Scleroderma Nicole Bundy, MD, MPH Assistant Professor Division of Rheumatology and Immunology

Learning Objectives  Describe the epidemiology and pathophysiology of systemic sclerosis (SSc)  Understand the typical disease presentation and clinical findings of SSc  Contrast limited cutaneous disease (lcSSc) and diffuse cutaneous disease (dcSSc)  Describe the prognosis and possible complications of SSc  Outline the approach to treating and monitoring patients with SSc

Terminology Scleroderma Localized Scleroderma Systemic Sclerosis (SSc) Morphea Linear Scleroderma Scleroderma en coup de sabre Diffuse cutaneous SSc Limited cutaneous SSc

Systemic Sclerosis Case September 2011  Previously healthy, 36 year old white female was referred to rheumatology by PCP for 3 months of hand and foot pain and swelling. She also complained of fatigue and painful, purple lesions on her fingertips.  PCP reported that she had a positive antinuclear antibody (ANA) test.  ROS: Denied other pertinent symptoms  PE: diffusely swollen hands and feet, painful lesions on fingertips

Systemic Sclerosis Case Later in September 2011  Patient’s hand and foot swelling continued and she had increasing pain in her joints. She had developed skin tightening around mouth and mild shortness of breath on exertion  LABS:ANA positive Anti-Scl 70 antibody positive ESR and CRP slightly elevated  Patient was started on low-dose prednisone and methotrexate. Chest CT was ordered.

Systemic Sclerosis Case October 2011  No change in joint pain and swelling  Developed Raynaud’s and acid reflux  Chest CT demonstrated ground-glass opacities at lung bases  Started on IV cyclophosphamide November 2011  No change in joint pain and swelling  Developed diffuse pruritus and progressive skin tightening and thickening on arms, legs and face

January – March 2012  Developed large pericardial effusion requiring repeated drainage  Developed multiple ischemic ulcers on hands  Progressive difficulty swallowing  Relentless progression of skin tightening, now extending mid-way up thighs and upper arms as well as face and chest Systemic Sclerosis Case

April 2012  Admitted to hospital with vomiting blood (hematemesis)  Found to be in acute renal failure  Large pericardial effusion persisted and new pleural effusions  Patient died one week into hospitalization

What is Systemic Sclerosis?  A chronic, multisystem autoimmune disease of unknown etiology characterized by inflammation, disordered connective tissue metabolism and functional and structural abnormalities in blood vessels, all contributing to progressive fibrosis of the skin and visceral organs

Epidemiology  Incidence in US of 9-19 cases per million per year  Prevalence in US of ~286 cases per million  Female to male ratio of 3-5:1  Peak age at onset is years  More common in African Americans than Caucasians; African Americans are also more likely to have more severe disease. Lowest incidence in Asians.  Genetic susceptibility is important but incompletely understood  Environmental exposure may play a role

Pathophysiology Vascular Injury Immune activation Fibrosis -Autoantibodies -Inappropriate inflammatory cell activation -Release of inflammatory mediators -Autoantibodies -Inappropriate inflammatory cell activation -Release of inflammatory mediators -Fibroblast activation -Collagen accumulation -Fibroblast activation -Collagen accumulation -Endothelial cell dysfunction -Blood vessel narrowing -Clot -Endothelial cell dysfunction -Blood vessel narrowing -Clot

Vascular Injury Immune activation Fibrosis ? ?

Pathophysiology Immune Activation and Vascular Injury Tissue Fibrosis

Disease Presentation Patient asymptomatic May have Raynaud’s + Autoantibodies Pre- clinical Diffusely puffy fingers Diffuse itching Joint pain Established Raynaud’s Very Early Progressive skin fibrosis and variable organ involvement Early Advanced

Typical Disease Presentation  year old female  Complains of joint pain, fatigue, and swollen hands and fingers  On review of systems admits to daily acid reflux and fingers becoming white and painful when exposed to cold (Raynaud’s phenomenon)

Disease Presentation  Physical Exam:  Diffusely swollen hands/fingers  Early skin tightening in most distal aspects of extremities and around face  Changes in nail fold capillaries

