Systemic scleroderma clinical guidelines. Systemic scleroderma: forms and signs, treatment and prognosis. Scleroderma - causes

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Treatment

Early diagnosis and adequate therapy largely determine the effectiveness of treatment and prognosis, especially in rapidly progressive diffuse SJS. Treatment is always prescribed individually, depending on the clinical form and course of the disease, the nature and severity of ischemic and visceral lesions.

Patient education. to convince the patient of the need for long-term treatment, strict adherence to recommendations, to acquaint with the possible side effects of drugs. draw the patient's attention to the need for constant medical supervision and regular examinations in order to early identify signs of disease progression and possible correction of therapy. Treatment goals. prevention and treatment of vascular complications. inhibition of fibrosis progression. prevention and treatment of lesions of internal organs.

Non-drug treatment

General recommendations
. Avoid psycho-emotional stress, prolonged exposure to cold and vibration, reduce exposure to the sun.

To reduce the frequency and intensity of attacks of vasospasm, it is recommended to wear warm clothes, including warm underwear, hats, woolen socks and mittens instead of gloves. For the same purpose, recommend that the patient stop smoking, stop drinking coffee and caffeine-containing drinks, avoid taking sympathomimetics (ephedrine, amphetamine, ergotamine), and β-blockers.

Medical treatment

The main areas of drug treatment are vascular, anti-inflammatory and antifibrotic therapy, as well as the treatment of visceral manifestations of SJS. Vascular therapy is aimed primarily at the treatment of Raynaud's phenomenon. In addition, the following drugs are used for SSc:
. Sildenafil is a phosphodiesterase inhibitor, at a dose of 50 mg per day, promotes the healing of digital ulcers in patients with SSc who did not respond to calcium channel blockers.

Bosentan (not registered in the Russian Federation) is a non-selective endothelin-1 receptor antagonist used to treat pulmonary hypertension; at a dose of 125 mg / day, it reduces the likelihood of new digital ulcers by 2 times.

Anti-inflammatory and cytotoxic drugs are used at an early (inflammatory) stage of SJS and a rapidly progressive course of the disease:
. NSAIDs in standard therapeutic doses are indicated for the treatment of musculo-articular manifestations of SJS, persistent subfebrile fever (high fever is uncharacteristic of SJS).

Glucocorticoids are indicated for progressive diffuse skin lesions and obvious clinical signs of inflammatory activity (myositis, alveolitis, serositis, refractory arthritis, tendosynovitis) in small (no more than 15-20 mg / day) doses. Higher doses increase the risk of normotensive scleroderma renal crisis.

Cyclophosphamide in combination with GCs is used to treat ILD (see Lung Injuries below).
. Methotrexate is able to reduce the prevalence and severity of skin hardening, but does not affect visceral pathology. The indication for methotrexate is the combination of SJS with RA or polymyositis.

Cyclosporine has a positive effect on the dynamics of skin changes, however, nephrotoxicity and a high likelihood of developing an acute renal crisis during treatment seriously limits the use of the drug in SJS.
Antifibrotic therapy is indicated at an early stage of the diffuse form of SJS.

D-penicillamine is the main drug that suppresses the development of fibrosis. The effective dose of the drug is 250-500 mg / day. Treatment with D-penicillamine leads to a significantly greater reduction in the severity and prevalence of skin compaction and increases 5-year survival compared with patients who did not receive this treatment.

Taking high doses of the drug (750-1000 mg / day) does not lead to a significant increase in the effectiveness of therapy, but much more often causes side effects that require interruption of treatment.

Treatment of visceral manifestations of SJS

Damage to the esophagus and stomach
Treatment is aimed at reducing the manifestations associated with gastroesophageal reflux and impaired peristalsis. For this purpose, patients are recommended frequent fractional meals, do not go to bed for 3 hours after eating, sleep on a bed with a raised head end, stop smoking and alcohol.

It should be borne in mind that calcium channel blockers can increase the manifestations of reflux esophagitis. Drug therapy includes the appointment of antisecretory drugs and prokinetics.

Omeprazole, a proton pump inhibitor, is the most effective antisecretory drug for the treatment of gastrointestinal reflux. In most cases, a single dose of 20 mg stops the manifestations of esophagitis during the day, if necessary, the dose of the drug is increased to 40 mg per day.

Ranitidine is a histamine H2 receptor blocker that reduces the manifestations of gastroesophageal reflux, but is inferior in effectiveness to proton pump inhibitors.

Metoclopramide is a prokinetic; long-term administration of metoclopramide is unacceptable, since it is possible to develop neurological disorders (parkinsonism) caused by exposure to dopaminergic structures of the brain.

The prokinetic cisapride, a serotonin 5-HT4 receptor agonist widely used in the 1990s, was banned due to cardiotoxic effects (arrhythmias).

Severe esophageal stricture is an indication for endoscopic dilatation. In case of violation of the evacuation function of the stomach, it is recommended to take semi-liquid food.

Intestinal lesion
. Disorders of intestinal motility contribute to the overgrowth of microflora and the development of malabsorption syndrome, for the treatment of which the following are used antibacterial drugs: tetracycline - 250 mg per day, amoxicillin + clavulanic acid 500 mg per day, ciprofloxacin 250 mg per day, cephalosporins.

Antibiotics should be alternated to prevent the development of microflora resistance. The duration of antibiotics depends on the severity of diarrhea and steatorrhea (usually 7-10 days per month). If diarrhea occurs while taking antibiotics, metronidazole is additionally prescribed (7-10 days) to suppress the anaerobic flora. The appointment of prokinetics (metoclopramide) is not advisable, since they do not have the expected effect.

Improvement in peristalsis in intestinal pseudo-obstruction has been observed with the long-acting somatostatin analogue octreotide 50 mg daily subcutaneously.

Lung damage
. Interstitial lung disease. Combination therapy with GC and cyclophosphamide is most effective. The effectiveness of D-penicillamine has not been proven

♦ Prednisolone is prescribed at a dose of 20-30 mg per day for 1 month with a gradual decrease to a maintenance dose of 10-15 mg per day; large doses of GCs should be avoided due to the risk of developing a scleroderma renal crisis.

♦ Cyclophosphamide is administered intravenously at a dose of 800-1000 mg once a month or per os 2 mg/kg per day. In / in the introduction is considered preferable, since there is a lower incidence of side effects (including hemorrhagic cystitis) compared with oral administration. Pulse therapy with cyclophosphamide is continued at this dose for at least 6 months (in the absence of side effects). With positive pulmonary dynamics functional tests and radiographic changes, the interval between pulse therapy with cyclophosphamide is increased up to 2 months, and while maintaining positive dynamics - up to 3 months. Pulse therapy with cyclophosphamide should be carried out for at least 2 years.

♦ The effectiveness of therapy is evidenced by the stabilization of the forced vital capacity of the lungs, since an improvement in the function of external respiration at the stage of reticular changes in the lungs is unlikely.

♦ In case of failure of drug therapy and progressive respiratory failure, transplantation of one lung is indicated (efficiency is comparable to transplantation of both lungs).

Pulmonary hypertension. Treatment of pulmonary hypertension should be started as early as possible (at the latent stage) due to the high mortality of patients (3-year survival less than 50%). Vasodilators (calcium channel blockers, synthetic prostacyclin analogues or endothelin receptor antagonists) and anticoagulants are used to treat pulmonary hypertension.

♦ Nifedipine. Prior to the appointment of long-term therapy for pulmonary hypertension with nifedipine, it is necessary to conduct a right ventricular catheterization with a test sample (measurement of pressure in the pulmonary artery before and after a single dose of nifedipine), since nifedipine causes a decrease in pressure in the pulmonary artery only in 25% of patients and does not affect the resistance of the pulmonary vessels in other patients. Calcium channel blockers do not affect the survival of patients.

♦ Warfarin. Long-term use of the drug improves the survival of patients with primary pulmonary hypertension. The daily dose is determined by the value of MHO, which should be kept within 2-3.

♦ Iloprost and epoprostenol (not registered in the Russian Federation) are synthetic analogues of prostacyclin, used for infusion therapy, effectively reducing pressure in the pulmonary artery. Prostacyclin preparations for subcutaneous and inhalation administration have also been developed.

♦ Bosentan (not registered in the Russian Federation) - the initial dose of the drug is 62.5 mg / day, which after 1 month increases to 125 mg / day. Daily intake of 125 mg of the drug for 12 weeks leads to a significant decrease in pressure in the pulmonary artery, an increase in exercise tolerance. Long-term use of the drug leads to an improvement in the survival of patients.

♦ Sildenafil reduces pulmonary vascular resistance, improves ventilation-perfusion ratio, increases arterial blood oxygenation. The hemodynamic effects of the drug at a dose of 50 mg per day are comparable to those of epoprostenol.

Kidney damage
Adequate control of blood pressure is central to the treatment of scleroderma renal crisis. Aggressive treatment of hypertension can stabilize or even improve renal function if therapy is initiated promptly, before irreversible changes in renal vessels develop.

The drugs of choice are:
. Angiotensin-converting enzyme inhibitors (captopril, enalapril, etc.). The dose of LS is selected in such a way as to maintain diastolic pressure at the level of 85-90 mm Hg. Angiotensin-converting enzyme (ACE) inhibitors may also improve the outcome of normotensive scleroderma renal crisis. Excessive hypotension and hypovolemia, which can lead to decreased renal perfusion and acute tubular necrosis, should be avoided. The effectiveness of angiotensin-H receptor antagonists in the treatment of acute renal crisis has not been proven.

With insufficient hypotensive effect of monotherapy with ACE inhibitors, calcium channel blockers (nifedipine) can be added to the treatment.

Approximately 20-50% of patients develop renal failure despite treatment with ACE inhibitors, requiring hemodialysis.

Heart failure
Manifestations of primary scleroderma of the heart (i.e., lesions that are not a consequence of systemic or pulmonary hypertension) can be pericarditis, arrhythmia, myocarditis, myocardial fibrosis.

Treatment of pericarditis is carried out in clinically manifest forms and includes the use of NSAIDs and GCs (15–30 mg/day). With significant effusion, pericardiocentesis or pericardiotomy is performed.

Myocarditis is usually observed in patients with inflammatory lesions of the skeletal muscles; GC treatment often results in an increase in left ventricular ejection fraction.

Rhythm disturbance usually does not require treatment. With severe arrhythmias (group and polytopic extrasystoles, ventricular tachycardia, etc.), the drug of choice is amiodarone. Reception (β-blockers may increase the manifestations of Raynaud's phenomenon.

SJS and pregnancy. Most patients with SJS have a history of one or more pregnancies and deliveries.

The limited form and chronic course of SJS are not a contraindication for pregnancy. However, during pregnancy, organ pathology may develop, which requires regular examination.

Contraindications for pregnancy: diffuse form of SJS, severe dysfunction of internal organs (heart, lungs and kidneys). In cases of detection of SJS during pregnancy, careful monitoring of kidney and heart function is necessary.

Management of patients with SSc

All patients with SJS are subject to dispensary observation in order to assess the current activity of the disease, timely detection of organ pathology and, if indicated, correction of therapy. A medical examination is carried out every 3-6 months, depending on the course of the disease, the presence and severity of visceral lesions. At the same time, general and biochemical analyzes blood and urine.

