Skin lesions are a common clinical sign of systemic vasculitis affecting small and medium-sized vessels. The nature of dermatological manifestations largely depends on the size of the vessels involved in the pathological process and the immunological specificity of vasculitis. Histological examination of the skin is important to confirm the diagnosis of vyskulitis, helps in early differentiated diagnosis and timely prescription of adequate therapy. An important task for the doctor is to suspect when severe systemic vasculitis with multiple organ damage is hidden with dermatological manifestations. This article presents clinical and histological data on skin lesions in various systemic vasculitis, as well as existing algorithms for differential diagnosis.

Systemic vasculitis is a heterogeneous group of diseases, the main morphological feature of which is inflammation of the vascular wall, and the range of clinical manifestations depends on the type, size and location of the affected vessels and the severity of concomitant inflammatory disorders. The incidence of vasculitis with skin lesions ranges from 15.4 to 29.7 cases per million population per year. Women and adults are more often affected than men, with the exception of hemorrhagic vasculitis, which occurs almost exclusively (90%) in children. Skin manifestations may be the first clinical symptoms of vasculitis, but as a rule they occur against the background of other systemic signs. Clinically, vasculitis with skin involvement can present with a whole arsenal of nonspecific or low-specific dermatological symptoms that include subcutaneous nodules, palpable purpura, vesicles, papules, livedo, ulcers, digital infarcts and gangrene. Skin lesions in patients with systemic vasculitis do not affect the prognosis of the disease, but may have a recurrent course and be difficult to treat. Given the wide range of manifestations of skin lesions in systemic vasculitis and the significant number of diseases that can mimic vasculitis, it is not surprising that in clinical practice there are often difficulties in diagnosing and correctly classifying patients with cutaneous vasculitis. Today, the most acceptable is the pathohistological classification of systemic vasculitis of the International Consensus Conference in Chapel Hill, 2012 (Table 1).

Table 1. Updated classification and nomenclature of systemic vasculitides (Chapel Hill, 2012)

Large vascular vasculitis		Giant cell arteritis (GCA)
		Takayasu arteritis
Medium vascular vasculitis		Polyarteritis nodosa (PA)
		Kawasaki disease
Small vessel vasculitis	ANCA-associated vasculitis	Microscopic polyangiitis (MPA)
		Granulomatosis with polyangiitis (Wegener's granulomatosis) (GPA)
		Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA)
	Immune complex vasculitis	Cryoglobulinemic vasculitis
		IgA-associated vasculitis (Henoch-Schönlein disease)
		Hypocomplementary urticarial vasculitis
		Vasculitis associated with autoantibodies to the basement membranes of the glomerular capillaries of the kidneys
Vasculitis with variable vascular lesions		Behcet's disease
		Cogan syndrome
Vasculitis affecting one organ		Cutaneous leukocytoclastic vasculitis
		Cutaneous arteritis
		Primary vasculitis of the central nervous system
		Isolated aortitis
Vasculitis associated with systemic diseases		Vasculitis associated with systemic lupus erythematosus (SLE)
		Vasculitis associated with rheumatoid arthritis (RA)
		Vasculitis associated with sarcoidosis
Vasculitis of known (suspected) etiology		HCV-associated cryoglobulinemic vasculitis
		Drug-induced immune complex vasculitis
		Drug-induced ANCA vasculitis
		Paraneoplastic vasculitis

Another commonly used classification of vasculitis is the American College of Rheumatology (ACR) classification, which is based primarily on clinical data. However, both classifications were developed to compare groups of patients with vasculitis, and not as diagnostic criteria for an individual patient.

Only some vasculitis have pathognomonic clinical, instrumental (PET angiography) and laboratory manifestations, which once again confirms the need for skin biopsy as the most accurate method of diagnosis (Fig. 1). On the other hand, histological confirmation of vasculitis cannot stand aside from medical history, clinical and laboratory examinations and/or angiographic features.

Figure 1. Histological classification (selection of the optimal biopsy method) of vasculitis with skin lesions (according to Carlson J.A., 2010)

Henoch-Schönlein disease and cutaneous leukocytoclastic vasculitis affect the superficial vessels of the skin, while polyarteritis nodosa and giant cell arteritis affect the deep muscular vessels that are found in the subcutaneous fat. Most other forms of vasculitis, such as cryoglobulinemic and ANCA-associated vasculitis, can affect both small and large vessels. The diagnostic value of a skin biopsy depends largely on the depth of the biopsy. For an accurate diagnosis of all vasculitis, with the exception of leukocytoclastic and Henoch-Schönlein disease, it is necessary to perform an incisional (cutting of tissue) or excisional (cutting out a piece of tissue) biopsy of subcutaneous fat.

A characteristic sign of skin lesions in patients with vasculitis of small-caliber vessels is purpura, which is palpable. This element of the skin rash is the result of extravasation of red blood cells through the vascular wall into the dermis. The predominant localization of purpura is symmetrical areas of the lower extremities and back (photo 1). With leukocytoclastic vasculitis, aseptic pustular elements may form at the apex of the purpura (photo 2), due to a large number of destroyed leukocytes. Purpura can be asymptomatic, sometimes causes itching or burning, and leaves behind hyperpigmentation.

Photo 1. Purpura of varying duration on the legs with hemorrhagic vasculitis

Photo 2. Purpura with pustular elements on the lower leg with leukocytoclastic vasculitis

Data on the association of certain types of skin rashes with different types of vasculitis are shown in Table 2.

Table 2. Elements of skin rash in patients with systemic vasculitis (according toXu L.Y.et al., 2009)

Type of vasculitis	Purpura that is palpable	Papules	Vesicles	Subcutaneous nodules	Livedo	Ulcers	Digital necrosis
Henoch-Schönlein disease	++++
Cryoglobulinemic vasculitis	++++
Hypocomplementary urticarial vasculitis
Cutaneous leukocytoclastic vasculitis	++++
Polyarteritis nodosa				++++	++++
Microscopic polyangiitis	++++
Granulomatosis with polyangiitis	++++

In 2009, Japanese dermatologist T. Kawakami created a diagnostic algorithm for cutaneous vasculitis, which is based on immunological (ANCA, cryoglobulin, IgA) and histological data (Fig. 2).

Figure 2. Diagnostic algorithm for primary cutaneous vasculitis (according to T. Kawakami, 2010)

The disadvantages of this algorithm are that the clinical picture of the disease and known immunological features are not taken into account (24% of patients with GPA are positive for MPO-ANCA, 26% of patients with MPA and less than 5% of patients with EGPA are positive for PR-3-ANCA), which once again proves the importance of an integrated approach to the diagnosis of systemic vasculitis.

Polyarteritis nodosa

Polyarteritis nodosa(UP) is a systemic necrotizing vasculitis, which is characterized by damage to medium and small arteries with the formation of microaneurysms, which leads to the development of tissue ischemia and infarction.