Laboratory Studies Autoantibodies:  Antinuclear antibodies (close to 90% of patients with SSc will be positive)  Systemic sclerosis specific antibodies:  Anti-Scl 70  Anti-centromere  Anti-U3-RNP Other labs:  Baseline kidney and liver function, CBC, ESR and CRP  Work-up for underlying malignancy if suggested by history and exam

VASCULAR -Raynaud’s SKIN -Tightening -Calciniosis -Telangiectasias -Pigment changes LUNG -Interstitial lung dz -Pulmonary hypertension RENAL -Scleroderma renal crisis GI -GERD -Dysmotility -Diarrhea -Malabsorption CARDIAC -Pericarditis -Pericardial effusion -Cardiomyopathy MSK -joint & muscle pain -tendon friction rubs -osteolysis

Vascular Manifestations dcSSclcSSc Raynaud’s phenomenon ✔✔ (may precede other manifestations by years) dcSSc= diffuse cutaneous SSc lcSSc = limited cutaneous SSc

Skin Manifestations dcSSclcSSc Diffuse extremity swelling (early stage) ✔✔ Progressive skin tightening/thickening ✔ (distal & proximal extremities; may be rapid) ✔ (distal extremities) Calcinosis ✔✔✔ Telangiectasias ✔✔ Cutaneous ulcers ✔✔ Hyper- and hypopigmentation ✔✔

Skin Manifestations Telangiectasias Sclerodactaly and ischemic ulcers Digital ulcer

Pulmonary Manifestations dcSSclcSSc Interstitial lung disease, pulmonary fibrosis ✔✔✔ ✔ Pulmonary arterial hypertension ✔✔✔✔

Renal Manifestations dcSSclcSSc Scleroderma renal crisis ✔✔✔✔

Gastrointestinal Manifestations dcSSclcSSc GERD ✔✔✔ GI tract dysmotility ✔✔ Bacterial overgrowth, diarrhea ✔✔ Malabsorption ✔✔ Gastric antral vascular ectasias (GAVE) ✔ ✔

Cardiac Manifestations dcSSclcSSc Pericarditis ✔✔ Pericardial effusion ✔✔ Cardiomyopathy ✔✔ Conduction defects ✔✔  Symptomatic cardiac disease is rare. It’s presence carries a poor prognosis.  The presence of a pericardial effusion may herald scleroderma renal crisis.

Musculoskeletal Manifestations dcSSclcSSc Joint pain (arthralgia) Joint swelling (arthritis) ✔✔ Muscle pain (myalgias) Muscle inflammation (myositis) ✔✔ Tendon friction rubs ✔✔ (poor prognostic indicator) ✔ Bone resorption (osteolysis) ✔✔

Diffuse cutaneous SSc vs Limited Cutaneous SSc Diffuse  Skin involvement on extremities above & below elbows and knees (plus face and trunk) Limited  Skin involvement on extremities and only below elbows and knees (plus face) = affected = unaffected

Diffuse cutaneous SSc vs Limited Cutaneous SSc DiffuseLimited Progression of skin tightening often rapid; may soften late in course Slower progression of skin tightening; rarely softens Early internal organ involvement Late internal organ involvement Most frequent serious complications are scleroderma renal crisis and interstitial lung disease Most frequent serious complication is pulmonary arterial hypertension

Diffuse cutaneous SSc vs Limited Cutaneous SSc DiffuseLimited More likely to have anti-Scl 70, anti-RNA polymerase III, and anti-U3RNP antibodies More likely to have anticentromere and anti-Th/To antibodies Poorer prognosis – overall survival 40-60% at 10 years Better prognosis – survival > 70% at 10 years “CREST” syndrome Calcinosis Raynaud’s Esophageal dysmotility Sclerodactaly Telangiectasias

Treatment  No effective therapy for underlying disease process  Treatment is targeted to specific organs involved  Early recognition of internal organ involvement and aggressive treatment improve quality of life and increases survival time Successful management of patients with SSc requires an understanding of the potential complications of the disease, close monitoring, and early institution of targeted therapies