During repeated visits to the doctor, it is necessary to actively question the patient in order to assess the dynamics of Raynaud's phenomenon, increase the manifestations of esophageal reflux, shortness of breath, cardiac arrhythmia, etc. When examining the patient, attention should be paid to the prevalence and severity of skin thickening, basal crepitus of the lungs, to increased blood pressure, the presence of digital ulcers and edema.

Respiratory function testing and echocardiography are recommended. In patients taking warfarin, the prothrombin index and MHO should be monitored, and in the treatment of cyclophosphamide - to investigate general analyzes blood and urine every 1-3 months.

Forecast

The prognosis for SJS is unfavorable and largely depends on the clinical form and course of the disease. Based on the results of a meta-analysis of 11 survival studies of 2000 patients with SSc, the 5-year survival rate ranges from 34% to 73%, with an average of 68%. The risk of death in SJS is 4.7 times higher than in the general population.

The predictors of poor prognosis are:
❖ diffuse form
❖ Age of onset over 45 years
❖ male gender
❖ pulmonary fibrosis, pulmonary hypertension, arrhythmia, kidney damage in the first 3 years of illness
❖ anemia, high ESR, proteinuria at the onset of the disease.

Nasonov E.L.

Synonym: sclerodermia systemica, diffuse scleroderma, universal scleroderma, progressive systemic sclerosis.

Systemic scleroderma - a diffuse connective tissue disease with a predominance of fibrosis and obliterating microangiopathy, characterized by indurative skin changes, lesions of the musculoskeletal system, internal organs (lungs, heart, digestive tract, kidneys), generalized vasospastic Raynaud's syndrome.

Etiology systemic scleroderma has not been identified. A viral and hereditary origin of the disease is assumed. Systemic scleroderma is preceded by infectious diseases or a moderate febrile state of unknown cause, chilliness, sweating, repeated sore throats, increased sensitivity of the hands to cold, paresthesia of the fingers (Raynaud's syndrome), muscle and joint pain, dyspepsia, headaches.

Systemic scleroderma is diagnosed predominantly in women (3:1) aged 35 to 64 years. The disease is rare in children and also in adults under 30 years of age. The incidence of systemic scleroderma is 6.3-12 cases per 1 million population.

Pathogenesis systemic scleroderma includes changes in connective tissue metabolism (increased collagen biosynthesis and neofibrillogenesis, tissue fibrosis), immune disorders (decrease in the level of T-suppressors with a normal content of B-lymphocytes in the blood, the appearance of antibodies to collagen, sometimes antinuclear antibodies) and damage to the microvasculature (cytotoxic lymphocytes damage the endothelium, which is accompanied by adhesion and aggregation of platelets, activation of coagulation, release of inflammatory mediators, an increase in the permeability of the vascular wall with its plasma impregnation and deposition of fibrin, narrowing of the lumen). Cytokines and growth factors secreted by lymphocytes, monocytes and platelets play an important role in the development of fibrosis. They cause hyperproduction of collagen and macromolecules of the basic substance of the connective tissue, followed by the development of areas of fibrosis.

Clinic . Systemic scleroderma includes cutaneous and extracutaneous syndromes. Skin syndrome: sclerodactyly; acrosclerosis; diffuse - generalized type; Thibierge-Weissenbach syndrome. Extracutaneous syndromes: musculo-articular, gastrointestinal, pulmonary, cardiovascular, renal, neurological.

Systemic or diffuse scleroderma (universal, generalized, progressive) begins more often in women in childhood or adolescence with lesions of the skin of the hands, face, and then the limbs and trunk. At diffuse scleroderma skin fibrosis is localized proximal to the elbow or knee joints, including the neck and trunk. Patients may experience Raynaud's phenomenon during the first year of the disease, more often internal organs are affected: lungs, kidneys, heart. Allocate also limited scleroderma, in which fibrosis of the skin of the hands, forearms and feet develops, but the face and neck can be affected. In patients of this group, Raynaud's phenomenon has been observed for years, they develop telangiectasias, calcifications in the skin, and later pulmonary hypertension joins.

Skin lesions is the leading symptom of the disease. Perhaps the appearance of acrosclerosis, sometimes numerous numerous subcutaneous calcareous nodules are formed with further ulceration. Thickening of the skin develops due to abnormal production of type I collagen by skin fibroblasts, as well as excessive deposits of glycosaminoglycans and fibronectin in the extracellular matrix. Outwardly, the patient has affected and unaffected areas of the skin. However, studies have shown the presence of procollagen-1 and adhesive molecules in all areas of the dermis, which indicates a generalized course of the pathological process.

Dense edema appears on the skin of the face, neck, hands, then thickening and sclerosis of the skin develop. Subsequently, its atrophy occurs and the face takes on a mask-like appearance: the folds are smoothed out, mimic movements are absent, the lips become thinner, radiant deep folds form around them, similar to a half-stretched pouch, the mouth does not close, the tongue does not protrude from the edge of the teeth, the eyelids often do not close; the nose becomes thinner, the skin on its wings becomes smooth, stretched, shiny. The voice weakens, it becomes as if from the depths. The auricles also noticeably atrophy and become thinner. The hair gradually falls out, the nails become thinner and then separated from the nail bed. There is marked dryness of the skin, hyperkeratosis of the palms and soles. Decreases and then stops the secretion of sweat and sebaceous glands. The process often captures the mucous membrane of the mouth, tongue, soft palate, larynx, esophagus, lungs and other internal organs, as well as muscles, joints, bones. Subsequently, the lesion can spread to the entire skin: forearms, shoulders, torso, thighs, legs and feet. The skin at the same time becomes waxy yellow, on it areas of pronounced hyperpigmentation alternate with depigmented foci; multiple telangiectasias are noted. The subcutaneous fat gradually disappears, the skin adheres to the underlying fascia and becomes motionless over the bones, it is not taken into a fold. As a result, stiffness of the whole body occurs. With a total lesion of the skin of the trunk and extremities, cachexia and mummification develop (“living relics”). The movements in the joints and even breathing are sharply limited, the patient has difficulty in eating.

Sometimes there is a deposition of calcium salts (calcinosis) in the subcutaneous tissue in the form of nodules of a stony consistency, which opens with the formation of fistulas and white crumbly discharge. Calcinosis is the deposits of hydroxyapatites in the skin, which are localized mainly on the hands in the region of the proximal interphalangeal joints and nail phalanges, around the joints and over the bony prominences (especially on the extensor surface of the elbow and knee joints). Periarticular deposition of calcium in the form of white foci translucent through the skin is called the Tibierge-Weissenbach syndrome. Calcium deposits are not always determined visually, in which case they are detected by radiography. Calcinosis persists for years and is difficult to treat.

There are multiple telangiectasias (dilated venules, capillaries, arterioles), which look like oval or irregular spots 2-7 mm in diameter and are located on the hands, face, lips and oral mucosa. Telangiectasias spontaneously disappear over time.

The state that appears to alcinosis, syndrome R eyno, uh zophagopathy, With clerodactyly and t called leangiectasia CREST-syndrome (according to the first letters of the symptoms). This syndrome is considered a favorable variant of the disease and refers to limited scleroderma.

The earliest sign of systemic scleroderma is Raynaud's syndrome, which is characterized by the sudden appearance of paresthesia (numbness, crawling) in the region of the II-IV fingers, feet, their sharp blanching. At the end of the attack, pain appears, a feeling of heat in the fingers, the skin is hyperemic. Raynaud's syndrome with systemic scleroderma captures not only the fingers, feet, but also the lips, the tip of the tongue, and parts of the face. In patients with Raynaud's syndrome, it is possible to confirm the presence of systemic scleroderma at an early stage using the following signs (research): the presence of antinuclear antibodies, antibodies to centromeres or antibodies to topoisomerase 1 (anti-Scl-70 antibodies); changes in the capillary bed of the nail bed - a decrease in the number of capillaries or their dilation; the phenomena of tendovaginitis (thickening along the tendons and friction noise in the area of ​​the tendon sheaths); dense swelling of the fingers or toes; associated reflux esophagitis.

Osteoarticular syndrome may be one of the early signs of systemic scleroderma. There are three main variants of the articular syndrome: polyarthralgia; scleroderma polyarthritis with a predominance of exudative-proliferative or fibrous-indurative changes; periarthritis with the development of contractures due to the involvement of periarticular tissues in the pathological process. Bone damage is characterized by acrosclerosis with osteolysis, usually of the nail phalanges, shortening and deformity of the fingers and toes. Bone damage is mainly associated with bone resorption. Often there are arthralgias and morning stiffness, ankylosis is observed.

muscle syndrome characterized different types muscle damage, which may be in the form of interstitial myositis or polymyositis; manifested by pain in the muscles, muscle weakness, a feeling of stiffness in the muscles. The first type of lesion is characterized by moderate weakness of the proximal muscles due to benign non-inflammatory myopathy. Histological examination reveals type 2 muscle fiber atrophy, which is associated with immobility and corticosteroid use. The concentration of muscle enzymes is within the normal range. The second type of lesion is characterized by a moderate increase in the concentration of muscle fibers and the presence of a symptom of “waxy” muscle weakness. Biopsy reveals interstitial fibrosis and muscle fiber atrophy. Moderate infiltration by inflammatory cells is revealed. The third type of lesion is manifested by inflammatory myopathy with an increase in the concentration of enzymes.

Gastrointestinal syndrome manifested by duodenitis, enteritis (with the development of malabsorption syndrome), colitis (with severe constipation, intestinal obstruction). Damage to the esophagus (esophagitis) is considered characteristic, which is manifested by dysphagia, diffuse expansion of the esophagus, its narrowing in the lower third, weakening of peristalsis and rigidity of the walls, reflux esophagitis, and sometimes the development of peptic ulcers, strictures.

Pulmonary syndrome manifested by the clinic of fibrosing alveolitis and diffuse pneumofibrosis with predominant localization in the basal parts of the lungs. Some patients develop pulmonary hypertension due to pulmonary vascular disease. Severe pneumosclerosis is sometimes combined with the development of bronchiectasis, pulmonary emphysema, and possibly pneumonia.

Cardiovascular Syndrome characterized by cardiosclerosis with an increase in the size of the heart, arrhythmias, cardiac arrhythmia and conduction disturbances, and the development of circulatory failure. Large-focal cardiosclerosis can mimic “infarction-like changes” on the ECG. The development of interstitial myocarditis leads to the appearance of clinical symptoms that are actually similar to cardiosclerosis. The defeat of the endocardium in the area of ​​the valvular apparatus leads to the formation of scleroderma heart disease, often mitral valve insufficiency. Some patients develop mitral valve prolapse. Perhaps the development of pericarditis.

renal syndrome manifested by the involvement of the kidneys in the pathological process. There are two forms - acute and chronic nephropathy. Acute nephropathy (true scleroderma kidney) is manifested by the following symptoms: oligoanuria, arterial hypertension, increasing proteinuria, microhematuria, cylindruria, retinopathy, encephalopathy. Acute nephropathy is based on generalized damage to the arterioles of the kidneys and the development of cortical necrosis, which leads to acute renal failure. The most common kidney disease in systemic scleroderma is chronic nephropathy. The morphological substrate of this type of kidney pathology is considered to be damage to the vessels and glomeruli of the kidneys, as well as tubules and interstitium. Clinical symptoms correspond to the symptoms of chronic glomerulonephritis (proteinuria, cylindruria, microhematuria, decreased glomerular filtration, arterial hypertension, development of chronic renal failure).

neurological syndrome characterized by damage to the peripheral nervous system in the form of polyneuropathy (pain in the arms and legs, impaired sensitivity in the form of hyperesthesia, followed by the development of distal-type hypesthesia, decreased tendon reflexes). Polyneuropathy acquires a long, persistent course. Persistent, recurrent trigeminitis (inflammation of the trigeminal nerve) is also characteristic. Damage to the central nervous system is rare; encephalitis, meningoencephalitis, ischemic strokes, cerebral hemorrhages are described.