According to the literature, skin manifestations are observed in 26-60% of patients with polyarteritis nodosa. Skin lesions are usually accompanied by other systemic manifestations of UP (fever, weight loss, myalgia, arthralgia, peripheral neuropathy). According to research by Agard C. et al, skin lesions (purpura, subcutaneous nodes) were the first symptoms in 11% of patients with polyarteritis nodosa. Systemic manifestations may not appear until 1-20 years after the onset of the skin rash. The most common dermatologic manifestations of polyarthritis nodosa are infarcts, ulcers, livedo reticularis, subcutaneous nodules, and ischemic changes in the distal phalanges of the fingers (Figure 3). The most common location of skin rash is the lower extremities (95%). Subcutaneous nodes from bright red to cyanotic color have dimensions of 0.5-2 cm, usually bilateral, localized on the legs and thighs, less often - the arms, torso, head, neck, buttocks. Due to ischemia of the nodes, ulcers appear (photo 4). Livedo reticularis can occur independently or simultaneously with subcutaneous nodules. The most common localization of livedo is the lower and upper extremities, less often - the torso. Livedo is a macular ring-shaped rash of cyanotic color that forms a mesh. The pathognomonic symptom of UP is the appearance of the so-called “stellate” or livedo tree, which differs from livedo reticularis in the shape of the rash (livedo tree consists of torn or irregular rings) (photo 5). Despite the clinical differences, in the literature the term “livedo reticularis” is very often used to refer to any livedo. Some patients with polyarteritis nodosa develop atrophic, star-shaped scars (white skin atrophy).

Photo 3. Gangrene of the distal phalanges of the fingers in a patient with polyarteritis nodosa

Photo 4. Leg ulcers in a patient with polyarteritis nodosa

Photo 5. Livedo tree in a patient with polyarteritis nodosa

Other manifestations of polyarthritis nodosa may include urticaria, transient erythema, superficial phlebitis, Raynaud's phenomenon, and subungual hemorrhages. Pustular changes are characteristic of UP and usually arise as a result of secondary infection of necrotic changes.

According to one retrospective study, skin lesions were observed in half (52%) of patients with polyarteritis nodosa (n=112). Typical manifestations were subcutaneous nodules and ulcerative-necrotic changes (in 20.7% of patients), livedo (in 15.5% of patients) and polymorphic rash (13.8%). Other elements of skin lesions were less common (Figure 3).

Figure 3. Structure of skin manifestations in patients with polyarteritis nodosa at the onset of the disease

The classic histological sign of polyarteritis nodosa is the presence of necrotic inflammation of medium-diameter vessels (Figure 6). There are four histoligic stages in the development of polyarteritis nodosa: degenerative, stage of acute inflammation, development of granulation tissue and terminal. The degenerative stage includes coagulative necrosis of the medial layer of vessels, fibrinous exudates around the outer elastic membrane, neutrophil infiltration and partial destruction of the outer and inner elastic membrane. The stage of acute inflammation is characterized by neutrophilic, lymphocytic and eosinophilic infiltration, complete destruction of the internal elastic membrane, fibrinous exudates of the entire vascular wall with complete destruction of the tunica media, proliferation of fibroblasts, edematous changes in the surrounding connective tissue and total obliteration of the lumen of blood vessels with the formation of a fibrin thrombus. During the development of granulation tissue, lymphocytes replace neutrophils, separating granulation tissue, which covers the middle and outer lining of the vessel and can penetrate through defects in the internal elastic membrane into the lumen of the vessels and contribute to intimal thickening. The terminal stage includes the formation of scar tissue in the vascular wall and perivascular proliferation of fibroblasts.

Photo 6. Polyarteritis nodosa. Necrotizing vasculitis of medium-sized vessels (according to Carlson J.A., 2010)

In ulcerative lesions, histological examination reveals vyskulitis of medium-diameter vessels of subcutaneous fat with neutrophilic infiltration, leukocytoclasia, endothelial edema and fibrosis with necrosis of the dermis and ulcerative defect of the epidermis. Subcutaneous nodes are histologically represented by neutrophilic vasculitis of muscular type vessels with predominant localization in the areas of bifurcations.

Microscopic polyangiitis

Microscopic polyangiitis(MPA) - systemic vasculitis with damage to small vessels (arterioles, capillaries and venules) without the formation of extravascular granulomas. Microscopic polyangiitis is characterized by the development of segmental necrotic glomerulonephritis, hemoptysis and association with ANCA (26% of patients are positive for antibodies to PR-3 and 58% of patients are positive for antibodies to MPO). In most patients with microscopic polyangiitis, the development of pulmonary and nephrological symptoms is preceded by arthralgia, myalgia and constitutional symptoms (fever, weight loss).

Dermatological manifestations are detected in 15% of patients at the onset of MPA and up to 65% of patients at the height of the disease. The most characteristic dermatological sign of microscopic polyangiitis is purpura, which is palpable and found in approximately 50% of patients, and is localized on the lower extremities. Other dermatologic manifestations include subungual hemorrhages, subcutaneous nodules, palmar erythema, livedo, hemorrhagic bullae, vesicles, infarctions, erythema annulare, ulcers, and telangiectasias. According to some data, among the skin manifestations of microscopic polyangiitis (n=14), palpable purpura, ulcerative necrotic changes, and livedo are more common.

The classic histological signs of MPA according to skin biopsy are neutrophilic vasculitis of small vessels of the dermis and subcutaneous fat. Involvement of medium-diameter vessels in the pathological process is rare. Other histologic features include lymphocytic perivascular infiltration of the upper dermis, mixed lymphocytic and neutrophilic perivascular infiltration of the middle and deep dermis, and mixed lymphocytic and histiocytic infiltration of the middle dermis. Livedo tree is histologically represented by vasculitis of the vessels of the deep layers of the dermis and subcutaneous fat. Involvement of small vessels is a diagnostic criterion for MPA, which includes the diagnosis of polyarteritis nodosa. The histological differentiated feature between GPA and MPA is the absence of granuloma formation in MPA.

Granulomatosis with polyangiitis (Wegener's granulomatosis)

Granulomatosis with polyangiitis(GPA) is a systemic vasculitis, which, according to the classification of the International Consensus Conference in Chapel Hill, includes the following triad: granulomatous inflammation of the respiratory tract, necrotic vasculitis of medium and small diameter vessels, necrotic glomerulonephritis. However, only 16% of patients with GPA meet all three classification criteria. Characteristic laboratory manifestations of GPA are positivity for antibodies to PR-3 (66%) and antibodies to MPO (24%). The clinical course of GPA is often accompanied by constitutional manifestations (fever, weight loss), arthralgia, myalgia and damage to the upper respiratory tract (rhinitis, sinusitis, ulcers of the nasal and oral mucosa, perforation of the nasal septum, saddle-shaped deformation of the nose, granulomatous inflammation of the trachea with the formation of subpharyngeal stenosis ).

Skin lesions in patients with GPA occur, according to various studies, with a frequency of 14 to 77% and in 10% of patients they are the first symptoms of the disease. The most common element of a skin rash in GPA is purpura, which is palpable, localized on the lower extremities.

Papulo-necrotic changes occur less frequently in patients with GPA, but are a more specific symptom compared to palpable purpura. Cutaneous extravascular necrotic granulomas or papulo-necrotic changes may appear in areas typical of rheumatoid nodes (Figure 7). Considering that one third of patients are positive for GPA according to the rheumatoid factor and the presence of articular syndrome at the onset, such patients are often diagnosed with rheumatoid arthritis. In such cases, the determination of antibodies to cyclic citrullinated protein, which are not detected in patients with GPA, is important in carrying out a differentiated diagnosis.

