Systemic scleroderma. Treatment, prognosis Systemic scleroderma national recommendations

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. Skin pigmentation changes, including mottled, salt-and-pepper hyperpigmentation, may be noted. Other important skin manifestations:

In the initial stages of the disease - skin itching and swelling.
Sclerodactyly.
Ulcers and depressions on the fingertips.
Telangiectasia.
Calcinosis of the skin.

Diagnosis of limited is based on the presence of typical thickening and compaction of the skin, limited to one lesion. The diagnosis of systemic sclerosis is suggested by typical thickening and hardening (sclerosis) of the skin that is not limited to one area (that is, not localized scleroderma). The combination of skin symptoms with one or more typical systemic signs supports the diagnosis of systemic sclerosis.

According to the American Rheumatological Association Criteria for the diagnosis of systemic sclerosis the presence of one main (major) or two additional (minor) criteria is 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 carpophalangeal or carpometacarpal joints, as well as elsewhere on the extremities, face, neck, or trunk (chest or abdomen) and almost always include sclerodactyly.

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

Tests for scleroderma

Systemic scleroderma is characterized by a positive AHA test with patchy, homogeneous or nucleolar staining. Anti-centromere antibodies are often associated with OKSS. Anti-DNA topoisomerase (Scl-70) antibodies are highly specific for systemic sclerosis and related interstitial diseases of the lungs and kidneys. Despite their low sensitivity, antibodies to anti-RNA polymerase I and III are specific for systemic sclerosis. Usually, other types of testing are performed when there is dysfunction of a specific organ.
A biopsy can be used to diagnose limited 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. Antinuclear antibody (ANA) testing usually helps establish the diagnosis.
Discoid lupus erythematosus presents as localized plaques that become scarred. A biopsy is usually performed to make the diagnosis.

Myxedema is associated with hypothyroidism and is characterized by thickening and roughening of the skin. Studies of thyroid hormone levels usually confirm the diagnosis.
Cutaneous amyloidosis may cause thickening and stiffness of the skin. A skin biopsy reveals an amyloid infiltrate.
Mycosis fungoides is represented by spots and plaques with a purple tint throughout the skin. The diagnosis is usually confirmed by biopsy.

Treatment of scleroderma

Lesions of localized scleroderma, including localized scleroderma (morphea), soften after treatment with UV-A rays. Other treatments include topical high-potency corticosteroids and topical calcipotriol. Methotrexate is started at 7.5 mg orally per week, and subsequently the dosage is adjusted as needed. A combination of high doses of systemic corticosteroids and low doses of methotrexate has been used successfully.
For symptomatic therapy, antipruritic treatment with topical emollients, histamine 1 (H1) and histamine 2 (H2) blockers, oral doxepin and low-dose oral glucocorticosteroids can be used.
Telangiectasia can be disguised with decorative cosmetics or treated with laser.
Calcium channel blockers, prasosin, prostaglandin derivatives, dipyridamole, aspirin, and topical nitrates may help with symptoms of Raynaud's phenomenon. Sildepafil (20 mg orally twice daily) has been shown to be effective in patients with primary Raynaud's disease. Patients are advised to avoid cold, stress, nicotine, caffeine, and drugs with sympathomimetic decongestant effects. For gastroesophageal reflux, acid-reducing drugs may be used empirically. For difficulty swallowing, prokinetic medications 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). The common skin disease was experimentally treated with D-penicillamine (250–1500 mg/day orally 2–3 times daily before meals on an empty stomach).

The main direction of treatment for kidney damage is blood pressure control using angiotensin-converting enzyme (ACE) inhibitors as first-line drugs. According to 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 daily for 4 weeks, then increased to 125 mg orally twice daily), the phosphodiesterase-5 inhibitor sildenafil, and various prostacyclin analogues (epoprosteol, treprostinil and iloprost). For pulmonary fibrosing alveolitis, cyclophosphamide can be used.

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

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

Patients with systemic sclerosis require regular medical supervision, at least every 3-6 months, to assess disease activity and progression.

Clinical example of scleroderma. A 35-year-old woman consulted a doctor about patches of shiny, dense skin on her abdomen that looked like plaques. Since the patient was generally healthy, the appearance of the lesions surprised her and raised concerns about their spread throughout the body. The skin changes caused some discomfort, but were not painful. A biopsy confirmed the clinical suspicion of limited scleroderma. The patient was prescribed topical clobetasol and calcipotriol, after which the skin condition improved slightly. The antinuclear antibody test was positive; however, the patient did not develop progressive systemic sclerosis.

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

These lesions are based on a widespread cascade of microcirculatory disturbances, inflammation, and generalized fibrosis. Life expectancy with 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 average statistical data, the primary incidence per year per 1,000,000 population ranges from 2.7 to 12 cases, and the overall prevalence of this pathology ranges from 30 to 450 cases per year per 1,000,000 population. The development of the disease is possible in various age groups, including young people (juvenile scleroderma).

However, its onset is most often noted between the ages of 30 and 50, although upon detailed study, the initial signs are often identified 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 morbidity statistics among children and among adults over 45 years of age.

Retrospective data from studies of patient survival (how long they live), depending on the course of the disease and 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 the survival rate is only 4%;
in a subacute, moderately progressive course, damage to the immune system predominates with initial symptoms in the form of articular syndrome; life expectancy can be up to 15 years, with survival rate in the first 5 years - 75%, 10 years - about 61%, 15 years - on average 50%;
in a chronic, slowly progressive course, vascular pathology predominates with initial signs in the form of Raynaud's syndrome; survival rate in the first 5 years of the disease is on average 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 currently believed to be a multifactorial disease caused by:

1. Genetic predisposition, the individual mechanisms of which have already been deciphered. An association of the disease with certain histocompatibility antigens, a connection of clinical manifestations with specific autoantibodies, etc. Previously, genetic predisposition was argued by the presence of cases of systemic scleroderma or other pathology close to it or immune disorders in family members or relatives.

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

3. The 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 household origin - vapors from petroleum products processing, vinyl chloride, pesticides, organic solvents;
some foods containing rapeseed oil and L-tryptophan supplements;
implants and certain medications, for example, bleomycin (antitumor antibiotic), vaccines;
neuroendocrine disorders, frequent stressful conditions, a tendency to vascular spastic reactions.

Schematic presentation of the complex mechanism of disease development

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

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

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

Connective tissue structures, which leads to defective cell membranes and increased fibroblast function. The result of this is excess production of collagen, fibrokinetin (a large glycoprotein of the intercellular matrix), proteoglycans and glycosaminoglycans, which are complex proteins that include immunoglobulins (antibodies), most protein hormones, interferon, etc.
Microvasculature, resulting in damage to the endothelium (epithelium of the inner wall of blood vessels). This, in turn, leads to the proliferation of myofibroblasts (cells similar to both fibroblasts and smooth muscle cells), sedimentation of platelets in small vessels and their adhesion (sticking) to the vascular walls, deposition of fibrin threads on the inner lining of small vessels, edema and impairment permeability of the latter.
The body's immune system, 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 disrupted and the latter are activated.

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

Excessive 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 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 like Raynaud's syndrome and disruption of the structure and function of internal organs.
Increased 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 in the pathogenetic chain are:

violation of the mechanisms of cellular and humoral immunity;
damage to small vessels with destruction and dysfunction of the endothelium of the vascular wall, with thickening of its inner membrane and microthrombosis, with narrowing of the lumen of the blood microcirculation channel and disruption of the microcirculation itself;
disruption of the 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 disruption of their function.

Classification of systemic scleroderma and brief characteristics 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 already after 3-6 months manifests itself with a multiplicity of syndromes. Within 1 year, extensive, generalized damage to the skin of the upper and lower extremities, face, and torso occurs. At the same time or somewhat later, Raynaud's syndrome develops. Damage to the tissues of the lungs, kidneys, gastrointestinal tract, and heart muscles occurs early. Videocapillaroscopy of the nail bed reveals a pronounced desolation (reduction) of small vessels with the formation of avascular areas (avascular zones) of the nail bed. Blood tests detect 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 presence of only 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 calcification of the skin, telangiectasia and damage to the digestive tract . When performing capillaroscopy, dilated small vessels without the presence of pronounced avascular zones are determined. Venous blood tests reveal specific anticentromere (antinuclear) autoantibodies against various components of the cell nucleus.

Cross

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

Scleroderma without scleroderma

Or the visceral form, which occurs 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, and the digestive tract. Autoimmune antibodies to Scl-70 (nuclear topoisomerase) are detected in the blood.

Juvenile systemic scleroderma

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

Induced

The development of which is clearly related in time to the influence of environmental factors (chemical, cold, etc.). Skin thickening is widespread, often diffuse, sometimes in combination with vascular lesions.

Prescleroderma

Clinically manifested by isolated Raynaud's syndrome, combined with a capillaroscopic picture and/or immunological changes characteristic of the disease.

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

Acute, rapidly progressing 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 has improved somewhat.
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 common cases.
Chronic, slowly progressive. This variant of systemic scleroderma is distinguished by: the predominance of vascular lesions - the long-term (for many years) existence of Raynaud's syndrome in the first stages of the disease, which is accompanied by the slow development of moderately pronounced skin changes; gradual increase in disorders associated with ischemia (malnutrition) of tissues; gradual development of pulmonary hypertension and damage to the digestive tract.

Stages of the disease

Initial - the presence of 1 to 3 localizations of the disease.
The stage of generalization, reflecting the systemic nature of the lesions with the polysyndromic nature of the manifestations of the process.
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 when formulating a diagnosis of a disease allows you to navigate in relation to drawing up a treatment program for the patient.

Main symptoms

Based on the mechanism of development of systemic scleroderma and the prevalence of lesions, the large number and variety of symptoms of this disease are understandable. However, taking into account the staged development of the process, there are certain possibilities for diagnosing pathology in 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:

Damage to the skin in the form of dense swelling.
Vascular disorders and Raynaud's syndrome.
Damage to the musculoskeletal system.
Changes in internal organs.

Complaints of patients in the early stages

Patients note general weakness, fatigue, malaise, often elevated temperature not exceeding 38 °, decreased 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 appearance 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 skin changes, localized mainly in the area of the face and hands, goes through the following stages in its development:

dense swelling;
inductive;
atrophic.

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

Changes in the hands are expressed in sclerodactyly, which is also characterized by dense swelling, fibrosis and induration of the skin, leading to a feeling of stiffness, especially in the morning, an increase in limited range of motion, and a change in the appearance of the fingers, taking on the shape of “sausages”.

These symptoms allow an unmistakable diagnosis to be made even with the first cursory visual examination of the patient.

In the diffuse form of the disease, swelling, induration and atrophy of the skin extend beyond the face and hands. They spread to the skin of the trunk, lower and upper extremities. Along with these signs, areas of 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 the formation of ulcers with the release of a mass of cheesy (in the form of crumbs) character.

To establish an early diagnosis, the 4-point “skin count” technique is important, allowing one to assess such early manifestations as the initial degrees of skin thickening due to its swelling. 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 inspection results are assessed in points:

absence of any changes - 0 points;
the density of the skin is insignificant, if the skin is relatively easy, but more difficult than usual, to be folded - 1 point;
moderate density, if the skin is difficult to fold - 2 points;
pronounced density, “board-shaped” - 3 points.

When examining a skin biopsy, intense fibrosis is determined.

Can systemic scleroderma cause a persistent runny nose?

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

Vascular pathology

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

Attacks are accompanied by a successive two- or three-phase change in color (pallor - cyanotic - redness) of the skin of the fingers, less often the toes, with the simultaneous occurrence of pain, paresthesia, and numbness. 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 (speech articulation disorder).