Endocrinological Syndrome marked by dysfunction of the thyroid gland (hypothyroidism, autoimmune thyroiditis is possible, rarely - hyperthyroidism), adrenal insufficiency, decreased function of the gonads. Perhaps a combination of systemic scleroderma with diabetes mellitus. The defeat of the endocrine glands is primarily due to the defeat of their vascular system.

With systemic scleroderma, weight loss is characteristic, up to cachexia, especially pronounced in the rapidly progressive course of the disease and with its pronounced exacerbation.

There are three variants of the course of systemic scleroderma: acute, subacute and chronic.

Acute course characterized by rapid (within a year) development of diffuse symptoms, steady progression of damage to internal organs, increasing fibrosis of organs and tissues, and development of a sclerotic kidney. The acute course is marked by pronounced changes in laboratory parameters, which reflect the activity of the inflammatory process.

For subacute course the clinic of the disease is characteristic with damage to the skin, joints, muscles, internal organs against the background of mildly pronounced vasomotor trophic disorders, an increase in ESR, fibrinogen,  2 - and -globulins in the blood, the presence of rheumatoid factor, antinuclear factor.

chronic course is characterized by a slowly progressive process over several years and is characterized by severe vascular and trophic disorders, thickening of the skin, periarticular tissue with the formation of contractures, osteolysis, slowly developing lesions of the esophagus, lungs, and heart. Typical skin changes can be focal in nature and remain the only manifestation of the disease for a long time.

initial stage scleroderma is manifested by Raynaud's syndrome, arthralgia, tachycardia, frequent respiratory tract infections. Complex treatment at this stage leads to long-term remission and even recovery.

Generalized stage proceeds with all the previously given symptoms, is characterized by a detailed picture of the disease.

terminal stage occurs with far-reaching changes and is accompanied by a pronounced loss of body weight, insufficiency of the functions of one or more organs. Treatment at this stage does not work.

According to the degree of activity of systemic scleroderma, there are: minimal(I) degree - vasospastic and trophic disorders, ESR less than 20 mm/h; moderate(II) degree - arthralgia, arthritis, adhesive pleurisy, cardiosclerosis, ESR within 20-35 mm/h; high(III) degree - fever, polyarthritis, myocardiosclerosis, nephropathy, ESR more than 35 mm/h.

Laboratory and instrumental methods . General blood analysis: signs of hypochromic anemia, leukopenia, sometimes leukocytosis, increased ESR. Analysis of urine: increased excretion of hydroxyproline, proteinuria. Blood chemistry: hyperproteinemia, an increase in the level of  2 - and -globulins, fibrin, seromucoid, C-reactive protein, haptoglobin, hydroxyproline (impaired collagen metabolism).

Immunological blood test : antibodies to the endothelium, antinuclear antibodies to the SCL-70 antigen, a decrease in the number of suppressor T-lymphocytes, hyper- and dysimmunoglobulinemia; detection of rheumatoid factor (40-45%), antinuclear antibodies (30-90%). Biopsy of a musculocutaneous flap Key words: fibrous tissue transformation, vascular pathology. Skin pathology: in the early stages, small infiltrates are detected around the vessels of the dermis and merocrine sweat glands, as well as infiltration of the subcutaneous tissue; in the later stages, the disappearance of the interpapillary wedges of the epidermis is noted; thickened homogeneous bundles of collagen fibers, brightly stained with eosin; bundle fusion, obliteration and disappearance of the interfascicular space; thickening of the dermis, replacement of adipose tissue (upper layers or all) with collagen, hyalinosis; a decrease in the number of vessels, thickening of the walls and narrowing of the lumen, hyalinosis; atrophy of the skin appendages; sweat glands are located in upper layers dermis; deposits of calcium salts in sclerosed subcutaneous tissue. Electrocardiogram: diffuse changes in the myocardium, sometimes blockade of the legs of the bundle of His and atrioventricular. X-ray examination: areas of calcification in the subcutaneous tissue, mainly the end sections of the fingers, less often - the feet, in the area of ​​the elbow, knee and other joints. Osteolysis in the nail phalanges of the fingers, feet, distal radius and ulna, posterior ribs. Periarticular osteoporosis, narrowing of the joint spaces, sometimes single erosions on the surface of the articular cartilage, bone ankylosis. Decreased tone and weakening of peristalsis of the gastrointestinal tract, which leads to the expansion of the esophagus, duodenum. Diffuse and cystic pneumosclerosis in the basal regions and an increase in the size of the heart.

Diagnostics . The American Institute of Rheumatology has developed diagnostic criteria for systemic scleroderma:

Main (large) criterion- scleroderma of the skin of the trunk (proximal to the metacarpophalangeal or metatarsophalangeal joints - proximal scleroderma).

Small Criteria- sclerodactyly, scars on the distal phalanges of the fingers, bilateral basal pulmonary fibrosis.

The diagnosis of systemic scleroderma requires a major and two minor criteria.

Diagnostic signs (basic and additional) of systemic scleroderma [N.G. Guseva, 1993, 1997].

Main features

Scleroderma skin lesion, passing successively through the stages of “dense” edema, induration and atrophy with predominant localization on the face (maskiness) and in the area of ​​the hands (sclerodactyly), a total lesion is possible. Usually the syndrome is combined with pigmentation.

Raynaud's syndrome.

Joint-muscular syndrome with the development of persistent contractures, which is based on rheumatoid-like arthritis, periarticular changes and fibrosing myositis.

Osteolysis of the nail, and sometimes the middle and main phalanges of the fingers, less often of the legs, which is manifested by shortening and deformation of the fingers.

Thibierge-Weissenbach syndrome - the deposition of calcium salts mainly in the area of ​​​​the fingers and periarticularly - around the elbow, shoulder and hip joints, in the subcutaneous tissue, sometimes along the fascia and tendons of the muscles.

Damage to the digestive tract (scleroderma esophagitis with physphagia, dilatation of the esophagus, gastritis, duodenitis, impaired intestinal motility up to intestinal obstruction, the development of malabsorption syndrome).

Damage to the heart according to the type of primary macrofocal cardiosclerosis.

Damage to the lungs according to the type of basal pneumosclerosis, cystic lung (on the x-ray - “honeycombs”).

True scleroderma kidney, diagnosed clinically on the basis of a sudden increase blood pressure and development of acute renal failure.

The presence of specific antinuclear antibodies (anti-Scl-70 and anticentromeric antibodies).

Capillaroscopic signs (according to wide-field capillaroscopy).

Additional (small) signs

Peripheral: hyperpigmentation of the skin, telangiectasia, trophic disorders, Sjögren's syndrome, polyarthralgia, polymyalgia, polymyositis.

Visceral: polyserositis (usually adhesive), chronic nephropathy, polyneuritis, trigeminitis.

General: weight loss (more than 10 kg).

Laboratory: increased ESR (more than 20 mm / h), hyperproteinemia (more than 85 g / l), hypergammaglobulinemia (more than 23%), antibodies to DNA or antinuclear factor, rheumatoid factor.

For a reliable diagnosis of systemic scleroderma, the presence of any three main signs or one of the main ones, if it is scleroderma skin lesions, osteolysis of the nail phalanges, or a characteristic lesion of the digestive tract, in combination with three or more auxiliary signs, is sufficient. With fewer symptoms, only a “probable” diagnosis is made.

Treatment. For the treatment of patients with systemic scleroderma, antifibrotic agents, non-steroidal anti-inflammatory drugs, immunosuppressants are used; microcirculation-improving agents, local therapy, massage.

Antifibrotic agents . The main basic drug in the treatment of systemic scleroderma is D-penicillinamine(kuprenil), which inhibits excess collagen synthesis by fibroblasts; binds and removes copper from the body, which leads to the activation of collagenase and causes the breakdown of collagen; violates the maturation of collagen and accelerates its decay; suppresses autoimmune inflammation. The effect of the drug is manifested by a decrease in dense edema and skin pigmentation, a decrease in arthralgia and myalgia, and a decrease in the manifestations of Raynaud's syndrome. Initially, the drug is prescribed at 150-300 mg per day for 2 weeks, then the dose is increased every 2 weeks by 300 mg to a maximum of 1800 mg. This dose is prescribed for 2 months, and then slowly reduced to maintenance - 300-600 mg per day. The effect of the drug is noted not earlier than two months from the start of treatment. Side effects of cuprenil: dermatitis, hair loss, dyspepsia, leukopenia, thrombocytopenia, kidney damage. With the development of side effects, it is necessary to reduce the dose of the drug or cancel it. Kuprenil is contraindicated in renal and hepatic pathology, leukopenia, thrombocytopenia.

Madecassol - preparation from the extract of the plant Centella asiatica, contains asiatic and madecassolic acids. Madecassol inhibits collagen synthesis, stabilizes lysosomal membranes. It is prescribed 10 mg orally 3 times a day for 3-6 months.

diucifon - antilepromatous drug, which also has a moderate antifibrotic and immunomodulatory effect. Assigned to 0.1-0.2 g 3 times a day inside.

Lidaza - an enzymatic preparation that acts on the hyaluronic acid - hyaluronidase system, slows down fibrosis. the drug is used in the chronic course of scleroderma and in focal scleroderma. A contraindication to the appointment of enzymatic preparations is the high activity of the process and a sharply increased vascular permeability. Lidaza - a drug containing hyaluronidase; causes the breakdown of hyaluronic acid to glucosamine and glucuronic acid and reduces its viscosity. Lidaza is injected subcutaneously or intramuscularly at 64 units (in 1 ml of 0.5% solution of novocaine), for a course of treatment 12-14 injections. The drug is contraindicated in peptic ulcer disease, a tendency to hemorrhage, renal failure.

Non-steroidal anti-inflammatory drugs . It is prescribed for severe articular syndrome, as well as for contraindications to glucocorticoids. Non-steroidal anti-inflammatory drugs are used in systemic scleroderma in combination with aminoquinolone compounds or with a decrease in the dose of glucocorticoids. Non-steroidal anti-inflammatory drugs inhibit the synthesis of pro-inflammatory prostaglandins, reduce the supply of energy to the site of inflammation, reduce platelet aggregation, and have a mild immunosuppressive effect. Of the drugs most commonly used: voltaren (diclofenac sodium, ortofen) 0.25 g 3-4 times a day; voltaren-retard 0.075 g 1-2 times a day; brufen (ibuprofen) 0.2-0.4 g 3 times a day.

Immunosuppressive agents (glucocorticoids, cytostatics, aminoquinolines) suppress the autoimmune inflammatory process in the connective tissue, inhibit excessive fibrosis.

