Systemic scleroderma national guidelines. Clinical guidelines for the treatment of scleroderma in children

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

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

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

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

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

Tests for scleroderma

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

Differential diagnosis of scleroderma

Idiopathic cases of diseases that are associated with systemic sclerosis, such as Raynaud's phenomenon, renal failure and gastroesophageal reflux.
Systemic lupus erythematosus presents with systemic symptoms and a typical rash that may scar. Antinuclear antibody (ANA) testing usually helps establish the diagnosis.
Discoid lupus erythematosus presents as localized plaques that become scarred. A biopsy is usually performed to make the diagnosis.

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

Treatment of scleroderma

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

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

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

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

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

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

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

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

RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2013

Progressive systemic sclerosis (M34.0)

Rheumatology

general information

Short description

Approved

minutes of the meeting of the expert commission

on health development issues of the Ministry of Health of the Republic of Kazakhstan

Definition: Systemic scleroderma (SSc) is an autoimmune connective tissue disease, the main clinical signs of which are caused by widespread microcirculation disorders, fibrosis of the skin and internal organs.

Protocol code:

ICD-10 codes:
M 34.0 Progressive systemic sclerosis
M 34.1 CREST syndrome
M 34.2 Systemic sclerosis caused by medicines and chemical compounds
M 34.8 Other forms of systemic sclerosis
J 99.1 with lung damage
G 73.7 with myopathy
M 34.9 Systemic sclerosis, unspecified
M 35.0 Sicca syndrome (Sjogren's)
M 35.1 Other crossover syndromes

Abbreviations used in the protocol:
AT antibodies
GC-glucocorticosteroids
Gastrointestinal tract - gastrointestinal tract
ILD - interstitial lung disease
CT - computed tomography
ICD - international classification of diseases
NSAIDs - non-steroidal anti-inflammatory drugs
UAC- general analysis blood
OAM - general urine analysis
RNA - ribonucleic acid
SSc - systemic scleroderma
CREST-calcinosis, Raynaud’s syndrome, esophageal dysmotility, sclerodactyly, telangiectasia.
ESR - erythrocyte sedimentation rate
SLE - systemic lupus erythematosus
Doppler ultrasound
FGDS - fibrogastroduodenoscopy
EMG-electromyography

Date of development of the protocol: year 2012

Protocol users: rheumatologists, therapists, general practitioners.

Indication that there is no conflict of interest.

Classification

Clinical classification (the most common approaches, for example: by etiology, by stage, etc.).

Clinical forms
- Diffuse form. Generalized skin lesions of the extremities, face and trunk during the year; Raynaud's syndrome appears simultaneously or after skin lesions. Early development of visceral pathology (interstitial damage to the lungs, damage to the gastrointestinal tract, myocardium, kidneys). Significant reduction of capillaries of the nail bed with the formation of vascular areas (according to capillaroscopy of the nail bed). Detection of antibodies to topoisomerase-1 (Scl-70).
- Limited form. Long period of isolated Raynaud's phenomenon. Skin involvement is limited to the face and hands/feet. Late development of pulmonary hypertension, gastrointestinal lesions, telangiectasia, calcification (CREST syndrome). Detection of anticentromere antibodies. Dilatation of nail bed capillaries without obvious avascular areas.
- Scleroderma without scleroderma. Scleroderma without scleroderma (sclerodermasines scleroderma) is characterized by: no skin thickening, Raynaud's phenomenon, signs of pulmonary fibrosis, acute scleroderma kidney, damage to the heart and gastrointestinal tract, detection of antinuclear antibodies (Scl-70, ACA, nucleolar).
- Cross shapes. Crossover forms (overlap-syndromes) are characterized by a combination of clinical signs of SSc and one or more systemic connective tissue diseases.
- Juvenile scleroderma. The onset of the disease is before 16 years of age. Skin lesions are often of the type of focal or linear (hemiform) scleroderma. Tendency to form contractures. Abnormalities in the development of the limbs are possible. Moderate visceral pathology (detected mainly by instrumental examination).
- Prescleroderma. There is also the so-called prescleroderma, which includes patients with isolated Raynaud's phenomenon in combination with capillaroscopic changes or immunological disorders characteristic of SSc.
Flow options

1. An acute, rapidly progressive course is characterized by the development of generalized fibrosis of the skin (diffuse form) and internal organs (heart, lungs, kidneys) in the first 2 years from the onset of the disease; previously it often ended in death; modern adequate therapy has improved the prognosis of this category of patients.
2. In a subacute, moderately progressive course, clinically and laboratory tests indicate a predominance of signs of immune inflammation (dense swelling of the skin, arthritis, myositis); overlap syndromes are not uncommon.
3. The chronic, slowly progressive course is characterized by a predominance of vascular pathology: at the onset of the disease - long-term Raynaud's syndrome with the gradual development of moderate skin changes (limited form), an increase in vascular ischemic disorders, visceral pathology (damage to the gastrointestinal tract, pulmonary hypertension). The prognostic differences in the course options are illustrated by 5- and 10-year survival rates, which in acute cases are 4 and 0%, in subacute cases 75 and 61%, and in chronic cases 88 and 84%, respectively. Currently, with more early diagnosis and modern therapy, the prognosis of patients with SSc has improved, but differences in the onset, main clinical appearances and evolution remain.

Stages of SSD:
- initial, when 1-3 localizations of the disease are identified.
- stage of generalization, reflecting the systemic, polysyndromic nature of the process.
- late (terminal), when there is already failure of one or more organs (heart, lungs, kidneys).
All 3 parameters of the classification of SSc are recommended to be used when making a diagnosis, determining the prognosis and choosing adequate therapy.