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

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 and/or unhealed single ulcers.
IV degree - multiple ulcers or areas of gangrene.

Vascular spasms and changes in their walls lead to disruption of tissue nutrition and trophic disorders - development, dryness and disruption of skin texture, deformation of nails, painful, long-term non-healing and recurrent ulcerations and suppuration.

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, pinpoint scars (a “rat bite” symptom) are often found, formed as a result of atrophic processes.

The fingertips decrease in volume and become thinner due to the resorption of the bones of the nail phalanges (acroosteolysis). In addition, skin necrosis and gangrene may develop, followed by self-amputation in the area of 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 extremities, on the mucous membranes of the lips, hard palate, and on the tongue, telangiectasia can often be found, occurring several months or even years after the onset of the disease and, like calcifications, being late manifestations of systemic scleroderma.

Musculoskeletal system

Lesions of joints and periarticular tissues

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

a symptom of “tendon friction”, which often precedes skin thickening; it occurs as a result of sclerosis of the tissue of the tendon sheaths and the tendons themselves and is defined as a “crunch” when palpating the joints during active movements in them;
polyarthralgia, less often rheumatoid-type 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;
development of flexion contracture in joints, caused mainly by changes in the synovial membranes, periarticular ligaments, tendons and muscles;
osteolysis (resorption) of bones in the area of the distal parts of the terminal phalanges of the fingers, manifested by deformation and shortening of the latter, as well as sometimes osteolysis of the mandibular processes and the distal third of the radial bones.

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

Muscle tissue involvement

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

non-progressive fibrous myopathy of a non-inflammatory nature is the most common form of this disease; manifested by moderate muscle weakness in proximal muscle groups and a slight increase in the level of creatine phosphokinase (an enzyme contained in muscle tissue) in the blood;
inflammatory, accompanied by weakness and pain in the muscles, an increase in creatine phosphokinase in the blood by 2 times or more, as well as inflammatory changes in the results of the study of muscle biopsies 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 (GIT)

Systemic scleroderma with gastrointestinal involvement occurs among 70% of patients. Any part 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 also to the entire gastrointestinal tract. Its morphological basis is fibrosis and widespread atrophy of the smooth muscles of the walls of the esophagus. Characteristic symptoms are difficulty swallowing, constant heartburn, a feeling of a lump of food behind the sternum, which intensifies after eating and/or in a horizontal position.

When carrying out esophagogastroscopy and x-ray examination, narrowed lower sections of the esophagus are determined, which makes eating solid and dry food much more difficult, and dilated upper (2/3) sections, the absence of waves of peristalsis and lack of elasticity of the walls (rigidity), sometimes the presence of a hiatal hernia is possible diaphragm holes. Due to the low tone of the lower esophageal sphincter, acidic gastric contents reflux into the esophagus (gastroesophageal reflux) and the formation of erosions, ulcers and cicatricial narrowing in it, accompanied by painful heartburn and severe chest pain.

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

Stomach and duodenum

Hypotension of the stomach and duodenum is the cause of impaired evacuation of 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 intestines

They occur much less frequently compared to the esophagus, with the exception of the large intestine, the frequency of which is almost the same. However, the symptoms of intestinal pathology in the entire clinical picture of systemic scleroderma often become the leading one. The most characteristic are:

signs of duodenitis resembling a peptic ulcer;
with the predominant development of pathology in the small intestine, absorption is impaired, manifested by bloating, symptoms of partial paralytic small intestinal obstruction (rarely), malabsorption syndrome - frequent diarrhea with a large amount of fat in the stool (steatorrhea), alternating with constipation and leading to a significant decrease in body weight ;
when the large intestine is damaged, persistent and frequent constipation occurs (less than 2 independent bowel movements per week), fecal incontinence, and 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 failure. Changes in the lungs occur in the form of two clinical and morphological options:

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 within 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 - a dry cough, often hacking, shortness of breath with difficulty exhaling, fatigue and the presence of crepitant wheezing, reminiscent of “cellophane crackling” (during auscultation) in the posterior lower parts 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 an x-ray), and a computed tomography scan reveals uneven darkening of the lung tissue (ground glass symptom) and a picture of “honeycomb lungs” (at later stages).
Isolated (primary) pulmonary hypertension, resulting from vascular lesions of the lungs, or secondary (in 10%), developing as a result of interstitial pathology in the later 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, which is usually fatal.

Changes in the heart

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

conduction disorders and heart rhythm disturbances (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 lining of the heart (endocardium) with the development of valve defects, mainly the bicuspid valve;
the development of adhesive or (less commonly) 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 long-term pain in the sternum and to the left of it, palpitations and cardiac arrest, a feeling of tremors in the heart.

Kidney damage

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

More often, these changes occur latently, 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 in the diffuse form of systemic scleroderma). It is characterized by sudden onset and rapidly progressive renal arterial hypertension, increased protein content in the urine and renal failure. Only 23% of patients with acute nephropathy survive for more than 5 years. In general, with kidney damage, only 13% survive longer than 15 years, while without this complication - about 72%.

The latest methods for diagnosing systemic scleroderma

Relatively new laboratory tests include methods for determining 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;
anticentromere antibodies - present in 20% of patients, usually with a limited form of pathology; also considered a marker of the disease 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 a poor prognosis.

The presence of other autoantibodies, the frequency of which in the disease is much less, is determined less often. 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 Association of Rheumatologists of Russia, include additional instrumental examination methods that make it possible 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 the technique of a single breath with breath holding;
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 counting” (described above).

Differential diagnosis

Differential diagnosis of systemic scleroderma is carried out with such connective tissue diseases and syndromes as systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, Raynaud's disease, limited scleroderma, Buschke's scleredema, 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 these purposes, the “Association of Rheumatologists of Russia” recommends using criteria such as basic and additional signs that allow 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:

Sclerodermic nature of skin lesions.
Raynaud's syndrome and digital ulcers and/or scars.
Musculo-articular lesions with the development of contractures.
Calcification of the skin.
Osteolysis.
Fibrosis of the basal regions of the lungs.
Lesions of the gastrointestinal tract of a sclerodermic nature.
Development of large-focal cardiosclerosis with conduction and heart rhythm disturbances.
Scleroderma acute nephropathy.
Typical results of video capillaroscopy of the nail bed.
Detection of specific antinuclear antibodies, mainly to Scl-70, anticentromere antibodies and antibodies to RNA polymerase III.

Additional signs:

Loss of body weight by more than 10 kg.
Disorders of tissue trophism.
The presence of polyserosite, usually of an adhesive (sticky) form.
Telangiectasia.
Chronic course of nephropathy.
Polyarthralgia.
Trigeminal neuralgia (trigymenitis), polyneuritis.
An increase in ESR values of more than 20 mm/hour.
Increased levels of gammaglobulins in the blood, exceeding 23%.
Presence of antinuclear factor (ANF) or autoantibodies to DNA.
Detection of rheumatoid factor.

Treatment of systemic scleroderma

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

The effectiveness of therapy is significantly reduced due to the presence of the above risk factors, as well as the presence of such provoking factors as unhealthy diet, smoking (!), consumption of 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 fairly high risk factors that can lead to an exacerbation of the disease. Therefore, staying in places unprotected from sunlight, especially during periods of increased solar activity, is undesirable. Holidays on the sea coast are 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 against ultraviolet rays.

Nutritional Features

Nutrition for systemic scleroderma is of particular importance, which should be multiple meals with short breaks between meals in small volumes, especially if the esophagus is affected. It is recommended to exclude allergenic dishes and consume foods with sufficient protein content (milk and fermented milk products, mild cheeses, meat and fish), micro- and macroelements, especially calcium salts.

In case of impaired renal function (nephropathy, renal failure), protein consumption should be strictly dosed, and if various parts of the digestive tract are affected, a diet and food processing should be followed that correspond to the disorders of these organs, taking into account the specific nutrition in scleroderma.

It is also desirable to limit the consumption 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:

achieving 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 progression of fibrosis;
prevention of damage to internal organs or correction of existing dysfunctions.

Therapy should be especially active in the first years after detection of the disease, when the main and most significant changes in the systems and organs of the body intensively occur. 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, it is still possible to influence already formed fibrotic changes in terms of their partial reverse development.

Cuprenil (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 realized only after application for six months to a year. Cuprenil is the drug of choice for 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 effects on the kidneys, impaired intestinal function, dermatitis, effects on the hematopoietic organs, etc.) observed in approximately 30% of patients, the drug is taken under constant medical supervision.
Immunosuppressants Methotrexate, Azathioprine, Cyclophosphamide and others. Methotrexate has an effective effect against skin syndrome, with damage to muscles and joints, especially in the early, inflammatory stage of the disease. Cyclophosphamide is used in cases of 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.
Enzyme agents (Lidase and Ronidase) - break down mucopolysaccharides and reduce the viscosity of hyaluronic acid. Prescribed for the chronic process in courses of subcutaneous or intramuscular injections, as well as in the form of iontophoresis and applications in the area of tissue induration or contractures.
Glucocorticosteroids (Dexamethasone, Metipred, Prednisolone, Triamcinolone) are prescribed for the activity of the II or III degree process, as well as in cases of acute or subacute course. Their use is carried out with constant monitoring of renal function.
Vascular drugs - the main ones are calcium channel blockers (Corinfar, Nifedipine, Cordaflex, Foridon), angiotensin-converting enzyme inhibitors (Captopril, Capoten, etc.), prescribed already in the initial stages of the disease, prostanoids (Iloprost, Vazaprostan), endothelin receptor antagonists (Traklir, Bosentan), which reduces resistance in both systemic and pulmonary vessels.
Antiplatelet agents (Curantil, Trental) and anticoagulants (small doses of acetylsalicylic acid, Fraxiparine).
Nonsteroidal anti-inflammatory drugs (Ibuprofen, Nurofen, Piroxicam, Indomethacin) and aminoquinoline drugs (Plaquenil).

A new method is the use of genetically engineered biological products for 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 connective tissue diseases.

These drugs 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, antimonocyte immunoglobulin, the cytostatic Imatinib, which suppresses excess synthesis of the intercellular matrix, as a result of which skin syndrome is reduced and lung function is improved in the diffuse form of systemic scleroderma, gama- and alpha-interferons.

Treatment with traditional medicine

It is advisable to include traditional medicine in the treatment complex. However, it is always necessary to remember that 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 minor addition (!) 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) in vegetable oil, which must be lubricated several times a day on the affected areas of the skin to soften them, improve nutrition and reduce the severity of inflammatory processes. It is beneficial for joints, skin and blood vessels to take warm baths with infusions of geranium, wavy rhubarb, pine buds or needles, birch leaves, and 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. John's wort, sweet clover, meadow geranium, meadow clover, yarrow, bird's eye knotweed, mint leaves, plantain and oregano, raspberries and lingonberries, dandelion roots. There are many other combinations of medicinal plants in the form of herbs.

Massage and exercises, physiotherapy

The system of complex therapy and rehabilitation also includes (in the absence of activity or insignificant activity of the process): massage and a set of exercises for systemic scleroderma, improving respiratory and cardiac function, regulating vascular tone, improving joint mobility, etc.; physiotherapy courses - iontophoresis with anti-inflammatory, vascular and enzyme drugs (Lidaza), thermal procedures (paraffin, ozokerite), applications with Dimethyl sulfoxide on the most affected joints; spa treatment (mud therapy and balneotherapy).