Glucocorticoids prescribed for subacute and acute course of systemic scleroderma. The chronic course of systemic scleroderma and I degree of activity does not require glucocorticoids. Mostly prednisolone is prescribed. The initial dose of the drug at the III degree of activity is on average 30 mg for 1.5-2 months until the clinical effect is achieved, followed by a decrease in the maintenance dose of 20-10 mg. At the II degree of activity, the initial daily dose of prednisolone is 20 mg for 2 months, followed by a dose reduction. Glucocorticoids have a positive effect on fever, polyarthritis, skin syndrome, visceral manifestations, myositis. To prevent osteoporosis, it is recommended to use anabolic drugs (retabolil, methandrostenolone), calcium gluconate against the background of glucocorticoid therapy.

Cytostatics prescribed for acute and subacute course of the disease with significant immune disorders and high activity of the process, with polymyositis, glomerulonephritis. Imuran (azathioprine) or cyclophosphamide 100-150 mg per day are used, methotrexate - 7.5-10 mg per week. Treatment with cytostatics is combined with the use of glucocorticoids. Treatment with cytostatics lasts 2-3 months.

Aminoquinoline agents have a weak immunosuppressive and anti-inflammatory effect, stabilize lysosomal membranes and inhibit the release of proteolytic enzymes from lysosomes. Aminoquinoline drugs are indicated for any course of systemic scleroderma in combination with basic drugs. Delagil is prescribed at 0.25 g per day or Plaquenil at 0.2-0.4 g per day continuously for a year, after which they switch to taking drugs with a break in the summer. Side effects of aminoquinoline drugs: headaches, dizziness, dyspepsia, retinal and cornea lesions.

Means that improve microcirculation are prescribed at the very beginning of the disease (calcium antagonists, antiplatelet agents, acetylsalicylic acid, rheopolyglucin, captopril, prostaglandins, andecalin, dilminal, solcoseryl, angioprotectors, nicotinic acid).

Local therapy . The goal of local therapy is to reduce the severity and prevent the progression of fibrotic changes in the skin, musculoskeletal system and vascular disorders. Applications of dimethyl sulfoxide (DMSO) are used, which has analgesic and anti-inflammatory effects, penetrates well through the skin and conducts various drugs through it, and is also able to inhibit fibroblast proliferation and inhibit the development of connective tissue. It is recommended to use applications of 50-70% DMSO solution for 30-40 minutes on the affected areas, the course of treatment is from 10 to 30 procedures. Local physiotherapy treatment is carried out in the absence or minimal activity of the process: electrophoresis with lidase or Ronidase, madecassol phonophoresis, electrophoresis with nicotinic acid, dimexide, laser therapy, EHF-therapy; acupuncture; phonopuncture; applications of paraffin, ozocerite.

The complex treatment of patients with systemic scleroderma includes the use of physiotherapy exercises and therapeutic massage, which are prescribed during the period of minimal activity of the process under the control of the general condition and the cardiovascular system.

Forecast . The disease progresses steadily, leading to sclerosis of the skin and internal organs. Ten-year survival exceeds 50%. The main cause of death is kidney failure; less often - damage to the heart and lungs. Spontaneous remissions are sometimes observed. The prognosis for CREST syndrome is more favorable.

Systemic scleroderma, or progressive systemic sclerosis, belongs to a group of autoimmune systemic inflammatory diseases of the connective tissue. It is characterized by a staged course and a large polymorphism of clinical manifestations associated with a characteristic lesion of the skin, some internal organs and the musculoskeletal system.

These lesions are based on a widespread cascading microcirculation disorder, inflammation, and generalized fibrosis. Life expectancy in systemic scleroderma depends on the nature of the course, stage and predominant damage to organs and body systems.

Age-related morbidity and survival of patients

In accordance with the average statistical data, the primary incidence in 1 year per 1,000,000 population is from 2.7 to 12 cases, and the overall prevalence of this pathology is from 30 to 450 cases per 1 year per 1,000,000 population. The development of the disease is possible in various age groups, including among young people (juvenile scleroderma).

However, its onset is most often noted between the ages of 30 and 50, although a detailed study of the initial signs often reveals itself at earlier ages. The disease affects women (according to various sources) 3-7 times more often than men. A smaller gender difference is noted in the incidence statistics among children and among adults whose age is over 45 years.

Retrospective data from studies of the survival of patients (how many live), depending on the variants of the course of the disease and with its natural development, show the following differences:

• in an acute, rapidly progressive course with a predominance of tissue fibrosis and initial symptoms in the form of skin lesions, life expectancy does not exceed 5 years, while survival is only 4%;
• in a subacute, moderately progressive course, damage to the immune system predominates with initial symptoms in the form of an articular syndrome; life expectancy can be up to 15 years, while survival in the first 5 years is 75%, 10 years is about 61%, 15 years is an average of 50%;
• in a chronic, slowly progressive course, vascular pathology predominates with initial signs in the form of Raynaud's syndrome; survival in the first 5 years of the disease - an average of 93%, 10 years - about 87%, and 15 years - 85%.

Etiology and pathogenesis of the disease

The reasons for the development of systemic scleroderma are not well understood. It is now considered to be a multifactorial disease caused by:

1. Genetic predisposition, the individual mechanisms of which have already been deciphered. The association of the disease with some antigens of tissue compatibility, the relationship of clinical manifestations with specific autoantibodies, etc., have been identified. Previously, a genetic predisposition was argued by the presence of cases of systemic scleroderma or another, close to it, pathology or immune disorders in family members or relatives.

2. Exposure to viruses, among which the main influence of cytomegalovirus and retroviruses is considered. Attention is also paid to the study of the role of an activated latent (latent) viral infection, the phenomenon of molecular mimicry, etc. The latter manifests itself in the production of humoral antibodies by the immune system that destroy antigens with the formation of immune complexes, as well as in the reproduction of cellular toxic T-lymphocytes. They destroy the cells of the body in which the viruses are located.

3. Influence of exogenous and endogenous risk factors. Particular importance is attached to:

• hypothermia and frequent and prolonged exposure to sunlight;
• vibrations;
• industrial silicon dust;
• chemical agents of industrial and domestic origin - vapors from petroleum products processing, vinyl chloride, pesticides, organic solvents;
• certain food products containing rapeseed oil, and food additives with L-tryptophan;
• implants and certain medical preparations, for example, bleomycin (antineoplastic antibiotic), vaccines;
• neuroendocrine disorders, frequent stressful conditions, a tendency to vascular spastic reactions.

Schematic presentation of the complex mechanism of the development of the disease

A characteristic feature of systemic scleroderma is the excessive production of collagen protein by fibroblasts. Normally, this contributes to the restoration of damaged connective tissue and leads to its replacement with a scar (sclerosis, fibrosis).

In autoimmune connective tissue diseases, physiological changes under normal conditions are excessively intensified, acquiring pathological forms. As a result of this violation, normal connective tissue is replaced by scar tissue, thickening of the skin and changes in the joints and organs occur. General scheme development of this process is as follows.

Viruses and risk factors against the background of a genetic predisposition affect:

1. Connective tissue structures, which leads to a defect in cell membranes and increased function of fibroblasts. The result of this is the excessive production of collagen, fibrokinetin (a large glycoprotein of the intercellular matrix), proteoglycans and glycosaminoglycans, which are complex proteins, which include immunoglobulins (antibodies), most of protein hormones, interferon, etc.
2. The microvasculature, resulting in damage to the endothelium (the epithelium of the inner wall of blood vessels). This, in turn, leads to the proliferation of myofibroblasts (cells similar at the same time to fibroblasts and smooth muscle cells), platelet sedimentation in small vessels and their adhesion (sticking) on ​​the vascular walls, to the deposition of fibrin filaments on the inner membrane of small vessels, edema and impaired permeability of the latter.
3. The immune system of the body, leading to an imbalance of T- and B-lymphocytes involved in the formation of the immune response, as a result of which the function of the former is impaired and the latter are activated.

All these factors, in turn, cause the further development of the following disorders:

• Excess formation of collagen fibers with subsequent progressive generalized fibrosis in the dermis, musculoskeletal system and internal organs. Fibrosis is an overgrowth of connective tissue.
• Excessive production of collagen proteins in the walls of small vessels, thickening of the basement membranes in them and vascular fibrosis, increased blood clotting and thrombosis in small vessels, narrowing of their lumen. All this leads to damage to small vessels with the development of vascular spasms of the type of Raynaud's syndrome and a violation of the structure and function of internal organs.
• An increase in the formation of cytokines (specific peptide information molecules), immune complexes and autoantibodies, also leading to inflammation of the inner lining of small vessels (vasculitis) and, accordingly, also to damage to internal organs.

Thus, the main links of the pathogenetic chain are:

• violation of the mechanisms of cellular and humoral types of immunity;
• damage to small vessels with destruction and dysfunction of the endothelium of the vascular wall, with a thickening of its inner membrane and microthrombosis, with a narrowing of the lumen of the blood microcirculation bed and a violation of the microcirculation itself;
• violation of the processes of formation of collagen proteins with increased formation of smooth muscle fibers and collagen, which is manifested by fibrous restructuring of the connective tissue of organs and systems with a violation of their function.

Classification of systemic scleroderma and a brief description of individual forms

When formulating a diagnosis, the signs of systemic scleroderma are specified in accordance with such characteristics as the clinical form of the disease, the variant of its course and the stage of development of the pathology.

The following clinical forms are distinguished

diffuse

It develops suddenly and after 3-6 months it manifests with a plurality of syndromes. Within 1 year there is an extensive, generalized lesion of the skin of the upper and lower extremities, face, torso. At the same time or somewhat later, Raynaud's syndrome develops. Early tissue damage occurs in the lungs, kidneys, gastrointestinal tract, heart muscles. When videocapillaroscopy of the nail bed is determined by a pronounced desolation (reduction) of small vessels with the formation of avascular areas (avascular zones) of the nail bed. Blood tests reveal antibodies to an enzyme (topoisomerase 1) that affects the continuity of the cellular DNA molecule.

Limited

It is characterized by less common indurative skin changes, later and slower development of pathology, a long period of Raynaud's syndrome, late development of hypertension in the pulmonary artery, limitation of skin lesions to the areas of the face, hands and feet, late development of skin calcification, telangiectasias and lesions of the digestive tract . When conducting capillaroscopy, dilated small vessels are determined without the presence of pronounced avascular zones. In venous blood tests, specific anticentromeric (antinuclear) autoantibodies against various components of the cell nucleus are detected.

cross

Characteristic of this form is the combination of symptoms of systemic scleroderma with symptoms of one or more other systemic connective tissue pathologies - with rheumatoid arthritis, with systemic lupus erythematosus, with dermatomyositis or polymyositis, etc.

Scleroderma without scleroderma

Or a visceral form that proceeds without thickening of the skin, but with Raynaud's syndrome and signs of damage to internal organs - with pulmonary fibrosis, the development of acute scleroderma kidney, damage to the heart, digestive tract. Autoimmune antibodies to Scl-70 (nuclear topoisomerase) are determined in the blood.

Juvenile systemic scleroderma

The onset of development before the age of 16 according to the type of linear (usually asymmetric) or focal scleroderma. With linear - skin areas with cicatricial changes (usually on the scalp, back of the nose, on the forehead and face, less often on the lower extremities and chest) are linear. With this form, there is a tendency to form contractures (limitation of movements in the joints) and the possibility of the presence of anomalies in the development of the limbs. Pathological changes in the internal organs are quite minor and are detected mainly during instrumental studies.

induced

The development of which is clearly related in time to the influence of factors environment(chemical, cold, etc.). Thickening of the skin is common, often diffuse, sometimes in combination with vascular lesions.

