Systemic scleroderma is a diffuse pathology of connective tissue, which is characterized by fibrotic-sclerotic changes in the skin, musculoskeletal system, internal organs and blood vessels. Typical signs of systemic scleroderma are Raynaud’s syndrome, skin thickening, masked face, telangiectasia, polymyositis, joint contractures, changes in the esophagus, heart, lungs, kidneys. Diagnosis of systemic scleroderma is based on a set of clinical data, determination of sclerodermic autoantibodies, skin biopsy. Treatment includes antifibrotic, anti-inflammatory, immunosuppressive, vascular agents, symptomatic therapy.
Meaning
Systemic scleroderma is collagenosis with polysyndromic manifestations, which is based on progressive fibrosclerosis of the skin, musculoskeletal system, visceral organs and vessels. Among connective tissue diseases, it ranks second in frequency of occurrence after systemic lupus erythematosus. Pathology was described in detail in the XVII century, however, the generally accepted term “scleroderma” was introduced into use only in the middle of the XIX century, and a detailed study of the disease in the framework of rheumatology began in the 40-50s of the last century. The prevalence of systemic scleroderma ranges from 6 to 20 cases per 1 million people. The female population falls ill 3-6 times more often than the male population; the majority of patients are people aged 30-60 years. Systemic scleroderma has a slowly progressive course, eventually leading to disability.
Causes
There are no precise ideas about the causes of systemic scleroderma. Accumulated observations only allow us to express individual etiological hypotheses. The genetic determinacy is supported by the facts of the family history of systemic scleroderma, as well as the presence of other scleroderma diseases, collagenosis (SLE, rheumatoid arthritis, Sjogren’s syndrome), microangiopathies, cardiopathies and nephropathies of unknown genesis in the closest relatives. The association of scleroderma with certain antigens and alleles of the HLA system determining the immune response was revealed, which also indicates the presence of a genetic trace in the genesis of pathology.
Along with the hereditary theory, the role of infection, primarily cytomegalovirus, is widely discussed. Some patients associate the onset of the disease with the flu or streptococcal sore throat. A number of observations indicate the trigger role of chemical agents: quartz and coal dust, solvents, medicines (in particular, bleomycin and other cytostatics). The involvement of vibration exposure, stress, cooling and frostbite, injuries in triggering immunopathological shifts in systemic scleroderma has been proven. Hormonal restructuring caused by puberty, childbirth, abortion, menopause can serve as a background for the development of systemic sclerosis. In some patients, the onset of the disease is preceded by surgery (tooth extraction, tonsillectomy, etc.) and vaccination. Thus, based on the available data, it can be concluded that the multifactorial genesis of systemic scleroderma combines a complex interaction of endo- and exogenous factors with hereditary predisposition.
The pathogenetic mechanisms of systemic scleroderma have been studied better than etiology. Disorders of cellular and humoral immunity play a key role in them, leading to an increase in the number of CD4+ and B-lymphocytes, and a hypersensitivity reaction that causes the formation of a wide range of autoantibodies (antinuclear, anticentromeric, anti-Scl-70, antineutrophilic, antiendothelial, cytoplasmic, AT to connective tissue, etc.) and circulating immune complexes. Such immune activation contributes to hyperactivity of fibroblasts and damage to the vascular endothelium. The specificity of the disease is determined by generalized sclerosis of organs and tissues (skin, musculoskeletal and musculoskeletal systems, gastrointestinal tract, heart, lungs, kidneys) and the development of obliterating microangiopathy. The considered mechanism makes it possible to attribute systemic scleroderma to autoimmune diseases.
Classification
To date, the term “scleroderma” refers to a group of diseases with similar pathogenetic mechanisms occurring with local or generalized fibrosis of connective tissue. From the standpoint of the international clinical classification, the following forms of scleroderma diseases are distinguished: systemic scleroderma, focal scleroderma, edematous scleroderma (Buschke’s scleredema), eosinophilic fasciitis, induced scleroderma, multifocal fibrosis, pseudoscleroderma.
Systemic scleroderma (diffuse or generalized scleroderma, progressive systemic sclerosis) can occur in several clinical forms:
- Prescleroderma has no dermatological manifestations and is accompanied only by Raynaud’s phenomenon.
