bubble_chart Overview

Scleroderma is a connective tissue disease characterized by the hardening of collagen fibers in various systems of the skin. Systemic scleroderma, which affects internal organs, is also known as systemic sclerosis. This disease ranks second among connective tissue diseases, following lupus erythematosus. It is more common in women, with a female-to-male ratio of approximately 3:1. The onset age is predominantly between 20 and 50 years.

bubble_chart Etiology

The exact cause remains unclear, but it can be summarized into the following aspects:

(1) Genetic factors: Some patients have a significant family history, with an increased incidence of HLA-B₈ in severe cases and chromosomal abnormalities observed in relatives. This suggests that genetic characteristics may involve a dominant allele on the X chromosome.

(2) Infectious factors: Many patients experience acute infections before onset, including pharyngitis, tonsillitis, pneumonia, scarlet fever, measles, sinusitis, etc. Paramyxovirus-like inclusions have been found in the striated muscles and kidneys of patients.

(3) Abnormal connective tissue metabolism: Patients exhibit widespread connective tissue lesions, with significantly increased collagen content in the skin. During active viral phases, skin lesions contain higher levels of soluble collagen and unstable intermolecular side chains. Fibroblast cultures from patients show markedly increased collagen synthesis activity.

(4) Vascular abnormalities: Many patients present with Raynaud's phenomenon, occurring not only in the extremities but also in visceral blood vessels. Histopathology reveals small vessel (stirred pulse) spasms and intimal hyperplasia in both skin lesions and visceral organs. Some consider this disease a primary vascular disorder, though vascular lesions are not observed in all patients, suggesting they may not be the sole disease cause.

(5) Immune abnormalities: This is the most emphasized perspective in recent years. Multiple autoantibodies can be detected in patients (e.g., antinuclear antibodies, anti-DNA antibodies, anti-ssRNA antibodies, antibodies against scleroderma skin extracts, etc.). B-cell counts are elevated, and humoral immunity is significantly enhanced. In systemic cases, circulating immune complex positivity rates exceed 50%, with most patients exhibiting hypergammaglobulinemia. Some cases are concurrent with lupus erythematosus, dermatomyositis, rheumatoid arthritis, Sjögren's syndrome, or Hashimoto's thyroiditis. Currently, the prevailing view is that this disease may be an autoimmune disorder triggered by persistent chronic infection against a specific genetic background.

bubble_chart Pathological Changes

Early-stage damage: Collagen fiber bundles swell and homogenize, with lymphocyte-dominated infiltration between collagen fibers and around blood vessels. Advanced-stage damage: The dermis thickens significantly, collagen fiber bundles hypertrophy and harden, blood vessel walls thicken, lumens narrow, and may even become occluded. Sebaceous glands atrophy, and sweat glands decrease. Visceral damage mainly involves interstitial and vascular wall collagen fiber proliferation and sclerosis.

bubble_chart Clinical Manifestations

(1) Localized scleroderma: According to the morphology and distribution of skin lesions, it can be further divided into: guttate scleroderma, plaque scleroderma, linear scleroderma, and generalized scleroderma.

(2) Systemic scleroderma: Depending on the extent of involvement, severity, progression rate, and prognosis, it can be further classified into: acral scleroderma and diffuse scleroderma.

(3) Localized scleroderma

1. Plaque lesions: Initially, they appear as round, oval, or irregular, pale red or purplish-red edematous hardened patches. After several weeks or months, they gradually enlarge, reaching diameters of 1–10 cm or larger, and the color fades to pale yellow or ivory, often surrounded by a faint purple or reddish halo. The surface is dry and smooth, with a waxy sheen, and feels leathery to the touch, sometimes accompanied by telangiectasia. There is no sweating or hair growth in the affected area. Lesions may be single or multiple. The progression is slow, and after several years, the hardness lessens, gradually giving way to white or light brown atrophic scars. They can occur anywhere but are most common on the trunk. Among the localized types, this form is the most prevalent, accounting for about 60%.