Prescleroderma

It is clinically manifested by an isolated Raynaud's syndrome, combined with a capillaroscopic picture and / or immunological changes characteristic of diseases.

Variants of systemic scleroderma, depending on the nature of the course and the rate of progression

1. Acute, rapidly progressive variant - during the first 2 years from the onset of the disease, generalized diffuse fibrosis of the skin and internal organs, mainly the lungs, heart and kidneys, develops. Previously, in most cases, the disease quickly ended in death. With the use of modern adequate therapy, the prognosis improved somewhat.
2. Subacute, moderately progressive. According to clinical symptoms and laboratory data, it is characterized by a predominance of signs of an immune inflammatory process - dense skin edema, myositis, arthritis. Cross-syndromes are not uncommon.
3. Chronic, slowly progressive. This variant of systemic scleroderma is distinguished by: the predominance of vascular lesions - a long (for many years) existence of Raynaud's syndrome in the early stages of the disease, which is accompanied by the slow development of moderately pronounced skin changes; a gradual increase in disorders associated with ischemia (malnutrition) of tissues; gradual development of pulmonary hypertension and lesions of the digestive tract.

Stages of the disease

1. Initial - the presence of 1 to 3 localizations of the disease.
2. The stage of generalization, reflecting the systemic nature of the lesions with the polysyndromic nature of the manifestations of the process.
3. Terminal, or late, which is characterized by insufficiency of the function of one or more organs - respiratory, cardiac or renal failure.

The use of the three listed parameters in the formulation of the diagnosis of the disease allows you to orient yourself in relation to the preparation of a patient treatment program.

Main symptoms

Based on the mechanism of development of systemic scleroderma and the prevalence of lesions, it is quite understandable a large number of and variety of symptoms of this disease. However, given the staging of the development of the process, there are certain possibilities for diagnosing pathology at the early stages of its development, predicting and influencing the life expectancy of patients.

Diagnosis is carried out taking into account the main characteristic initial and more distant signs:

1. The defeat of the skin in the form of dense edema.
2. Vascular disorders and Raynaud's syndrome.
3. Damage to the musculoskeletal system.
4. Changes in internal organs.

Complaints of patients in the early stages

Patients note general weakness, fatigue, malaise, often fever, not exceeding 38 °, loss of appetite, body weight, etc. These manifestations occur mainly in diffuse forms of systemic scleroderma, are not specific and do not allow one to suspect the onset of pathology before the onset of characteristic symptoms.

Skin and mucous membranes

Skin lesions are one of the main diagnostic symptoms of the disease and develop in most patients with systemic scleroderma. The process of characteristic changes in the skin, localized mainly in the face and hands, in its development goes through the following stages:

• dense edema;
• inductive;
• atrophic.

They lead to the impoverishment of facial expressions ("hypomimia"). The face of a sick person acquires a characteristic "mask-like" appearance - the skin of the face is thickened, compacted and stretched, the tip of the nose becomes sharper, vertical folds and wrinkles appear around the mouth, collected like a pouch ("pouch" symptom), the diameter of the entrance to the mouth decreases. oral cavity. Systemic scleroderma can be combined with Sjögren's syndrome.

Changes in the hands are expressed in sclerodactyly, which is also characterized by dense edema, fibrosis and induration of the skin, leading to a feeling of stiffness, especially in the morning, an increase in limitation of range of motion, a change appearance fingers, acquiring the shape of "sausages".

These symptoms make it possible to accurately establish the diagnosis even at the first cursory visual examination of the patient.

In the diffuse form of the disease, edema, induration and atrophy of the skin go beyond the face and hands. They spread to the skin of the trunk, lower and upper extremities. Along with these signs, areas of the skin with limited or diffusely widespread reduced pigmentation or completely depigmented, as well as with focal or diffuse hyperpigmentation, are often observed.

Under the skin, as a later manifestation, calcifications (accumulations of calcium salts) are formed, which can lead to cheesy necrosis, tissue destruction and ulceration with the release of a cheesy mass (in the form of crumbs) in nature.

To establish an early diagnosis, a 4-point “skin score” technique is important, which makes it possible to assess such early manifestations as the initial degree of skin compaction due to its edema. The method is based on palpation of the skin in 17 areas - in the face, chest, abdomen and symmetrical areas of the upper and lower extremities. The results of the examination are evaluated in points:

• the absence of any changes - 0 points;
• the density of the skin is insignificant, if the skin is relatively light, but more difficult than usual, can be folded - 1 point;
• the density is moderate, if the skin is hardly folded - 2 points;
• pronounced density, "board-like" - 3 points.

When examining a skin biopsy, intense fibrosis is determined.

Can systemic scleroderma cause a persistent runny nose?

Mucous membranes are affected quite often simultaneously with the skin. This is manifested by subatrophic or atrophic rhinitis, accompanied by persistent dryness and nasal congestion that is difficult to correct, pharyngitis, stomatitis, increased thickness, atrophy and shortening of the frenulum of the tongue, which is hallmark involvement in the process of mucous membranes.

Vascular pathology

Often associated with skin disorders. It is an early and frequent manifestation of systemic scleroderma, which reflects the generalized (common) nature of the disease. The most characteristic sign of vascular pathology is Raynaud's syndrome. It is a symmetrical vascular spastic crises of the terminal arteries and arterioles, as a result of which the blood supply to the tissues is disturbed (ischemia).

Attacks are accompanied by a sequential two- or three-phase color change (pallor - cyanosis - redness) of the skin of the fingers, less often the toes, with the simultaneous occurrence of pain, paresthesia, numbness in them. Although the main localization is the fingers, these symptoms tend to spread directly to the entire hand, feet, and sometimes to the tips of the nose, tongue and chin, causing dysarthria (disorder of speech articulation).

Due to the fact that spasms occur in vessels with already altered walls, seizures are prolonged. Raynaud's syndrome attacks can occur spontaneously, but more often they develop under the influence of a cold or psychogenic factor.

Their severity is assessed in degrees or points:

• I degree - the presence of only changes in skin color without subjective sensations and trophic changes.
• II degree - a feeling of pain, tingling or numbness in the fingers during an attack of the syndrome. There may be single scars on the skin of the fingers.
• III degree - severe pain during an attack or / and unhealed single sores.
• IV degree - multiple ulcers or areas of gangrene.

Vascular spasms and changes in their walls lead to tissue malnutrition and trophic disorders - development, dryness and violation of the skin relief, nail deformities, painful, long-term non-healing and recurrent ulcers and suppurations.

Trophic ulcers are located mainly on the terminal phalanges of the fingers (“digital ulcers”), as well as in places of greatest mechanical impact - in the area of ​​the elbow and knee joints, heel bones and ankles. On the distal phalanges of the fingers, dotted scars are often found (a symptom of a "rat bite"), formed as a result of atrophic processes.

Fingertips decrease in volume, become thinner due to resorption of the bones of the nail phalanges (acroosteolysis). In addition, skin necrosis and gangrene may develop, followed by self-amputation in the distal and even middle phalanges.

In the chronic course of the process on the face, anterior and posterior surfaces of the chest, on the limbs, on the mucous membranes of the lips, hard palate, and tongue, telangiectasias can often be detected that occur after several months or even years from the onset of the disease and are, like calcifications, late manifestations of systemic scleroderma.

Musculoskeletal system

Damage to the joints and periarticular tissues

The most frequent, and sometimes the first manifestations of systemic scleroderma are joint damage, manifested by:

• symptom of "tendon friction", which often precedes hardening of the skin; it occurs as a result of sclerosis of the tissue of the tendon sheaths and the tendons themselves and is defined as a “crunch” on palpation of the joints during active movements in them;
• polyarthralgia, less often rheumatoid polyarthritis, but without pronounced destructive changes in the joints; at the same time, erosive changes in the articular surfaces are found in 20% of patients;
• stiffness in the joints, especially the hands, mainly after a night's sleep;
• the development of flexion contracture in the joints, mainly due to changes in the synovial membranes, periarticular ligaments, tendons and muscles;
• osteolysis (resorption) of bones in the area of ​​the distal end phalanges of the fingers, manifested by deformation and shortening of the latter, and sometimes osteolysis of the mandibular processes and the distal third of the radius bones.

The onset of the disease with arthritis is most characteristic of the cross form of systemic scleroderma and its subacute course.

Involvement of muscle tissue

It is expressed by one of the forms of myopathy (muscular dystrophy):

• non-progressive fibrous myopathy of a non-inflammatory nature - the most common form in this disease; manifested by moderate muscle weakness in proximal muscle groups and a slight increase in blood levels of creatine phosphokinase (an enzyme found in muscle tissues);
• inflammatory, accompanied by weakness and pain in the muscles, an increase in blood levels of 2 times or more creatine phosphokinase, as well as inflammatory changes in the results of the study of muscle biopsy specimens and in the results of electromyography.

In addition, the diffuse form of the disease is accompanied by the development of muscle atrophy caused by contractures and impaired joint mobility.

Internal organs

Gastrointestinal tract (GI)

Systemic scleroderma with lesions of the gastrointestinal tract occurs among 70% of patients. Any parts of the digestive tract can be affected, but in 70-85% it is the esophagus (scleroderma esophagitis) and intestines.

Esophagus

Hypotension (decreased tone) of the esophagus is the most common form of damage not only to the latter, but to the entire gastrointestinal tract. Its morphological basis is fibrosis and widespread atrophy of the smooth muscles of the esophageal walls. Characteristic symptoms are difficulty in swallowing, constant heartburn, a feeling of a food bolus behind the sternum, aggravated after eating and/or in a horizontal position.

During esophagogastroscopy and x-ray examination the narrowed lower sections of the esophagus are determined, due to which the intake of solid and dry food is significantly difficult, and the expanded upper (2/3) sections, the absence of peristalsis waves and the lack of elasticity of the walls (rigidity), sometimes a hiatal hernia is possible. Due to the low tone of the lower esophageal sphincter, acidic gastric contents are thrown into the esophagus (gastroesophageal reflux) and the formation of erosions, ulcers and cicatricial narrowing in it, accompanied by excruciating heartburn and severe pain behind the sternum.

With a long course of gastroesophageal reflux disease in some patients, replacement of the esophageal mucosal epithelium with cells identical to the epithelium of the mucous membranes of the stomach or even the small intestine (metaplasia) may occur, which predisposes to the development of esophageal cancer.

Stomach and duodenum

Hypotension of the stomach and duodenum is the cause of the violation of the evacuation of the food mass and its retention in the stomach. This causes a feeling of rapid satiety while eating, frequent belching, pain and a feeling of heaviness in the epigastric region, sometimes gastric bleeding due to the formation of multiple telangiectasias, erosions and ulcers in the mucous membrane.

Changes in the gut

They occur much less frequently than in the esophagus, with the exception of the large intestine, the frequency of which is almost the same. However, the symptomatology of intestinal pathology in the entire clinic of systemic scleroderma often becomes the leading one. The most characteristic are:

• signs of duodenitis resembling peptic ulcer;
• with the predominant development of pathology in the small intestine, absorption is disturbed, manifested by bloating, symptoms of partial paralytic small bowel obstruction (rarely), malabsorption syndrome - frequent diarrhea with a large amount of fat in the feces (steatorrhea), alternating with constipation and leading to a significant decrease in body weight ;
• with damage to the large intestine, persistent and frequent constipation occurs (less than 2 independent acts of defecation per week), fecal incontinence, partial recurrent intestinal obstruction may develop.