Is pregnancy possible and is there a chance of carrying 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 disease, as well as a risk for the fetus and unborn child. However, it is possible. Systemic scleroderma is not an absolute contraindication for pregnancy and childbirth, even naturally. There is a particularly high chance of bearing 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 coordinated with the treating specialist to resolve the issue of the possibility of discontinuing certain medications and correcting treatment in general with the use of hormonal, cytostatic, vascular, antiplatelet drugs, drugs that help improve tissue metabolism, etc. In addition, in During pregnancy, it is necessary to be observed and examined at least once a trimester not only by an obstetrician-gynecologist, but also by a rheumatologist.

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

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 the survival prognosis and improve the quality of life.

It is characterized by a staged course and a large polymorphism of clinical manifestations associated with characteristic damage to the skin, some internal organs and the musculoskeletal system.

Age-related morbidity and survival of patients

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

Retrospective data from studies of patient survival (how long they live), depending on the course of the disease and 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 the survival rate is only 4%;
in a subacute, moderately progressive course, damage to the immune system predominates with initial symptoms in the form of articular syndrome; life expectancy can be up to 15 years, with survival rate in the first 5 years - 75%, 10 years - about 61%, 15 years - on average 50%;
in a chronic, slowly progressive course, vascular pathology predominates with initial signs in the form of Raynaud's syndrome; survival rate in the first 5 years of the disease is on average 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 currently believed to be a multifactorial disease caused by:

3. The 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 household origin - vapors from petroleum products processing, vinyl chloride, pesticides, organic solvents;
some foods containing rapeseed oil and L-tryptophan supplements;
implants and certain medications, for example, bleomycin (antitumor antibiotic), vaccines;
neuroendocrine disorders, frequent stressful conditions, a tendency to vascular spastic reactions.

Schematic presentation of the complex mechanism of disease development

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

Connective tissue structures, which leads to defective cell membranes and increased fibroblast function. The result of this is excess production of collagen, fibrokinetin (a large glycoprotein of the intercellular matrix), proteoglycans and glycosaminoglycans, which are complex proteins that include immunoglobulins (antibodies), most protein hormones, interferon, etc.
Microvasculature, resulting in damage to the endothelium (epithelium of the inner wall of blood vessels). This, in turn, leads to the proliferation of myofibroblasts (cells similar to both fibroblasts and smooth muscle cells), sedimentation of platelets in small vessels and their adhesion (sticking) to the vascular walls, deposition of fibrin threads on the inner lining of small vessels, edema and impairment permeability of the latter.
The body's immune system, 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 disrupted and the latter are activated.

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

Excessive 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 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 like Raynaud's syndrome and disruption of the structure and function of internal organs.
Increased 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 in the pathogenetic chain are:

violation of the mechanisms of cellular and humoral immunity;
damage to small vessels with destruction and dysfunction of the endothelium of the vascular wall, with thickening of its inner membrane and microthrombosis, with narrowing of the lumen of the blood microcirculation channel and disruption of the microcirculation itself;
disruption of the 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 disruption of their function.

Classification of systemic scleroderma and brief characteristics of individual forms

The following clinical forms are distinguished:

Scleroderma without scleroderma

Juvenile systemic scleroderma

Clinically manifested by isolated Raynaud's syndrome, combined with a capillaroscopic picture and/or immunological changes characteristic of the disease.

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

Acute, rapidly progressing 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 has improved somewhat.
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 common cases.
Chronic, slowly progressive. This variant of systemic scleroderma is distinguished by: the predominance of vascular lesions - the long-term (for many years) existence of Raynaud's syndrome in the first stages of the disease, which is accompanied by the slow development of moderately pronounced skin changes; gradual increase in disorders associated with ischemia (malnutrition) of tissues; gradual development of pulmonary hypertension and damage to the digestive tract.

Initial - the presence of 1 to 3 localizations of the disease.
The stage of generalization, reflecting the systemic nature of the lesions with the polysyndromic nature of the manifestations of the process.
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 when formulating a diagnosis of a disease allows you to navigate in relation to drawing up a treatment program for the patient.

Main symptoms

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

Damage to the skin in the form of dense swelling.
Vascular disorders and Raynaud's syndrome.
Damage to the musculoskeletal system.
Changes in internal organs.

Complaints of patients in the early stages

Skin and mucous membranes

These symptoms allow an unmistakable diagnosis to be made even with the first cursory visual examination of the patient.

absence of any changes - 0 points;
the density of the skin is insignificant, if the skin is relatively easy, but more difficult than usual, to be folded - 1 point;
moderate density, if the skin is difficult to fold - 2 points;
pronounced density, “board-shaped” - 3 points.

When examining a skin biopsy, intense fibrosis is determined.

Can systemic scleroderma cause a persistent runny nose?

Vascular pathology

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 and/or unhealed single ulcers.
IV degree - multiple ulcers or areas of gangrene.

Vascular spasms and changes in their walls lead to disruption of tissue nutrition and trophic disorders - the development of diffuse baldness, dryness and disruption of skin texture, deformation of nails, painful, long-term non-healing and recurrent ulcerations and suppuration.

Musculoskeletal system

Lesions of joints and periarticular tissues

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

a symptom of “tendon friction”, which often precedes skin thickening; it occurs as a result of sclerosis of the tissue of the tendon sheaths and the tendons themselves and is defined as a “crunch” when palpating the joints during active movements in them;
polyarthralgia, less often rheumatoid-type 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;
development of flexion contracture in joints, caused mainly by changes in the synovial membranes, periarticular ligaments, tendons and muscles;
osteolysis (resorption) of bones in the area of the distal parts of the terminal phalanges of the fingers, manifested by deformation and shortening of the latter, as well as sometimes osteolysis of the mandibular processes and the distal third of the radial bones.

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

Muscle tissue involvement

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

non-progressive fibrous myopathy of a non-inflammatory nature is the most common form of this disease; manifested by moderate muscle weakness in proximal muscle groups and a slight increase in the level of creatine phosphokinase (an enzyme contained in muscle tissue) in the blood;
inflammatory, accompanied by weakness and pain in the muscles, an increase in creatine phosphokinase in the blood by 2 times or more, as well as inflammatory changes in the results of the study of muscle biopsies 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 (GIT)

Stomach and duodenum

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

Respiratory system

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 within 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 - a dry cough, often hacking, shortness of breath with difficulty exhaling, fatigue and the presence of crepitant wheezing, reminiscent of “cellophane crackling” (during auscultation) in the posterior lower parts 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 an x-ray), and a computed tomography scan reveals uneven darkening of the lung tissue (ground glass symptom) and a picture of “honeycomb lungs” (at later stages).

Isolated (primary) pulmonary hypertension, resulting from vascular lesions of the lungs, or secondary (in 10%), developing as a result of interstitial pathology in the later 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, which is usually fatal.

Changes in the heart

conduction disorders and heart rhythm disturbances (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 lining of the heart (endocardium) with the development of valve defects, mainly the bicuspid valve;
the development of adhesive or (less commonly) exudative pericarditis, which can cause cardiac tamponade;
heart failure, which develops very rarely, but is characterized by resistance to the use of corrective drugs.

Kidney damage

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

The latest methods for diagnosing systemic scleroderma

Relatively new laboratory tests include methods for determining 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;
anticentromere antibodies - present in 20% of patients, usually with a limited form of pathology; also considered a marker of the disease 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 a poor prognosis.

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 the technique of a single breath with breath holding;
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 counting” (described above).

Differential diagnosis

Diagnosis of systemic scleroderma is carried out on the basis of a combination of clinical symptoms (preference is given), instrumental and laboratory methods. For these purposes, the “Association of Rheumatologists of Russia” recommends using criteria such as basic and additional signs that allow 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:

Sclerodermic nature of skin lesions.
Raynaud's syndrome and digital ulcers and/or scars.
Musculo-articular lesions with the development of contractures.
Calcification of the skin.
Osteolysis.
Fibrosis of the basal regions of the lungs.
Lesions of the gastrointestinal tract of a sclerodermic nature.
Development of large-focal cardiosclerosis with conduction and heart rhythm disturbances.
Scleroderma acute nephropathy.
Typical results of video capillaroscopy of the nail bed.
Detection of specific antinuclear antibodies, mainly to Scl-70, anticentromere antibodies and antibodies to RNA polymerase III.

Loss of body weight by more than 10 kg.
Disorders of tissue trophism.
The presence of polyserosite, usually of an adhesive (sticky) form.
Telangiectasia.
Chronic course of nephropathy.
Polyarthralgia.
Trigeminal neuralgia (trigymenitis), polyneuritis.
An increase in ESR values of more than 20 mm/hour.
Increased levels of gammaglobulins in the blood, exceeding 23%.
Presence of antinuclear factor (ANF) or autoantibodies to DNA.
Detection of rheumatoid factor.

Treatment of systemic scleroderma

Is it possible to sunbathe with systemic scleroderma?

Nutritional Features

It is also desirable to limit the consumption 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:

achieving 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 progression of fibrosis;
prevention of damage to internal organs or correction of existing dysfunctions.

Cuprenil (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 realized only after application for six months to a year. Cuprenil is the drug of choice for 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 effects on the kidneys, impaired intestinal function, dermatitis, effects on the hematopoietic organs, etc.) observed in approximately 30% of patients, the drug is taken under constant medical supervision.
Immunosuppressants Methotrexate, Azathioprine, Cyclophosphamide and others. Methotrexate has an effective effect against skin syndrome, with damage to muscles and joints, especially in the early, inflammatory stage of the disease. Cyclophosphamide is used in cases of 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.
Enzyme agents (Lidase and Ronidase) - break down mucopolysaccharides and reduce the viscosity of hyaluronic acid. Prescribed for the chronic process in courses of subcutaneous or intramuscular injections, as well as in the form of iontophoresis and applications in the area of tissue induration or contractures.
Glucocorticosteroids (Dexamethasone, Metipred, Prednisolone, Triamcinolone) are prescribed for the activity of the II or III degree process, as well as in cases of acute or subacute course. Their use is carried out with constant monitoring of renal function.
Vascular drugs - the main ones are calcium channel blockers (Corinfar, Nifedipine, Cordaflex, Foridon), angiotensin-converting enzyme inhibitors (Captopril, Capoten, etc.), prescribed already in the initial stages of the disease, prostanoids (Iloprost, Vazaprostan), endothelin receptor antagonists (Traklir, Bosentan), which reduces resistance in both systemic and pulmonary vessels.
Antiplatelet agents (Curantil, Trental) and anticoagulants (small doses of acetylsalicylic acid, Fraxiparine).
Nonsteroidal anti-inflammatory drugs (Ibuprofen, Nurofen, Piroxicam, Indomethacin) and aminoquinoline drugs (Plaquenil).

Treatment with traditional medicine

Massage and exercises, physiotherapy

Is pregnancy possible and is there a chance of carrying a child?

