, nose, and ears. Nail-fold capillary microscopy demonstrates fewer capillaries than normal

Nail-fold capillary microscopy capillary loop drop/numerous dilated capillary loops

The American College of Rheumatology criteria for the classification of systemic sclerosis Major criterion: Minor criteria: (2 of the 3) Proximal scleroderma Sclerodactyly Digital pitting scar Interstitial change on chest x-ray

Thick skin of fingers and hands (proximal scleroderma)

Thick skin of forearms (proximal scleroderma)

(proximal scleroderma) Thick skin of torso (proximal scleroderma)

Thick skin of face (proximal scleroderma)

Atrophic (thin) skin changes of face (proximal scleroderma)

Systemic sclerosis criteria Major criterion: Minor criteria: Proximal scleroderma Sclerodactyly

Sclerodactyly (early puffy fingers)

Taut, thick skin of fingers

Taut, thin skin of fingers

Digital tip pitting scars

Systemic sclerosis criteria Major criterion: Minor criteria: (2 of the 3) Proximal scleroderma Sclerodactyly Digital pitting scar Interstitial change on chest x-ray

Interstitial change (x-ray)

Systemic sclerosis (SSc) criteria LeRoy & Medsger have suggested two additional criteria to diagnose mild SSc: Raynaud’s phenomenon (plus both): nailfold capillary abnormalities SSc-specific antibodies (anti-centromere, anti-SCL-70, anti-PM-Scl, etc)

Lab Studies Antinuclear antibodies are present in about 95% of affected patients, Topoisomerase I antibodies ( Scl-70) 30% of patients with diffuse disease (absent in limited disease) associated with pulmonary fibrosis. Anticentromere antibodies : 80-90% in limited disease and are rare in diffuse disease.

Imaging Studies HRCT scan evaluate pulmonary involvement. ground-glass appearance first abnormality observed during the development of lung fibrosis Chest radiography is an insensitive, shows late findings of pulmonary fibrosis, Extremity radiography should be performed to reveal calcinosis and resorption of the distal tufts of the digits. Echocardiography: evaluate the patient's pulmonary artery pressure and to assess septal fibrosis or pericardial effusions. Roughly 30% of patients have asymptomatic pericardial effusions Right-heart catheterization: This remains the standard criterion for diagnosing pulmonary hypertension and is performed after echocardiographic screening Esophagraphy: Perform this test to document esophageal dysmotility and an incompetent LES.

Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach due to chronic gastroesophageal reflux. This is the most common cause of dysphagia, or difficulty swallowing, in scleroderma.

Medical Care the US Food and Drug Administration (FDA) has not approved any therapies for systemic sclerosis. Skin thickening can be treated with D-penicillamine and other experimental drugs or interventions Myositis :steroids (first choice), methotrexate, and azathioprine. Arthralgias can be treated with acetaminophen and NSAID

Con. A wide spectrum of clinical manifestations and severity Disease modifying interventions (?) - penicillamine - methotrexate - immunosuppressive agent: cyclosporin, IFN- - recombinant human relaxin Symptomatic (organ-specific) treatment

Raynaud’s phenomenon and ischemia 1) avoid cold exposure layers of warm, loose-fitting clothing 2) quit smoking 3) vasodilator therapy- calcium channel blocker (nifedipine), 4) finger / toe necrosis - intravenous prostaglandin (PGE1, PGI2) - sympathetic block - amputation

Gastrointestinal 1) reflux esophagitis and dysphagia - elevation of head of bed - small frequent meal - avoid lying down within 3-4 hours of eating - abstaining from caffeine-containing beverages, cigarette smoking - proton-pump inhibitors 2) gastroparesis: promotility agent (metoclopramide) 3) malabsorption syndrome: broad spectrum antibiotics

Pulmonary 1) Interstitial fibrosis - corticosteroids - cyclophosphamide, azathioprine 2) pulmonary artery hypertension - calcium channel blocker - prostacyclin - transplantation

Renal 1) renal crisis - early detection and ACE inhibitor 1 year survival without captopril 15% 1 year survival with captopril 76% - dialysis Doses of prednisone greater than 40 mg/d are associated with a higher incidence of sclerodermal renal crisis.

Prognosis 1. quite variable and difficult to predict 2. cumulative survival diffuse limited 5 yr 70% 90% 10 y 50% 70% 3. major causes of death 1) renal involvement 2) cardiac involvement 3) pulmonary involvement