Photo 7. Papulo-necrotic rash on the elbow in a patient with GPA

Other manifestations of skin lesions in patients with GPA include subcutaneous nodules, vesicles, digital infarcts, subungual hemorrhages, ulcers that resemble pyoderma gangrenosum, and polymorphic rash. Unlike polyarteritis nodosa, GPA is not characterized by the presence of livedo. In patients with GPA who were under observation (n=25), skin lesions occurred in 52% of cases, including necrotic papules - in 28%, digital infarctions - in 16%, polymorphic rash - in 12%.

There are four histological changes in skin biopsies in patients with GPA:

1. Necrotic neutrophilic vasculitis of small and medium-sized dermal vessels.
2. Palisade granuloma with a central core of basophilic collagen surrounded by histiocytes and neutrophils (the so-called “blue” granuloma).
3. Granulomatous vasculitis with perivascular lymphohistiocytic infiltrates and the presence of infiltration of the walls of muscle-type vessels of subcutaneous fatty tissue with giant cells.
4. Perivascular infiltration with atypical lymphocytes.

Biopsy of skin lesions in patients with GPA often demonstrates granulomatous changes and rarely reveals evidence of vasculitis.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Eosinophilic granulomatosis with polyangiitis(EGPA) is a systemic vasculitis, which is characterized by the presence of bronchial asthma (usually with a late onset), allergic symptoms (allergic rhinitis, nasal polyps), peripheral and tissue eosinophilia and necrotic vasculitis of small and medium-sized vessels. Antibodies to MPO are detected in 40% of patients with EGPA, and antibodies to PR-3 are found in 5% of patients. Skin lesions that are accompanied by peripheral neuropathy are a characteristic sign of Churg-Strauss syndrome. Other clinical signs include pulmonary infiltrates, abdominal pain, intestinal obstruction, arthralgias, myalgias, and constitutional symptoms. Skin lesions are observed in 40-75% of patients with EGPA and in 6% of patients they are the first symptoms of the disease. As with other ANCA-associated vasculitides, the characteristic skin lesion for EGPA is palpable purpura, with a typical localization on the lower extremities, which is detected in half of patients with cutaneous manifestations. Subcutaneous nodules and papulo-necrotic changes in the lower extremities, extensor ulnar surface, fingers and scalp are detected in a third of patients. Other dermatologic manifestations of EGPA include livedo reticularis, ulcers, vesicles, erythema multiforme, digital arteritis, panniculitis, and facial edema. Among patients with EGPA, skin lesions were found in 36% of cases, mainly ulcerative-necrotic changes, digital arteritis, palpable purpura, and panniculitis. The relatively low frequency of dermatological manifestations may be due to the fact that most patients with this vasculitis came to the attention of a rheumatologist, already receiving glucocorticoid treatment prescribed by a pulmonologist.

Skin biopsy shows three main histological features of EGPA:

1. Eosinophilic and neutrophilic vasculitis of small and medium-sized vessels of the superficial and middle layers of the dermis.
2. Interstitial infiltration of the dermis with eosinophils.
3. Formation of a “red” granuloma (photo 8). The “red” granuloma consists of a central core, represented by eosinophil breakdown products and collagen fibers, and histiocytes located along the periphery.

Photo 8. Eosinophilic granulomatosis with polyangiitis. Vasculitis of medium-diameter vessels with eosinophilic infiltrates (according to Carlson J.A., 2010)

Skin lesions in patients with systemic vasculitis are common clinical signs of this disease. The range of skin lesions is quite wide, while some variants of dermatological changes are specific to certain forms of systemic vasculitis (for example, for polyarthritis nodosa - livedo tree, gangrene of the distal parts of the fingers, for GPA and EGPA - papulo-necrotic changes). For early diagnosis and prescription of adequate treatment for systemic vasculitis with dermatological manifestations, in addition to clinical symptoms and immunological data, it is important to conduct a histological examination of the skin and subcutaneous tissue.

is a disease of the stomach of a chronic, recurrent nature, accompanied by the formation of a defect in the gastric mucosa and the tissues located underneath it. The main symptom is epigastric pain on an empty stomach or after eating, often radiating to the back and chest. Vomiting, belching, heartburn, and nausea are often observed. The most dangerous complications are bleeding, perforation of the stomach wall, pyloric stenosis, and malignant degeneration of an ulcer. Diagnosed by gastroscopy and x-ray of the stomach, tests for Helicobacter pylori infection. Uncomplicated gastric ulcers are treated conservatively; in complicated cases, surgery is used.

General information

Drug-induced ulcers

Gastric ulcer has the same development mechanisms as duodenal ulcer and is also classified.

Symptoms of a stomach ulcer

Unlike duodenal ulcers, gastric ulcers are characterized by pain that occurs and intensifies immediately after eating. Vomiting with a stomach ulcer brings relief. A common symptom is heartburn, as well as heaviness in the stomach (associated with impaired emptying), flatulence. Appetite is usually reduced. However, sometimes an ulcer localized in the antrum of the stomach can manifest itself as hunger pain and night pain.

Just like a duodenal ulcer, a gastric ulcer is dangerous due to complications such as bleeding and gastric perforation. If the ulcer is localized in the pyloric region, stenosis of the pyloroduodenal region may develop. Ulcers localized in the stomach also have a high risk of malignancy, unlike duodenal ulcers.

Diagnostics

Gastroscopy, an endoscopic examination of the stomach, provides the main information for accurately diagnosing gastric ulcers. Also, severe ulceration can be detected with contrast radiography of the stomach. When examining gastric contents, a bacterial culture is performed to identify Helicobacter. For the same purpose, a breath test and Helicobacter detection using PCR and ELISA are used. A general and biochemical blood test may show signs of anemia if there is bleeding from the ulcerated wall; laboratory tests cannot identify specific signs of an ulcer. Stool may also be tested to look for hidden bleeding (fecal occult blood test).

Treatment of stomach ulcers

In the treatment of gastric ulcers, strict adherence to the diet is of great importance - avoidance of foods that irritate the stomach wall and increase the production of gastric juice. Patients suffering from stomach ulcers should exclude spicy, salty, sour, fried and smoked foods, and foods rich in coarse fiber from their diet. It is recommended to consume food boiled or steamed. Drug therapy includes:

• proton pump inhibitors (omeprazole, rebeprazole, esomeprazole and analogs) or H2-histamine receptor blockers to suppress gastric secretion (ranitidine group drugs);
• gastroprotective (bismuth, sucralfate) and antacids;
• antibacterial drugs to suppress Helicobacter pylori infection (metronidazole). Drug therapy aimed at eradicating H. Pylori is usually carried out for 10-14 days, after which maintenance therapy with acid-lowering drugs is continued.

An uncomplicated gastric ulcer does not require surgical treatment. Surgical removal of part of the stomach (resection) is prescribed only in case of severe complications: perforation, obstruction, malignancy of the ulcer with the development of stomach cancer. Surgical treatment is rarely used for persistent, often relapsing disease that is refractory to conservative therapy.

Treatment of symptomatic gastric ulcers requires, first of all, removal of the factor that provoked the ulcer. As a rule, this is enough for a positive effect. As additional therapy, agents that reduce the secretion of hydrochloric acid (proton pump inhibitors, H2-gastroprotectors) are used. A decrease in secretory activity in gastric ulcers can be achieved surgically - by performing vagotomy.