Respiratory system

They are affected in more than 70% of cases and in recent decades have become the main cause of death among patients with systemic scleroderma. Lung damage is accompanied by repeated perifocal pneumonia, the formation of emphysema, subpleural cysts, abscesses, pleurisy, the occurrence of repeated spontaneous pneumothorax, lung cancer, which occurs 3-5 times more often than in the corresponding age groups without systemic scleroderma, gradual (within 2-10 years) development of pulmonary insufficiency. Changes in the lungs occur in the form of two clinical and morphological variants:

1. According to the interstitial type of lesion (interstitial lung disease), characterized by pulmonary fibrosis and diffuse pneumosclerosis, most pronounced in the lower parts of the lungs. Pathological changes develop already during the first five years of the disease and are most pronounced in people with a diffuse form of the disease. The clinical symptoms of systemic scleroderma are not specific - dry cough, often hacking, shortness of breath with difficulty exhaling, fatigue and the presence of crepitant wheezing, resembling "cellophane crackling" (during auscultation) in the posterior lower sections of the lungs.
   The examination reveals a decrease in the vital capacity of the lungs, an enhanced and deformed pulmonary pattern in the lower sections (on the x-ray), with computed tomography - an uneven darkening of the lung tissue (ground glass symptom) and a picture of "honeycomb lungs" (at later stages).
2. Isolated (primary) pulmonary hypertension resulting from vascular lesions of the lungs, or secondary (in 10%), developing as a result of interstitial pathology in the late stages of systemic scleroderma. Pulmonary hypertension of both types often develops 10 years after the onset of the disease in 10-40%. Its main symptom is rapidly progressing (over several months) shortness of breath. The main complications of pulmonary hypertension are cor pulmonale with right ventricular failure, as well as thrombosis of the pulmonary arteries with a fatal outcome, as a rule.

Changes in the heart

They represent one of the most unfavorable and frequent (16-90%) localizations of the disease and are in the first place among the causes of sudden death in patients with systemic scleroderma. The changes are:

• conduction disorders and cardiac arrhythmias (in 70%), which especially worsen the prognosis of the disease;
• the development of myocarditis (in this case, the survival rate is the lowest), especially among people with polymyositis;
• damage to the inner heart membrane (endocardium) with the development of valvular defects, mainly the bicuspid valve;
• the development of adhesive or (less often) exudative pericarditis, which can cause cardiac tamponade;
• heart failure, which develops very rarely, but is characterized by resistance to the use of corrective drugs.

The main symptoms are shortness of breath with minor physical exertion or at rest, a feeling of discomfort and dull prolonged pain in the sternum and to the left of it, palpitations and fading of the heart, a feeling of tremors in the region of the heart.

Kidney damage

Due to the availability of modern effective drugs, it is relatively rare. They are based on changes in the arterioles of the kidneys, which are the cause of limited necrosis of the renal tissue due to a violation of its adequate blood supply.

More often these changes are latent, with minor functional disorders, determined only by urine and blood tests. Less commonly, glomerulonephritis or latent chronic nephropathy develops.

Pronounced changes in the form of scleroderma renal crisis (acute nephropathy) develop among 5-10% (mainly with a diffuse form of systemic scleroderma). It is characterized by sudden onset and rapidly progressive renal arterial hypertension, an increase in high protein content in the urine, and renal failure. Only 23% of patients with acute nephropathy survive beyond 5 years. In general, with kidney damage for more than 15 years, only 13% survive, while without this complication, about 72%.

The latest methods for diagnosing systemic scleroderma

Relatively new laboratory tests include methods for the determination of antinuclear antibodies (ANA):

• antibodies to topoisomerase-1 (Scl-70), which, in the presence of isolated Raynaud's syndrome, are harbingers of the development of systemic scleroderma (usually diffuse);
• immunogenetic markers HLA-DR3/DRw52; their presence in combination with antibodies to Scl-70 represents a 17-fold increase in the risk of pulmonary fibrosis;
• anticentromeric antibodies - present in 20% of patients, as a rule, with a limited form of pathology; also considered a disease marker in the presence of isolated Raynaud's syndrome;
• antibodies to RNA polymerase III - found in 20-25%, mainly in diffuse form and kidney damage; they are associated with poor prognosis.

Less often, the presence of other autoantibodies is determined, the frequency of which is much less in the disease. These include antibodies to Pm-Scl (3-5%), to U 3 -RNP (7%), to U 1 -RNP (6%) and some others.

Clinical recommendations for systemic scleroderma, proposed by the Russian Association of Rheumatologists, include additional instrumental examination methods to clarify the nature and extent of lesions of various organs:

• for the digestive tract - esophagogastroduodenoscopy, contrast radiography, pressure manometry in the esophagus, endoscopic gastric pH-metry, biopsy of the metaplastic area of ​​the esophagus;
• for the respiratory system - body plethysmography, high-resolution computed tomography, determination of external respiration and pulmonary diffusion capacity through spirometry and a single breath technique with a breath hold;
• to determine pulmonary hypertension and heart damage - Doppler echocardiography, electrocardiography and catheterization of the right heart, Holter electrocardiographic monitoring, radioisotope scintigraphy;
• for skin, muscles, synovial membrane of joints and tissues of internal organs - biopsy studies;
• wide-field video capillaroscopy of the nail bed, "skin score" (described above).

Differential Diagnosis

Differential diagnosis of systemic scleroderma is carried out with such diseases and syndromes of connective tissue as systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, Raynaud's disease, limited scleroderma, Buschke's scleroderma, pseudoscleroderma, multifocal fibrosis, tumor-associated scleroderma, Werner and Rothmund-Thomson syndromes.

Diagnosis of systemic scleroderma is carried out on the basis of a combination of clinical symptoms (preference is given), instrumental and laboratory methods. For this purpose, the Association of Rheumatologists of Russia recommends using criteria such as basic and additional features that allow for differential diagnosis. To establish a reliable diagnosis, it is sufficient to have 3 of the main signs listed below or one of the main ones (scleroderma skin changes, characteristic changes in the digestive organs, osteolysis of the nail phalanges) in combination with three or more additional ones.

The main features include:

1. Sclerodermic skin lesions.
2. Raynaud's syndrome and digital ulcers and/or scars.
3. Muscular-articular lesions with the development of contractures.
4. Skin calcification.
5. Osteolysis.
6. Fibrosis of the basal parts of the lungs.
7. The defeat of the gastrointestinal tract scleroderma character.
8. The development of macrofocal cardiosclerosis with conduction and heart rhythm disturbances.
9. Scleroderma acute nephropathy.
10. Characteristic results of video capillaroscopy of the nail bed.
11. Detection of such specific antinuclear antibodies, as mainly to Scl-70, anticentromeric antibodies and antibodies to RNA polymerase III.

Additional signs:

• Loss of body weight more than 10 kg.
• Tissue trophic disorders.
• The presence of polyserositis, as a rule, of an adhesive (adhesive) form.
• Telangiectasias.
• Chronic course of nephropathy.
• Polyarthralgia.
• Trigeminal neuralgia (trigimenitis), polyneuritis.
• Increase in ESR more than 20 mm/hour.
• Elevated levels of gamma globulins in the blood, exceeding 23%.
• The presence of antinuclear factor (ANF) or autoantibodies to DNA.
• Identification of rheumatoid factor.

Treatment of systemic scleroderma

Treatment of the disease is long, usually lifelong. It should be carried out comprehensively, depending on the form of pathology, the nature of the course and the involvement of certain organs and systems in the process.

The effectiveness of therapy is significantly reduced against the background of the presence of the above risk factors, as well as the presence of such provoking factors as unhealthy diet, smoking (!), drinking alcohol and energy (!) Drinks, coffee and strong brewed tea, physical and neuropsychic stress, insufficient rest.

Is it possible to sunbathe with systemic scleroderma?

Ultraviolet radiation is one of the rather high risk factors that can lead to an exacerbation of the course of the disease. Therefore, staying in places unprotected from sunlight, especially during periods of increased solar activity, is undesirable. Rest on the sea coast is not contraindicated, but only in the autumn months and subject to staying in the shade. It is also necessary to always use creams with the maximum degree of protection from ultraviolet rays.

Nutrition Features

Of certain importance is nutrition in systemic scleroderma, which should be reusable with short breaks between meals in small volumes, especially with damage to the esophagus. It is recommended to exclude allergenic foods and consume foods with a sufficient content of proteins (milk and dairy products, non-spicy cheeses, meat and fish), micro- and macroelements, especially calcium salts.

In case of impaired renal function (nephropathy, renal failure), protein intake should be strictly dosed, and in case of damage to various parts of the digestive tract, a diet and food processing should be observed that correspond to the disorders of these organs, taking into account the specifics of nutrition in scleroderma.

It is also desirable to limit the intake of carbohydrates, especially when taking glucocorticosteroid drugs, and a sufficient amount of vegetables, berries and fruits with a low sugar content.

Principles of drug treatment and rehabilitation

The main goals of therapy are:

• achievement of the stage of remission or the maximum possible suppression of the activity of the process;
• stabilization of the functional state;
• prevention of complications associated with changes in blood vessels and the progression of fibrosis;
• prevention of damage to internal organs or correction of existing violations of their functioning.

Especially active therapy should be in the first years after the detection of the disease, when the main and most significant changes in the systems and organs of the body occur intensively. During this period, it is still possible to reduce the severity of inflammatory processes and reduce the consequences in the form of fibrotic changes. Moreover, there is still an opportunity to influence the already formed fibrotic changes in terms of their partial reverse development.

1. Kuprenil (D-penicillamine) in tablets, which has an anti-inflammatory effect, an effect on metabolic processes in connective tissues and a pronounced anti-fibrotic effect. The latter is implemented only after application for six months - a year. Kuprenil is the drug of choice for the rapid progression of pathology, diffuse skin indurative process and active fibrosis. It is prescribed in gradually increasing and then decreasing dosages. Maintenance doses are taken for 2 to 5 years. Due to possible side effects (toxic effect on the kidneys, impaired bowel function, dermatitis, effects on hematopoietic organs, etc.), observed in approximately 30% of patients, the drug is taken under constant medical supervision.
2. Immunosuppressors Methotrexate, Azathioprine, Cyclophosphamide and others. Methotrexate has an effective effect on skin syndrome, with damage to muscles and joints, especially at an early, inflammatory stage of the disease. Cyclophosphamide is used with high activity of the process, interstitial lung damage with the formation of pulmonary fibrosis (an absolute indication for use), the presence of pronounced immunological changes and in cases where there is no noticeable effect from the previously used treatment.
3. Enzymatic agents (Lidase and Ronidase) - break down mucopolysaccharides and reduce the viscosity of hyaluronic acid. They are prescribed for a chronic process by courses of subcutaneous or intramuscular injections, as well as in the form of iontophoresis and applications in the area of ​​tissue induration or contractures.
4. Glucocorticosteroids (Dexamethasone, Metipred, Prednisolone, Triamcinolone) - are prescribed for the activity of the process of II or III degree, as well as in cases of acute or subacute course. Their use is carried out with constant monitoring of kidney function.
5. Vascular drugs - the main ones are calcium channel blockers (Corinfar, Nifedipine, Cordaflex, Foridon), angiotensin-converting enzyme inhibitors (Captopril, Kapoten, etc.), prescribed already at the initial stages of the disease, prostanoids (Iloprost, Vazaprostan), endothelin receptor antagonists (Traklir, Bosentan), which reduces resistance in both systemic and pulmonary vessels.
6. Antiplatelet agents (Curantil, Trental) and anticoagulants (small doses of acetylsalicylic acid, Fraxiparine).
7. Non-steroidal anti-inflammatory (Ibuprofen, Nurofen, Piroxicam, Indomethacin) and aminoquinoline (Plaquenil) agents.