Diagnostics

Diagnostic criteria:
To verify the diagnosis of SSc, the criteria of the American Rheumatological Association are used.
A. “Big” criterion. Proximal scleroderma: symmetrical thickening, induration, and induration of the skin of the fingers and proximal to the metacarpophalangeal and metatarsophalangeal joints. Changes may affect the face, neck, torso ( rib cage and stomach).
B. “Small” criteria.
1. Sclerodactyly: the above skin changes limited to the fingers.
2. Digital scars - areas of skin retraction on the fingertips
or loss of pad substance.
3. Bilateral basal pulmonary fibrosis: bilateral reticular or linear nodular shadows, most pronounced in the basal areas of the lungs with standard x-ray examination; There may be “honeycomb lung” type manifestations. These changes should not be associated with primary lung disease.
The criteria allow us to exclude patients with local forms of scleroderma, eosinophilic fasciitis and various types pseudoscleroderma. The patient must have either a major criterion or at least 2 minor criteria. Sensitivity - 97%, specificity - 98%. These criteria are suitable for identifying characteristic and quite severe SSc, but do not cover all clinical forms of the disease, including early limited, cross-sectional and visceral SSc.

Complaints: weakness, fatigue, weight loss, low-grade fever, etc. are observed at the onset of the disease (mainly in patients with the diffuse form) and present diagnostic difficulties before the appearance of characteristic skin and visceral signs of SSc.