- Diffuse scleroderma is pathognomonically characterized by rapid development, damage to the skin, blood vessels, musculoskeletal system and internal organs during the first year of the disease.
- The limited form proceeds with slowly developing fibrous changes, predominant skin lesions and late involvement of internal organs.
- With scleroderma without scleroderma, only visceral and vascular syndromes without typical skin manifestations are noted.
- The cross form can manifest itself as a combination of systemic scleroderma with dermatomyositis, polymyositis, SLE, RA, vasculitis.
Systemic scleroderma can occur in chronic, subacute and acute forms. With a chronic course for many years, the only indication of the disease is Raynaud’s syndrome; other typical lesions develop gradually and for a long time. In the subacute variant of systemic scleroderma, skin-articular (scleroderma, polyarthritis, polymyositis) and visceral syndrome (cardiopulmonary) prevail with minor vasomotor disorders. The acute form of pathology is characterized by rapid (within 12 months) formation of systemic fibrosis and microvascular disorders. There are three degrees of activity of systemic scleroderma: I – minimal, typical for the chronic variant; II – moderate, usually occurring in the subacute process; III – maximum, accompanying the course of acute and sometimes subacute forms.
Symptoms
The clinical specificity of systemic scleroderma lies in the polymorphism and polysyndromicity of manifestations. Variants of the development of the disease can vary from poorly expressed forms with a relatively favorable prognosis to rapidly progressive diffuse lesions with an early fatal outcome. In the debut of systemic scleroderma, even before the appearance of specific lesions, weight loss, weakness, and subfebrility are noted.
The earliest sign of the disease is Raynaud’s syndrome, characteristic of 99% of patients and occurring with transient paroxysms of vasospasm. Under the influence of stress or cooling, the fingers turn pale sharply, then the skin acquires a bluish-purple color. Vascular spasm may be accompanied by a feeling of chilliness and numbness of the hands. After the vasoconstriction is resolved, the stage of reactive hyperemia occurs: the skin becomes bright pink, there is a feeling of ache and pain in the fingers. Raynaud’s phenomenon in scleroderma may be systemic, i.e. spread to the vessels of the skin of the face, tongue, kidneys, heart, etc. organs.
The skin syndrome is present in most patients with systemic scleroderma. In its evolution, it goes through 3 phases: inflammatory edema, induration and skin atrophy. The initial stage is characterized by the appearance of dense swelling of the skin of the hands and feet, accompanied by itching. In the future, sclerodactyly develops (thickening of the skin of the fingers), trophic ulcers form, nails are deformed. The frontal and nasolabial folds are smoothed out, as a result of which the face acquires a mask-like expression. Due to atrophy of the sebaceous and sweat glands, the skin becomes dry and rough, devoid of hair. Telangiectasia, depigmentation or hyperpigmentation of the skin, subcutaneous calcifications are often detected.
Musculoskeletal syndrome also often accompanies systemic scleroderma. Typical are swelling and stiffness of the joints, arthralgia – this symptom complex is called sclerodermic polyarthritis. Due to the compaction of the skin, flexion contractures of the joints are formed, tenosynovitis develops. Osteolysis of the nail phalanges is possible, leading to shortening of the fingers. Muscle damage in systemic scleroderma occurs by the type of polymyositis or non-inflammatory myopathy.
Visceral lesions can affect the gastrointestinal tract (90% of cases), lungs (70%), heart (10%), kidneys (5%). Dysphagia, heartburn, nausea and vomiting are noted from the digestive organs. Reflux esophagitis develops, aggravated by the formation of ulcers and strictures of the esophagus. Against this background, patients with systemic scleroderma have an increased risk of Barrett’s esophagus formation and adenocarcinoma. When the small intestine is affected, diarrhea, flatulence, weight loss occurs; when the large intestine is involved, constipation and intestinal obstruction occur.
Lung damage in systemic scleroderma can be expressed in the form of pneumofibrosis and pulmonary hypertension. Both syndromes are manifested by unproductive cough, progressive expiratory dyspnea and respiratory failure. Lung damage is the leading cause of death in patients with systemic scleroderma, therefore it is regarded as a prognostically unfavorable factor. With the involvement of the heart, arrhythmias, pericarditis (adhesive or exudative), endocarditis, heart failure may develop.