A new method is the use of genetically engineered biological products in systemic scleroderma. Currently, the study of their effectiveness and prospects for use in severe forms of systemic scleroderma continues. They represent a relatively new direction in the therapy of other systemic diseases of the connective tissue.

These agents include Etarnecept and Inflixicamb, which suppress autoimmune reactions, the immunosuppressant Rituximab, which is a monoclonal antibody to B-lymphocyte receptors (in combination with low doses of glucocorticosteroids), antibodies to transforming growth factor beta-I, antimonocytic immunoglobulin, the cytostatic Imatinib, which suppresses excess synthesis of intercellular matrix, resulting in reduced skin syndrome and improved lung function in diffuse form of systemic scleroderma, gamma- and alpha-interferons.

Treatment with traditional medicine

In the complex of treatment it is desirable to include means traditional medicine. However, it must always be remembered that the treatment of systemic scleroderma with folk remedies should never be the only one or used as the main one. It can only serve as a secondary supplement (!) To the main therapy prescribed by specialists.

For these purposes, you can use vegetable oils, as well as infusions of medicinal plants (St. John's wort, calendula) on vegetable oil with which it is necessary to lubricate the affected skin several times a day to soften them, improve nutrition and reduce the severity of inflammatory processes. It is useful for joints, skin and blood vessels to take warm baths with infusions of geranium, rhubarb, pine buds or needles, birch leaves, oat straw.

Alcohol tinctures or infusions (for oral administration) of saponaria officinalis, Sakhalin buckwheat, harpagophytum root tea, infusions of horsetail, lungwort and knotweed herbs have anti-inflammatory and immunosuppressive properties. An infusion of the following mixture of plants has anti-inflammatory and vasodilating effects: immortelle, St. There are many other combinations of medicinal plants in the form of fees.

Massage and exercise, physiotherapy

The system of complex therapy and rehabilitation also includes (in the absence of activity or slight activity of the process): massage and a set of exercises for systemic scleroderma, which improve the function of breathing and heart, the regulation of vascular tone, improve joint mobility, etc .; physiotherapy courses - iontophoresis with anti-inflammatory, vascular and enzyme preparations (Lidase), thermal procedures (paraffin, ozocerite), applications with Dimethyl sulfoxide on the most affected joints; sanatorium treatment (mud therapy and balneotherapy).

Is pregnancy possible and is there a chance to bear a child?

Pregnancy is accompanied by significant hormonal changes in the body, which is a fairly high risk for a woman in terms of exacerbation of the course of the disease, as well as a risk to the fetus and unborn child. However, it is possible. Systemic scleroderma is not an absolute contraindication for pregnancy and childbirth, even naturally. A particularly high chance of carrying a child in the initial stages of the disease with a subacute or chronic course in the absence of process activity and pronounced pathological changes in the internal organs, especially the kidneys and heart.

However, pregnancy planning must be agreed with the attending specialist to resolve the issue of the possibility of canceling certain drugs and correcting treatment in general with the use of hormonal, cytostatic, vascular, antiplatelet agents, drugs that improve tissue metabolism, etc. In addition, in the period of pregnancy must be observed and examined at least 1 time per trimester, not only by an obstetrician-gynecologist, but also by a rheumatologist.

In order to decide the possibility of prolonging the pregnancy, a woman should be hospitalized in the first trimester, and in the future - if there is a suspicion of an activation of the disease or complications of the course of pregnancy.

The implementation of timely adequate treatment, proper employment, patient compliance with the rules of constant dispensary observation, elimination or minimization of provoking factors, the influence of risk factors can slow down the progression of the disease, significantly reduce the degree of aggressiveness of its course, improve survival prognosis and improve the quality of life.

Treatment of patients with SJS should be as early as possible, complex and is determined depending on the clinical form, the rate of progression and the severity of organ pathology. Long-term treatment is needed, which can be lifelong. Treatment for SJS includes medical vascular and anti-inflammatory and immunosuppressive drugs. The goal of treatment is to restore vascular homeostasis, reduce damage due to inflammation and fibrotic changes.

3.1 Conservative treatment.

decrease in activity and suppression of the progression of the disease;
prevention and treatment of Raynaud's syndrome and vascular complications;
prevention and treatment of visceral manifestations of the disease.
The main place in the treatment of SJS is occupied by vascular, anti-inflammatory and immunosuppressive drugs.
Based on international experience and in accordance with EULAR versions, the recommendations are grouped by organ systems or the most severe clinical syndromes.
In Raynaud's syndrome associated with SJS, all patients are recommended to carry out long-term drug therapy. Treatment is considered successful when the severity of vasospasm is reduced and no new ischemic lesions appear.
The choice of specific therapy depends on clinical condition and severity, which are classified according to the WHO functional scale. The first functional class includes asymptomatic patients or those with symptoms that minimally limit normal physical activity, and the IV functional class includes patients with the greatest limitations. physical activity that occur even at rest. In patients with functional classes I, II and III, the first-line drugs are bosentan and sildenafil. In addition to these drugs, inhaled iloprost can be used in patients with functional class III. With the development of the IV functional class, as a rule, combined therapy with these drugs is prescribed.
Recommended as first-line drugs (reduce the frequency and severity of Raynaud's syndrome attacks compared with placebo and for the treatment of Raynaud's syndrome associated with systemic scleroderma) - calcium channel blockers (calcium antagonists) of the dihydropyridine group (mainly nifedipine ** orally).

Comments. Preferred are long-acting calcium antagonists;
Recommended for the ineffectiveness of calcium antagonists for the treatment of severe Raynaud's syndrome - prostanoids for intravenous use (iloprost, alprostadil **).
The level of persuasiveness of recommendations A.
Prostanoids (predominantly IV iloprost) not only reduce the frequency and severity of Raynaud's syndrome attacks compared with placebo, but also have a positive effect on healing, and therefore are recommended for the treatment of active digital ulcers.
The level of persuasiveness of recommendations A.
Iloprost is prescribed at 20-50 mcg per infusion in 3-5 day courses several times a year at the rate of 0.5-2 ng / kg per minute intravenously for at least 6 hours a day. Alprostadil** is prescribed in courses of 10-15 injections 2-3 times a year, 20-60 mcg per IV infusion (at least 3 hours a day).

Comments. Calcium antagonists and prostanoids can cause the same hemodynamic effects, which requires increased attention to the monitoring of possible side effects in the combined use of drugs of these classes. Patients treated with prostanoids are more likely to experience ischemic cardiovascular complications, so cardiovascular risk should be carefully assessed in all patients before treatment with prostanoids.
Non-selective type I endothelin receptor blockers (ET-1) are recommended for the treatment of multiple and recurrent digital ulcers in diffuse form of the disease when calcium antagonists and prostanoids are ineffective: bosentan** reduces the frequency and duration of Raynaud's attacks, and the frequency of new or recurrent digital ulcers.

Recommended for the treatment of severe Raynaud's syndrome and digital ulcers, including the ineffectiveness of calcium antagonists and prostanoids - phosphodiesterase type 5 inhibitors sildenafil and tadalafil.
Level of persuasiveness of recommendations B/A.
It is recommended to take drugs that inhibit platelet aggregation along with vasodilators.

It is recommended to relieve pain in digital ulcers by taking NSAIDs, paracetamol and weak opioids (tramadol**) in adequate doses.
The level of persuasiveness of recommendations C.
Recommended for the treatment of infected digital ulcers is the local and / or systemic use of broad-spectrum antibiotics, which are advisable to prescribe after sowing the contents of the wound for flora and sensitivity to antibiotics.
The level of persuasiveness of recommendations C.
The main goal of pharmacotherapy of skin lesions in SJS is to reduce the severity and prevalence of skin thickening. The effectiveness of drugs against skin fibrosis can be assessed by the dynamics of the skin score (after 6 and 12 months).
It is recommended at an early stage (during the first 3-5 years of the disease) or with an increase in the severity and prevalence of skin thickening in patients with diffuse systemic scleroderma D-penicillamine ** (250-500 mg per day). .
Level of persuasiveness of recommendations C).
Recommended for the treatment of early diffuse SJS - Methotrexate ** in doses of 10-15 mg / day.