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Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
Radboud University Medical Center, Nijmegen, The Netherlands
Rheumatology A Department, Cochin Hospital, Paris Descartes University, Paris, France
University Hospital Charité, Berlin, Germany
University Hospital Zurich, Zurich, Switzerland
University of California at Los Angeles, Los Angeles, California, USA
Research Laboratories and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS AOU San Martino, Genova, Italy
Department of Rheumatology and Immunology, Medical Center, University of Pecs, Pecs, Hungary
University of Belgrade, Belgrade, Serbia
University of Leeds, Leeds, UK
University College London, London, UK
University of Erlangen-Nuremberg, Erlangen, Germany
Hamburg Center for Pediatric and Adolescence Rheumatology, Hamburg, Germany
FESCA, London, UK
University of Giessen, Bad Nauheim, Germany
University of Florence, Florence, Italy
University of Cologne, Cologne, Germany
University of Michigan School of Medicine, Ann Arbor, Michigan, USA
University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester, UK
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
University of Lübeck, Lübeck, Germany
Medical University of South Carolina, Charleston, South Carolina, USA
Ghent University Hospital, Ghent University, Ghent, Belgium
Basel University, Basel, Switzerland
FESCA Patient Research Partner, Ede, The Netherlands
Johns Hopkins University, Baltimore, Maryland, USA
Second University of Naples, Naples, Italy
University of Padua, Padua, Italy

for contact Professor Otylia Koval Bielecka, Department of Rheumatology and Internal Medicine, Medical University Bialystok, ul. M. Sklodowskiej Curie 24a, Bialystok 15-276, Poland; [email protected] annotation The aim was to update the 2009 European League Against Rheumatism (EULAR) recommendations for the treatment of systemic scleroderma (SSc), with attention to new therapeutic issues. The update of previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the Federation of European Scleroderma Associations (FESCA), a clinical epidemiologist and 2 research fellows. All centers from the EULAR group The EULAR Scleroderma Trials and Research (EUSTAR) were asked to submit and select clinical questions relating to SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for the systematic literature review. The new recommendations were based on available evidence and developed in a consensus meeting with clinical specialists and patients. The procedure led to 16 recommendations being developed (instead of 14 in 2009), targeted treatment of a number of complications associated with organ lesions: Raynaud's phenomenon (RP), digital ulcers digital ulcers (DUs) , pulmonary arterial hypertension (PAH), skin and lung lesions, scleroderma renal crisis and gastrointestinal tract lesions. Compared to 2009 recommendations, by 2015 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-RP and DUs, riociguat, new aspects related to endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for related SSD PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and hematopoietic stem cell transplantation for selected patients with rapidly progressing SSc have also been added. In addition, several comments regarding other treatments are addressed in clinical issues and suggestions for an SSc research agenda have been formulated. These updated data and consensus recommendations will help rheumatologists manage patients with SSc in an evidence-based manner. These recommendations also provide directions for future clinical research in SSc. Statistics from Altmetric.com Introduction Systemic sclerosis (SSc) is a connective tissue disease (CTD) that affects the skin, blood vessels, heart, lungs, kidneys, gastrointestinal (GI) tract and musculoskeletal system. Internal organ involvement results in significant morbidity and mortality in patients with SSc. The clinical complexity and heterogeneity of SSc makes the treatment of this disease very challenging. The creation of the first European League Against Rheumatism (EULAR) guidelines for the treatment of SSc in 2009 was a significant milestone for improving the care of patients with SSc, and they were well received by the international scleroderma expert community. Given some recent developments regarding the treatment of internal organs associated with SSc, the need to update the EULAR 2009 recommendations was recognized by the EULAR Scleroderma Trials and Research (EUSTAR) group and recognized by EULAR. Following EULAR standardized operational procedures, an Ad Hoc Expert Committee was established by EULAR and EUSTAR. As with previous recommendations, the global community of SSc experts collaborating within EUSTAR was involved. Based on published data and expert opinion, 16 updated recommendations regarding drug treatment of SSc specific organ lesions were formulated. It should be recognized that the scope of management of patients with SSc is more than just isolated pharmacological management. Management of SSc also includes (early) diagnosis of the disease, early diagnosis of internal organ damage, identification of patients at risk of developing complications of new organs and exacerbation of the disease, as well as non-drug therapy, most of which are beyond the scope of this project. There are also several drugs (potential), including new promising treatments, that may be useful in treating patients with SSc that cannot be included in these evidence-based guidelines due to insufficient data at this time. Actual recommendations aim to guide drug treatment of SSc to specific organ involvement. These recommendations are not intended to replace the clinical judgment of a physician or patient-physician decision making. They must be considered in light of the clinical understanding of the individual patient and the physician and patients deciding the balance between the effectiveness and toxicity of treatment. Although some treatment-related toxicities are mentioned in the text of the recommendation, it is still the responsibility of the physician to recognize and monitor all possible toxicities/adverse effects according to information provided by the manufacturer and all other available sources. Methods Design These recommendations are an update of the 2009 EULAR recommendations for the treatment of SSc. The evidence for existing recommendations has been updated to take into account new evidence published since then, and all existing recommendations have been recently discussed and formulated as necessary. Existing recommendations may also be removed, for example, when a certain drug (class) has been withdrawn from the market. New evidence-based recommendations have been added. Group of Experts The expert panel consisted of 32 clinical experts in SSc (29 rheumatologists, 1 dermatologist, 2 pediatric rheumatologists with experience in minor SSc), 2 SSc patients (KF, JW) and 1 clinical epidemiologist (JF) in total, representing 11 countries. Clinical experts are internationally recognized specialists in SSc with many years of experience in the diagnosis and treatment of patients with this disease. Pan European SSc Patients Association (FESCA) two patients were nominated. Unfortunately, at the time of forming the task force, we were unable to identify medical specialists with experience in the treatment of patients with SSc who were able to participate in the work. Potential conflicts of interest were acknowledged by all participants. There was no involvement of third parties throughout the entire process of making these recommendations. Clinical Question Selection Process To create a comprehensive list of topics of interest, clinical experts from all EUSTAR centers were asked via email to select clinical questions related to drug treatment of SSc. As a result, 170 clinical questions were provided by experts from 41 EUSTAR centers. These questions were then classified by drug (class) and aggregated with the clinical questions from 2009; duplicates have been removed. Clinical questions were formulated in the “PICO” format (Patients, Intervention, Comparator, Outcome). Subsequently, clinical questions were presented in three rounds of web-based Delphi exercises to EUSTAR member centers as previously described. Delphi was completed before May 2014. For more information on the Delphi implementation, look online. The results of the Delphi exercise were presented by the panel of experts at their first meeting in June 2014. In this meeting, the nominal group method was used, based on the results of the Delphi exercise. Finally, clinical questions were selected and subjected to a systematic literature search (See online). Systematic literature search A systematic literature search was performed by two fellows (AK, MB) supervised by a Task Force member (JA), under the guidance of a clinical epidemiologist (JF). For new clinical questions, a literature search was performed for all articles published between 1966 and, as agreed by the group, up to 30 September 2014 in PubMed, EMBASE, the Cochrane Database for Meta-Analysis and the Cochrane Controlled Trials Register, and 2012 and 2013 EULAR and American College of Rheumatology (ACR) Convention abstract archives. For clinical questions already included in existing guidelines then use the same strategy, search from February 2007 to September 30, 2014. A standardized strategy search was used for all clinical questions (see online). Medical Subject Heading (MeSH) Search (study) was used for PubMed and keyword searches were used for 2012 – 2014, or if the MeSH term was not available. For each question, clinical publications found were shown for selection by reading the title and abstract. To find additional studies, the reference lists of meta-analyses, reviews, or systematic reviews were reviewed. For information regarding study selection, classification and assessment of evidence, and data extraction, view online. Recommendations Evidence from individual studies was pooled to arrive at a recommendation consistent with the SCORING system. Accordingly, an evidence profile and summary table summary were made for each question, clinical AK or MB. Using these results, a number of draft recommendations were prepared by OK-B, JF, UM-L, YA and OD. The draft recommendations were sent to the expert group prior to the second face-to-face consensus meeting in October 2014. The draft recommendations were presented one at a time, along with the evidence profile and results table, moderated by JF. Based on the nominal group technique, all recommendations were discussed, revised, and the level of evidence was assigned until consensus was reached among all participating experts. Results The procedure as described above resulted in 16 recommendations being developed (instead of 14 in 2009). These recommendations address several organ-related complications of SSc: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung diseases, scleroderma renal crisis (SRC), and GI (gastrointestinal )gastrointestinal involvement. The final set of recommendations, grouped by organ system and future research agenda, are provided in and , respectively. Box 1 Research program

To evaluate the effectiveness and safety of cyclophosphamide in the treatment of early diffuse systemic scleroderma (SSc);
Evaluation of the effectiveness and safety of Mycophenolate mofetil and azathioprine in the treatment of SSc;
Assessing the effectiveness and safety of anti-CD20 therapy in the treatment of SSc;
Evaluation of calcium antagonists in the prevention of SSc-associated pulmonary arterial hypertension;
Evaluation of calcium antagonists in the treatment of digital ulcers in SSc;
Evaluation of statins in the treatment of digital ulcers in SSc;
Assessing the effectiveness and safety of ACE inhibitors in preventing scleroderma renal crisis;
Evaluation of the effectiveness of non-drug therapy for SSc.

Table 1 Updated recommendations EULAR for the treatment of systemic scleroderma, according to visceral involvement, including recommendations and results of the internal assessment within the Task Force

Organ damage	Recommendation	Level of evidence	The Power of Recommendation	Internal assessment results
SSc-RP	Dihydropiridine-type calcium antagonists, usually oral nifedipine, should be considered for first-line therapy for SSc-RP. PDE-5 inhibitors should also be considered in the treatment of SSc-RP.	1A	A	8.19
	Intravenous iloprost should be considered for severe SSc-RP. Experts recommend that intravenous iloprost should be used to treat attacks of SSc-RP after oral therapy.	1A	A	8.29
	Fluoxetine may be considered in the treatment of SSc-RP attacks.	3	C	6.06
Digital ulcers in patients with SSc	Intravenous iloprost should be considered in the treatment of digital ulcers in patients with SSc.	1B	A	8.39
	PDE-5 inhibitors should be considered in the treatment of digital ulcers in patients with SSc.	1A	A	8.03
	Bosentan should be prescribed to reduce the number of new digital ulcers, especially in patients with multiple digital ulcers, despite the use of calcium channel blockers, PDE-5 inhibitors or iloprost therapy.	1B	A	8.19
III. SSc-PAH	ERA, PDE-5 inhibitors, or riociguat should be considered for the treatment of SSc-related PAH.	1B	B	8.32
	For the treatment of patients with severe SSc-PAH, intravenous epoprostenol (Class III and IV) should be considered.	1B	A	8.10
	Prostacyclin analogues should be considered for the treatment of patients with SSc-PAH.	1B	B	8.10
skin and pulmonary lesions	Methotrexate may be considered for the treatment of cutaneous manifestations of early diffuse SSc.	1B	A	7.42
	Given the results of two high-quality RCTs and despite its known toxicity, cyclophosphamide should be considered for the treatment of SSc-ILD, particularly for SSc patients with advanced ILD(ILD).	1B	A	7.84
	HSCT should be considered for the treatment of patients with rapidly progressive SSc at risk of multiple organ failure. Due to the high risk of treatment-related side effects and early mortality associated with treatment, careful selection of patients with SSc for this type of treatment and the experience of the medical team are key.	1B	A	8.03
	Experts recommend the immediate use of ACE inhibitors in the treatment of SRC.	3	C	8.52
	Blood pressure and renal function should be closely monitored in patients with SSc receiving glucocorticoids.	3	C	8.10
SSc-associated gastrointestinal diseases	PPI should be used for the treatment of SSc-associated gastroesophageal reflux and the prevention and stricture of esophageal ulcers.	1A	C	8.58
	Prokinetic medications should be used for the management of SSc-related symptomatic dysmotility disorders (dysphagia, GERD, early satiety, bloating, pseudo-obstruction, etc.).	3	C	7.97
	Antibiotics intermittent or alternating courses should be used to treat symptoms of small intestinal bacterial overgrowth in patients with SSc.	3	D	8.10

ACE, angiotensin converting enzyme angiotensin-converting enzyme; ERA, endothelin receptor antagonist; endothelin receptor antagonist; EULAR, European League Against Rheumatism; GERD gastroesophageal reflux disease GERD, gastroesophageal reflux disease; HSCT, haematopoietic stem cell transplantation; transplantation of hematopoietic stem cells; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5PDE-5, phosphodiesterase type 5; PPI, proton pump inhibitors; RCT, randomized controlled trial RCT, randomized controlled trial; SRC, scleroderma renal crisis; scleroderma renal crisis; SSc, systemic sclerosis; systemic sclerosis; SSc-RP, Raynaud phenomenon in patients with systemic sclerosis, Raynaud's phenomenon in patients with systemic sclerosis.

