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  1. 1. Scleroderma is a group of rare, progressive diseases that involve the hardening and tightening of the skin and connective tissues — the fibers that provide the framework and support for your body. Localized scleroderma affects only the skin. Systemic scleroderma also harms internal organs, such as the heart, lungs, kidneys and digestive tract. Scleroderma is a chronic autoimmune disease characterized by fibrosis (or hardening), vascular alterations, and autoantibodies. There are two major forms: Limited systemic sclerosis/scleroderma's cutaneous manifestations mainly affect the hands, arms and face. Previously called CREST syndrome in reference to the following complications: Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasias. Additionally, pulmonary arterial hypertension may occur in up to one third of patients and is the most serious complication for this form of scleroderma. Diffuse systemic sclerosis/scleroderma is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys,
  2. 2. esophagus, heart and lungs. This form of scleroderma can be quite disabling. There are no treatments for scleroderma itself, but individual organ system complications are treated.Other forms of scleroderma include Systemic sine scleroderma, which lacks skin changes, but has systemic manifestations, and two localized forms which affect the skin, but not the internal organs: morphea, and linear scleroderma. Prognosis is generally good for limited cutaneous scleroderma patients that escape pulmonary complications. Prognosis is worse for diffuse cutaneous disease, particularly in older age, and for males. Death occurs most often from pulmonary, heart and kidney complications. The term systemic sclerosis is used to describe a systemic disease characterized by skin induration and thickening accompanied by various degrees of tissue fibrosis and chronic inflammatory infiltration in numerous visceral organs, prominent fibroproliferative vasculopathy, and humoral and cellular immune alterations.
  3. 3. The American College of Rheumatology (ACR) criteria for the classification of systemic sclerosis require one major criterion or two minor criteria, as follows: Major criterion: - Proximal scleroderma is characterized by symmetric thickening, tightening, and induration of the skin of the fingers and the skin that is proximal to the metacarpophalangeal or metatarsophalangeal joints. These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen) Minor criteria - Sclerodactyly is characterized by thickening, induration, and tightening of the skin, limited to only the fingers. - Digital pitting scars or a loss of substance from the finger pad: As a result of ischemia, depressed areas of the fingertips or a loss of digital pad tissue occurs. - Bibasilar pulmonary fibrosis includes a bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar portions of the lungs
  4. 4. on standard chest roentgenography. These densities may assume the appearance of diffuse mottling or a honeycomb lung and are not attributable to primary lung disease. Pathophysiology- Systemic sclerosis is a systemic disease that affects many organ systems. It is most obvious in the skin; however, the GI tract; the respiratory, renal, cardiovascular, and genitourinary systems; and numerous vascular structures are frequently involved. The symptoms result from inflammation and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagens. The levels of other macromolecules (eg, glycosaminoglycans, tenascin, fibronectin) found in the connective tissue are also increased. The vascular alterations show a predilection for the small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis and may represent the initiating event in its pathogenesis. 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.
  5. 5. Causes- The exact etiology of systemic sclerosis is unclear; however, the following pathogenic mechanisms are always present: - Endothelial cell injury - Fibroblast activation - Cellular and humoral immunologic derangement Environmental factors (eg, triggers or accelerators) for the development of systemic sclerosis include the following: - Silica exposure - Solvent exposure (vinyl chloride, trichloroethylene, epoxy resins, benzene, carbon tetrachloride) - Radiation exposure or radiotherapy Cytomegalovirus, human herpesvirus 5, and parvovirus B19 have been proposed as viral accelerating factors, but evidence of their involvement is inconclusive. Drugs: Bleomycin and pentazocine may be involved in the development of systemic sclerosislike disorders. Clinical
  6. 6. History Skin - Skin tightness and induration - Skin pigmentary changes (hyperpigmentation or hypopigmentation) - Diffuse pruritus - Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair. Vascular system - Raynaud phenomenon (recurrent vasospasm of the fingers and toes and usually occurs in response to stress or cold exposure) - Healed pitting ulcers in fingertips - Cutaneous and mucosal telangiectasis. Gastrointestinal system - Gastroesophageal reflux caused by lower esophageal sphincter (LES) incompetence and decreased or absent peristalsis in the lower two thirds of the esophagus (may lead to hoarseness, aspiration pneumonia, and dysphagia)
  7. 7. - Dyspepsia, bloating, and early satiety - Constipation alternating with diarrhea (may lead to malabsorption) Respiratory system - Progressive dyspnea - Chest pain (precordial) due to pulmonary artery hypertension - Dry persistent cough due to restrictive lung disease Musculoskeletal system - Arthralgia - Myalgia - Loss in joint range of motion and joint flexion contractures - Symptoms of carpal tunnel syndrome - Muscle weakness Cardiovascular system - Dyspnea due to pericardial effusion, congestive heart failure, or myocardial fibrosis
  8. 8. - Palpitations, irregular heart beats, and syncope due to conduction abnormalities - Congestive heart failure Genitourinary system - Erectile dysfunction - Dyspareunia (painful sexual intercourse) 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 with vocal cord inflammation or fibrosis Endocrine system -Hypothyroidism Renal system - Hypertension - Renal crisis - Chronic renal insufficiency
  9. 9. Neurologic - Facial pain and decreased sensation due to trigeminal neuralgia - Hand paresthesias and weakness due to carpal tunnel sensory peripheral entrapment neuropathy - Headache and stroke during hypertensive renal crisis Constitutional - Fatigue - Weight loss Physical Skin- Skin pigmentary changes include a salt-and-pepper appearance, with areas of hyperpigmentation alternating with hypopigmentation, or an overall appearance of tanned skin that persists long after sun exposure. - Telangiectasias are 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.