Recommended for reducing skin billing is Mycophenolate Mofetil** (MMF) at a therapeutic dose of 2 g/day. .
Level of persuasiveness of recommendation B/C.
Recommended for progressive diffuse skin lesions as monotherapy or in combination with the above drugs - Glucocorticoids (GC).
Comments. In addition to skin lesions, GCs are also recommended for obvious clinical signs of inflammatory activity (serositis, myositis, IPL, refractory synovitis and / or tenosynovitis) in small doses - up to 15-20 mg per day, etc.; taking GCs increases the risk of developing sderoderma renal crisis (SRC).
In many patients with SSc, lung involvement is relatively benign, with no obvious progression, so not all patients with ILD need to be treated. The choice - whom and how to treat - is made taking into account the initial severity of ILD and the obvious risk of progression. The appointment of treatment is indicated for patients with shortness of breath in the first 5-7 years from the onset of the disease, if.
according to HRCT of the chest, the volume of lung damage exceeds 20% and / or;
FVC ≤ 70% and/or;
there was a decrease in FVC by ≥ 10% over the previous 3-12 months.
The effectiveness of therapy is monitored by the level of forced vital capacity, which must be determined at least once every 6 months.
The level of persuasiveness of recommendations B.
Comments. The effectiveness of therapy is evidenced by the stabilization or increase in the level of FVC.
Recommended for the treatment of ILD in SSc is the use of GCs orally at doses of 10-15 mg/day. In combination with immunosuppressants.
The level of persuasiveness of recommendations C.
Comment. There was no significant association between improvement in pulmonary function and the use of high doses of HA. It must be remembered that the appointment of high doses of glucocorticoids increases the risk of developing a scleroderma renal crisis;
It is recommended as an induction therapy for interstitial lung disease (ILD) in SJS - Cyclophosphamide ** (CF) in combination with low doses of GC. ZF is administered intravenously at doses of 500 mg/m2 - 750 mg/m2 per month or orally at doses of 1 mg/kg/day - 2 mg/kg/day, depending on the effectiveness and tolerability of the drug.
Level of persuasiveness of recommendations A.
Comments. The route of administration of CF (oral or intravenous) does not significantly affect the level of changes in the parameters of functional pulmonary tests and the frequency of adverse reactions. The duration of the course of cyclophosphamide should be at least 6 months (Recommendation grade C), however, if the drug is well tolerated, the duration of therapy may be 12 months or more until the IPI stabilizes.
MMF is recommended, both as an induction therapy for IPL (in case of intolerance or inefficiency, including secondary, CF in combination with GC), and as a maintenance after stabilization of the pulmonary process against the background of CF therapy.
Level of persuasiveness of recommendations A.
Comments. MMF is prescribed from a dose of 1000 mg / day. (in two doses), increasing it to 2000-3000 mg / day. (in two doses) in case of good tolerance.
It is recommended in case of failure or intolerance of CF and / or MMF therapy, the use of Azathioprine ** (100 mg / day) or Cyclosporine A ** (at doses not exceeding 2.5 mg / kg / day) for 12-18 months.
The level of persuasiveness of recommendations C.
Tactics of managing a patient with interstitial lung disease.
Treatment of PAH includes traditional therapy: diuretics, cardiac glycosides (if supraventricular arrhythmias occur).
Recommended for deep hypoxemia (saturation less than 90%) - oxygen therapy;
Anticoagulants are recommended only for thrombotic complications;
It is not recommended to prescribe beta-blockers, ACE inhibitors, angiotensin-2 receptor antagonists, ivabradine in PAH, unless these drugs are necessary.
AT last years PAH-specific therapy has been introduced into practice, which is prescribed to improve exercise tolerance, slow down the progression of the disease, it causes regression of changes in the pulmonary vessels, improves the quality of life and survival prognosis. Drugs for PAH-specific therapy promote vasodilation and reduce pulmonary artery pressure through different mechanisms.
Endothelin-1 (ET-1) receptor antagonists. Bosentan** is recommended at a starting dose of 62.5 mg twice daily. After 4 weeks, with good tolerance, increase the dose to 125 mg 2 times a day. It is recommended to monitor the levels of transaminases and bilirubin monthly. Women taking bosentan need reliable contraception, given the possible teratogenic effect.
The level of persuasiveness of recommendations C.
Comments. ET-1 receptor antagonists suppress the vasoconstrictive effect of ET-1 by binding to type A and B receptors (non-selective ET-1 antagonists) or only to type A receptors (selective ET-1 antagonists). The former include bosentan and macitentan, while ambrisentan iloprost is a representative selective ET-1 antagonist.
Analogues of prostacyclin. Recommended from 6 to 12 inhalations of iloprost per day to maintain a stable effect. Inhaled iloprost effectively reduces pressure in the pulmonary artery.
The level of persuasiveness of recommendations C.
Comments. Iloprost is a chemically stable prostacyclin analogue that is available as an infusion for IV, oral, and aerosol applications. The half-life of iloprost is 20-25 minutes, the duration of action is 45-60 minutes. When using an ultrasonic nebulizer, the duration of inhalation is 5 minutes. Prostacyclin analogues are also epoprostenol (in infusion form) and treprostenil (for intravenous and subcutaneous administration and in the form of an aerosol).
Prostacyclin receptor agonists Selexipag 10 mg once daily is recommended. Selexipag is an oral selective prostacyclin IP receptor agonist;
Phosphodiesterase type 5 inhibitors (PDE-5) inhibit the inactivation of cyclic GMP in cells. It is recommended to use Sildenafil at a dose of 20 mg x 3 times a day, if it is ineffective, it is possible to increase the dose to 200 mg per day. It is recommended to take Tadalafil (selective PDE-5 inhibitor) once a day (2.5-40 mg). Recommended Vardenafil (selective PDE-5 inhibitor) at a dose of 20 mg 2 times a day;
Soluble guanylate cyclase stimulators increase the synthesis of GMF. Riociguat is recommended orally 3 times a day, 1 mg (maximum daily dose of 7.5 mg).
The level of persuasiveness of recommendations C.
Comments. The combination of guanylate cyclase stimulants and PDE-5 inhibitors is contraindicated due to arterial hypotension and other serious side effects.
Scheme for defining therapy for pulmonary arterial hypertension.
The most prognostically unfavorable manifestation of SJS is acute nephropathy (scleroderma renal crisis (SRC) or "acute scleroderma kidney"), the lethality of which exceeds 40-50%. The main manifestations of SPC are the sudden development of acute kidney injury and arterial hypertension, which quickly becomes malignant. In 10-20% of cases, normotensive SPC is diagnosed, which can be suspected in patients with SJS at risk for developing SPC. In patients with SJS, renal function should be assessed regularly. To assess renal function in patients with SJS, as in the general population, it is advisable to determine the glomerular filtration rate using the CKD-EPI calculation formula. Risk factors for SPC: diffuse form of the disease, early stage diseases (especially 1-3 years), rapid progression of the skin syndrome, rapid formation of articular contractures, male gender, old age, the presence of antibodies to ribonucleoprotease III, taking large doses of CS.
Criteria for acute kidney injury: increase in creatinine level ≥26.5 mmol/l (≥0.3 mg/dl) within 48 hours or increase in serum creatinine level ≥1.5 times the initial level, significantly or presumably developed within 7 days .
It is not recommended to prescribe GC more than 15 mg per day and potentially nephrotoxic drugs (D-penicillamine **, Cyclosporine A **) to patients with risk factors for SEC due to the possibility of provoking SEC.
The level of persuasiveness of recommendations C.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) are recommended as first-line drugs in the treatment of SPC. Aggressive antihypertensive therapy may stabilize or improve renal function. Treatment is recommended to start with captopril ** at 12.5-25 mg with dose titration up to the maximum (50 mg 3 times a day).
The level of persuasiveness of recommendations C.

Diagnosis of systemic sclerosis and concomitant diseases is based primarily on characteristic clinical signs. Skin lesions are characterized by varying degrees of thickening and compaction. There may be changes in skin pigmentation, in particular mottled hyperpigmentation of the "salt and pepper" type. Other important skin manifestations:

In the initial stages of the disease - skin itching and swelling.
Sclerodactyly.
Ulcers and depressions on the tips of the fingers.
Telangiectasias.
Skin calcification.

Limited Diagnosis is based on the presence of a typical thickening and hardening of the skin, limited to one focus. The diagnosis of systemic sclerosis is suggested by typical thickening and induration (sclerosis) of the skin that is not limited to one area (i.e., is not localized scleroderma). Combination skin symptoms with one or more typical systemic features supports the diagnosis of systemic sclerosis.

According to the American Rheumatological Association Criteria for the diagnosis of systemic sclerosis one main (major) or two additional (minor) criteria are required.
The main criteria are typical scleroderma skin changes: tension, thickening, dense swelling that does not leave marks after indentation, and also (with the exception of localized forms of scleroderma):
- Sclerodactyly: the above changes are limited to the fingers and toes.
- Proximal scleroderma: The changes described above are found proximal to the carpo-phalangeal or carpometacarpal joints, as well as other areas of the limbs, face, neck or trunk (chest or abdomen) and almost always include sclerodactyly.

Additional (minor) criteria for scleroderma:
- Depressed scars or loss of tissue on the pads of the fingers.
- Bilateral swelling of the fingers or palms.
- Abnormal skin pigmentation: often hyperpigmentation with pitted or patchy hypopigmentation.
- Raynaud's phenomenon.
- Bilateral basilar fibrosis of the lungs.
- Immobility of the lower esophagus.
- Formation of protrusions in the colon: diverticula of the colon with wide openings are located along the antimesenteric edge.

Tests for scleroderma

Characteristic of systemic scleroderma is a positive AHA test with patchy, homogeneous, or nucleolar staining. Anti-centromeric antibodies are often associated with OCSS. Anti-DNA topoisomerase (Scl-70) antibodies are highly specific for systemic sclerosis and related interstitial diseases of the lungs and kidneys. Despite the low sensitivity, antibodies to anti-RNA polymerase I and III are specific for systemic sclerosis. Usually, other types of testing are performed when a specific organ is dysfunctional.
A biopsy can be used to diagnose localized and systemic scleroderma.

Differential diagnosis of scleroderma

Idiopathic cases of diseases that are associated with systemic sclerosis, such as Raynaud's phenomenon, renal failure and gastroesophageal reflux.
Systemic lupus erythematosus presents with systemic symptoms and a typical rash that may scar. Testing for antinuclear antibodies (ANA) usually helps establish the diagnosis.
Discoid lupus erythematosus is represented by localized plaques that are scarring. A biopsy is usually performed to establish the diagnosis.

Myxedema is associated with hypothyroidism and is characterized by thickening and roughening of the skin. Research on hormone levels thyroid gland usually confirm the diagnosis.
Amyloidosis of the skin may present with thickening and rigidity of the skin. The skin biopsy showed an amyloid infiltrate.
Fungal mycosis is represented by spots and plaques with a purple tint throughout the skin. The diagnosis is usually confirmed with a biopsy.

Treatment of scleroderma

Localized scleroderma, including localized (morphea) scleroderma, softens after UV-A therapy. Other treatments include high-potency topical corticosteroids and topical calcipotriol. Methotrexate is started at 7.5 mg orally per week, then the dosage is adjusted as needed. A combination of high doses of systemic corticosteroids and low doses of methotrexate has been successfully used.
For symptomatic therapy, antipruritic treatment with emollient topical drugs, histamine 1 (H1) and histamine 2 (H2) blockers, oral doxepin, and low doses of oral glucocorticosteroids can be used.
Telangiectasias can be masked with makeup or treated with a laser.
Raynaud's symptoms may be treated with calcium channel blockers, prasosin, prostaglandin derivatives, dipyridamole, aspirin, and topical nitrates. In patients with primary Raynaud's disease, sildepafil (20 mg orally twice a day) has been shown to be effective. Patients are advised to avoid cold, stress, nicotine, caffeine, drugs with sympathomimetic decongestant action. Acid-reducing drugs may be used empirically for gastroesophageal reflux. For difficulty swallowing, prokinetic drugs may be helpful.

Some localized lesions may be excised.
Unapproved therapies for skin lesions include interferon-gamma, mycophenolate mofetil (1–1.5 g orally per day), and cyclophosphamide (50–150 mg/day orally as a single dose). A common skin disease was experimentally treated with D-penicillamine (250-1500 mg/day orally 2-3 times a day before meals on an empty stomach).

The main direction of treatment for kidney damage is the control of blood pressure with the use of angiotensin-converting enzyme (ACE) inhibitors as first-line drugs. According to the indications, hemodialysis or peritoneal dialysis is used.

Treatments for pulmonary hypertension associated with systemic scleroderma include the endothelial receptor antagonist bosentan (62.5 mg orally twice a day for 4 weeks, then increased to 125 mg orally twice a day), sildenafil, a phosphodiesterase-5 inhibitor, and various prostacyclin analogues (epoprosteiol, treprostinil and iloprost). In pulmonary fibrosing alveolitis, cyclophosphamide may be used.

Myositis is treated with steroids, methotrexate, and azathioprine (50–150 mg/day). Doses of prednisone above 40 mg/day increase the incidence of sclerodermal renal crises. Arthralgias can be treated with acetaminophen and non-steroidal anti-inflammatory drugs.

Recommendations for patients with scleroderma. The patient should avoid injury to the skin (especially the fingers) and exposure to cold, as well as refrain from smoking. The patient should be aware of potential complications and self-monitor for signs and symptoms of disease progression.

Patients with systemic sclerosis require regular follow-up with a doctor, at least every 3-6 months, to assess the activity and progression of the disease.

Clinical example of scleroderma. A 35-year-old woman consulted a doctor about patchy patchy patchy patches on her abdomen. Since the patient was generally healthy, the appearance of the lesions surprised her and raised concern about their spread throughout the body. Skin changes caused some discomfort, but were not painful. The biopsy confirmed the clinical suspicion of localized scleroderma. The patient was prescribed clobetasol and calcipotriol topically, after which the skin condition improved somewhat. The test for antinuclear antibodies was positive, however, the patient did not develop progressive systemic sclerosis.