In addition to the main recommendation, the experts decided to formulate several comments addressing the therapeutic procedures in the research questions, of which, at present, literature-based evidence nor clinical experience allowed precise recommendations to be made (see online). I. RP in patients with SSc (SSc-RP) Recommendation: calcium antagonistsA dihydropiridine type, usually oral nifedipine, should be considered in first line therapy forSSc-R.P. Phosphodiesterase type 5 (PDE5) inhibitors should also be considered in the treatmentSSc-R.P. One meta-analysis, including eight randomized controlled trials (RCTs): seven with nifedipine and one with nicardipine, with 109 patients with SSc participating, indicated that dihydropiridine-type calcium antagonists reduced the incidence and severity of ischemic attack in SSc-RP. The weighted mean difference (WMD) of all calcium antagonists compared with placebo (six trials) for reducing ischemic attacks over the 2-week period was −8.31 (95% CI −15.71 to −0.91). When five RCT evaluations of nifedipine (10 to 20 mg three times daily) versus placebo were analyzed separately, the reduction was greater with a TMR of −10.21 (95% CI −20.09 to −0.34). None of the studies included in the meta-analysis directly examined the side effects of calcium antagonists in SSc. Hypotension, dizziness, hyperemia, secondary edema and headaches are considered to be fairly common side effects of these agents. Another meta-analysis of six RCTs (two with sildenafil), three with tadalafil and one with vardenafil including 236 patients with CTD-related RP, of which 95% were patients with SSc, showed that PDE-5 inhibitors reduced the frequency, severity and duration of attacks R.P. The treatment effect (mean difference; 95% CI) for daily frequency (−0.49, −0.71 −0.28), severity (−0.46, −0.74 −0.17), and daily RP duration (−14.62, −20.25 −9.00 min) although significant was moderate. Side effects associated with the use of PDE5 inhibitors have been common and include various forms of vasomotor reactions, myalgias, allergic reactions, chest pain, dyspepsia, nasal congestion and visual abnormalities. Taking into account many years of experience and good security profile, Experts recommend that calcium channel blockers should be used as first line therapy forSSc-RP andPDE-5 inhibitors in patients with severe SScRP and/or those who do not respond satisfactorily to calcium channels. Recommendation: Intravenous iloprost should be considered for severeSSc-R.P.(strength recommendation: A). Experts recommend that intravenous iloprost should be used to treat attacksSSc-RP after oral therapy. One meta-analysis, including five RCTs with intravenous iloprost, one RCT with oral iloprost, and one RCT with oral cisaprost, 332 patients with SSc in total, indicates that iloprost is effective in reducing the incidence and severity of SSc-RP. Iloprost, intravenously (0.5–3 ng/kg/min for 3–5 consecutive days) or orally (50–150 mcg twice daily) significantly reduced the incidence of ischemic attacks and improved RP severity scores compared with placebo (VRS; 95 % CI −17.46; −19.19 −15.73 and −0.69 −1.12 for the indicator, respectively). Oral prostanoids appear to be generally less effective than intravenous iloprost in the treatment of SSc-RP, although some beneficial effects may be seen at higher doses. Two RCTs comparing intravenous iloprost (0.5–2 ng/kg/min for 3–5 days, every 6–8 weeks) with nifedipine (30–60 mg/day) indicate that iloprost is only slightly superior to nifedipine in improving symptoms SSc-RP. Taking into account costs and feasibility, experts recommended that i.v.prostanoids is indicated when oral therapy (including calcium channel blockers and PDE5 inhibitors) is not effective. As most drugs used to treat RP can cause vascular side effects, experts recommend special attention ifprostanoids are combined with other vasodilators. Recommendation: Fluoxetine could be considered in treatmentSSc-RP attacks One small study, including a subgroup analysis of 27 patients with SSc, related to RP indicated that fluoxetine (oral, 20 mg/day) was superior to nifedipine LA (oral, 40 mg/day) in reducing the severity of RP and comparable to nifedipine in reducing seizure frequency RP in patients with SSc. The latter effect was not significant in patients with SSc for either fluoxetine or nifedipine, which may be due to the small number of patients with SSc included. The safety results available for the combined group of patients with primary RP (n = 26) and SSc-related RP (n = 27) indicated that fluoxetine was better tolerated than nifedipine: findings due to adverse effects were more than twice as high in the group nifedipine versus fluoxetine. The main reasons leading to discontinuation of treatment in the fluoxetine group were: apathy, lethargy and impaired concentration. Despite the relatively low quality of published evidence, experts acknowledge that fluoxetine is used in practice and believe that fluoxetine is a useful alternative for treatmentSSc-R.P., particularly in patients with SSc who cannot tolerate or do not respond to vasodilators. Because data regarding the use of fluoxetine in patients with SSc are limited and fluoxetine, as a serotonin reuptake inhibitor and antidepressant, may have potential effects on the central nervous system or heart, it is important to consider potential contraindications before initiating treatment and carefully monitor patients for adverse effects on fluoxetine. particularly during long-term treatment. Please note, withdrawal symptoms when treatment is stopped are common, especially if discontinued abruptly. II. DUs in patients with SSc Recommendation: Intravenous iloprost should be considered in the treatment of patients with SSc.DUs(strength recommendation: A). Intravenous iloprost (0.5 – 2 ng/kg/min for 3 – 5 consecutive days) significantly reduced the number of DUs compared with placebo in one small RCT (Jadad Score 3), and improved DUs healing in another RCT (Jadad Score 4) including 73 SSc patients with active DUs (p = 0.06 vs placebo at 50%). In addition, two RCTs comparing intravenous iloprost with oral nifedipine suggest that both drugs have a beneficial effect on DUs, but the number of patients with DUs in both studies was small. One meta-analysis published in 2013 included, in addition to the above two RCTs with intravenous iloprost, two additional RCTs, one with oral iloprost (100 or 200 mcg/day versus placebo for 6 weeks) and with oral treprostinil (slow release up to 16 mg twice daily for 20 weeks). This analysis revealed a trend toward a beneficial effect of prostanoids over placebo for healing DUs (hazard ratio (RR); 95% CI) for the number of patients with DUs improved or healed (1.33, 0.97 to 1.84, p = 0.08) . The largest mean effect was seen with intravenous iloprost (RR; 95% CI 3.00, 0.76 to 11.81). The results of this meta-analysis, a summary of the effects of four RCTs (two with intravenous iloprost, one with oral iloprost, and one with oral beraprost) show no significant effect of prostanoids in preventing new SSc DUs (RR; 95% CI number of patients with new DUs: 0.85 ; 0.68 to 1.08, p = 0.19). Again, the largest effect was seen with intravenous iloprost (RR; 95% CI 1.18, 0.30 to 4.72). When the results of a small study, Wigley etal were evaluated separately, they suggest that intravenous iloprost may prevent new DUs in patients with SSc (standardized difference (SMD); 95% CI number of DUs: −0.77; −1.46 −0.08, p = 0.03). In addition, RCT with epoprostenol, continuously performed for severe SSc-associated PAH (SSc-PAH), showed a trend towards a reduction in the number of new DUs (by 50%). Given the fact that oral prostanoids have shown lower efficacy for the treatment of SSc-related RP, compared to intravenous iloprost (see section on RP), experts decided, based on the results of the above two RCTs, recommend intravenous iloprost for treatmentDUs in patients with SSc. Further studies are needed to confirm the beneficial effects of intravenous iloprost in preventing the development of DUs in patients with SSc. Given the risk of side effects and management usually requiring hospitalization, intravenous iloprost should be considered particularly in patients with SSc with DUs unresponsive to oral therapy. In severe cases, combination therapy with an oral vasodilator and intravenous iloprost can be used. However, the increased risk of side effects should be taken into account. Recommendation:PDE-5 inhibitors should be considered in the treatment of patients with SScDUs(strength recommendation: A). One meta-analysis of three RCTs examining different selective PDE5 inhibitors (Sildenafil 50 mg twice daily, extended-release sildenafil 100 mg/day increased to 200 mg/day or Tadalafil 20 mg every other day) in patients with SSc with RP, from of which 39 had baseline DUs indicated that selective PDE5 inhibitors improved healing of DUs in patients with SSc. Although DUs healing was a co-primary outcome in only one of the three RCTs included in the meta-analysis and all three RCTs were below that required to detect a difference between active treatment and placebo, the pooled effect shows a significant benefit of PDE-5 inhibitors over placebo on DUs healing. Although the number of patients with DUs healed and the number of patients with improvement in DUs were significantly higher for PDE5 inhibitors compared with placebo (RR; 95% CI 3.28; 1.32 at 8.13, p< 0.01 DUs исцеления и 4.29; 1,73 до 10,66, p < 0,002 для улучшения DUs, соответственно). Результаты этого мета анализа подтверждаются независимой мультицентрового РКИ, оценке влияния тадалафил (20 мг/день с чередованием в течении 8 недель как дополнительная терапии для предыдущих вазодилататоры) на DUs, исцеление, как один из двух совместно начальных конечные точки совместно с эффект на RP, в 31 больных с базовой DUs с ССД. После 8 недель лечения, DUs излеченная достигнуто в 14 из 18 пациентов в группе тадалафил по сравнению с 5 из 13 пациентов в плацебо (p < 0,05). Результаты этого исследования, включая всех 53 пациентов с ССД с ССД, ассоциированных RP указывают, что тадалафил было также связано с значительно более низкий риск новой DUs: новый DUs, отмеченный у 1 из 27 пациентов из группы тадалафил по сравнению с 9 из 26 пациентов из группы плацебо (p < 0,05). Тадалафил (20 мг/день с чередованием в течении 6 недель с 1 неделя «промываю» в период, как дополнительная терапии для предыдущих вазодилататоры) препятствуют развитию новых DUs в другой сингл кросс центре RTC, включая 24 пациентов с ССД с вторичной RP, 23 (95%), из которых были SSc, цитируется в мета анализе, Tingey and etc. In this study, only 1 new DUs developed during tadalafil treatment compared with 13 new DUs that developed in six patients during placebo treatment (p< 0,05). Побочные эффекты ингибиторов ФДЭ-5, рассматриваются в предыдущем пункте относительно PDE-5 ингибиторов в лечении RP. Based on these data, experts concluded thatPDE-5 inhibitors may be effective in treating SSc-relatedDUs. In addition to tadalafil, PDE-5 inhibitors may prevent the development of new DUs in SSc patients, which needs to be clarified in further studies. annotation: The recently published SEDUCE study did not reach statistical significance regarding the effect of sildenafil (20 mg 3 times daily for 12 weeks) on the healing time of DUs, in part due to the unexpectedly high healing rates in the placebo group. The study does not show a significant reduction in the number of patient DUs/week 8 (1.23±1.61 in the sildenafil group vs. 1.79±2.40 in the placebo group, p=0.04) and week 12 (0.86±1.62 vs. 1.51±2.68, p=0.01. accordingly) resulting in a greater healing rate. Because the experts acknowledged the consequences of the study are not clear and, the dose of sildenafil used in the SEDUCE study was lower than in the studies included in the above meta-analysis, Tingey etal The results of this study, which were published after the data was closed for recommendations, do not change the relevant recommendations. Recommendation: to reduce the number of newDUs in SSc, especially in patients with multipleDUs despite the use of calcium channel blockers,PDE-5 inhibitors or iloprost therapy should be consideredBosentan (strength recommendation:A). The effects of bosentan, a dual receptor antagonist, on DUs prevention and treatment were conducted in two high-quality RCTs (RAPIDS -1 and RAPIDS -2) including a total of 310 patients with a history of SSc or at least one active DUs at baseline. Bosentan, administered orally at a dose of 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 12 weeks in RAPIDS -1 or 20 weeks in RAPIDS -2, significantly reduced the number of new DUs in both studies. In a recent meta-analysis of RAPIDS -1 and RAPIDS -2, treatment with bosentan was associated with a significant reduction in the mean number of new DUs per patient in the overall trial population (SMD; 95% CI −0.34; −0.57 −0.11, p = 0.004) and in patients with SSD with baseline DUs (SMD; 95% CI −0.36; −0.61 −0.11, p = 0.005). The effect of bosentan was greatest in SSc patients with several (four or more) DUs at baseline (Effect Size (ES); 95% CI −0.52; −1.01 −0.02) compared with SSc patients with fewer DUs at baseline (ES; 95% CI −0.08 −0.44 to 0.28) in RAPIDS-2. The reduction in the number of patients with new DU was not statistically significant in any of the RAPIDS trials or their meta-analyses. No studies have demonstrated that bosentan is superior to placebo in healing SSc-related active DUs, as assessed by time to complete or partial healing of DUs present at baseline, time to healing of all DUs, or percentage of patients with complete healing of DUs (p > 0. 05 vs placebo for all comparisons). There is currently insufficient evidence that endothelin receptor antagonists (ERAs) have beneficial effects on SSc-RP attacks either. There are two major concerns associated with the use of bosentan and other ERAs: potential liver damage and teratogenicity. Hormonal contraceptives may may not be reliable if co-administered with bosentan because bosentan may reduce their effectiveness by interfering with the cytochrome P450 system.Based on the results of the RAPIDS trial and given the toxicity potential associated with bosentan experts recommend the usebosentan especially in patients who have severalDUs when treated with other vasodilators such as calcium channel blockers,PDE-5 inhibitors and iloprost to prevent the development of newDUs. The results of the RAPIDS-2 study, which were published in full in 2011, do not support a difference in bosentan response between patients with limited and diffuse SSc manifestations, in an aspect that was suggested by a subanalysis of the RAPIDS-1 study. Because of these data, the experts decided This recommendation states that bosentan should be considered for the reduction of new DUs in all patients with SSc with DUs, regardless of disease symptom profile. The note: It should be noted that bosentan has not been shown to have an effect on preventing new SSc DUs in ERA. Results from two double-blind RCTs (DUAL-1 and DUAL-2), which were published after the end of the literature study period, show no significant difference between macitentan, a selective endothelin-1 (ET-1) receptor antagonist, and placebo in preventing new DUs in patients with SSc with active DUs in initial manifestations over 16 weeks. III. PAHs associated with SSD Recommendation:ERA,PDE-5 inhibitors orriociguat should be considered for treatmentSSc-PAH(strength of recommendation: B extrapolation from RCTs including patients with SSc/CTD). High-quality RCTs involving patients with various forms of PAH, including CTD-related PAH, indicate that endothelin antagonists (bosentan, ambrisentan, and macitentan) improve performance and time clinical deterioration in patients with PAH. Adverse events associated with ERA treatment in these clinical trials included abnormal liver function tests, peripheral edema, palpitations, headache, chest pain, nasal congestion, and anemia, but the safety profile differs for specific agents. Sitaxentan, a selective ERA that was included in the 2009 EULAR recommendation for the treatment of SSc, was withdrawn from the market in December 2010 due to its hepatotoxicity. High-quality RCTs involving heterogeneous patients with PAH, including CTD-PAH, indicate that selective PDE5 inhibitors (sildenafil and tadalafil) improve performance in patients with PAH and (tadalafil 40 mg/day) reduce the risk of clinical worsening. The most common side effects associated with PDE-5 inhibitors include flushing, dyspepsia, diarrhea, headache and myalgia. Another RCT, including patients with various forms of PAH, including patients with CTD-PAH, showed that riociguat, a soluble guanylate cyclase stimulator, improves exercise performance, clinical deterioration time, and hemodynamic parameters in patients with PAH. Serious adverse events associated with drugs included syncope, increased liver enzyme levels, dizziness, acute renal failure, hypotension. Based on the results of these high-quality RCTs, ERAs (bosentan, ambrisentan, and macitentan), selective PDE5 inhibitors (Sildenafil and tadalafil), and riociguat were approved for the treatment of PAH associated with CTDs. The evidence regarding the use of these drugs specifically in SSc-PAH is less robust. Experts recommend that the era of selective PDE5 inhibitors andriociguat should be considered in treatmentSSc-PAH in accordance with international guidelines for handlingPAH. This was highlighted through the publication of new Society of Pulmonology and Cardiology guidelines recently published. In severe or progressive PAH, cases of combination therapy with different PAH-specific drugs should be considered. Although at the time of development of these recommendations RCTs comparing combination therapy with PAH specific drugs versus monotherapy in patients with SSc-PAH were not available, this approach is generally consistent with recent guidelines from the European Societies of Cardiology and Pulmonology regarding the management of PAH and appears to be particularly important in patients with SSc-PAH - PAH, and are more significant in the progressive course of the disease than patients with other forms of PAH. Recommendation: Intravenous epoprostenol should be considered for the treatment of patients with severeSSc- PAH (classIII andIV)(strength recommendation: A). For the treatment of patients withSSc- PAH should be considered prostacyclin analogues(Strength of recommendation: B: extrapolation from RCTs including patients with SSc/CTD). One RCT (Jadad Evaluation 3), involving 111 patients with SSc-PAH, showed that epoprostenol (continuous intravenous infusion, starting at a dose of 2 ng/kg/min and increasing based on clinical symptoms and tolerability) in combination with conventional therapy (diuretics , oral anticoagulants, oxygen and glycosides), improves physical endurance, functional status and hemodynamic parameters in SSc-PAH, compared with conventional therapy. Mean 6-minute walk test distance 6 minute walk test (6MWT), improved to 108 m (95% CI 55 to 180; p = 0.001; epoprostenol vs control group), New York Heart Association (NYHA) functional class improved in 21 patients (38%) receiving epoprostenol and none in the control group (number needed to treat (NNT) 2.7) and Borg dyspnoea index and dyspnoea fatigue score also improved significantly. Positive hemodynamic effects of epoprostenol included statistically significant decreases in pulmonary vascular resistance, mean pulmonary artery pressure and right atrial pressure, as well as a significant increase in cardiac index.Based on the results of an RCT and two large long-term observational studies that documented improved survival in patients with idiopathic PAH treated with epoprostenol, intravenous epoprostenol was approved by the Food and Drug Administration (FDA) for the treatment of severe (those in class III or IV) PAH. As a result, epoprostenol has a very short half-life when administered through an indwelling central venous catheter, which may cause adverse events: infection, pneumothorax, and bleeding. Sudden interruption/withdrawal of IV epoprostenol (due to catheter/thrombosis and/or patient decision) may result in a life-threatening rise in PAH. Based on overall risk-benefit considerations and in agreement with current guidelines, experts recommend intravenous epoprostenol as the drug of choice in severe, therapy-resistantSSc-PAH, which are consistent with recently published guidelines from other societies. Based on the results of high-quality RCTs involving patients with various forms of PAH, including patients with CTD-PAH, other prostacyclin analogs such as treprostinil (intravenous, subcutaneous, or inhaled) and iloprost (airway) have been approved for the treatment of PAH, including PAH associated with CTD. Side effects associated with the use of intravenous treprostinil are similar to intravenous epoprostenol and include headache, jaw pain, diarrhea, abdominal pain, anorexia, vomiting, photosensitivity, skin flushing and arthralgia, as well as the risk of complications associated with continuous catheter infusion . Subcutaneous infusion of prostanoids is often associated with pain at the infusion site. Inhaled prostanoids may cause cough, headache, flushing, nausea, and fainting. Although there are no specific RCTs evaluating these drugs exclusively in patients with SSc, experts recommend considering these prostacyclin analogs for treatmentSSc-PAH, in agreement with international guidelines for treatmentPAH. Experts came to the conclusion that combining different classesPAH specific treatments may be considered in the treatment of patients withSSc-PAH, especially in those with serious or progressive disease. As discussed in the previous paragraph, this approach is broadly consistent with recently published management guidelines PAH and seems especially important in patients with SSc- PAH, are significant for more progressive disease than patients with other forms PAH. IV. skin and lung diseases Recommendation: Methotrexate may be considered for the treatment of cutaneous manifestations of early diffuse SSc.