Physical examination:
Constitutional symptoms - weakness, fatigue, weight loss, low-grade fever, etc. are observed at the onset of the disease (mainly in patients with the diffuse form) and present diagnostic difficulties before the appearance of characteristic skin and visceral signs of SSc.
Vascular damage:
- Raynaud's phenomenon is a symmetrical paroxysmal spasm of the digital arteries, cutaneous arterioles and arteriovenous shunts, induced by cold or emotional stress, is characterized by a consistent change in the color of the skin of the fingers (whitening, cyanosis, redness). Vasospasm is often accompanied by numbness of the fingers and pain. In many patients with SSc, Raynaud's attacks are prolonged due to structural changes in blood vessels and permanently reduced blood flow.
- Telangiectasias - dilated capillaries and venules with a characteristic localization on the fingers, palms and face, including the lips, are a late sign of the disease.
- Skin damage:
Skin thickening (scleroderma) always begins in the fingers (sclerodactyly). The severity of skin compaction is assessed by palpation using a 4-point system: 0 - no compaction; 1 - slight compaction; 2 - moderate compaction; 3 - pronounced compaction (impossible to fold). To objectify skin lesions, a skin score is determined, which represents the sum of the scores for the severity of skin compaction in 17 anatomical areas: on the face, chest, abdomen and on symmetrical parts of the limbs - fingers, hands, forearms, shoulders, thighs, legs and feet. In SSD, there are stages of skin damage: edema, induration, atrophy.
The severity of skin thickening varies between individual patients and reaches a maximum in the first 3-4 years of the disease. Skin count correlates with visceral pathology and is one of the predictors of unfavorable outcome of SSc.
· The “pouch-purse” symptom is a decrease in the oral aperture, thinning of the red border of the lips, around which radial folds form.
· Digital ulcers - a characteristic sign of SSc (included in the classification criteria), develops on the distal phalanges of the fingers; can be sharply painful, characterized by torpidity to treatment and recurrent course.
Ulcerative skin lesions are also observed in areas exposed to mechanical stress, - above the elbows and knee joints, in the ankles and heels.
· Dry gangrene - necrosis of the skin and subcutaneous soft tissues begins with the distal phalanges of the fingers and can spread to the middle phalanges, followed by demarcation and self-amputation.
· Hyperpigmentation - limited or diffuse, with areas of hypo- or depigmentation (“salt and pepper”).
- Digital scars are pinpoint areas of skin atrophy of the distal phalanges of the fingers (“rat bite”).
- Due to atrophy of hair follicles, sweat and sebaceous glands, the skin in areas of compaction becomes dry and rough, and hair disappears.
- Calcifications - small sizes subcutaneous deposits of calcium salts, usually appear on the fingers and in areas frequently exposed to injury. Calcifications can open with the release of a curdled mass.
- Damage to mucous membranes, characteristic feature SSD is thickening and shortening of the frenulum of the tongue.
Damage to joints and bones
- Polyarthralgia and morning stiffness are common manifestations of SSc, especially in the early stages of the disease.
- Arthritis is not typical for SSc, but at the same time, erosive arthropathy is detected in 20% of patients.
- Acroosteolysis - resorption of the terminal sections of the distal phalanges of the hands due to prolonged ischemia, manifested by shortening and deformation of the fingers. - In some cases, resorption of the distal radius and processes of the mandible is observed.
- A symptom of tendon friction is crepitus, determined by palpation in patients with a diffuse form of SSD with active flexion and extension movements of the fingers and hands; is a predictor of subsequent diffuse skin lesions.
- Flexion contractures, mainly of the joints of the hands, are the result of local thickening of the skin involving the tendons and their sheaths. - Occur more often in patients with a diffuse form of SSD, in which contractures of large joints of the extremities can be detected. Increased contractures are associated with disease activity and progression.
Muscle damage:
- Muscle involvement is manifested by two various forms myopathies:
Non-inflammatory, non-progressive fibrous myopathy is a more common form of muscle damage in SSc, characterized by slight weakness of proximal muscle groups and a minimal increase in CPK levels.
Inflammatory myopathy - manifested by myalgia, proximal muscle weakness, a significant (2 or more times) increase in CPK, inflammatory changes in EMG and biopsy specimens.
- In the diffuse form of SSD, muscle atrophy may develop, associated with impaired mobility and contractures.
Damage to the gastrointestinal tract:
- Esophageal hypotension is the most common form of damage to the esophagus and gastrointestinal tract in general; manifested by dysphagia, a feeling of a lump behind the sternum after eating, persistent heartburn, worsening in a horizontal position.
- Stricture is a narrowing of the lumen of the lower third of the esophagus, as a result of which it becomes impossible to eat solid food. The formation of strictures leads to a significant reduction in the severity of heartburn.
- Erosion and ulcers of the esophagus appear as a result of gastroesophageal reflux, accompanied by severe heartburn and chest pain.
- Gastric hypotension - pain in the epigastrium and a quickly onset feeling of satiety due to impaired evacuation of stomach contents.
- Gastric bleeding is a rare but serious complication that can occur with multiple telangiectasias of the gastric mucosa.
- Malabsorption syndrome - manifested by flatulence, steatorrhea, alternating constipation and diarrhea, weight loss.
- Intestinal pseudo-obstruction is a rare complication, manifested by the symptoms of paralytic ileus.
- Colon damage leads to constipation (less than 2 spontaneous bowel movements per week) and fecal incontinence; occurs with the same frequency as esophageal hypotension.
Lung damage:
Involvement of the lungs is observed in 70% of patients with SSc and is second in frequency only to damage to the esophagus. The main clinical and morphological types of lung damage in SSc are interstitial lung disease (pulmonary fibrosis) and pulmonary hypertension.
- Interstitial lung disease (ILD) develops mainly in the first 5 years of the disease and is more pronounced in the diffuse form of SSc. Clinical manifestations ILDs are nonspecific and include shortness of breath, dry cough, and weakness. The characteristic auscultatory sign of ILD is bilateral basal crepitus, often described as “cellophane crackling.” Risk factors for ILD are: diffuse form of SSc, decreased forced vital capacity at the onset of the disease, and the presence of Scl-70 AT. The progression of pulmonary fibrosis is indicated by a decrease in the forced vital capacity of the lungs and the diffusion capacity of CO over the previous 6-12 months; propagation of type changes frosted glass and a picture of a “honeycomb” lung on HRCT; an increase in the number of neutrophils and/or eosinophils in the lavage fluid. The clinical equivalent of progressive ILD is increased dyspnea.
Pulmonary hypertension is defined as an increase in pulmonary artery pressure above 25 mmHg at rest or 30 mmHg at physical activity. Pulmonary hypertension can be primary (isolated) - due to vascular damage or secondary - as a result of damage to the interstitial tissue of the lungs; it develops on average in 10% of patients, mainly in the late stages of the disease and with a limited form of SSc. The main clinical sign of pulmonary hypertension, as with ILD, is shortness of breath, which tends to progress rapidly over several months. An auscultatory sign of pulmonary hypertension is the accent and bifurcation of the second tone on the pulmonary artery and tricuspid valve, especially obvious at the height of inspiration. A predictor of pulmonary hypertension is an isolated decrease in the diffusion capacity of CO (<60% от должной величины).
Heart damage:
Symptoms of heart damage are a feeling of discomfort or prolonged dull pain in the precordial region, palpitations and arrhythmias, shortness of breath at rest or during exercise. Chest pain can also be caused by damage to the esophagus or the muscles of the chest wall. In many cases, cardiac damage in SSc is asymptomatic and is detected during instrumental examination.
Fibrosis of the ventricular myocardium is a characteristic pathomorphological sign of scleroderma heart disease and is the cause of systolic and diastolic dysfunction of the left ventricle with a decrease in ejection fraction.
Arrhythmias and cardiac conduction disorders are detected in 70% of patients and are very diverse. Frequent rhythm disturbances are supraventricular tachycardia, polytopic and group extrasystoles. The severity of arrhythmias correlates with the severity of cardiac damage and significantly worsens the prognosis, especially in patients with simultaneous involvement of skeletal muscles, and can cause sudden death. Cardiac conduction disorders are manifested mainly by prolongation of the P-Q interval, intraventricular conduction defects, and left anterior bundle branch block. Signs of myocarditis are observed almost exclusively in patients with symptoms of polymyositis; myocarditis is associated with poor patient survival. Damage to the pericardium in the form of adhesive and, less commonly, exudative pericarditis is detected in 70-80% of patients during a special study and is often asymptomatic. In rare cases, there is significant pericardial effusion, which can lead to cardiac tamponade. Heart failure develops rarely, but when it does occur, it is refractory to therapy and has a poor prognosis.
Changes in the heart can develop secondarily, due to pathology of the lungs (pulmonary hypertension) or kidneys (scleroderma renal crisis).
Kidney damage:
In clinical studies, on average, 50% of patients show certain signs of renal dysfunction: proteinuria, hematuria, a slight increase in blood creatinine levels, arterial hypertension. It should be borne in mind that these changes can be caused by other reasons, such as heart failure, pulmonary hypertension, nephrotoxic effects of drugs, etc.
- Severe kidney damage - scleroderma renal crisis, develops in 5-10% of patients, mainly in patients with a diffuse form of SSc. Characteristic manifestations of scleroderma renal crisis are: acutely developed and rapidly progressive renal failure, usually in the absence of previous kidney disease; malignant arterial hypertension associated with high renin levels; normal urinary sediment or minor changes (microscopic hematuria and proteinuria). Proteinuria can be detected long before the development of a renal crisis and intensifies with the development of this complication, but is usually not significant.
- Changes associated with renal vascular damage and arterial hypertension, including microangiopathic (non-immune) hemolytic anemia, thrombocytopenia, hypertensive encephalopathy and retinopathy.
A feature of scleroderma renal crisis is its sudden onset, without previous warning signs. In approximately 10% of patients, no increase in blood pressure is observed - the so-called normotensive scleroderma renal crisis. Without treatment (usually within 1-2 months), end-stage renal failure develops. Risk factors for scleroderma renal crisis are the diffuse form, taking high doses of GC (more than 15 mg/day), and AT to RNA polymerase III.
Damage to the nervous system: Polyneuritic syndrome, which may be associated with Raynaud's phenomenon or primary damage to peripheral nerves. Trigeminal sensory neuropathy occurs in 10% of patients and is manifested by unilateral or bilateral facial numbness, sometimes in combination with pain or paresthesia. Patients with the diffuse form of SSc often develop carpal tunnel syndrome. Other manifestations of SSc include Sjogren's syndrome (20%), damage to the thyroid gland (Hashimoto's thyroiditis, de Quervain's thyroiditis), leading to the development of hypothyroidism; primary biliary cirrhosis in patients with a limited form of SSc.