  10. 10. - The skin of the hands may be edematous or swollen early in the disease, and the patient may initially report this as puffy changes. This edematous stage precedes the indurated sclerotic stage; longer time to progression to the sclerotic phase indicates a better prognosis. A rapid progression of sclerosis is associated with a worse prognosis and, often, more extensive and aggressive visceral organ involvement with an increased risk of renal crisis or interstitial lung disease development. - In the sclerotic phase, the skin may appear tight and shiny, with a characteristic loss of hair, decreased sweating, and loss of the ability to make a skin fold. This process of thickening generally begins distally on the fingers. Structures such as skin creases and dorsal veins begin to fade. The skin induration usually progresses proximally in a continuous symmetrical fashion. - Calcinosis may develop on the fingers and extremitiesusually the extensor side of the forearms and the prepatellar areas; however, any area can be affected.
  11. 11. - Limited cutaneous systemic sclerosis involves areas distal to the elbow and knee but may involve the face and neck. CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias [not all are needed to be called CREST]) syndrome is an older term used to describe this subset of limited cutaneous systemic sclerosis. - Diffuse cutaneous systemic sclerosis refers to skin thickening on the trunk and proximal aspects of the extremities in addition to involvement of the face and distal aspects of the extremities. - Reduced oral aperture (microstomia) due to perioral involvement (measure incisor-to-incisor distance) may develop. - Edema may be the result of hydrophilic glycosaminoglycan deposits in the dermis. These changes (edema) may also reflect vascular changes, inflammation, and hydrostatic changes. The mechanism by which the edema resolves is not clear. Possibly, the edema becomes less apparent owing to a reduction of the hydrophilic glycosaminoglycan deposits as they are replaced
  12. 12. by the less hydrophilic fibrous collagens. Alternatively, the edema does not resolve but becomes clinically less apparent because of dermal thickening. The edema usually does not improve with the use of diuretic therapy. 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. A confirmatory minor salivary gland biopsy may show fibrosis without the pronounced lymphocytic aggregates that would be expected with primary Sjögren syndrome. In addition, patients with systemic sclerosis typically do not harbor anti-Ro and antiLa antibodies. - Oropharyngeal and esophageal cancers are more common in persons with diffuse systemic sclerosis. Vascular changes - Raynaud phenomenon results in characteristic color changes of pallor, cyanosis, and then redness
  13. 13. (white, blue, red), which are usually accompanied by numbness, tingling, or pain. These events may be triggered by cold, smoking, or emotional stress. Subintimal hyperplasia, typically present in systemic sclerosis vessels, can reduce the luminal diameter by more than 75%, limiting blood flow. This baseline reduction, in addition to the natural response to cold, accounts for the exaggerated response. - Raynaud phenomenon occurs in 5-15% of the general population. The female-to-male ratio is 4:1, with onset occurring during the teenaged years. - Raynaud phenomenon may precede obvious systemic sclerosis features by months or even years. Symptoms may last longer than 2 years. If this occurs without the development of characteristic connective-tissue diseases, a benign primary Raynaud phenomenon is generally indicated, with an excellent prognosis. However, 5-10% of this population may eventually develop systemic sclerosis.
