gives Connective Disease a

bad name!

1. Scleroderma (limited and diffuse) always causes significant skin tightening. 2. ANA abs are always positive. 3. Symptoms can include lung, skin, GI, vascular, heart, and renal. 4. Raynauds is always bad in the scleroderma conditions.

5. Treatment of the various 0% 0% 0% 0% 0% symptoms is almost always easy. 1 2 3 4 10 5

Countdown • Major criterion or two minor criteria for diagnosis • Major criterion • Proximal Scleroderma • Minor criteria • Sclerodactyly, digital pitting or , or loss of substance from finger pad, bibasilar pulmonary fibrosis

• Localized scleroderma • Systemic sclerosis Diffuse cutaneous Limited cutaneous Linear scleroderma CREST syndrome “En coup de sabre” Systemic sclerosis sine scleroderma

• Overlap syndromes

• Scleroderma-like syndromes • Toxin- or drug-induced scleroderma Vinyl chloride Organic solvents and epoxy resins Eosinophilic syndrome (L-tryptophan) Toxic oil syndrome Bleomycin • Vibration injury

• Scleromyxedema

• Scleredema

• Eosinophilic fasciitis

• Graft-versus-host disease

• Prevalence Clinical Associations • Anti-Topoisomerase 20-40% Diffuse skin disease ILD, Increased Mortality, cardiac Disease • Anti-Centromere 20-40% CREST, Digital loss, Pulmon HTN, PBC • RNA Polymerase 4-20% Renal crisis, card- iac disease, diff- use skin disease • PM-SCL 1% Myositis • RNP 5% MCTD • U3RNP 8% African-american males, diffuse skin disease, pulmonary disease,

• Episodic, reversible digital skin color change white to blue to red well-demarcated

• Due to vasospasm

• Usually cold-induced

• Primary (Raynaud’s disease) and secondary forms • Connective tissue diseases Scleroderma, systemic erythematosus, MCTD, undifferentiated CTD, Sjogren’s syndrome,

• Occlusive arterial disease Atherosclerosis, anti-phospholipid antibody syndrome, Buerger’s disease

• Vascular injury Frostbite, vibratory trauma

• Drugs and toxins Beta blockers, vinyl chloride, bleomycin, ergot, amphetamines, cocaine

• Hyperviscosity/cold-reacting proteins Paraproteinemia, polycythemia, , cryofibrinogenemia, cold agglutinins

Feature Primary Raynauds Systemic Sclerosis • Sex F:M 4:1 F:M 3:1 • Age at Onset Puberty 25 yrs or older • Frequency Usually <5/day >5-10/day • Precipitants Cold, emotional stress Cold • Ischemic injury Absent Present • Other vasomotor Yes Yes • Phenomenon • ANAs Absent 90-95% • Anti-Centromere Absent 50-60% • Anti-SCL-70 ab Absent 20-30% • Abn capillaroscopy Absent >95% • The diagnosis of MCTD can be made if 3 (one of which must be myositis or synovitis) of 5 clinical criteria and anti-RNP are present

• Serologic criteria • anti-RNP

• Clinical criteria • swollen hands, synovitis, clinical or biopsy-proven myositis, Raynaud’s phenomenon, acrosclerosis with or without proximal systemic sclerosis

• Major criterion or two minor criteria for diagnosis Episodic, reversible digital skin color change white to blue to red • Major criterion well-demarcated • ProximalDue scleroderma to vasospasm Usually cold-induced

• Minor criteria Primary (Raynaud’s disease) and secondary

• Sclerodactyly forms • Digital pitting or scars or loss of substance from finger pad • Bibasilar pulmonary fibrosis

System 0 (normal) 1 (mild) 2 (moderate) 3 (severe) 4 (end-stage) General Normal Weight loss of 5.0- Weight loss of 10.0- Weight loss of 15.0- Weight loss of 20+kg 9.9kg or hematocrit 14.9kg or hematocrit 19.9kg or hematocrit or hematocrit <25.0 33.0-36.9 29.0-32.9 25.0-28.9

Raynaud’s Normal Vasodilator requiring Digital pitting scars Active digital pit Digital gangrene ulceration Skin score 0 1-14 15-29 30-39 40+ Finger to palm (cm) <1 1.0-1.9 2.0-3.9 4.0-4.9 5.0+ Proximal Weakness None Mild Moderate Severe Cannot walk GI Status Normal Requires antireflux High dose antireflux Malabsorption TPN required medication or medication or syndrome or episodes abnormal small bowel antibiotics for of pseudo-obstruction series bacterial overgrowth