(strength recommendation: A). In one RCT (Jadad Evaluation 3) involving 29 patients with diffuse SSc or limited SSc (mean duration of skin lesions 3.2 years), methotrexate (IM at a dose of 15 mg per week for 24 weeks) showed a trend towards improvement in total skin score. counts (p = 0.06 vs placebo). In a second RCT (Jadad Score 5), involving 73 patients with diffuse early SSc, oral methotrexate 10 mg per week for 12 months decreased skin score University of California Los Angeles (UCLA) ) skin score (ES 0.5, 95% CI 0.0 to 1.0) and modified Rodnan modified Rodnan skin score (mRSS, ES 0.5; 95% CI 0.0 to 0.9) compared with placebo in an intention-to-treat analysis. treatment. The beneficial effect of methotrexate (over placebo) on skin manifestations was confirmed in a reanalysis of the Pope study etal which, using Bayesian methodology, showed that the probability that methotrexate improves mRSS and UCLA skin scores were 94% and 96%, respectively. No significant effects on other organs have been shown. In a study evaluating patients with early diffuse systemic sclerosis (dSSc), 11 of 36 patients (31%) in the placebo group and 12 of 35 patients (34%) in the methotrexate group left before completion of the study, mainly due to ineffective treatment. There were some premature unplanned due to adverse events (number of harms 16 and 34.5 in both RCTs, respectively). There were no significant differences in mortality rates (3 vs. 7; p = 0.18), although the trend was in favor of methotrexate. Safety concerns associated with methotrexate include liver toxicity, pancytopenia, its potential teratogenicity and possible induction of lung injury. It should be noted that in both RCTs evaluating methotrexate in SSc, relatively low doses of methotrexate were used. Higher doses of methotrexate, which are used in the treatment of rheumatoid arthritis and other inflammatory diseases, may improve the effectiveness of treatment without significantly increasing the risk of side effects, remains to be determined. In pediatric patients, methotrexate at a dose of 25 mg/m2 per week orally or subcutaneously is well tolerated. Thus, experts confirmed previous recommendations for methotrexate in early diffuse SSc. It should be recognized that cyclophosphamide (CYC) has also been shown in RCTs to improve skin changes in patients with SSc, and other agents such as mycophenolate mofetil or azathioprine are used to treat skin involvement, although their effectiveness has not been widely studied. Recommendation: Based on the results of two high-quality RCTs and despite its known toxicity,CYC should be considered for the treatment of interstitial lung diseaseS Sc (SSc-ILD), in particular for patients with SSc with progressiveILD(strength recommendation: A). The evidence regarding the effectiveness of CYC in SSc-ILD results mainly from two high-quality (Jadad Score 5) RCTs and their sub-analyses. The first study (Scleroderma Lung Study, SLS), involving 158 SSc patients with active alveolitis, demonstrated that oral CYC at a dose of 1-2 mg/kg per day improved lung volume, dyspnea scores, and quality of life over 12 months compared with placebo. Placebo adjusted mean (95% CI) improvement in vital capacity (FVC) and total lung capacity (TLC) 2.5% (0.3% to 4.8%) and 4.1% ( 0.5% to 7.7%), respectively (p = 0.03 for both measures). A statistically significant effect on diffusing lung capacity for carbon monoxide (DLCO) can be demonstrated. CYC also improved the Transitional Dyspnea Index, Health Assessment Questionnaire (HAQ), Health Assessment Questionnaire (HAQ), Health Assessment and Vitality, and Transition Health Domains Short Form 36 (p< 0,05 против плацебо для всех мер). Субанализ SLS показал, что CYC терапии также ассоциировался с значительное улучшение в высоким разрешением компьютерная томография (HRCT) Оценка. Расширение SLS исследования показали, что ФЖЕЛ продолжали улучшаться после прекращения лечения CYC, достигая максимума в 18 месяцев: 6 месяцев после прекращения терапии CYC (средняя разница ЦФВ против плацебо: 4,16%, p = 0.01). Благотворное влияние CYC исчез 1 год после того, как CYC было прекращено. Эффект CYC было больше у пациентов с более серьезными легких и/или заболевание кожи. Улучшение ФЖЕЛ больных с базовой ЦФВ меньше 70% предсказал составлял 18 месяцев 4,62% в 12 месяцев и 6,8% (p < 0,006 для обеих точек времени), в то время как у больных с базовой ЦФВ >70% predicted, mean treatment effect was 0.55% at 12 months and 2.67% at 18 months (p > 0.05 for both time points). Another subanalysis of the SLS study showed that HRCT Score and skin disease were independently predictive of response to CYC therapy. In patients with 50% or more involvement of any lung zone, reticular infiltrates on HRCT, and/or mRSS of at least 23/51, the treatment effect of CYC was 9.81% at 18 months (p< 0,001) против не эффект лечения (0.58% разницы, p >0.05) in patients with less severe HRCT findings and a decrease in mRSS from baseline. The second study evaluated CYC (intravenous dose 600 mg/m2/month) compared with placebo in 45 SSc patients with SSc-ILD. Active treatment included six infusions of CYC at 4-week intervals followed by oral azathioprine (2.5 mg/kg/day) or placebo for 6 months. Additionally, in the active treatment group, prednisolone was prescribed (20 mg every other day). The mean between-group adjusted difference in FVC was 4.2% in favor of CYC, which simply missed statistical significance (p = 0.08). Diffusing lung capacity for carbon monoxide and other outcomes did not improve. Given the results of RCTs and the fact that the benefit of CYC is mainly due to the inhibition of progression of SSc-ILD, experts recommend that CYC therapy be particularly considered in patients with advanced pulmonary diseases. Like previous recommendations from 2009 there there was a unanimous opinion of experts regardingCYC dosage and duration of treatment are individually dependent on clinical condition and response. The potential risks of bone marrow, teratogenicity, gonadal injury and hemorrhagic cystitis should always be considered. Recommendation: hematopoietic stem cell transplantation (Haematopoieticstemcelltransplantation (HSCT)), should be considered for the treatment of patients with rapidly progressiveSSc at risk of multiple organ failure. Due to the high risk of treatment-related side effects and early treatment-related mortality, careful selection of patients with SSc for this type of treatment and the experience of the medical team are key(strength recommendation: A). To date, the results of two RCTs have been published to evaluate the efficacy and safety of high-dose immunosuppressive therapy followed by HSCT. First single-center study (Jadad 3), including 19 patients with SSc with mRSS > 14 involvement and visceral or mRSS involvement< 14 и SSc-ILD, показали, что HSCT (200 мг/кг CYC и кроличий antithymocyte глобулин 6,5 мг/кг внутривенно в общей сложности, предшествовали CYC 2 г/м 2 и filgastrim в рамках мобилизации шаг до лейкафереза) превосходит CYC (внутривенно, 1 г/м 2 / месяц на 6 месяцев) терапии в отношении улучшения счета поражения кожи и обьема легких. Нет статистически значимого влияния на диффундирующих ёмкость лёгких моноксида углерода может быть доказана. Еще одна мультицентрового РКИ (ASTIS) в сравнении HSCT (200 мг/кг CYC и кролик antithymocyte глобулина 7,5 мг/кг внутривенно в общей сложности, предшествовали CYC 4 г/м 2 и Филграстим как часть шага мобилизации) с CYC пульс терапии (внутривенно, 750 мг/м 2 / месяц за 12 месяцев) в 156 больных с ССД с ранним диффузным ССД, mRSS≥15 и поражением внутренний орган или mRSS >20 without damage to internal organs. HSCT was associated with increased treatment-related mortality in the first year (eight deaths in the HSCT group versus none in the CYC group, p = 0.007) but significantly improved long-term survival (HR; 95% CI 0.52, 0.28 to 0.96 , p = 0.04 and 0.34; 0.16 to 0.74, p = 0.006 at 1 year and 3 years through 10-year follow-up) and overall survival (HR; 95% CI 0.48; 0. 25 to 0.91, p = 0.02 and 0.29; 0.13 to 0.64, p = 0.002 at 1 year and 3 years at 10 year follow-up). HSCT therapy resulted in a significant improvement in mRSS (mean difference; 95% CI 11.1; p 7.3 to 15.0< 0,001), ФЖЕЛ (означает разницу; 95% ДИ 9.1; 14,7 до 2,5, p = 0,004) и TLC (означает разницу; 95% ДИ 6.4; 11,9 до 0,9, p = 0.02) в последующие 2 года. Статистически значимого влияния на DLCO может быть найдено. Означает изменение клиренса креатинина было значительно хуже в группе ТГСК, чем в контрольной группе (означает разницу; 95% ДИ 10,9; 1,5 до 20,3, p = 0.02). Причины смертей, связанных с HSCT, включали возобновление вирус Эпштейна – Барр, лимфома, сердечная недостаточность, инфаркт миокарда и острого респираторного дистресс-синдрома. HSCT терапии также был связан с более высоким риском вирусных инфекций (27,8% в HSCT группы против 1,3% в контрольной группе, p < 0,001). С учетом результатов двух РКИ и с учетом риска потенциальных связанных с лечением смертности и заболеваемости experts recommend consideringHSCT for the treatment of patients with rapidly progressiveSSc risk of multiple organ failure. To reduce the risk of treatment-related side effects, HSCT should be performed in selected centers with experience in this type of treatment. Careful assessment of the benefit of the risk ratio in individual patients with SSc selected for HSCT must be done by experts. Further research should help identify the subgroups of patients with SSc that would benefit most. HSCT. V. renal scleroderma crisis Recommendation: Experts recommend immediate use of ACE inhibitors in treatmentSRC(strength recommendation: C). There are no RCTs evaluating the effectiveness of ACE inhibitors in the treatment of SRC. Since the presentation of the first report demonstrating the beneficial effect of ACE inhibitors in two patients with SRC, numerous reports and uncontrolled studies have reported on ACE inhibitors in SRC. A prospective analysis of 108 patients with SRC suggested that patients on ACE inhibitors (captopril in 47) and enalapril in 8 had significantly better survival at 1 year (76%) and 5 years (66%), compared with patients not on ACE inhibitors ( 15% for 1 year and 10% for 5 years, respectively). The beneficial effect of ACE inhibitors on survival in SRC remained significant after adjustment for age and blood pressure (p = 0.001). Another prospective, uncontrolled study of 145 patients with SRC treated with ACE inhibitors demonstrated survival rates at 5 and 8 years after onset of SRC of 90% and 85%, respectively. Two recent retrospective studies, including 91 and 110 patients with SRC, respectively, the majority of whom (91% and 98%, respectively) were treated with ACE inhibitors and/or angiotensin receptor antagonists (ARAs) reported survival rates of 71% to 82% in 1 year, 59% to 60% for 5 years and 42% to 47% for 10 years. In comparison, 3 of 7 patients (43%) without ACEI/Ara-2 died within the first months after initiation of SRC. It is highly unlikely that formal RCTs will be conducted in these rare conditions with high mortality. Despite the paucity of RCTs, experts recommend the use of ACE inhibitors in the treatment of SCR. experts believe that prompt initiation of high-dose ACE inhibitors in patients who developSRC is key to improving their results. ACE inhibitors should be continued in the long term while there is potential for further improvement in renal function. The experts also decided to emphasize that the published data do not support preventive use of ACE inhibitors to reduce the risk of developing or improve outcomeSCR. Recommendation: Blood pressure and renal function should be closely monitored in patients with SSc receiving glucocorticoids.(Strength recommendation: C). Evidence regarding the effects of steroid use on the development of SRC comes primarily from retrospective studies, most of which have shown a significant association between steroid exposure and the occurrence of SRC. A case-control analysis including 220 patients with SSc found that 36% of patients with SRC received prednisolone 15 mg/day or more in the 6 months before onset of SRC, compared with 12% of controls (or; 95% CI 4.4 ; 2.1 to 9.4; p< 0,001). Еще один анализ основных факторов риска для SRC предложил, что пациенты с высоким кожным счетом, суставных контрактур и преднизон использования (10 мг/день в 9 из 10 пациентов) имели более высокому риску (43% против 21% пациентов без стероидов) SRC. В двух более недавние исследования, в том числе 518 и 410 больных с ССД, соответственно, получавшие стероидов (скорректированное или; 95% ДИ 4.98; 1,52 до 16,3, p = 0,008 и HR; 95% ДИ 1.105; 1.004-1,026, p = 0,006, соответственно) был независимым предиктором SRC. Риск для развивать SRC выросли на 1,5% за каждый мг преднизолона/ в день употреблять в течении триместра до развития SRC. Ретроспективный анализ, включая 140 пациентов, лечившихся с SRC, показали, что высокие дозы стероиды (преднизолон ≥30 мг/день) использовались более часто у больных с ССД с нормотензивной SRC (64 процента) по сравнению с те, с гипертонической SCR (16%), предлагая ассоциацию между применение высок дозы стероидов и риск нормотензивной SRC, который связан с худшим прогнозом. Эксперты признают, что глюкокортикоидов, которые используются в ССД, являются частью терапевтические стратегии в управлении ILD, диффузный кожные болезни или мышечно-скелетного вовлечения, хотя доказательств относительно их эффективности в ССД является ограниченным. Учитывая потенциальный риск SRC связанные с стероидов, Experts recommend that patients with SSc treated with steroids should be closely monitored for the development ofSRC. VI SSc-GI related diseases Recommendation:PPIs should be used to treat SSc-associated gastroesophageal reflux and prevent esophageal ulcers and strictures(strength recommendation: C). Large, dedicated RCTs on the effectiveness of PPI in patients with SSc are lacking. A small RCT indicated that PPI may improve upper GI symptoms in patients with SSc. The effectiveness of PPI for the treatment of GERD in the general population is well documented in meta-analyses of RCTs. In asymptomatic patients with SSc, PPIs should be used with caution, since long-term therapy with PPIs may lead to malnutrition, possibly due to decreased intestinal absorption, or an increased risk of infection. Recommendation: Prokinetic medications should be used to controlSSc associated symptomatic motility disorders (dysphagia, GERD, fullness, bloating, pseudo-obstruction, etc.)(strength recommendation: C). Small RCTs in patients with SSc or CTD indicate that short-term use of cisapride has a beneficial effect on gastric emptying and lower esophageal sphincter pressure. However, in many countries, cisapride has either been withdrawn or has limited availability as a result of reports of long QT syndrome caused by cisapride, which predisposes to severe arrhythmias. Long-term effectiveness RCTs of other prokinetic agents in SSc have not been found. Some non-randomized or uncontrolled studies suggest that prokinetics may improve GI signs and symptoms in patients with SSc. Several prokinetic drugs have shown beneficial effects in RCTs involving patients other than SSc-related motor disorders or are under evaluation (for review, see References and ). Experts conclude that all available prokinetic medications can be used for patients with SSc with GI involvement on an individual basis, taking into account the potential benefit to the risk ratio. Whether these drugs will be effective in the treatment of SSc-related symptomatic motor impairment in general is currently only speculative and needs to be urgently investigated. Recommendation: Antibiotics intermittent or rotation should be used to treat symptomatic small intestinal bacterial overgrowth (SIBO)symptomaticsmallintestinebacterialovergrowth (SIBO) in patients with SSc(strength recommendation: D). Two small, uncontrolled, non-randomized studies suggest that antibiotic treatment may improve symptoms in SSc patients with SIBO. There are no RCTs on the effectiveness of antibiotics in the treatment of SSc-associated bacterial overgrowth or malabsorption. In general, treatment of symptomatic small bowel bacterial overgrowth is based on empirical courses of one or more broad-spectrum antibiotics with activity against aerobic and anaerobic Enterobacteriaceae quinolones, amoxicillin and clavulanic acid, metronidazole, neomycin, or doxycycline. An excellent review summarizes the principles of diagnostic and treatment strategies for this condition.