Generalized morphea is rare. Its onset and development resemble plaque scleroderma, but it is characterized by numerous lesions, extensive areas of skin hardening, and widespread distribution without systemic involvement. It commonly affects the chest, abdomen, and proximal limbs but may also involve the face, neck, scalp, forearms, and calves. It is often associated with arthralgia, neuralgia, abdominal pain, migraine, and mental disorders. A few patients may progress to systemic scleroderma.

2. Linear lesions: These often follow a linear distribution along limbs or intercostal regions but may also occur on the scalp or forehead. The course resembles plaque lesions, but the skin lesions show significant depression, and sometimes the underlying muscles or even bones may exhibit decalcification, thinning, or absorption. This type is more common in children.

3. Guttate lesions: These mostly occur on the neck, chest, shoulders, and back. The lesions are small hardened spots the size of mung beans to soybeans, clustered or arranged linearly. The surface is smooth and shiny, with a nacreous or ivory color, surrounded by pigmentation. Over time, atrophy may develop. This type is relatively rare.

(4) Systemic sclerosis: The main differences between the acral and diffuse types lie in the fact that the acral type begins in the hands, feet, face, and other areas, with relatively limited involvement, slower progression, and a better prognosis. Given the clinical similarities between the two types, they are summarized as follows:

1. Skin: Can be divided into the edema, hardening, and late-stage (third-stage) atrophy phases.

(1) Edema phase: The skin becomes tense and thickened, with loss of wrinkles, appearing pale or yellowish, with reduced skin temperature and non-pitting edema. In the acral type, edema often starts in the hands, feet, and face, spreading to the arms, neck, and shoulders. In the diffuse type, it typically begins on the trunk and then extends outward.

(2) Hardening phase: The skin hardens, with a waxy sheen, and cannot be pinched. Depending on the affected area, symptoms may include restricted finger movement, fixed facial expression, difficulty opening the mouth or closing the eyes, and a tight sensation in the chest. The affected skin shows pigmentation, interspersed with hypopigmented patches, sparse hair growth, and may also experience cutaneous pruritus or paresthesia.

(3) Atrophy phase: The skin atrophies and thins, resembling parchment, and even the subcutaneous tissue and muscles may atrophy and harden, adhering tightly to the bones, forming board-like plaques. Stubborn ulcers are prone to develop at the fingertips and joints, accompanied by reduced sweating and hair loss in the affected area. A few cases may exhibit telangiectasia.

The above skin manifestations are common in various forms of scleroderma, but it is worth noting that there are cases of sclerosis without any skin symptoms.

2. Muscles: Involvement is not uncommon, with symptoms including muscle weakness and diffuse pain. Some cases may resemble polymyositis clinically, and significant muscle involvement may lead to muscle atrophy.

3. Bones and Joints Initial symptoms of joint redness, swelling, and pain account for about 12%. During the course of the disease, 46% develop joint changes, ranging from Grade I restricted movement to joint stiffness and even contracture deformities. Hand changes are the most common, with fingers becoming completely stiff, shortened, or deformed. Absorption of the terminal phalanges may present as a truncated appearance.

4. Viscera

(1) Digestive system: Tongue movement may be restricted due to frenulum contracture, teeth may become loose due to root resorption, and esophageal involvement is quite common (45-90%), manifested as dysphagia, often accompanied by vomiting, retrosternal or epigastric fullness, or a burning pain sensation (caused by reflux esophagitis). Gastrointestinal involvement may include loss of appetite, abdominal pain, abdominal distension and fullness, and alternating diarrhea and constipation.

(2) Cardiovascular system: Approximately 61% of patients have varying degrees of cardiac involvement. Myocarditis, pericarditis, or endocarditis may occur. Clinical manifestations include shortness of breath, chest tightness, colicky heart pain, and arrhythmias. Severe cases may lead to left-sided or total heart failure (or right heart failure due to pulmonary damage causing cor pulmonale), and even sudden cardiac death. Electrocardiograms show abnormal findings.

(3) Respiratory system: When the lungs are involved, widespread pulmonary interstitial fibrosis may occur, with reduced vital capacity. Clinical manifestations include cough and progressive dyspnea.