Prognosis and prevention

Prevention of gastric ulcer, as well as duodenal ulcer, is the timely detection and treatment of Helicobacter pylori infection of the gastrointestinal tract, avoidance of stressful situations, uncontrolled use of medications and regular balanced nutrition. Uncomplicated gastric ulcers can be successfully cured if detected early and adequately treated. Poor prognosis if complications develop.

Systemic scleroderma (SSc) is a systemic connective tissue disease characterized by fibrosis, vascular damage and immunological abnormalities with varying degrees of involvement of internal organs. Although SSc is often clinically divided into two subtypes based on the extent of skin involvement: diffuse and localized, Raynaud's phenomenon and its complications are a universal feature of the disease, occurring in more than 95% of patients. This is a potentially dangerous symptom, as it quite often progresses to ulceration (in 50% of patients) and leads to gangrene of the limb. The seriousness of the situation is associated with the formation of structural abnormalities and functional vascular abnormalities in Raynaud's phenomenon within SSc, in contrast to the primary (idiopathic) forms of Raynaud's phenomenon, when vascular abnormalities are completely reversible and never progress to irreversible tissue injury/ischemia. Thus, digital vasculopathy is one of the factors leading to chronic ischemic pain and disability in patients with SSc.

Primary Raynaud's phenomenon is a temporary, reversible vasospastic phenomenon. Raynaud's phenomenon is an episode of transient digital ischemia due to vasospasm of the small arteries of the fingers, precapillary arterioles and cutaneous arteriovenous anastomoses under the influence of cold temperature and emotional stress. It most often affects the fingers and toes, tips of the ears, nose and nipples. Typically, changes in skin color undergo three phases: initial pallor, cyanosis, and finally erythema as an expression of compensatory vasodilation. Clinical manifestations of Raynaud's phenomenon can be grouped as follows:

• Most often, color changes are noted on the fingers.
• The changes begin on one finger, then spread to other fingers and become symmetrical on both hands.
• The II–IV fingers of the hands are most often involved; the thumb usually remains intact.
• Changes in skin color can also be observed in other areas - the ears, tip of the nose, face, above the knees.
• During attacks, livedo reticularis may appear on the extremities, which disappears after the completion of vasospasm.
• In rare cases, damage to the tongue is observed, which is manifested by numbness and transient speech disorders (speech becomes slurred, blurred).
• A significant proportion of patients complain of sensory disturbances (numbness, tingling, pain) during an attack.

The prevalence of Raynaud's phenomenon is less than 10% in the general population. N.A. Flavahan (2015) in a recent review emphasizes thermoregulatory mechanisms as a basis for understanding Raynaud's phenomenon, emphasizing the role of arteriovenous anastomoses and increased activity of α2-adrenergic receptor blockers in reducing blood flow.

Raynaud's phenomenon in SSc is a consequence of structural and functional vascular disorders with pronounced proliferation of the intima of the distal arteries of the extremities (digital arteries). Vascular changes are of a twofold nature. On the one hand, significant proliferation and fibrosis of the intima, endothelial damage lead to increased release of vasoconstrictor mediators and a simultaneous decrease in the level of vasodilator molecules. On the other hand, frequent episodes of vasospasm ultimately lead to progressive tissue ischemia, the production of free superoxide radicals and further enhance pathological changes in tissues and create conditions against which trophic disorders - digital ulcers - can occur.

Ulceration of the fingertips (pads) is generally considered to be “ischemic,” whereas ulceration on the extensor surface of the fingers is “traumatic.” To date, there has been little evidence for this theory. However, in a study by B. Ruaro et al (2015) involving 20 patients with SSc and finger ulcers, they demonstrated a significant decrease in blood flow at the site of finger ulcer formation and its improvement during healing. Tissue ischemia also underlies the development of osteolysis, mainly of the nail phalanges.

R. Saigusa et al (2015) conducted a series of experiments to study the role of CCN1 (Cysteine-rich Protein 61 - a secreted heparin-binding protein rich in cysteine), which has an antifibrotic effect, in SSc and reported a decrease in its circulating levels in patients with current or previous digital ulcers. They also postulated that the reduced levels of this protein were at least partially caused by Fli1 (Friend leukemia integration-1) deficiency. Fli1 is a member of a family of transcription factors that is constitutively downregulated in various cell types in the skin of patients with SSc, at least in part by an epigenetic mechanism. Thus, Fli1 deficiency is a potential predisposing factor for SSc and vascular complications, reflecting environmental influences. The pathogenetic role of Fli1 is clearly defined in the development of vasculopathies; today the possibility of its use as a biomarker and early predictor of vascular disorders in SSc is being studied. In Fig. 1. Schematically shows the effect of Fli1 deficiency on the development of vascular pathology in SSc.

Effect of Fli1 deficiency on the development of vascular pathology in SSc. Fli1 deficiency, caused by an epigenetic mechanism in endothelial cells, leads to suppression of cadherin-5 type 2, PECAM-1, PDGF-B and increased production of MMP-9. As a result, capillary dilation, vascular fragility and arteriolar stenosis develop, which are histological signs of vasculopathy in SSc. Clinically, the development of telangiectasia is associated with a typical capillaroscopic picture of the nail bed - giant capillary loops and hemorrhages. The development of digital ulcers and gangrene is associated with pulmonary arterial hypertension in SSc. Adapted by us from: Y. Asano, A.M. Bujor, M. Trojanowska (2010).

MMP - matrix metalloproteinases; VE-cadherin - type 2 cadherin-5, cell adhesion protein of the vascular endothelium of the cadherin family; PECAM-1 - platelet/endothelial cell adhesion molecule 1, a membrane protein of the immunoglobulin superfamily, belongs to the class of cell adhesion molecules; PDGF-B - Platelet-derived growth factor subunit B, the protein encoded by this gene, is a member of the platelet-derived growth factor family.

A review article by I. Chora et al (2015) summarized the correlations between a large number of biomarkers with capillaroscopic changes in the nail bed and digital ulcers. Vascular biomarkers may become useful predictors of vascular damage in SSc, allowing for earlier stratification of patients and earlier treatment of vascular complications. Accurately predicting which patients with SSc are most likely to develop digital ulcers is of great clinical importance, as it will identify a group of patients requiring targeted preventive interventions and systematic monitoring.

Recently, several studies have described predictors and prognostic factors for ulceration in SSc. A large prospective study of 623 patients with SSc found that the strongest risk factors for the development of new digital ulcers over the next 6 months were: capillary density on the middle finger of the dominant hand (abnormal capillaroscopic pattern), number of gastrointestinal ulcers, and the presence of baseline critical ischemia . Other predictors of fingertip ulceration include anti-topoisomerase antibodies (anti-Scl-70), the presence of endothelin receptor type A (ET)-1 antibodies and increased circulating levels of ET-1, as well as the severity of thermography changes. In another systematic review PRISMA I. Silva et al (2015) summarized the risk factors for the development of digital ulcers, which are: subtype of diffuse skin lesions in SSc, early onset of Raynaud's phenomenon, presence of antibodies to topoisomerase (anti-Scl-70), abnormal picture nail capillaroscopy, increased ET-1 levels and low vascular endothelial growth factor (VEGF) levels.

At the same time, experts widely recognize that the presence of digital ulcers is associated with a severe course of the disease and even increased mortality. In a multivariate analysis of 3196 patients from the EUSTAR database, a history of digital ulcers was a significant predictor of patient mortality (odds ratio 1.53).

