1.Early symptoms: The most common initial manifestations of systemic sclerosis are Raynaud’s phenomenon and insidious swelling of the extremities and face, with gradual thickening of the skin of the fingers. In about 70% of cases, the first symptom is Raynaud’s phenomenon, which can precede other symptoms of scleroderma (finger swelling, arthritis, visceral involvement) by 1~2 years or occur simultaneously with other symptoms. Polyarthrosis is also a prominent early symptom. Gastrointestinal disorders (heartburn and dysphagia) or respiratory symptoms are occasionally the first manifestations of the disease. Patients may have irregular fever, decreased appetite and weight loss before the onset of the disease. 2. Skin: In almost all cases, skin sclerosis begins in the hands, with shiny, tight fingers and back of the hands, disappearance of finger folds, and sparse sweat hair, followed by involvement of the face and neck. Patients have a feeling of tightness in the upper chest and shoulders. Transverse thick stripes may appear in front of the neck, and when tilting the head, patients may feel tightness in the skin of the neck, which is rarely seen in other diseases. Facial skin involvement may present as a mask-like appearance. There may be radiolucency around the mouth, thinning of the lips, and a pointed nose. There may be hyperpigmentation or depigmentation of the affected skin. Skin lesions may be confined to the fingers (toes) and face or may extend centripetally to the upper arms, shoulders, forehead, back, abdomen, and legs. Some may involve the entire skin within a few months, some progress gradually over several years, and some progress intermittently, usually with the extent and severity of skin involvement peaking within three years. Clinically, skin lesions can be divided into edematous, sclerotic, and atrophic phases. In the edema phase, the skin is non-concaveable and swollen, with a tough feeling when touched; in the sclerosis phase, the skin is waxy and shiny, clinging to the subcutaneous tissue and not easily pinched up; in the atrophy phase, the superficial dermis becomes thin and brittle, and the epidermis is loose. 3, bone and joint: polyarthralgia and muscle pain are often early symptoms, but can also appear obvious arthritis. About 29% may have erosive arthropathy. Due to the thickening of the skin and the tightening of the joints under it, the joints are contracted and function is limited. Due to fibrosis of the tendon sheath, a leather-like friction sensation can be detected when the affected joint is moved actively or passively, especially at the wrist, ankle, and knee. X-ray shows narrowing of the joint space and osteosclerosis of the joint surface. Due to intestinal malabsorption, disuse and reduced blood perfusion, there is often osteoporosis. 4, digestive system: digestive tract involvement is a common manifestation of scleroderma, second only to skin involvement and Raynaud’s phenomenon. Any part of the digestive tract can be involved, with esophageal involvement being the most common (90%), followed by anal and rectal (50-70%), and less frequent in the small intestine and colon (40% and 10-50%). (1) Oral cavity: restricted mouth opening, shortened tongue tie, widened periodontal space, gingival recession, tooth loss, and atrophy of the alveolar process bone. (2) Esophagus: Impaired function of the lower esophageal dilator muscle can lead to retrosternal burning sensation and acid reflux. Long-term can cause complications such as erosive esophagitis, bleeding, and lower esophageal stricture. Weak peristalsis in the lower 2/3 of the esophagus can cause dysphagia and painful swallowing. Histopathology showed atrophy of the smooth muscle of the esophagus, fibrosis of the submucosa and lamina propria, and varying degrees of mucosal thinning and erosion. Barrett’s metaplasia may occur in 1/3 of patients with scleroderma, and these patients are at increased risk for complications such as stricture and adenocarcinoma. Esophageal function can be examined by esophageal manometry, prone dilute barium meal imaging, esophagoscopy and other methods. (3) Small intestine: It can often cause mild abdominal pain, diarrhea, weight loss and malnutrition. Malnutrition is due to slow intestinal peristalsis and excessive growth of microorganisms in the intestinal fluid, and the application of broad-spectrum antibiotics such as tetracycline is often effective. Occasionally, pseudo-intestinal obstruction may occur, manifested by abdominal pain, distention and vomiting. Similar to esophageal involvement, fibrosis and muscle atrophy are the main causes of these symptoms. After the degeneration of the mucosal muscle layer of the intestinal wall and