(4) Urinary system: Renal involvement occurs in about 75% of cases, leading to sclerosing glomerulitis, chronic proteinuria, hypertension, and azotemia. Severe cases may result in acute renal failure.

(5) Neuropsychiatric system: A few cases present with polyneuritis (including cranial nerves), convulsions, epileptic seizures, personality changes, cerebral arteriosclerosis, cerebral hemorrhage, as well as elevated cerebrospinal fluid protein and abnormal electroencephalograms.

5. Others: Raynaud's phenomenon may also occur (mostly in the extremities); calcium deposits may form in soft tissues around fingers or other joints or on the extensor surfaces of limbs; some cases exhibit intermittent irregular fever, lack of strength, and weight loss during the active phase of the disease.

Some authors refer to the combination of calcinosis, Raynaud's phenomenon, sclerodactyly, and telangiectasia as CRST syndrome. When esophageal involvement is also present, it is termed CREST syndrome, considered a subtype of systemic sclerosis with a relatively better prognosis.

bubble_chart Auxiliary Examination

Whether localized or systemic, the sensory chronaxy measurement of both affected and unaffected skin is significantly prolonged compared to normal (prolonged by 5–12 times).

In the systemic type, the erythrocyte sedimentation rate is often accelerated. In some cases, lupus cells can be found in the blood. The positive rate of fluorescent antinuclear antibodies can reach about 95%, with the speckled pattern being the most common fluorescent nuclear pattern. The nucleolar pattern can also be observed, and anticentromere staining can be seen in CRST syndrome. The detection of anti-Scl-70 antibodies using immunodiffusion techniques has high specificity for the diffuse type. Examination of the nail fold with skin capillary microscopy reveals blurred capillaries in most cases, with exudation and edema, a significant reduction in the number of vascular loops, obvious dilation and tortuosity of vascular branches, sluggish blood flow, and often accompanied by petechiae.

X-ray examination of systemic patients often shows: ① Widening of the periodontal membrane; ② Disappearance of esophageal and gastrointestinal motility, with narrowing at the lower end and dilation proximally, reduced small intestine motility, proximal small intestine dilation, and spherical changes in the colonic haustra; ③ Osteolysis of the fingertips; ④ Thickening of lung markings or the presence of small cystic changes; ⑤ Shadows of calcium salt deposition in soft tissues.

bubble_chart Diagnosis

The diagnosis of this disease can be confirmed based on skin sclerosis. Sensory chronaxy measurement, skin capillary microscopy, and histopathological examination provide reference value for diagnosing the condition.

bubble_chart Treatment Measures

There is currently no specific treatment for this disease, and some cases may stop progressing or improve after treatment. There is no significant difference in treatment between the two types.

(1) General treatment: Remove infectious foci, improve nutrition, keep warm, and avoid severe mental stimulation.

(2) Vasoactive agents: Mainly used to dilate blood vessels, reduce blood viscosity, and improve microcirculation.

1. Salvia injection: Each milliliter contains 2g of raw Salvia miltiorrhiza. Administer 8–16ml added to 500ml of low-molecular-weight dextran intravenously once daily for 10 sessions as one course, either continuously or intermittently. It has some effect on skin sclerosis, difficulty in opening the mouth and swallowing, pigmentation, joint stiffness and pain, and Raynaud's phenomenon, but it is not suitable for those with bleeding tendencies or poor kidney function.

2. Guanethidine: Initial dose of 12.5mg/d, gradually increasing to 25mg/d, and after 3 weeks, adjusted to 37.5mg/d. Effective for Raynaud's phenomenon (efficacy rate about 50%).

3. Methyldopa: 125mg three times daily (or 1–2g/d). Can inhibit Raynaud's phenomenon.

(3) Connective tissue formation inhibitors:

1. D-penicillamine: Can interfere with the cross-linking complexes of collagen molecules and inhibit new collagen biosynthesis. Start with 250mg/d, gradually increasing to a full dose of 1g/d, taken continuously for 2–3 years. It shows significant efficacy for skin thickening and nutritional changes, improves microcirculation and lung function, reduces the incidence of organ involvement, and increases survival rates. During medication, it may irritate the Yaodui kidneys and suppress bone marrow, leading to leukopenia and thrombocytopenia. If taken with L-glutamine (0.2g three times daily), the efficacy is better than D-penicillamine alone.