Clinical and serological associations of digital ulcers in patients with SSc are summarized in Table. 1 and 2. Many of these associations have been proposed as biomarkers of ulcer development and merit further research to confirm their predictive value.

The mechanism of development of digital ulcers in SSc is explained by several factors, which include repetitive microtrauma, thinning of the skin, dry skin and the presence of calcification. It is believed that 8–12% of ulcers arise from calcification of the skin and subcutaneous tissue. However, prolonged tissue ischemia due to Raynaud's phenomenon is the most important mechanism. Digital ulcers vary in size and borders, the presence of exposed underlying tissue (bone, tendon), and the presence of tissue calcification. Ulcers are considered acute for up to 3 months, chronic for more than 6 months. The clinical outcome of ulcers depends on numerous factors. It has been established that about 30% of patients with SSc and digital ulcers have loss of soft tissue and bone. When analyzing complications of patients with ulcers during 7-year monitoring, it was revealed that gangrene was diagnosed in 11% of patients; subject to ineffective treatment, its absence and recurrent ischemic attacks, the development of gangrene was subsequently noted in 100% of patients. 12% of patients with digital ulcers require hospitalization and surgery.

Table 1

Clinical associations of digital ulcers in patients with SSc

Increase the risk of digital ulcers	Disease related	History of digital ulcers
		Joint contractures
		Diffuse skin lesions
		Early onset of the disease
		Duration of Raynaud's phenomenon and duration of the disease
		Increased erythrocyte sedimentation rate
		Absence or late administration of vasodilation therapy
	Involvement of internal organs	Lung damage: interstitial lung disease
		Esophageal damage
		Heart damage
	Antibodies	Antibodies to topoisomerase (anti-Scl-70)
		Anticentromere antibodies
		Antibodies against fibrillarin
		Antiendothelial antibodies
Conflicting evidence for digital ulceration	Other	Smoking
		Pulmonary arterial hypertension
		Floor
No association with digital ulceration		Scleroderma renal crisis

table 2

Serological and vascular associations of digital ulcers in patients with SSc

Serological markers	Increased asymmetric dimethylarginine (ADMA)
	Increased angiopoietin-2 and angiopoietin-like protein 3 (ANGPTL3)
	Increase in soluble endoglin
	Reduction of endothelial cell precursors
	Increased ET-1 and autoantibodies to ET A receptors
	Increased galectin-1 (associated with decreased number of digital ulcers)
	Increased expression of interferon type 1 gene
	Increase in mean platelet volume
	Pentraxin-3 (PTX-3) enhancement
	Increased placental growth factor (PIGF)
	Increased platelet-activated factor acetylhydrolase (associated with decreased number of ulcers)
	Increase in soluble CD40 ligand (sCD40L)
Vascular markers	Capillaroscopy of the nail bed
	Increased stiffness of renal vessels
	Local ratio of thermal hyperemia to peak load ≥1 (according to laser Doppler flowmetry)

Management of patients with Raynaud's phenomenon, digital ulcers/necrosis in SSc includes non-pharmacological, pharmacological approaches and surgical intervention (Table 3). Non-pharmacological modalities used include avoidance of triggers that precipitate ischemic episodes, including cold exposure, emotional stress, or drugs that promote vasoconstriction, including beta-blockers, antimigraine drugs (such as sumatriptan and ergotamine), birth control pills, certain chemotherapy agents (such as cisplatin, vinblastine, targeted tyrosine kinase blockers, etc.) and amphetamines. Smoking cessation is absolutely necessary to prevent further vascular damage to already vulnerable ischemic tissue.

Table 3

List of therapeutic interventions for Raynaud's phenomenon and digital ulcers/necrosis

Non-pharmacological treatment

To give up smoking

Avoid cold, stress, and the use of vasoconstrictors, such as beta-adrenergic blockers and amphetamines

Using hand/foot warmers and protective clothing

Pharmacological treatment for Raynaud's phenomenon

Calcium channel blockers

Angiotensin receptor blockers

α-adrenergic receptor blockers

Treatment for digital ulcers

Phosphodiesterase inhibitors

Prostacyclin analogues

ET receptor antagonists

Nitrates

Statins

Local treatment for ulcers

Skin moisturizing, vitamin E gel

Topical/systemic antibiotic therapy with concomitant infections

Adequate pain control

Debridement if indicated

Surgical treatment for Raynaud's phenomenon and digital ulcers

Central sympathectomy (endoscopic thoracic sympathectomy)

Digital sympathectomy

Botulinum toxin

Autologous fat transplantation

Surgical amputation

Vasoactive therapies are central to the pharmacological treatment of vascular complications of SSc. E. Hachulla et al (2007) reported that vasodilation therapy significantly delayed the development of digital ulcerations (hazard ratio (RR) 0.17, 95% confidence interval (CI) 0.09–0.32). Doses of vasodilating drugs most often used in therapy for Raynaud's phenomenon and its complications are presented in Table. 4.

Calcium channel blockers have been little studied in the treatment/prevention of digital ulcers, although many clinicians use calcium channel blockers (most often nifedipine) in the treatment of severe Raynaud's phenomenon. A randomized, double-blind study compared oral nifedipine (30 mg daily for 4 weeks followed by 60 mg daily for 12 weeks) and intravenous iloprost for the treatment of patients with severe Raynaud's phenomenon. Moreover, the average number of digital ulcers decreased from 4.3 to 1.4 after 16 weeks of treatment with nifedipine. When using iloprost, the number of digital injuries decreased from 3.5 to 0.6. An increase in hand temperature and improvement in microcirculation was noted only with the use of iloprost.

Table 4

Doses of vasodilating drugs in therapy for Raynaud's phenomenon and digital ulcers

Drug class	A drug	Usual dosages of drugs
Calcium channel blockers	Nifedipine (slow release)	10 mg 2 times a day → 40 mg 2 times a day
	Amlodipine	5 mg once daily → 10 mg once daily
	Diltiazem	60 mg 2 times a day → 120 mg 2 times a day
Blockers angiotensin I receptors	Losartan	25 mg once daily → 100 mg once daily
α-adrenergic receptor blockers	Prazosin	0.5 mg 2 times a day → 2 mg 2 times a day
Angiotensin-converting enzyme inhibitors	Lisinopril	5 mg once daily → 20 mg once daily
Inhibitors PDE-5*	Sildenafil	20/25 mg 3 times a day → 50 mg 3 times a day
	Tadalafil	10 mg every other day → 20 mg once a day

Although there is a strong therapeutic rationale for the role of angiotensin-converting enzyme inhibition in SSc and vascular complications as vascular remodeling agents (as used in patients with coronary artery disease), there is currently insufficient evidence to support the efficacy of this intervention. In a multicenter, double-blind, randomized clinical trial of 210 patients with limited SSc or autoimmune Raynaud's phenomenon (scleroderma-specific autoantibodies), 3 years of quinapril treatment was not associated with a significant reduction in the number of new digital ulcers (RR –0.08; 95% CI 0 .23–0.06) .

An important and promising direction is the use of PDE-5 inhibitors. PDE5 inhibitors inhibit the degradation (and therefore increase the bioavailability) of cyclic guanosine monophosphate (GMP) with subsequent clinically significant vasodilation. In a meta-analysis of digital ulcer therapy that included 31 randomized controlled trials, the use of PDE5 inhibitors (based on three included RCTs with a total of 85 patients) was associated with ulcer healing and patient improvement. However, the authors noted that studies were insufficient to detect significant benefit from PDE5 inhibitors.