  14. 14. - Infarction and dry gangrene of the fingers and toes may be due to severe vasospasm or to structural vascular occlusion. - Nail-fold capillary microscopy demonstrates fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated capillary loops. Musculoskeletal system - Patients may present with generalized arthralgias and morning stiffness that may mimic other systemic autoimmune diseases. 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. - The following palpable tendon friction rubs may be found 1)Shoulder - Scapula 2)Elbow - Olecranon 3)Knee - Patella
  15. 15. 4)Wrists - Flexor or extensor 5)Fingers - Flexor or extensor (rare) 6)Ankle - Anterior tibia, posterior tibia, peroneal, Achilles - 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. Respiratory system - Dry rales may be the only physical examination finding that suggests pulmonary involvement in systemic sclerosis. - An accentuated pulmonic second heart sound (P2) or right ventricular heave may indicate the presence of pulmonary artery hypertension. - Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure. A systolic pulmonary artery pressure of greater than
  16. 16. 35 mm Hg is considered to represent pulmonary artery hypertension. However, right-sided heart catheterization provides the most accurate pulmonary artery pressure - Pulmonary function testing is important in all patients with systemic sclerosis, although lung volumes can correlate poorly with extent of interstitial lung disease. Results of pulmonary function testing are ultimately abnormal in 80% of the patients.. - Patients are at risk for aspiration pneumonia due to lower esophageal sphincter incompetence 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
  17. 17. - Primary biliary cirrhosis (PBC) associated with antimitochondrial antibodies - Wide-mouth colonic diverticula - Malabsorption - Atrophy of smooth muscle and fibrotic changes leading to decreased peristalsis throughout the GI tract (gastroesophageal reflux disease [GERD], gastroparesis, constipation, pseudo-obstruction; - Anal sphincter incompetence Renal system - Patients with diffuse, rapid skin involvement have the highest risk (approximately 20-25%) of developing scleroderma renal crisis. Renal crisis occurs in about 10% of all patients with systemic sclerosis. - Renal crisis presents as accelerated hypertension, oliguria, headache, dyspnea, edema, and rapidly rising serum creatinine levels. - Scleroderma renal crisis that is not treated aggressively invariably leads to renal failure, requiring dialysis or renal transplantation, or even death.
  18. 18. - Preventing renal crisis is critical. Check blood pressure, monitor serum creatinine, and start angiotensin-converting enzyme (ACE) inhibitors early in at-risk patients. - Avoid high doses of corticosteroids since this is a significant risk factor for renal crisis. Cardiovascular system - Cardiac involvement indicates a worse prognosis. Pericardial effusion is usually asymptomatic and may develop in up to one third of patients with systemic sclerosis. Clinically significant pericarditis is rare. - Cor pulmonale may develop secondary to longstanding pulmonary fibrosis or pulmonary artery hypertension. - Conduction abnormalities, including complete A-V block, may be revealed with routine ECG or, more frequently, with 24-hour Holter monitor or echocardiography. - Infiltrative cardiomyopathy with replacement of cardiac muscle by fibrous tissue can lead to arrhythmias, heart failure, or both.
  19. 19. - Contraction band necrosis results from global ischemia and reperfusion. Patients may have recurrent episodes of vasospasm that are caused by the same mechanism involved in Raynaud phenomenon. This process can lead to cardiomyopathy and heart failure. Neurologic system: - Trigeminal neuralgia (uncommon) and carpal tunnel symptoms may result from peripheral entrapment neuropathies. Although rare, sensory neuropathies unrelated to entrapment may be present. Obstetrics and gynecology - Women may experience vaginal dryness, dyspareunia, and menstrual irregularities. - Pregnancy in women with systemic sclerosis is considered a high risk because of a higher risk of pregnancy loss and higher complication rates, but a diagnosis of systemic sclerosis is not an absolute contraindication for pregnancy. - Some symptoms may increase during pregnancy (eg, edema, arthralgias, GERD). Skin
  20. 20. manifestations are not reported to worsen, but the data on this matter are incomplete. Raynaud symptoms may improve during pregnancy, only to worsen after delivery. - Certain medications, such as D-penicillamine, cytotoxic agents, and ACE inhibitors, should be discontinued prior to pregnancy. Genitourinary system - Erectile dysfunction is common in males and is the presenting symptom in some cases. - Urinary bladder fibrotic infiltration may cause microhematuria. Differential Diagnosis - Eosinophilia Fibrosis Syndrome - Nephrogenic Systemic - Eosinophilia-Myalgia - Primary Biliary Cirrhosis -Eosinophilic Fasciitis -Primary Pulmonary Hypertension - Bleomycin-induced scleroderma -Digital sclerosis of diabetes mellitus