Renal syndrome in systemic scleroderma more often occurs in the form of latent nephropathy with moderate functional disorders. However, a number of patients in the first five years from the onset of the disease develop a formidable, potentially lethal complication – acute scleroderma kidney, which proceeds with hyperreninemia, malignant arterial hypertension, thrombocytopenia and hemolytic anemia, rapidly increasing renal failure. Among other syndromic manifestations of systemic scleroderma, there are polyneuropathy, Sjogren’s syndrome, autoimmune thyroiditis, primary biliary cirrhosis of the liver, etc.
Diagnostics
The American College of Rheumatology has developed criteria on the basis of which a diagnosis of systemic scleroderma can be made. Among them, there are large criteria (proximal scleroderma – compaction of the skin of the hands, face and trunk) and small (sclerodactyly, digital scars, bilateral pneumofibrosis). If two small or one large signs are detected, the clinical diagnosis can be considered confirmed. Differential diagnostic measures are carried out both within the group of scleroderma diseases and among other systemic diseases: Sjogren’s syndrome, polymyositis, dermatomyositis, obliterating thrombangiitis and many others.
General clinical analyses are uninformative, and the changes detected in them are non–specific. On the part of the blood, hypochromic anemia, leukocytopenia or leukocytosis, a moderate increase in ESR is noted. In the general analysis of urine, proteinuria, leukocyturia, microhematuria can be detected. Biochemical indicators indicate signs of inflammation (increased levels of seromucoid and fibrinogen, CRP, RF). The results of the immunological examination are of the greatest importance. In systemic scleroderma, sclerodermic autoantibodies-markers are detected in the blood: AT to Scl-70 and anti-centromeric AT.
Among the instrumental techniques for the early diagnosis of systemic scleroderma, the most valuable is capillaroscopy of the nail bed, which allows to identify the initial signs of the disease. To assess the state of the bone system, an X-ray of the hands is performed. In order to detect interstitial pneumofibrosis, it is advisable to perform radiography and CT of the lungs. For the study of the gastrointestinal tract, radiography of the esophagus is prescribed, radiography of the passage of barium through the intestine. Electrocardiography and EchoCG are necessary to detect cardiogenic lesions and pulmonary hypertension. Electromyography allows you to confirm myopathic changes. For histological verification of systemic scleroderma, a biopsy of the skin, muscles, kidneys, lungs, and pericardium is performed.
Treatment
Persons suffering from systemic scleroderma should avoid stressful factors, vibration, hypothermia, insolation, contact with household and industrial chemical agents, give up smoking and caffeine, and taking vasoconstrictors. Pharmacotherapy, its dosage and duration depend on the clinical form, activity and rate of progression of the disease, severity of visceral lesions.
Pathogenetic therapy of systemic scleroderma is carried out using vascular, antifibrotic and immunosuppressive drugs. Vasodilators (nifedipine, verapamil, diltiazem, cinnarizine, etc.), antiplatelet agents (acetylsalicylic acid, pentoxifylline) and anticoagulants (heparin, warfarin) are prescribed to prevent episodes of vascular spasm and prevent ischemic complications. In order to suppress the development of systemic fibrosis, D-penicillamine is used. Anti-inflammatory therapy for systemic scleroderma includes taking NSAIDs (ibuprofen, diclofenac, nimesulide) and glucocorticoids. Drugs of this group help to reduce the signs of inflammation (myositis, arthritis, tendosinovitis) and immunological activity. Methotrexate, cyclosporine, pulse therapy with cyclophosphane can be used to slow the progression of systemic fibrosis.
Symptomatic therapy for systemic scleroderma is aimed at reducing digestive disorders, heart failure, pulmonary hypertension. With the development of a sclerodermic renal crisis, captopril, enalapril is prescribed; in some cases, hemodialysis may be required. Surgical treatment – thoracic sympathectomy – is indicated for a complicated form of Raynaud’s syndrome.
Forecast
The prognosis for systemic scleroderma is generally unfavorable. The lowest five-year survival rate (30-70%) is associated with a diffuse form. Predictors of an unfavorable prognosis are pulmonary and renal syndromes, the onset of the disease in patients older than 45 years. The limited form and chronic course of the disease have a more favorable prognosis and better survival, with them it is possible to plan pregnancy and a safe delivery. Patients with systemic scleroderma are subject to dispensary registration and monitoring every 3-6 months.