2. Colchicine: Can prevent the conversion of procollagen to collagen and inhibit collagen accumulation. Dosage is 0.5–1.5mg daily, taken continuously for 3 months to several years. It has some effect on skin sclerosis, Raynaud's phenomenon, and esophageal changes. If diarrhea occurs during treatment, reduce the dose or administer β-galactosidase.

3. Asiaticoside: An active ingredient extracted from the Chinese medicinal herb Centella asiatica. Experiments have shown it can inhibit fibroblast activity and soften connective tissue. Usage: Tablets (each containing 10mg of asiaticoside), take 3–4 tablets three times daily; injection (each 2ml ampoule contains 20mg of asiaticoside), intramuscular injection 2–3 times weekly, one ampoule each time. It is quite effective for softening sclerotic skin, reducing tissue edema, relieving joint pain, and healing ulcers (efficacy rate about 80%). Effects usually begin to appear after about one month.

(4) Anti-inflammatory agents: Glucocorticoids are effective for early-stage inflammation, edema, and joint symptoms in systemic scleroderma. Typically, start with prednisone 30mg/d orally, then gradually reduce to a maintenance dose of 5–10mg/d. Avoid use if proteinuria, hypertension, or azotemia is present.

(5) Immunosuppressants: Such as azathioprine (75–150mg/d), chlorambucil (6mg/d), and cyclophosphamide (50–200mg/d) can be selected. They have some efficacy for joint, skin, and kidney lesions. Combined use with glucocorticoids often enhances efficacy and reduces glucocorticoid dosage.

(6) Physical Therapy Includes audio frequency electrotherapy, tuina, and hot baths, among which audio frequency electrotherapy has a relatively good therapeutic effect on this disease. For localized cases, it can lead to complete recovery, while for systemic cases, it can soften the skin, improve tissue nutrition, and promote ulcer healing. Initially, treatment is administered 1–2 times daily, lasting 20–30 minutes each session. Once the condition improves, the frequency can be reduced to once every other day, with a longer duration of treatment.

(7) Others: Such as block therapy, vitamin E, compound phosphoesterase tablets, and testosterone propionate can be appropriately selected for combined use.

bubble_chart Prognosis

Some mild cases may resolve spontaneously. Late abortion or normal delivery can exacerbate the condition. Once the lungs, heart, kidneys, or other organs are involved, the condition deteriorates rapidly, with 20–40% of patients dying from renal failure. Patients with serum creatinine levels >6 mg/dl have a particularly poor prognosis. Dialysis and kidney transplantation may help prolong the patient's life.

bubble_chart Differentiation

(1) Localized scleroderma needs to be differentiated from the following diseases.

1. Atrophoderma: The early lesions vary in size, appearing skin-colored or bluish-white, slightly depressed or raised, with a wrinkled surface and no hardness upon touch.

2. Lichen sclerosus et atrophicus: The skin lesions are shiny, pale purple, flat papules of varying sizes, often clustered but not merging. The surface has follicular keratotic plugs, sometimes with blisters, gradually leading to skin atrophy.

(2) Systemic sclerosis needs to be differentiated from the following diseases.

1. Adult scleredema: Skin lesions usually start from the head and neck, spreading to the shoulders and back, with deep dermal swelling and stiffness. There is no local pigmentation, atrophy, or hair loss, and it tends to resolve spontaneously.

2. Mixed connective tissue disease: Patients exhibit a combination of systemic lupus erythematosus, scleroderma, dermatomyositis, or polymyositis, including Raynaud's phenomenon, non-pitting edema of the face and hands, sausage-like finger swelling, fever, non-erosive polyarthritis, muscle weakness, or myalgia. Antibodies to extractable nuclear antigen (ENA) and RNP may show high-titer positive reactions.