In a recent multicenter, double-blind, randomized controlled trial of 84 patients, treatment with sildenafil for 12 weeks was associated with a significant reduction in the number of new digital ulcers (0.86 vs. 1.51). However, the healing time of these ulcers (the study's primary endpoint) was not reduced. Three commercially available PDE5 inhibitors include sildenafil, vardenafil, and tadalafil. Sildenafil and vardenafil have a shorter half-life of about 4 hours, while tadalafil has a much longer half-life of 18 hours.

Prostanoids are potent vasodilators and also inhibit platelet aggregation and proliferation of vascular smooth muscle cells. Iloprost, approved in Europe for the treatment of digital ulcers associated with SSc, is a chemically stable prostacyclin analogue with dual vasodilator and platelet effects. Iloprost is a synthetic analogue of prostacyclin, suppresses platelet aggregation and activation, dilates arterioles and venules, increases capillary density and reduces increased vascular permeability caused by mediators such as serotonin and histamine in the microcirculation system. It activates endogenous fibrinolysis, provides an anti-inflammatory effect, inhibits the adhesion and migration of leukocytes after endothelial damage, as well as the accumulation of leukocytes in ischemic tissues.

Intravenous prostanoids generally have a high incidence of side effects and poor tolerability, including systemic hypotension, dizziness, hot flashes, gastrointestinal distress, jaw pain, and myalgia.

Intravenous prostanoid therapy should be considered in cases of refractory Raynaud's phenomenon, especially in patients with a generalized form of SSc and especially in the cold season. The most commonly used are intravenous iloprost (3–5 days of treatment at a rate of 0.5±2 ng/kg/min for 6–8 hours) and epoprostenol. If side effects occur during drug infusion, it is recommended to slow down the rate of drug administration.

Intravenous prostanoid therapy has also been reported to improve healing of digital ulcers and reduce the incidence of new ones. In two multicenter, double-blind, randomized trials, intravenous prostanoid therapy (iloprost 0.5–2.0 ng/kg/min over 6 hours for 5 consecutive days) was associated with significantly greater healing of digital ulcers than placebo.

The second of these studies included 126 patients who completed the infusion course. After 3 weeks of treatment, 14.6% of patients receiving iloprost had ≥50% of digital ulcers resolved. The average weekly number of Raynaud's attacks decreased by 39.1% with iloprost and by 22.2% with placebo (p=0.005). In addition, the average proportion of improvement in global Raynaud's severity score over the entire 9-week follow-up was greater in patients receiving iloprost (34.8%) than in patients receiving placebo (19.7%) (p=0.011). Side effects were very common, with 92% of patients receiving iloprost experiencing one or more prostanoid-related side effects (although 57% of patients taking placebo also reported side effects).

In severe cases of vasculopathy and recurrent non-healing ulcers, patients should receive repeated courses of prostanoids; Continuous or extended courses of intravenous therapy should be considered in clinically impasses.

It should be noted that oral prostanoid drugs (iloprost, as well as new drugs - beraprost, cisaprost, treprostinil) have not demonstrated any improvement in the healing of digital ulcers.

Another prostaglandin analogue, alprostadil, administered intravenously for 5 consecutive days, has also been used in patients with persistent Raynaud's phenomenon.

Prazosin, an α1-adrenergic receptor antagonist, demonstrated improvement in Raynaud's phenomenon in two randomized trials. A dose of 1 mg 3 times daily was reported to improve the course and prognosis of Raynaud's phenomenon compared with placebo and was tolerated with fewer side effects compared with higher doses. Unfortunately, there is insufficient published data on its effect on digital ulcerations.

Topical nitrates have been used to improve local blood flow, but given the relatively complex interdigital application and potential side effects due to variable systemic absorption, there is less enthusiasm for their routine use today. M.E. Anderson et al (2002) examined the effect of topical glyceryl trinitrate gel on blood flow measured by scanning laser Doppler imaging in patients with primary and secondary Raynaud's phenomenon associated with limited scleroderma. After 1-minute application of 2% glycerol trinitrate gel, statistically significant improvements in blood flow were noted compared to fingers using placebo gel (p=0.004). There were no systemic side effects observed with topical administration of the drug in this small cohort of patients, which may make it a viable option for patients intolerant to oral vasodilators.

Two other randomized controlled trials examined the relatively new topical nitroglycerin drug MQX-503 for the treatment of patients with Raynaud's phenomenon. The first study demonstrated an improvement in Raynaud's phenomenon relative to the placebo group, but showed no statistical difference in the frequency or duration of Raynaud's phenomenon attacks. The second study showed an improvement in blood flow, as measured by laser Doppler, but there were no changes in pain scores or changes in skin temperature.

ET-1 is not only a powerful vasoconstrictor, but also has a pronounced proliferative effect on smooth muscle cells and fibroblasts, acting through two receptors (type A - ETA and type B - ETB). In general, ETA and ETB found on smooth muscle cells promote vasoconstriction and hyperplasia, whereas ETB, which is also found on endothelial cells, promotes vasodilation.

Bosentan is a dual ET-1 receptor antagonist licensed in Europe for the treatment of pulmonary arterial hypertension and the prevention of recurrent digital ulcers. Two large multicenter, double-blind, randomized controlled trials demonstrated that treatment with bosentan significantly reduced the incidence of new ulcerations. In a randomized, double-blind, placebo-controlled study of the effect of bosentan on the healing and prevention of ischemic digital ulcers in patients with SSc, which included 188 patients with SSc, 24 weeks of bosentan (62.5 mg twice daily for 4 weeks and 125 mg twice daily) day) was associated with a 30% reduction in the number of new digital ulcers. Bosentan was approved in Europe for the prevention of digital ulcers in scleroderma, but the FDA, after careful review, has not approved it. Bosentan may be an important treatment option given its oral administration and potentially unique ability to prevent the formation of new digital ulcerations.

In patients with intractable, recalcitrant digital ulcers refractory to PDE5 inhibitor therapy and intravenous prostanoid infusions, ET-1 receptor antagonists may be particularly beneficial.

To date, two new ET-1 receptor antagonists have been approved for the treatment of patients with arterial pulmonary hypertension in Europe: Macitentan and Ambrisentan, and are being studied in the treatment of patients with digital ulcers in SSc.

Calcification of the tissue surrounding the ulcer may require surgical debridement if other measures to heal it are unsuccessful. Digital (palmar) sympathectomy may provide significant benefit to patients who have not responded to conservative treatment methods. An unconditional limitation is that this technique is performed in separate specialized surgical centers.

Digital ulcers (on the fingers and toes) are a serious manifestation of SSc vasculopathy. They usually occur on the tips of the fingers or on the extensor surfaces of the hands over small joints, or in areas of calcification on the fingers. Typically, half of patients with digital ulcers report a previous history of ulcers, so digital ulcers usually have a recurrent course. They are associated with significant pain and disability and negatively affect quality of life and the ability to perform normal work. It has been established that smoking patients have a three times higher risk of developing digital vasculopathy than non-smoking patients; they more often require intravenous vasodilators, surgical debridement, and amputation. Digital ulcers have a high risk of infection, most often by Staphylococcus aureus, which can progress to the development of osteomyelitis. Therefore, early detection of ulcerations at an early stage of the disease is a priority to prevent the ulcer from increasing in size and becoming infected.