Lung Normal FVC or DLCO 70-80% FVC or DLCO 50-69% FVC or DLCO 50% Oxygen required predicted or rales or predicted or mild predicted or fibrosis on chest x-ray pulmonary moderate-severe hypertension pulmonary hypertension

Heart Normal ECG conduction Arrhythmia or RVE + LVEF <40% Congestive heart defect of LVEF 45- LVE or LVEF 40-44% failure or arrhythmia 49% requiring medication Kidney Normal Creatinine 1.3-1.6 or Creatinine 1.7-2.9 or Creatinine 3.0+ Requires dialysis uprot 2+ uprot 3-4+ • This is the really difficult part of the disease process • There is no specific drug that is available that is known for sure to stop the fibrotic process. 1. Calcium Channel Blockers 2. ACE Inhibitors, ARBs 3. PDE4 Inhibitors? 4. Bosentan (Tracleer) 5. Surgery (Which can include debridement of necrotic tissue or abcess drainage but un- fortunately often is amputation of part or all of a digit) 1. Fluoxetine 20 mg/day 2. Omega-3 10 caps/day marine triglycerides 3. Gamolenic acid 12 caps/day 4. Thymoxamine 40-80 mg QID (2 wk trial) 5. Iloprost IV Up to 3 ug/hour over 6 hrs for 3-7 days 6. Prostaglandin E1 60 ug in 250 cc over 3h for 3-7 days 1. for brief periods of time early in the disease and primarily for edema 2. Methotrexate 3. D-Penicillamine 4. Cytoxan or Imuran 5. Gleevac 6. Thalidomide type compounds may have future promise 1. Bosentan 2. PDE4-Inhibitors (Sildenafil) 3. Prostaglandin vasodilators 1. ACEs or ARBs and strict BP control (benefits early without hypertension?) 2. High dose corticosteroids should be avoided for any manifestations in general as they may lead to a renal crisis and should not usually exceed 15 mg/day 1. Aggresssive use of PPIs and H2s (higher doses than usual?) 2. Metoclopramide ? 3. Dilatation 4. Surgery? 1. This is where high dose steroids may be used especially for severe myositis but with close monitoring of blood pressure

2. Methotrexate, Imuran, Cytoxan 1. Diuretics

2. ACEs 1. Monoclonal Antibodies or Anticytokine Compounds that inhibit profibrotic signaling pathways 2. Immune Modulators-Belimumab, and Abatacept 3. Stem Cell Transplants

• This patient is 55 year old female with about a 10 year history of slight facial tightening but no sclerodactyly and no widespread skin tightening. She has a + SCL-70 ab. The raynauds has caused severe digital ischemia and loss of the ends of 3 fingers. About 3 years she began to develop severe SOB. Subsequently by open lung biopsy she was found to have sever interstitial pneumonitis and fibrosis. IV cytoxan times 6 months has helped stabilize her. Does she have Scleroderma? I believe so in spite of no skin involvment. • This patient is a 55 yr old female with a + ANA of 1:640 in a speckled pattern. She has very severe GERD, very resistant to treatment and pretty severe Raynauds also difficult to treat with frequent pitting ulcers on her finger tips and periungual infections. There has been no skin involvement and no CP or renal disease. Does she have Scleroderma? I believe she best fits into a “sine scleroderma” type picture. • This patient is a 60 year old female with about 8-10 years of moderate Raynauds with a + SCL-70 ab. She has prominent facial and moderate facial tightening and mild Sclerodactyly but no proximal sclerodermatous changes. She has borderline pulmonary HTN but no other internal manifestations. She does have distal finger pulp loss and significant acroosteolysis. Does she have Scleroderma? Yes and even though she clinically sounds like she has CREST this is probably better classified as diffuse SCL.

1. Scleroderma (limited and diffuse) always causes significant skin tightening. 2. ANA abs are always positive in the scleroderma syndromes. 3. Symptoms can involve lung, skin, GI, vascular, heart, and renal. 4. Raynauds is always bad in the scleroderma conditions.

5. Treatment of various symptoms is 0% 0% 0% 0% 0% always easy. 1 2 3 4 10 5

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