the entry of air beneath the mucosa of the intestinal wall, a cystic pneumatosis sign of the intestinal wall may occur. (4) Large intestine: Barium enema may reveal large intestine involvement in 10-50% of patients, but the clinical symptoms are often mild. Constipation, lower abdominal distention and fullness, and occasionally diarrhea may occur after involvement. Due to muscle atrophy of the intestinal wall, there can be characteristic enteritis (diverticula) with large openings in the transverse and descending colon, and rectal prolapse and fecal incontinence can occur if the anal sphincter is involved. (5) CREST syndrome: Patients may develop biliary cirrhosis. (5) Lung: Lung involvement is prevalent in scleroderma. The most common symptoms at the beginning of the disease are shortness of breath during exercise and reduced tolerance of activity; dry cough appears later. As the disease progresses, the chance of lung involvement increases, and once involved, it is progressive and does not respond well to treatment. Interstitial pulmonary fibrosis and pulmonary artery vasculopathy often coexist, but often one of these pathologic processes predominates. In patients with diffuse scleroderma with anti-Scl-70 positivity, interstitial fibrosis is often more severe; in CREST syndrome, pulmonary arterial hypertension is often more pronounced. Interstitial fibrosis is often preceded by eosinophilic alveolitis. During the alveolitis phase, high-resolution CT may show hairy glass-like changes in the lungs, and bronchoalveolar lavage may reveal an increase in cells in the lavage fluid. x-ray chest radiographs show coarse interstitial texture and, in severe cases, reticulonodular changes, most notably at the base. Pulmonary function tests show restrictive ventilation, reduced lung volume, reduced lung compliance, and reduced gas diffusion. Small bursting sounds can be heard on physical examination, especially at the base of the lungs. Occlusion, fibrosis and inflammatory changes are the causes of lung involvement. Pulmonary hypertension is often a difficult problem and is the result of prolonged fibrosis of the interstitial and peribronchial lung or intimal hyperplasia of the small interstitial arteries. Pulmonary hypertension often progresses slowly and is not usually clinically detectable unless severe irreversible lesions develop in later stages. Early pulmonary hypertension can be detected by noninvasive echocardiography. Autopsies show small to medium-sized pulmonary artery intimal hyperplasia and mucinous aneurysm-like changes in the intima in about 29-47% of patients. Cardiac catheterization revealed pulmonary hypertension in 33% of patients. 6. Heart: Pathological examination showed lamellar myocardial fibrosis in 80% of patients. Clinical manifestations are shortness of breath, chest tightness, palpitations, and edema. Clinical examination may include ventricular gallop rhythm, sinus tachycardia, congestive heart failure, and occasionally pericardial friction sounds may be heard. Echocardiography shows pericardial hypertrophy or fluid accumulation in about half of the cases, but clinical myocarditis and pericardial tamponade are uncommon. 7. Kidney: The renal lesions in scleroderma are most prominent in the interlobular arteries, arcuate arteries and small arteries, the most prominent of which is the small interlobular artery. The intima has fibroblast proliferation, mucinous changes, acidic mucopolysaccharide deposition and edema. The vascular smooth muscle cells undergo hyaline degeneration. There was fibrosis in the extravascular membrane and surrounding interstitium. The glomerular basement membrane is irregularly thickened and cleaved. The clinical manifestations of scleroderma nephropathy vary. Some patients have years of skin and other visceral involvement without renal damage; some develop renal crisis during the course of the disease, i.e., sudden onset of severe hypertension and acute renal failure, and if left untreated, often die of heart failure and uremia within a few weeks. Although the initial phase of renal crisis may be asymptomatic, most patients feel increased fatigue, shortness of breath, severe headache, blurred vision, convulsions, confusion and other symptoms. Laboratory tests reveal normal or increased creatinine, proteinuria and/or microscopic hematuria, and there may be microvascular hemolytic anemia and thrombocytopenia. Predictors of renal crisis are the following: (i) systemic scleroderma; (ii) disease duration less than 4 years; (iii) rapid disease progression; (iv) positive anti-RNA polymutase III antibody; (v) taking large amounts of hormones or small doses of cyclosporine; and (vi) sudden increase in serum renin levels.