If ulcers occur, optimization of vasodilatory therapy or addition of intravenous prostanoid therapy is indicated. The choice of treatment depends on the severity of the ulcer. If the patient is managed on an outpatient basis, oral vasodilating therapy is combined: the dose is increased or an alternative drug is added. In severe and resistant cases, prostanoid therapy is prescribed.

In Fig. Figures 2 and 3 present adapted recommendations from the British Scleroderma Study Group for the management of patients with Raynaud's phenomenon and digital ulcerations. They present a stepwise approach to escalate therapy based on the effectiveness or failure of prior therapy, based on best clinical practice.

Management of patients with Raynaud's syndrome in real clinical practice in accordance with the recommendations of the British Scleroderma Study Group (adapted by us from: Herrick A.L. (2016) and Hughes M., Ong V.H., Anderson M.E. et al. (2015)). ACE - angiotensin-predominant enzyme; CCBs - calcium channel blockers; ARBs - angiotensin receptor blockers; IV - intravenously; SSRIs - serotonin reuptake inhibitors

Management of patients with digital ulcers in accordance with the recommendations of the British Scleroderma Study Group (adapted from: Herrick A.L. (2016) and Hughes M., Ong V.H., Anderson M.E. et al. (2015)). IV - intravenously

SSc-associated vasculopathy (Raynaud's phenomenon, digital ulcerations and critical ischemia) is a serious and pressing problem that significantly aggravates the course of SSc. Therefore, the search and development of well-tolerated, inexpensive, accessible therapeutic options for the treatment of Raynaud's phenomenon and its complications in the form of digital ulcers remains a priority. The use of the proposed multifaceted therapeutic approach to optimize the management of patients with Raynaud's phenomenon and digital ulcerations will allow adequate supervision of such patients and prevent the formation of new lesions to provide patients with a decent quality of life.

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RAYNAUD'S PHENOMENON AND DIGITAL VIRAZES IN SYSTEMIC SCLERODERMA: NUTRITION PATHOPHYSIOLOGY AND MANAGEMENT AT THE CLERODERMIA STAGE

I.Yu. Golovach, T.M. Chipko, N.M. Korbut

Summary.The article presents current insights into the mechanisms of development of vasculopathy (Raynaud's phenomenon and digital lesions) associated with systemic scleroderma. Clinical, capillaroscopic and immunological predictors of the development and severe progression of vasculopathy have been described. Affected leg, heart and circulatory system, troubling reversal of Raynaud's phenomenon, diffuse skin lesions, early onset of illness, high activity, late start of vasodilative therapy and potential factors for the development and progression of digital and sometimes The presence of anti-topoisomerase antibodies (anti-Scl-70), an abnormal capillaroscopy pattern, elevation of endothelin-1 and low levels of vascular endothelial growth factor (VEGF) are serological markers of severe vasculopathy. The article presents current approaches to the treatment of Raynaud's phenomenon and digital manifestations, as well as an algorithm for the management of patients. Management of patients with Raynaud's phenomenon and digital disorders includes non-pharmacological, pharmacological and surgical approaches. Vasoactive methods of therapy are central to the pharmacological treatment of patients with criminal manifestations of systemic scleroderma.

Key words:systemic scleroderma, vasculopathy, Raynaud's phenomenon, digital disorders, pathogenesis, predictors, treatment.

RAYNAUD’S PHENOMENON AND DIGITAL ULCERS IN SYSTEMIC SCLEROSIS: PATHOPHYSIOLOGY QUESTIONS AND MANAGEMENT AT THE PRESENT STAGE

I.Yu. Golovach, T.M. Chipko, N.N. Korbut

Summary. The article presents modern views on the mechanisms of development of vasculopathy (the Raynaud’s phenomenon and digital ulcers) associated with systemic sclerosis. Clinical, capillaroscopic and immunological predictors of development and severe course of vasculopathies are described. The lesions of the lungs, heart and esophagus, the long course of the Raynaud’s phenomenon, diffuse skin lesions, early onset of the disease, high activity, late onset of vasodilating therapy are potential factors in the development and progression of digital ulcers. The presence of antibodies to topoisomerase (anti-Scl-70), an abnormal picture of nail capillaroscopy, an increase in endothelin-1levels and a low level of vascular endothelial growth factor (VEGF) are serological markers of severe vasculopathy. The article presents modern approaches to the treatment of the phenomenon of Raynaud and digital ulcers, as well as an algorithm for long-term patient management. Management of patients with Reynaud’s phenomenon, digital ulcers includes non-pharmacological, pharmacological approaches and surgical intervention. Vasoactive methods of therapy are central to the pharmacological treatment of vascular complications of systemic sclerosis.

Key words: systemic sclerosis, vasculopathy, Raynaud 's phenomenon, digital ulcers, pathogenesis, predictors, treatment

Correspondence address:
Golovach Irina Yurievna
03680, Kyiv, st. Academician Zabolotnogo, 21
Clinical Hospital "Feofania"
Email: [email protected]

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:

1. 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.
2. 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.
3. 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

1. 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.
2. Subacute, moderately progressive. According to clinical symptoms and laboratory data, it is characterized by a predominance of signs of an immune inflammatory process - dense skin edema, myositis, arthritis. Cross syndromes are common cases.
3. 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

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

The use of the three listed parameters 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:

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

Complaints of patients in the early stages

Patients note general weakness, fatigue, malaise, often 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:

1. According to the interstitial type of lesion (interstitial lung disease), characterized by pulmonary fibrosis and diffuse pneumosclerosis, most pronounced in the lower parts of the lungs. Pathological changes develop 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).
2. Isolated (primary) pulmonary hypertension, resulting from vascular lesions of the lungs, or secondary (in 10%), developing as a result of interstitial pathology in the 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:

1. Sclerodermic nature of skin lesions.
2. Raynaud's syndrome and digital ulcers and/or scars.
3. Musculo-articular lesions with the development of contractures.
4. Calcification of the skin.
5. Osteolysis.
6. Fibrosis of the basal regions of the lungs.
7. Lesions of the gastrointestinal tract of a sclerodermic nature.
8. Development of large-focal cardiosclerosis with conduction and heart rhythm disturbances.
9. Scleroderma acute nephropathy.
10. Typical results of video capillaroscopy of the nail bed.
11. 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.

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Antiplatelet agents (Curantil, Trental) and anticoagulants (small doses of acetylsalicylic acid, Fraxiparine).
7. 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.

In our country, the term “peptic ulcer of the stomach and duodenum” has been adopted. However, in adolescence, localization of ulcers in the stomach practically does not occur, so the term “duodenal ulcer” is used.

Duodenal ulcer– This is a chronic relapsing disease characterized by the formation of ulcers in the duodenum due to a disorder of the mechanisms of nervous and humoral regulation of the gastroduodenal system.

Etiology. Of primary importance is burdened heredity, which is realized through the following factors:

§ leukocyte histocompatibility antigens, some of them are often found in patients;

§ blood group 0 (I), Rh (+);

§ the total number and reactivity of parietal cells, which determine the production of hydrochloric acid;

§ the number and reactivity of the main cells producing pepsinogen;

§ number and reactivity of accessory cells (mucus);

§ the nature of the blood supply to the mucous membrane;

§ the presence of Helicobacter pylori - a bacterium that supports, and possibly causes an exacerbation of the disease. It is localized in the submucosal layer of the prepyloric region, affects the mucous membrane, changing its epithelium, and is resistant to hydrochloric acid. Its toxins block the inhibition of hydrochloric acid secretion.