Laboratory research:

- General blood analysis: hypochromic anemia, moderate increase in ESR (in approximately half of the patients), decrease in hematocrit; an increase in ESR does not correlate with the clinical activity of SSc and may be associated with a latent infection (usually bronchopulmonary).
- General urine analysis: hyposthenuria, microhematuria, proteinuria, cylindruria, leukocyturia. The severity of urinary syndrome varies depending on the clinical form of kidney damage.
- Blood chemistry: no characteristic changes.
- IMMUNOLOGICAL STUDIES. ANF ​​is detected in 95% of patients with SSc, usually in a moderate titer. The determination of so-called scleroderma-specific autoantibodies is important.
- ATScl-70, or AT to topoisomer-ze-1, is more often detected in diffuse than in limited form of SSc. The presence of AT in combination with carriage of - - - HLA-DR3/DRw52 increases the risk of developing pulmonary fibrosis in SSc by 17 times. AT titer correlates with the extent of skin lesions and disease activity. Detection of ATScl-70 in patients with isolated Raynaud's phenomenon is associated with the subsequent development of the clinical picture of SSc.
- Anticentromere AT (ACA) are found in 20% of patients with SSc, mainly in the limited form. Also detected in 12% of patients with primary biliary cirrhosis (half of whom have signs of SSc), very rarely in chronic active hepatitis and primary pulmonary hypertension. - ACAs are considered as a marker of the development of SSD in isolated Raynaud's phenomenon.
- AT to RNA polymerase III are detected in 20-25% of patients, mainly with a diffuse form and kidney damage, and are associated with a poor prognosis.
In addition to the listed autoantibodies, other antinucleolar antibodies are detected with less frequency in SSc, including:
- AT to Pm-Scl are detected in approximately 3-5% of patients with SSc in combination with polymyositis (SSD-po-lymyositis cross syndrome);
- AT to iZ-RNP are detected in 7% of patients and are associated with a diffuse form of the disease, primary pulmonary hypertension, damage to skeletal muscles and early onset of the disease;
- AT to U1-RNP are detected on average in 6% of patients with SSc and are associated with SSc-SLE crossover syndrome, arthritis, isolated pulmonary hypertension and early onset of the disease.
RF is detected in 45% of patients, mainly when combined with Sjögren's syndrome.

Instrumental studies
Capillaroscopy of the nail bed reveals changes characteristic of SSc (dilatation and reduction of capillaries) at an early stage of the disease, and has high sensitivity and specificity.
Since SSc is characterized by damage to many visceral systems, which can be asymptomatic (especially at an early stage of the disease), for their timely detection and assessment of the extent of damage, it is necessary to conduct appropriate instrumental studies, the nature and frequency of which are determined by the clinical form, course of the disease and the need to monitor the effectiveness of therapy (Table 1).
Table 1. Special studies of internal organs in systemic scleroderma.

Organ being examined	Type of lesion	Diagnostic
Esophagus	Hypotension	Manometry
	Reflux esophagitis	Endoscopy/pH-metry
	Stricture	X-ray/endoscopy
Stomach	Paresis	Scintigraphy
	NSAID-induced ulcer	Endoscopy
Small intestine	Hypotension	X-ray contrast study
	Excessive growth of microflora	Hydrogen breath test
	Pseudo-obstruction, NSAID-induced ulcer, pneumatosis	Survey radiography
Colon	Hypotony, pseudodiverticula	Barium enema
	Pseudo-obstruction	Survey radiography
Anorectal department	Sphincter lesion	Manometry
Lungs	Interstitial fibrosis	X-ray, high-resolution computed tomography, pulmonary function, bronchoalveolar lavage, scintigraphy, thoracoscopic lung biopsy
	Pulmonary hypertension	Doppler-ECHO-CG, ECG, radiography
Heart	Arrhythmias	Choletr-ECG monitoring
	Focal myocardial fibrosis	ECG, ECHO-CG, scintigraphy
	Myocardial dysfunction	Doppler-ECHO-KG
	Perikadite	Echo-CG, radiography
Kidneys	Scleroderma renal crisis	Blood pressure monitoring, creatinine content, reninia in the blood, CBC (hemoglobin, schistocytes, platelets), ophthalmoscopy, kidney biopsy