Treatment Raynaud’s Pulmonary arterial hypertension Scleroderma renal crisis Vascular Interstitial lung disease Cutaneous/Musculoskeletal Immune suppressors/anti- inflammatories Gastroesophageal reflux GI dysmotility Symptomatic

Treatment of Raynaud’s Phenomenon  Behavioral  Maintain warm core body temperature  Avoidance of smoking, sympathomimetic drugs (decongestants), and repeated trauma/vibration of the hands and fingers  Pharmacologic  First line: Long-acting calcium channel blockers (amlodipine, nifedipine)  Selective serotonin reuptake inhibitors (fluoxetine)  Phosphodiesterase-5 inhibitors (sildenafil)  Angiotensin II receptor blockers (losartan)  Topical nitrates  α 1-adrenergic receptor antagonists (prazosin)

Treatment of Severe Raynaud’s and Digital Ulcers  Potent vasodilators  Intravenous prostaglandin (iloprost, epoprostenol)  Endothelin antagonist (bosentan)

Treatment of Pulmonary Arterial Hypertension  Potent vasodilators  Parenteral prostaglandins (epoprostenol)  Inhaled prostacyclin (iloprost)  Endothelin receptor antagonist (bosentan)  Phosphodiesterase inhibitors (sildenafil)

Treatment of Scleroderma Renal Crisis  Close Monitoring!  Home blood pressure readings daily  If BP rises, evaluate for evidence of kidney damage/dysfunction (blood in urine and rise in creatinine) and new anemia  Treatment  ACE-INHIBITORS ( Treat aggressively to maximum dose as tolerated)  Dialysis if necessary (with continued Ace-inhibitor)  Use of Ace-inhibitors has changed what used to be an almost universally fatal complication of SSc to one with 1- year survival >70%, 5-year survival 60% (and long-term renal survival is 50-80%)

Treatment of Inflammatory Manifestations  Interstitial Lung Disease  Cyclophosphamide (+/- low-dose glucocorticoids)  Azathioprine  Mycophenolate mofetil  Investigational approaches: hematopoetic stem cell transplant, imatinib, rituximab, tadalafil  Cutaneous/Musculoskeletal  Physical therapy  Methotrexate  Azathioprine  Low-dose glucocorticoids – with caution because of risk of SRC

Monitoring for Complications  Consider annual transthoracic echocardiography and pulmonary function tests to screen for pulmonary arterial hypertension (more frequent screening if symptoms develop)  Pulmonary function tests and high resolution chest CT to assess for interstitial lung disease  In patients at high risk for scleroderma renal crisis - home blood pressure readings daily and regular testing of kidney function and urine

Prognosis dcSSc 40-60% at 10 years lcSSc >70% at 10 years Overall survival: Rapidly progressive skin involvement Older age at disease onset African- or Native-American race Severe lung involvement Large pericardial effusion Proteinuria, hematuria, renal failure Anemia Elevated ESR Abnormal ECG Anti-Scl 70 (anti-topoisomerase) antibodies – increased risk of severe pulmonary fibrosis Anti-RNA-polymerase antibodies – increased risk of scleroderma renal crisis Poor prognosis associated with:

Highlights  Systemic sclerosis is a multisystem autoimmune disease characterized by inflammation, disordered connective tissue metabolism and functional and structural abnormalities in blood vessels, all contributing to progressive fibrosis of the skin and visceral organs  Primary target organs: skin, lungs, kidney, GI tract  Cardinal clinical features: Raynaud’s, skin tightening, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, GI tract dysmotility

Highlights  Important aspects of management include:  Close monitoring for complications (including home BP and close monitoring for lung involvement)  Calcium channel blockers for Raynaud’s  Ace-inhibitors for scleroderma renal crisis  Vasodilators for pulmonary arterial hypertension  Immunosuppression for interstitial lung disease  There is no cure but many trials are on-going

Additional Resources Cleveland Clinic Center for Continuing Education management/rheumatology/systemic-sclerosis/ 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis Nov 1;72(11):

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