  21. 21. - Linear scleroderma -Radiation exposure -Vibration disease - Intestinal obstruction cardiomyopathy -Infiltrative -Amyloidosis DiagnosisLaboratory Studies - People with scleroderma usually have elevated blood levels of certain antibodies produced by the immune system like Topoisomerase I antibodies, Anticentromere antibodies., Fibrillarin antibodies and antibodies to ribonucleoprotein (RNP) & AntiRNA polymerase I and III antibodies - Cell-mediated abnormalities involve lymphocytes, mononuclear phagocytes, and mast cells. Imaging Studies - CT scan: HRCT scan is required to evaluate pulmonary involvement. Imaging may reveal a ground-glass appearance, possibly indicating active alveolitis. Ground-glass appearance on HRCT scan is the first abnormality observed during the development of lung fibrosis and is
  22. 22. subsequently replaced by honeycombing and traction bronchiectasis or bronchiolectasis. - Radiography: Chest radiography is an insensitive imaging procedure that shows only late findings of pulmonary fibrosis, such as increased interstitial markings. Extremity radiography should be performed to reveal calcinosis and resorption of the distal tufts of the digits. - Echocardiography: Conduct this test to evaluate the patient's pulmonary artery pressure and to assess septal fibrosis or pericardial effusions. - Right-heart catheterization: This remains the standard criterion for diagnosing pulmonary hypertension and is performed after an elevated pulmonary artery pressure is found on echocardiographic screening. - Esophagraphy: Perform this test to document esophageal dysmotility Procedures - Nail-fold capillary microscopy: This study demonstrates fewer capillaries than normal (ie,
  23. 23. capillary loop drop; see image below) and numerous dilated capillary loops. - Bronchoscopy with bronchoalveolar lavage: This is used to assess for active lung inflammation - Tissue sample- removal a small tissue sample (biopsy) of affected skin to be examined in the laboratory for abnormalities TreatmentMedication-The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Primary drug treatment aims at inhibiting tissue fibrosis and vascular and immune system alterations, which may be primarily responsible for the wide variety of systemic morbidity. Glucocorticosteroids-These agents are used to treat inflammatory complications (eg, myositis, pneumonitis). Prednisone (Sterapred)- Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone is inactive and must be metabolized to prednisolone.
  24. 24. Metabolism may be impaired in patients with liver disease. 2.5-5 mg PO qam initially, titrate upward prn to control symptoms, gradually decrease to maintain at lowest possible dose; doses >40 mg/d can increase risk of adrenal crisis Immunosuppressive agents- These agents inhibit key steps in immune reactions. Azathioprine (Imuran)- Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. 50-150 mg/d PO qam Methotrexate- Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. May suppress immune system. Satisfactory response observed in 3-6 wk following administration. 7.5-25 mg/wk PO/IV/IM/SC; adjust dose gradually to attain satisfactory response Cyclophosphamide - Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-
  25. 25. linking of DNA, which may interfere with growth of normal and neoplastic cell 50-150 mg/d PO single am dose; fluid intake is important (2-3 L/d); empty bladder hs Mycophenolate Mofetil- Used to help limit collagen formation. Potent selective, noncompetitive, and reversible inhibitor of purine synthesis. Has cytostatic effects on lymphocytes. 1-1.5 g PO bid Chelating agents- These agents may improve certain aspects of the disease. Penicillamine-Inhibits the formation of mature collagen crosslinks, rendering un-crosslinked molecules more susceptible to proteolytic degradation. 750 mg/d PO on empty stomach divided bid/tid Endothelin receptor antagonist- These agents bind to endothelin receptor present in endothelium and vascular smooth muscle. The effect can result in vasodilation. Bosentan-Dual endothelin A and B receptor antagonist for treatment of pulmonary arterial hypertension. Decreases both pulmonary and systemic vascular
  26. 26. resistance and increases cardiac output without increasing heart rate. 62.5 mg PO bid for 4 wk, then increase to 125 mg PO bid Phosphodiesterase type 5 inhibitor, peripheral vasodilator- These agents may increase vasodilation in the pulmonary vascular bed. E.g Tadalafil Sildenafil (Revatio)- Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting PDE-5. This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output. 20 mg PO tid; adjust dose in liver or renal failure. Therapy - Physical or occupational therapy. Therapists can help you manage pain, improve your strength and mobility, and work on performing essential daily tasks to maintain your independence. - Cosmetic procedures. The appearance of skin lesions associated with scleroderma may be helped by exposure to ultraviolet light. Laser
  27. 27. surgery also may help camouflage or eliminate these lesions. Surgery - Amputation. If finger ulcers caused by severe Raynaud's disease have developed gangrene, amputation may be necessary. - Lung transplants. People who have developed high blood pressure in the arteries to their lungs (pulmonary hypertension) may be candidates for lung transplants.