Indications for consultation with specialists
- If there are signs of kidney damage, the patient should be referred to a nephrologist for a kidney biopsy.
- Consultation with a neurologist is indicated in case of development of neurological symptoms to clarify the nature and extent of damage to the nervous system and select symptomatic therapy.
Patients with visual impairments need to consult an ophthalmologist to clarify the genesis of these disorders (retinal vascular pathology within the framework of SSD, manifestations of side effects of GCs or Sjögren's syndrome).List of diagnostic measures:
A) Main:

1. Biochemical blood test (creatinine, K+, Na+, ALT, AST, total and direct bilirubin, lipid spectrum, glucose)

B) Additional:

1. Coagulogram
2. Daily proteinuria
3. ECHO-KG
4. Doppler ultrasound of the vessels of the upper and lower extremities, kidney vessels
5. Ultrasound of obstructive kidneys, kidneys
6. FGDS, pH-metry, esophageal manometry
7. X-ray of the esophagus, stomach, duodenum with barium contrast
8. CT lungs
9. Spirography
10. Biopsy of myocutaneous flap, kidney

Consultation with a neurologist, nephrologist, ophthalmologist, gynecologist.

Differential diagnosis

Differential diagnosis:
Differential diagnosis of SSc is carried out with other diseases of the scleroderma group, most of which do not have Raynaud's phenomenon or damage to internal organs.
· Diffuse eosinophilic fasciitis - skin induration begins with the forearms and/or lower legs with possible spread to the proximal limbs and trunk; fingers and face remain intact. It is characterized by “orange peel” skin lesions, flexion contractures, eosinophilia, hypergammaglobulinemia and increased ESR. In approximately 1/3 of cases, there is a connection with previous excessive physical activity or injury. The development of aplastic anemia is possible.
· Buschke's sclerodrema - severe induration in the face, neck, and shoulder girdle. Often associated with a previous upper respiratory tract infection.
· Limited scleroderma - focal (plaque) and linear (“saber strike”, hemiform) damage to the skin and underlying tissues.
· Multifocal fibrosis. Main localizations: retroperitoneal, intraperitoneal and mediastinal fibrosis; less often - foci of fibrosis in the lungs, orbit (orbital pseudotumor), thyroid gland (Riedel's thyroiditis), etc. Minor forms also include Dupuytren's contractures and keloids. Often a combination of 2-3 or more localizations of the process.
· Tumor-associated (paraneoplastic) scleroderma is a variant of paraneoplastic syndrome, which is manifested by the predominant development of fibrosis in periarticular tissues, contractures, or a type of SSD that is torpid to therapy with a predominance of peripheral symptoms.
· Pseudoscleroderma - skin changes observed with congenital or acquired metabolic disorders: porphyria, phenylketonuria, amyloidosis, Werner syndrome, Rothmund syndrome; diabetic pseudoscleroderma; scleromyxedema, etc.
· Werner's syndrome (adult progeria, lamin gene defect) is manifested by scleroderma-like changes in the skin (especially extremities) and skeletal muscles, the development of cataracts, hypogenitalism, premature arteriosclerosis, insular failure, and an increased risk of developing osteosarcoma; observed more often in men aged 20-30 years. Rothmund-Thomson syndrome (atrophic poikiloderma). Clinically: poikiloderma of the face and limbs, bilateral cataracts, hair dystrophy (nails and teeth), hypogonadism, endochondral ossification disorders, arteriosclerosis and dwarfism, skin hyperpigmentation, telangiectasia, atrophic dermatosis, anemia, increased risk of osteogenic sarcoma . Synonyms: cataract, Rothmund's dystrophy.
. Raynaud's phenomenon is one of the main symptoms that determine the need for differential diagnosis of SSc with other systemic connective tissue diseases: mixed connective tissue disease, antisynthetase syndrome within poly/dermatomyositis.

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Treatment

Treatment goals:
- prevention and treatment of vascular complications
- suppression of fibrosis progression
- prevention and treatment of damage to internal organs.
Treatment tactics:
. Early diagnosis and adequate therapy largely determine the effectiveness of treatment and prognosis, especially in rapidly progressive diffuse SSc. Treatment should be individualized as much as possible depending on the clinical manifestations and disease activity.

Non-drug treatment:
Avoid psycho-emotional stress, prolonged exposure to cold and vibration, and reduce exposure to the sun. To reduce the frequency and intensity of vasospasm attacks, it is recommended to wear warm clothing, including heat-preserving underwear, hats, woolen socks and mittens instead of gloves. For the same purpose, recommend that the patient stop smoking, stop drinking coffee and caffeine-containing drinks, and avoid taking sympathomimetics (ephedrine, amphetamine, ergotamine), beta-blockers.

Drug treatment:
The main directions of drug treatment are vascular, anti-inflammatory and antifibrotic therapy, as well as treatment of visceral manifestations of SSc.
1. Vascular therapy is aimed primarily at treating Raynaud's phenomenon. In addition, the following drugs are used for SSD:
Sildenafil, a phosphodiesterase inhibitor, at a dose of 50 mg per day promotes the healing of digital ulcers in patients with SSc who have not had an effect when using calcium channel blockers.
Bosentan is a non-selective endothelin-1 receptor antagonist used to treat pulmonary hypertension; at a dose of 125 mg/day reduces the likelihood of new digital ulcers by 2 times.
2. Anti-inflammatory and cytotoxic drugs are used at the early (inflammatory) stage of SSc and the rapidly progressive course of the disease:
· NSAIDs in standard therapeutic doses are indicated for the treatment of muscular and joint manifestations of SSc, persistent low-grade fever (high fever is not typical for SSD).
· Glucocorticoids are indicated for progressive diffuse skin lesions and obvious clinical signs of inflammatory activity (myositis, alveolitis, serositis, refractory arthritis, tenosynovitis) in small (no more than 15-20 mg/day) doses. Taking higher doses increases the risk of developing normotensive scleroderma renal crisis.
· Cyclophosphamide in combination with GC is used to treat ILD (see below Lung damage).
· Methotrexate is able to reduce the prevalence and severity of skin thickening, but does not affect visceral pathology. The indication for methotrexate is the combination of SSc with RA or polymyositis.
· Cyclosporine has a positive effect on the dynamics of skin changes, however, nephrotoxicity and the high likelihood of developing acute renal crisis during treatment seriously limits the use of the drug in SSc

1. Antifibrotic therapy is indicated at an early stage (during the first 5 years of the disease) or when the severity and prevalence of skin thickening increases in patients with diffuse systemic scleroderma. D-penicillamine is the main drug that suppresses the development of fibrosis. The effective dose of the drug is 250-500 mg/day.