In the presence of a burdened heredity, the development of the disease is facilitated by pathogenic types of upbringing - emotional rejection by parents and treatment as a family idol. Often a duodenal ulcer develops against the background of chronic duodenitis.

Factors such as irregular food intake, so-called. “nervous feelings”, deviations from a healthy lifestyle, irrational diet, smoking, alcohol abuse considered challenging exacerbation of the disease.

Thus, an ulcer is formed as a result imbalances between factors of protection and factors of aggression.

Factors of aggression include: high acid formation, its continuity, including at night, high proteolytic activity of gastric juice, accelerated gastric emptying, reduced resistance of the duodenal mucosa.

Clinic.

Patient complaints:

§ Pain - long-lasting, lasts for hours, often has a gnawing character, its intensity varies from person to person. There may be no pain, then its equivalent is heartburn, nausea. The pain disappears after eating and warm drinking, taking alkalis or bleeding. Localization of pain: more often in epigastrium along the midline or in the so-called gastroduodenal zone, sometimes in the right hypochondrium. The pain is rhythmic and occurs 1.5 – 2 hours after eating, i.e. at the height of digestion (“late”), with long breaks between meals (hungry, at night and on an empty stomach). Exacerbations occur more often in spring and autumn. The nature of the pain changes with concomitant lesions in other parts of the digestive system.

§ Dyspeptic complaints– nausea and vomiting as a result of hypertonicity of the vagus nerve. Vomiting brings relief, eliminates pain and easily becomes established in the form of “habitual vomiting” syndrome. Appetite is preserved or increased.

Features of duodenal ulcer in adolescents.

The disease often begins in adolescence. Clinical manifestations of the disease in children atypical, in the initial period they dominate asthenic complaints. In addition, adolescents pay less attention to their illness; they rarely undergo X-ray and endoscopic examinations, which contributes to late diagnosis diseases. Characteristic is the rapid involvement of other digestive organs (biliary tract, pancreas, colon) in the pathological process; in girls, ovarian-menstrual function is disrupted.

M.V.Lukasheva (1976) identifies latent and acute forms.

At latent form there is a blurred onset, the pain is arrhythmic, not associated with food intake; painful nausea and profuse vomiting occur at any time of the day. Heartburn, hiccups, belching of air and hypersalivation are characteristic. Appetite is reduced, there is a lack of body weight. Fatigue, excitability and irritability are sharply expressed.

Acute form The onset of the disease manifests itself after neuro-emotional stress or during the formation of the menstrual cycle in girls. The pain is rhythmic, associated with food intake, often nocturnal with typical localization. There is heartburn, vomiting due to pain, constipation.

The rise in incidence coincides with puberty. After puberty, the incidence rate is several times higher in boys than in girls.

Diagnostics.

Identification of burdened heredity.

Determination of the type of character accentuation (emotionally labile and labile-hysterical), psychological characteristics with a tendency to fixate anxiety.

Instrumental methods - fibrogastroduodenoscopy, which reveals changes in the mucous membrane of the stomach and duodenum.

X-ray of the stomach and duodenum is used as an auxiliary diagnostic method.

Complications. Bleeding, perforation, penetration, stenosis.

Treatment.

1. Bed rest during an exacerbation helps reduce the tone and motility of the stomach, reduce pain and rapid healing of the ulcer;

2. Creation of physical and mental peace;

3. Nutrition – Diet No. 1 is traditionally prescribed, but recently its use has been abandoned. Regular 4-5 meals a day are recommended with thermal, mechanical and chemical sparing of the gastrointestinal tract. Food is enriched with proteins, fats, vitamins and iron.

4. Inpatient treatment for adolescents is mandatory; for adults, an intermittent inpatient treatment regimen is possible.

5. Psychotherapy.

6. Drug treatment involves a minimum of drugs aimed at reducing the aggressive properties of gastric juice, suppressing H. pylori, eliminating motility disorders, excessive acid and enzyme formation, protecting the mucous membrane, stimulating recovery processes:

§ Non-absorbable antacids that neutralize HCl and have an enveloping effect (contain magnesium trisilicate or aluminum hydroxide) - Almagel 1 tbsp. spoon 4 times a day 1 hour after meals; alfogel, anacid, gelusil, Maalox.

§ Enveloping antacids – sucralfate, venter, andapsin, ulcogant. These drugs create a protective film on the mucous membrane and adsorb pepsin, HCl and bile acids.

§ Peripheral M-anticholinergics - gastrocepin (gastrozem) suppresses the secretion of HCl and the production of pepsinogen, slows down gastric emptying, prescribed 50-75 mg orally 2 times a day.

§ H 2 receptor blockers - reduce the secretion of hydrochloric acid and pepsinogen, increase mucus secretion, normalize the motility of the stomach and duodenum, helping to accelerate the healing of ulcers.

There are five generations of H2 blockers on the market:

1st generation – cimetidine (Histodil) – should not be used;

2nd generation – ranitidine (ranisan, zantac), 4-5 times stronger than cimetidine, does not affect the liver and gonads;

3rd generation – famotidine (gastrostdin, quamatel).Side effects are very rare;

4th and 5th generation – nizatidine and roxatidine.

§ Proton pump blocker – omeprazole (losec, omeprol, omez).

Blocks the synthesis of hydrochloric acid.

§ Destruction of H. Pylori – De-Nol (tribimol, ventrisol).

This drug suppresses H. Pylori, protects the mucous membrane in the area of ​​the ulcer, adsorbs pepsin and hydrochloric acid, and accelerates the healing of the ulcer. Use 1-2 tablets or 1-2 teaspoons 3 times a day 30 minutes before meals, as well as at night.

It is used for the same purpose bismofalk.

Antibacterial therapy is also carried out:

v semisynthetic penicillins – ampicillin, ampiox 0.5 g 4 times a day for 10-14 days. More efficient amoxicillin and its more stable derivative Augmentin.

v Erythromycin-type drugs – clarithromycin.

Combinations of drugs are used: metronidazole, De-Nol, tetracycline or amoxicillin; omeprazole, De-Nol, augmentin.

§ Reparants – dalargin, - promotes mucosal regeneration.

New generation reparants include prostaglandins E 2 and I – enprostil, misoprostol, cytotec, rioprostil.

After a course of treatment, secondary prevention is necessary, especially for patients with a high risk of relapses and complications: heavy smokers, with a long history of ulcers, in a hyperacid state.

Surgical treatment is necessary in case of complications or their threat. An uncomplicated ulcer is treated conservatively.

Local treatment - laser therapy, UV irradiation, injection with heparin or lidase.

Dispensary observation provides for regular examination by a gastroenterologist, consultation with a surgeon, ENT doctor according to indications, monitoring of body weight, physical and sexual development, FGDS at least once a year.

A gentle diet for 1 month after an exacerbation, then a free diet with 4-5 meals a day. Drinking alcohol and smoking are prohibited. Sanitation of foci of infection. Anti-relapse treatment.

Physical education classes in special group no earlier than a year after the end of treatment, that is, with stable remission.

Schoolchildren are exempt from final exams.