Aliment Pharmacol Ther. 2013 Oct;38(7):674-88. doi: 10.1111/apt.12456. Epub 2013 Aug 20. Review article: small intestinal bacterial overgrowth–prevalence, clinical features, current and developing diagnostic tests, and treatment. Grace E 1, Shaw C, Whelan K, Andreyev HJ.

Internal evaluation of recommendations All members of the Task Force participated in the online assessment-based updated recommendations. The results of this assessment are presented in . All but one recommendation received a mean score of more than 7, indicating a high level of agreement. The mean recommendation score for fluoxetine for the treatment of SSc-related RP was 6.06, which is consistent with the average level of agreement. Research program In addition to expert recommendations, a research program was developed that addressed the use of pharmacological agents in SSc or SSc-related organ complications that were considered of particular interest (). This research program may be useful in developing further clinical trials in SSc. Discussion Compared to the previous EULAR (2009) recommendation for the treatment of SSc, the updated recommendations include several new treatments to target specific SSc-related organs. The greatest changes have been made in the treatment of vascular complications of SSc and reflect the progress that has been made in this area over the past few years. These include the introduction of PDE-5 inhibitors for SSc-related RPs and DUs, riociguat and new considerations for ERAs, prostacyclin analogues and PDE-5 inhibitors for SSc-PAH. New recommendations regarding the use of fluoxetine for SSc-related RP have also been added. Regarding treatment, in addition to vascular complications of CC, a recommendation for HSCT was added for selected patients with rapidly progressive SSc at risk of multiple organ failure. Similar to the 2009 recommendations, these recommendations represent only pharmacological agents that were considered most relevant and received consensus from a panel of experts. SSc is an uncommon and clinically heterogeneous disease; appropriate therapy testing is quite difficult. The actual support for present recommendations is often limited, and few of the recommendations are supported by evidence extrapolated from studies involving patients with conditions other than SSc or based solely on expert opinion. As with the 2009 recommendation, there is still insufficient evidence to make specific recommendations for pediatric patients. It would be important to have research on at least the effective pediatric dose of each medication in order to be used safely. It should be recognized that there are several other promising therapies, including immunosuppressive drugs or new biological agents, that cannot be included in these guidelines because the evidence for their effectiveness was considered insufficient at the time these guidelines were developed. The results of RCTs evaluating new therapies in patients with SSc that were published after the closure of the systematic literature of studies are presented online. The first of these trials evaluates the effectiveness of sildenafil in DUs, healing patients with SSc and is discussed in the commentary, recommendations regarding the treatment of DUs. Another phase of double-blind, 2 RCT included 87 patients with early diffuse SSc and elevated acute phase reactants. Treatment with tocilizumab (subcutaneous 162 mg/week) was associated with a favorable trend in Skin Score improvement compared with placebo after 24 weeks (p = 0.09) and 48 weeks (p = 0.06). In addition, encouraging changes in FVC were noted. Given the promising effects of tocilizumab on skin and lung involvement, it is concluded that further research is needed before definitive conclusions can be drawn about its risks and benefits in SSC. . Results from another RCT comparing mycophenolate mofetil SLS-2 with CYC in patients with SSc-ILD are expected to be published soon. Preliminary results from this study, recently published as an abstract at the 2015 ACR Annual Congress, indicate that mycophenolate mofetil (up to 3 g/day orally for 2 years) was comparable to oral CYC (2 mg/kg/day for 1 year followed by matching placebo for the second year) regarding FVC course for 24 months. However, definitive conclusions regarding the place of Mycophenolate mofetil in the treatment of SSc-ILD are not yet possible. Other therapies considered promising by experts have been reviewed in the research program (). Since “lack of evidence of effectiveness” does not mean “no effectiveness,” the absence of positive recommendations for a particular drug should not be interpreted as a contraindication for its use. It should also be emphasized that there are other treatment options, such as education, physical therapy or local management of ischemic lesions, that are beyond the scope of the project or cannot be included in these recommendations due to lack of consensus among experts. In conclusion, it is believed that these updated recommendations will help improve the care of patients with SSc in an evidence-based manner and provide direction for further clinical research. Given the significant complexity and heterogeneity of SSc and the limited evidence for treatment, it is recommended that patients with SSc be referred to specialized centers with appropriate experience in the management of SSc.