TREATMENT OF VISCERAL MANIFESTATIONS OF SSc
1. Damage to the esophagus and stomach. Treatment is aimed at reducing symptoms associated with gastroesophageal reflux and impaired peristalsis. For this purpose, patients are recommended to eat frequent small meals, not lie down for 3 hours after eating, sleep on a bed with the head end elevated, and give up smoking and alcohol.
2. It should be borne in mind that calcium channel blockers can increase the manifestations of reflux esophagitis. Drug therapy includes the prescription of antisecretory drugs and prokinetics.
Omeprazole, a proton pump inhibitor, is the most effective antisecretory drug for the treatment of gastrointestinal reflux.
In most cases, a single dose of 20 mg stops the manifestations of esophagitis within 24 hours; if necessary, the dose of the drug is increased to 40 mg per day.
Famotidine is a histamine H2 receptor blocker, reduces the manifestations of gastroesophageal reflux
Ranitidine is a blocker of histamine H2 receptors, reduces the manifestations of gastroesophageal reflux, but is inferior in effectiveness to proton pump inhibitors.
Metoclopramide is a prokinetic agent; long-term administration of metoclopramide is unacceptable, since the development of neurological disorders (parkinsonism) caused by the effect on dopaminergic structures of the brain is possible.
Erythromycin also has a prokinetic effect, the use of which in a dose of 100-150 mg 2 times a day or azithromycin 400 mg 1 time a day for 4 weeks reduces nausea, vomiting and attacks of pain in the epigastric region. A combination of prokinetics and antisecretory drugs improves the condition of patients with reflux esophagitis.
Severe esophageal stricture is an indication for endoscopic dilatation. If the evacuation function of the stomach is impaired, it is recommended to take semi-liquid food.
2. Intestinal damage. Disturbances in intestinal motility contribute to excessive growth of microflora and the development of malabsorption syndrome, for the treatment of which the following antibacterial drugs are used: tetracycline - 250 mg per day, amoxicillin + clavulanic acid 500 mg per day, ciprofloxacin 250 mg per day, cephalosporins. Antibiotics should be alternated to prevent the development of microflora resistance. The duration of taking antibiotics depends on the severity of diarrhea and steatorrhea (usually 7 - 10 days per month). If diarrhea appears while taking antibiotics, metronidazole is additionally prescribed (7-10 days) to suppress the anaerobic flora. Prescribing prokinetics (metoclopramide) is not advisable, since they do not have the expected effect. Improvement in peristalsis in intestinal pseudo-obstruction is observed with the use of a long-acting somatostatin analogue, octreotide 50 mg per day subcutaneously.
3. Lung damage.
· Interstitial lung disease. Combination therapy with GC and cyclophosphamide is most effective. The effectiveness of D-penicillamine has not been proven. Prednisolone is prescribed at a dose of 20-30 mg per day for 1 month with a gradual reduction to a maintenance dose of 10-15 mg per day; Large doses of GC should be avoided due to the risk of scleroderma renal crisis. Cyclophosphamide is prescribed intravenously in doses of 500 mg/m2 - 750 mg/m2 per month or orally in doses of 1 mg/kg/day - 2 mg/kg/day, depending on the effectiveness and tolerability of the drug. IV administration is considered preferable, as there is a lower incidence of side effects (including hemorrhagic cystitis) compared to oral administration. Pulse therapy with cyclophosphamide is continued at this dose for at least 6 months (in the absence of side effects). If the dynamics of pulmonary function tests and radiological changes are positive, the interval between pulse therapy with cyclophosphamide is increased to 2 months, and if the positive dynamics are maintained - to 3 months. Pulse therapy with cyclophosphamide must be continued for at least 2 years. The effectiveness of therapy is evidenced by the stabilization of the forced vital capacity of the lungs, since improvement in the function of external respiration at the stage of reticular changes in the lungs is unlikely.
· MMF can be prescribed to patients with SSc and IPD in case of intolerance or ineffectiveness (including secondary) of CP in combination with GC. MMF is prescribed at a dose of 1000 mg/day. (in two doses), increasing it to 2000 mg/day. (in two doses) if well tolerated. The duration of the MMF course must be at least 6 months.
· In case of ineffectiveness of drug therapy and progressive respiratory failure, transplantation of one lung is indicated (efficacy is comparable to transplantation of both lungs).
. Pulmonary hypertension. Treatment of pulmonary hypertension should begin as early as possible (at the latent stage) due to the high mortality of patients (3-year survival rate less than 50%). To treat pulmonary hypertension, vasodilators (calcium channel blockers, synthetic prostacyclin analogues or endothelin receptor antagonists) and anticoagulants are used.
- Nifedipine. Before prescribing long-term therapy for pulmonary hypertension with nifedipine, it is necessary to carry out catheterization of the right ventricle with a test sample (measurement of pressure in the pulmonary artery before and after a single dose of nifedipine), since nifedipine causes a decrease in pressure in the pulmonary artery in only 25% of patients and does not affect the resistance of the pulmonary vessels in the remaining patients. Calcium channel blockers have no effect on patient survival.
- Warfarin. Long-term use of the drug improves survival of patients with primary pulmonary hypertension. The daily dose is determined by the MHO value, which should be kept within 2-3.
- Iloprost and epoprostenol are synthetic analogues of prostacyclin, used for infusion therapy, and effectively reduce pressure in the pulmonary artery. Prostacyclin preparations have also been developed for subcutaneous and inhalation administration.
- Kidney damage. Adequate blood pressure control is central to the treatment of scleroderma renal crisis. Aggressive treatment of arterial hypertension can stabilize or even improve renal function if therapy is initiated promptly, before irreversible changes in the renal vessels develop. The drugs of choice are angiotensin-converting enzyme inhibitors (lisinopril, captopril, enalapril, etc.). The drug dose is selected in such a way as to maintain diastolic pressure at the level of 85-90 mm Hg. Angiotensin-converting enzyme (ACE) inhibitors may also improve the outcome of normotensive scleroderma renal crisis. It is recommended to start treatment with captopril, prescribing 6.25-12.5 mg every 8 hours, and gradually increase the dose to the maximum (50 mg 3 times a day). At the beginning of treatment, a daily increase in the dose of ACEI should reduce the level of systolic blood pressure by 10-20 mmHg, since too rapid a decrease in blood pressure (as well as hypovolemia) can lead to an undesirable decrease in renal perfusion (worsening ischemia). When blood pressure stabilizes, you can switch to taking a longer-acting ACE inhibitor. Captopril is not discontinued even if kidney function continues to deteriorate. If the maximum dose of captopril does not normalize blood pressure within 72 hours, add calcium channel blockers, nitrates (especially if congestion occurs in the lungs) or other vasodilating agents. If the oliguric stage of acute renal failure persists, the issue of hemodialysis is considered. Recovery or improvement of kidney function after SKC occurs slowly over 2 years. If after this period the need for hemodialysis continues, the question should be raised about
- kidney transplantation.
· Heart damage. Manifestations of primary scleroderma heart disease (i.e. lesions that are not a consequence of systemic or pulmonary hypertension) can be pericarditis, arrhythmia, myocarditis, myocardial fibrosis. Treatment of pericarditis is carried out in clinically manifest forms and includes the use of NSAIDs and GK (15 - 30 mg/day). If the effusion is significant, pericardiocentesis or pericardiotomy is performed. Myocarditis is usually observed in patients with inflammatory lesions of skeletal muscles; treatment with GC often results in an increase in left ventricular ejection fraction. Rhythm disturbances usually do not require treatment. For severe arrhythmias (group and polytopic extrasystoles, ventricular tachycardia, etc.), the drug of choice is amiodarone. Taking beta-blockers can increase the manifestations of Raynaud's phenomenon.
· SSD and pregnancy. Most patients with SSc have a history of one or more pregnancies and births. The limited form and chronic course of SSc are not a contraindication for pregnancy. However, during pregnancy organ pathology may develop, which requires regular examination. Contraindications to pregnancy: diffuse form of SSD, severe dysfunction of internal organs (heart, lungs and kidneys). In cases of SSc detection during pregnancy, careful monitoring of renal and cardiac functions is necessary.
List of essential medications:
Nonsteroidal anti-inflammatory drugs
Glucocorticoids

