| disease | Progressive Systemic Sclerosis |
| alias | Systemic Sclerosis, Scleroderma |
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 most frequently observed between 20 and 50 years.
bubble_chart Etiology
It remains unclear, but can be summarized into the following aspects:
(1) Genetic factors: Some patients have a clear family history, with an increased incidence of HLA-B8 in severe cases and chromosomal abnormalities in relatives. It is suggested that the genetic characteristics may lie in the dominant allele of the X chromosome.
(2) Infectious factors: Many patients often 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 the active phase of the disease, there is an abundance of soluble collagen and unstable intermolecular side chains in skin lesions. Fibroblast cultures from patients show markedly increased collagen synthesis activity.
(4) Vascular abnormalities: Many patients experience Raynaud's phenomenon, which is not limited to the extremities but also occurs 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, but since vascular lesions are not observed in all patients, others argue that vascular abnormalities are not 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.). Patients have an increased number of B cells and significantly enhanced humoral immunity. In systemic cases, the positive rate of circulating immune complexes exceeds 50%, and most patients exhibit hypergammaglobulinemia. Some cases are often concurrent with lupus erythematosus, dermatomyositis, rheumatoid arthritis, Sjögren's syndrome, or Hashimoto's thyroiditis. Currently, it is widely believed that this disease may be an autoimmune disorder resulting from persistent chronic infection superimposed on a certain genetic background.bubble_chart Pathological Changes
Early-stage lesions show swelling and homogenization of collagen fiber bundles, with lymphocyte-dominated infiltration between collagen fibers and around blood vessels. Advanced-stage lesions exhibit significant thickening of the dermis, hypertrophy and sclerosis of collagen fiber bundles, thickening of blood vessel walls, narrowing of the lumen, and even occlusion. Sebaceous glands atrophy and sweat glands decrease. Visceral lesions mainly involve interstitial and vascular wall collagen fiber proliferation and sclerosis.
bubble_chart Clinical Manifestations
(1) Localized scleroderma Based on the morphology and distribution of skin lesions, it can be further divided into: guttate scleroderma, plaque scleroderma, linear scleroderma, and generalized morphea.
(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.
1. Plaque lesions Initially, the lesions appear as round, oval, or irregularly shaped, pale red or purplish-red edematous hardened patches. After weeks or months, they gradually enlarge, reaching diameters of 1–10 cm or more. The color fades to pale yellow or ivory, often surrounded by a faint purple or reddish halo. The surface is dry, smooth, and waxy in appearance, with a leather-like texture upon touch, sometimes accompanied by telangiectasia. There is no sweating or hair growth in the affected area. The lesions may be single or multiple. The progression is slow, and after several years, the hardness lessens, gradually forming white or light brown atrophic scars. These can occur anywhere but are most common on the trunk. This form is the most prevalent in localized scleroderma, accounting for about 60%.
Generalized morphea is rare. Its onset and development resemble plaque scleroderma, but it is characterized by numerous lesions, extensive 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 cases 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 progression is similar to plaque lesions, but the skin lesions exhibit significant depression. Sometimes, the underlying muscles or even bones may show decalcification, thinning, or absorption. This type is more common in children.
(4) Systemic sclerosis The main differences between acral and diffuse types lie in the fact that the acral type begins in the hands, feet, face, etc., with relatively limited involvement, slower progression, and a better prognosis. Given the similarities in clinical manifestations between the two types, they are summarized as follows:
1. Skin Can be divided into the edematous, sclerotic, and atrophic late stages (third stage).
(1) Edematous stage: The skin becomes tense, thickened, and loses wrinkles, appearing pale or yellowish with reduced temperature, presenting as 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 usually begins on the trunk and then extends outward.
(2) Sclerotic stage: The skin hardens, with a waxy sheen, and cannot be pinched. Depending on the affected area, symptoms may include limited finger flexion and extension, 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 exhibit cutaneous pruritus or paresthesia.
(3) Atrophic stage: The skin becomes thin and atrophic, resembling parchment, and the subcutaneous tissue and muscles may also atrophy and harden, adhering tightly to the bones, forming board-like plaques. Stubborn ulcers are prone to develop on fingertips and joints, accompanied by reduced sweating and hair loss in the affected area. A few cases may show telangiectasia.
The above skin manifestations are common in various types of scleroderma, but it is worth noting that some cases of sclerosis may present with no skin symptoms at all.
2. Muscles Muscle 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 About 12% of patients initially present with joint redness, swelling, and pain, while 46% develop joint changes during the course of the disease. These changes range from grade I restricted movement to joint stiffness and even contracture deformities. Hand deformities are the most common, with fingers becoming completely stiff, shortened, or misshapen. The absorption of terminal phalanges may present as a truncated appearance.
4. Viscera
(1) Digestive system: Tongue movement may be restricted due to frenulum contracture, teeth become loose due to root resorption, and esophageal involvement is quite common (45-90%), manifesting as dysphagia, often accompanied by vomiting, retrosternal or epigastric fullness, or a burning pain sensation (caused by reflux esophagitis). Gastrointestinal involvement may present with 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. Electrocardiogram abnormalities may be observed.
(3) Respiratory system: When the lungs are affected, widespread pulmonary interstitial fibrosis may occur, reducing 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 may present with polyneuritis (including cranial nerves), convulsions, epileptic seizures, personality changes, cerebral arteriosclerosis, cerebral hemorrhage, as well as elevated cerebrospinal fluid protein and abnormal electroencephalogram findings.