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Treatment

Early diagnosis and adequate therapy largely determine the effectiveness of treatment and prognosis, especially in rapidly progressive diffuse SSc. 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. convince the patient of the need for long-term treatment, strict adherence to recommendations, and familiarize the patient with the possible side effects of the drug. draw the patient's attention to the need for constant medical supervision and regular examination in order to early identify signs of disease progression and possible correction of therapy. Treatment goals. prevention and treatment of vascular complications. suppression of fibrosis progression. prevention and treatment of damage to internal organs.

Non-drug treatment

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

To reduce the frequency and intensity of vasospasm attacks, it is recommended to wear warm clothing, including heat-preserving 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, and avoid taking sympathomimetics (ephedrine, amphetamine, ergotamine), beta-blockers.

Drug treatment

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

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

Anti-inflammatory and cytotoxic drugs are used at the early (inflammatory) stage of SSc and the rapidly progressive course of the disease:
. NSAIDs in standard therapeutic doses are indicated for the treatment of muscular and joint manifestations of SSc and persistent low-grade fever (high fever is not typical for SSD).

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

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

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

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 thickening and increases 5-year survival compared to 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 SSc

Damage to the esophagus and stomach
Treatment is aimed at reducing symptoms associated with gastroesophageal reflux and impaired peristalsis. For this purpose, patients are recommended to eat frequent small meals, not lie down for 3 hours after eating, sleep on a bed with the head end elevated, and give up smoking and alcohol.

It should be borne in mind that calcium channel blockers may increase the manifestations of reflux esophagitis. Drug therapy includes the prescription 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 within 24 hours; 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 agent; long-term administration of metoclopramide is unacceptable, since the development of neurological disorders (parkinsonism) caused by the effect on dopaminergic structures of the brain is possible.

The prokinetic drug cisapride (a serotonin 5-HT4 receptor agonist), widely used in the 1990s, has been banned for use due to cardiotoxic effects (arrhythmia).

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

Intestinal damage
. Disturbances in intestinal motility contribute to excessive growth of microflora and the development of malabsorption syndrome, for the treatment of which the following antibacterial drugs are used: 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 taking antibiotics depends on the severity of diarrhea and steatorrhea (usually 7 - 10 days per month). If diarrhea appears while taking antibiotics, metronidazole is additionally prescribed (7-10 days) to suppress the anaerobic flora. Prescribing prokinetics (metoclopramide) is not advisable, since they do not have the expected effect.

Improvement in peristalsis in intestinal pseudo-obstruction is observed with the use of a long-acting somatostatin analogue, octreotide 50 mg per day 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 reduction to a maintenance dose of 10-15 mg per day; Large doses of GC should be avoided due to the risk of scleroderma renal crisis.

♦ Cyclophosphamide is prescribed intravenously at a dose of 800-1000 mg once a month or per os 2 mg/kg per day. IV administration is considered preferable, as there is a lower incidence of side effects (including hemorrhagic cystitis) compared to oral administration. Pulse therapy with cyclophosphamide is continued at this dose for at least 6 months (in the absence of side effects). If the dynamics of pulmonary function tests and radiological changes are positive, the interval between pulse therapy with cyclophosphamide is increased to 2 months, and if the positive dynamics are maintained - to 3 months. Pulse therapy with cyclophosphamide must be continued for at least 2 years.

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

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

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

♦ Nifedipine. Before prescribing long-term therapy for pulmonary hypertension with nifedipine, it is necessary to carry out catheterization of the right ventricle 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 in only 25% of patients and does not affect the resistance of the pulmonary vessels in the remaining patients. Calcium channel blockers have no effect on patient survival.

♦ Warfarin. Long-term use of the drug improves survival of patients with primary pulmonary hypertension. The daily dose is determined by the MHO value, 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, and effectively reduce pressure in the pulmonary artery. Prostacyclin preparations have also been developed for subcutaneous and inhalation administration.

♦ 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 and an increase in tolerance to physical activity. Long-term use of the drug leads to improved survival of patients.

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

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

The drugs of choice are:
. Angiotensin-converting enzyme inhibitors (captopril, enalapril, etc.). The dose of drugs 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 outcome in normotensive scleroderma renal crisis. Avoid excessive blood pressure reduction and hypovolemia, which can lead to decreased renal perfusion and acute tubular necrosis. The effectiveness of angiotensin-H receptor antagonists in the treatment of acute renal crisis has not been proven.

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

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

Heart damage
Manifestations of primary scleroderma heart disease (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 GK (15 - 30 mg/day). If the effusion is significant, pericardiocentesis or pericardiotomy is performed.

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

Rhythm disturbances usually do not require treatment. For severe arrhythmias (group and polytopic extrasystoles, ventricular tachycardia, etc.), the drug of choice is amiodarone. Taking beta-blockers can increase the manifestations of Raynaud's phenomenon.

SSD and pregnancy. Most patients with SSc have a history of one or more pregnancies and births.

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

Contraindications to pregnancy: diffuse form of SSD, severe dysfunction of internal organs (heart, lungs and kidneys). In cases of SSc detection during pregnancy, careful monitoring of renal and cardiac functions is necessary.

Management of patients with SSc

All patients with SSc are subject to clinical 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 blood and urine tests are carried out.

During repeated visits to the doctor, it is necessary to actively question the patient in order to assess the dynamics of Raynaud's phenomenon, increased 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, increased blood pressure, presence of digital ulcers and edema.

Pulmonary function testing and echocardiography are recommended. In patients taking warfarin, the prothrombin index and MHO should be monitored, and when treated with cyclophosphamide, general blood and urine tests should be examined every 1-3 months.

Forecast

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

Predictors of an unfavorable prognosis are:
❖ diffuse form
❖ age of onset of disease 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.