1. Prednisolone, 5 mg, tab
2. Methylprednisolone 4 mg, 16 mg, tab.
3. Methylprednisolone 250 mg, 500 mg, vial.
4. Prednisolone, 30 mg, amp

Basic antifibrotic drugs

1. D-penicillamine (cuprenil) 250 mg, tab.

Immunosuppressive drugs

1. Cyclosporine 25 mg, 100 mg, caps
2. Cyclophosphamide 50 mg, tablets
3. Cyclophosphamide 200 mg, vial
4. Methotrexate 2.5 mg, tablet

List of additional medications:
Vascular therapy:

1. Pentoxifylline 2%, 5 ml, amp
2. Vazaprostan 20 mg/5ml

Anticoagulants:

1. Heparin 5000 IU, bottle
2. Clexane 0.4 ml, syringe
3. Fraxiparine 0.3 ml, 0.4 ml, syringe
4. Warfarin

Gastroprotectors(omeprazole)
Prokinetics(domperidone, metoclopramide)
Antihypertensive drugs(nifedipine, amlodipine, enalapril)
Antibacterial agents (macrolides, cephalosporins, combination a/b)

Patient management: patients with SSc are subject to clinical observation in order to assess the current activity of the disease, timely detection of organ pathology and, if indicated, correction of therapy. A medical examination is carried out every 3-6 months, depending on the course of the disease, the presence and severity of visceral lesions. At the same time, general and biochemical blood and urine tests are carried out. During repeated visits to the doctor, it is necessary to actively question the patient in order to assess the dynamics of Raynaud's phenomenon, increased manifestations of esophageal reflux, shortness of breath, cardiac arrhythmia, etc. When examining the patient, you should pay attention to the prevalence and severity of skin thickening, basal crepitus of the lungs, increased blood pressure, the presence of digital ulcers and edema. Pulmonary function testing and echocardiography are recommended. In patients taking warfarin, the prothrombin index and MHO should be monitored, and when treated with cyclophosphamide, general blood and urine tests should be examined every 1-3 months.