5. Others: Raynaud's phenomenon may also occur (often affecting the extremities); calcinosis may develop in soft tissues around fingers or other joints or on the extensor surfaces of limbs; some cases may 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 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 (5–12 times longer).
In systemic cases, the erythrocyte sedimentation rate is often accelerated. Lupus cells can be found in the blood of some patients. The positive rate of fluorescent antinuclear antibodies can reach about 95%, with the speckled pattern being the most common fluorescent nuclear pattern, and nucleolar CRST may show anti-centromere staining. The detection of anti-Scl-70 antibodies using immunodiffusion techniques has high specificity for the diffuse type. Capillaroscopy of the nail fold reveals blurred capillaries, exudation and edema, a significant reduction in the number of capillary loops, marked dilation and tortuosity of vascular branches, sluggish blood flow, and often accompanying petechiae.
X-ray examination of systemic patients often shows: ① widening of the periodontal membrane; ② loss of peristalsis in the esophagus and gastrointestinal tract, with narrowing at the lower end and dilation proximally, reduced peristalsis in the small intestine, proximal small intestine dilation, and spherical changes in the colonic haustra; ③ bone resorption at the fingertips; ④ thickening of lung markings or small cystic changes; ⑤ shadows of calcium salt deposition in soft tissues.
The disease can be diagnosed based on skin sclerosis. Sensory chronaxy measurement, skin capillary microscopy, and histopathological examination provide reference value for the diagnosis.
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: Contains 2g of raw Salvia per milliliter. 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 shows some efficacy for skin sclerosis, difficulty opening the mouth and swallowing, pigmentation, joint stiffness and pain, and Raynaud's phenomenon. However, it is not suitable for those with bleeding tendencies or poor kidney function.
2. Guanethidine: Initial dose of 12.5mg/day, gradually increasing to 25mg/day, and adjusted to 37.5mg/day after 3 weeks. Effective for Raynaud's phenomenon (efficacy rate about 50%).
3. Methyldopa: 125mg, three times daily (or 1–2g/day). Can inhibit Raynaud's phenomenon.
(3) Connective Tissue Formation Inhibitors
1. D-Penicillamine: Interferes with the cross-linking of collagen molecules and inhibits new collagen biosynthesis. Start with 250mg/day, gradually increasing to a full dose of 1g/day, 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 treatment, it may irritate the Yaodui kidneys and suppress bone marrow, potentially causing leukopenia and thrombocytopenia. If taken with L-glutamine (0.2g, three times daily), the efficacy is better than D-penicillamine alone.
2. Colchicine: Prevents the conversion of procollagen to collagen and inhibits collagen accumulation. Dosage is 0.5–1.5mg/day, taken continuously for 3 months to several years. It shows some efficacy for skin sclerosis, Raynaud's phenomenon, and esophageal changes. If diarrhea occurs during treatment, reduce the dose or administer β-galactosidase.
3. Asiaticoside: An active component extracted from Chinese medicinal herb Asiatic pennywort. Experiments show it inhibits fibroblast activity and softens connective tissue. Usage: tablets (10mg asiaticoside per tablet), 3–4 tablets three times daily; injection (20mg asiaticoside per 2ml vial), intramuscularly 2–3 times weekly, one vial each time. It is effective for softening sclerotic skin, reducing tissue edema, alleviating joint pain, and healing ulcers (efficacy rate about 80%). Effects usually become noticeable 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/day orally, then gradually reduce to a maintenance dose of 5–10mg/day. Avoid use if proteinuria, hypertension, or azotemia is present.
(5) Immunosuppressants: Such as azathioprine (75–150mg/day), chlorambucil (6mg/day), and cyclophosphamide (50–200mg/day) can be selected. They show 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 relatively good efficacy for 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 once or twice daily, lasting 20 to 30 minutes each session. As the condition improves, the frequency can be reduced to once every other day, but the treatment duration should be prolonged.
(7) Others: Such as block therapy, vitamin E, composite phosphoesterase tablets, and testosterone propionate can be appropriately selected and used in combination.
Some mild cases may resolve spontaneously. Late abortion or full-term delivery can exacerbate the condition. Once the lungs, heart, kidneys, or other organs are affected, the disease rapidly worsens, with 20–40% of patients dying from renal failure. Patients with serum creatinine levels above 6 mg/dl have a particularly poor prognosis. Dialysis and kidney transplantation may help prolong the patient's life.
(1) Localized Scleroderma Needs to be differentiated from the following diseases.
1. Atrophia Maculosa Early lesions vary in size, appearing skin-colored or bluish-white, slightly depressed or raised, with a wrinkled surface and no hardness on palpation.
2. Lichen Sclerosus et Atrophicus The skin lesions are shiny, pale purple flat papules, varying in size, often clustered but not merging, with follicular keratotic plugs on the surface. Blisters may sometimes occur, followed by gradual skin atrophy.
(2) Systemic Sclerosis Needs to be differentiated from the following diseases.
1. Scleredema Adultorum: Lesions usually start from the head and neck, extending to the shoulders and back, with deep dermal swelling and stiffness. There is no local pigmentation, atrophy, or hair loss, and the condition tends to resolve spontaneously.
2. Mixed Connective Tissue Disease: Patients exhibit a combination of symptoms from systemic lupus erythematosus, scleroderma, dermatomyositis, or polymyositis, including Raynaud's phenomenon, non-pitting edema of the face and hands, sausage-like swelling of the fingers, fever, non-erosive polyarthritis, muscle weakness or pain, etc. Antibodies to extractable nuclear antigen (ENA) and RNP may show high-titer positive reactions.