Indicators of treatment effectiveness and safety of diagnostic and treatment methods described in the protocol: Reducing the activity of the inflammatory process.

Hospitalization

Indications for hospitalization:
- Newly diagnosed SSD, especially the early stage of the diffuse form.
- Multiple recurrent ulcerative skin lesions and gangrene of the fingers and toes.
- Progressive damage to the lungs (fibrosing alveolitis, pulmonary hypertension), heart (exudative pericarditis), gastrointestinal tract (abdominal pain, pseudo-ileus, malabsorption syndrome).
- Development of scleroderma renal crisis (malignant hypertension, increased blood creatinine).

Prevention

Preventive actions: The etiology of SSc is unknown, and therefore primary prevention of the disease is not carried out. Preventive measures are reduced to preventing exacerbation of the disease and the development of side effects of drug therapy.

Information

Sources and literature

1. Minutes of meetings of the Expert Commission on Health Development of the Ministry of Health of the Republic of Kazakhstan, 2013
   1. List of used literature: 1. Rheumatic diseases. Ed. J.H. Klippela, J.H. Stone, L.J. Crofford, P.H. White, 2012 2. Rheumatology, Ed. ON THE. Shostak, 2012 3. Diagnosis and treatment in rheumatology. Problematic approach, Pyle K., Kennedy L. Translation from English. / Ed. ON THE. Shostak, 2011 4. Rheumatology: Clinical guidelines / ed. Academician RAMS E.L. Nasonova. – 2nd ed., rev. and additional - M.: GEOTAR-Media, 2010. – 752 p. 5. Smolen J.S., Landewe R., Breedveld F.C. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. AnnRheumDis, 2010; 69:964–75. 6. Diffuse connective tissue diseases: a guide for doctors / ed. prof. IN AND. Mazurova. – St. Petersburg: SpetsLit, 2009. 192 p. 7. West S.J. - Secrets of rheumatology, 2008 8. Rheumatology: national guide / ed. E.L. Nasonova, V.A. Nasonova. - M.: GEOTAR-Media, 2008 - 720 9. Federal guidelines for the use of medicines (formulary system). Issue VIII. Moscow, 2007. 10. Belousov Yu.B. - Rational pharmacotherapy of rheumatic diseases, 2005. 11. Differential diagnosis of internal diseases: algorithmic approach. P.M. Healy, E.J. Jacobson. Binom, Moscow, 2003. 12. Vasculitis. Grinshtein Yu.I., Krasnoyarsk: IPK "Platina", 2003., 224 p. 13. Systemic lupus erythematosus - Donetsk: KP Region, 2003 - 464 p.. 14. Rational pharmacotherapy of rheumatic diseases. Guide for practicing physicians. Edited by V.A. Nasonova, E.L. Nasonova. Litterra, Moscow, 2003. 15. Rheumatic diseases: nomenclature, classification, standards of diagnosis and treatment - V.N. Kovalenko, N.M. Shuba - K.: Katran Group LLC, 2002. - 214 p. 16. Vasculitis and vasculopathies. E.L. Nasonov, A.A. Baranov, N.P. Shilkina. Upper Volga, Yaroslavl, 1999. 17. Rare and atypical syndromes and diseases in the clinic of internal diseases - Ganja I.M., Decik Yu.I., Peleshchuk A.P. et al.; Ed. I. M. Gandzhi. - Kyiv: Zdorov, 1983. - 544 p.

Information

Evaluation criteria for monitoring and auditing the effectiveness of protocol implementation

Reviewer: Kushekbaeva A.E., Ph.D., Associate Professor, Department of Rheumatology, ASIUV

External review results: positive rating, recommended for use

List of protocol developers with qualification information
1. Togizbaev G.A. - Doctor of Medical Sciences, chief freelance rheumatologist of the Ministry of Health of the Republic of Kazakhstan, head of the Department of Rheumatology, AGIUV
2. Seisenbaev A.Sh. - Doctor of Medical Sciences, Professor
3. Aubakirova B.A. - chief freelance rheumatologist in Astana
4. Sarsenbayuly M.S. - chief freelance rheumatologist of the East Kazakhstan region
5. Omarbekova Zh.E. - chief freelance rheumatologist of Semey
6. Nurgalieva S.M. - chief freelance rheumatologist of the West Kazakhstan region
7. Kuanyshbaeva Z.T. - chief freelance rheumatologist of Pavlodar region

Indication of the conditions for reviewing the protocol: the presence of new diagnostic and treatment methods, deterioration of treatment results associated with the use of this protocol.

Attached files

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

3.1 Conservative treatment.

reduction of activity and suppression of disease progression;
prevention and treatment of Raynaud's syndrome and vascular complications;
prevention and treatment of visceral manifestations of the disease.
The main place in the treatment of SSc is occupied by vascular, anti-inflammatory and immunosuppressive drugs.
Taking into account international experience and in accordance with EULAR versions, recommendations are grouped by organ systems or the most severe clinical syndromes.
For Raynaud's syndrome associated with SSc, long-term drug therapy is recommended for all patients. Treatment is considered successful when the severity of vasospasm decreases and there is no emergence of new ischemic lesions.
The choice of specific therapy depends on the clinical condition and severity, which are classified according to the WHO functional scale. Functional class 1 includes asymptomatic patients or those with symptoms that minimally limit normal physical activity, and functional class 4 includes patients with the greatest limitations in physical activity that occur even at rest. In patients with functional classes I, II and III, the first-line drugs are bosentan and sildenafil. In addition to these drugs, inhaled iloprost can be used in patients with functional class III. With the development of functional class IV, combination therapy with these drugs is usually prescribed.
Recommended as first-line drugs (reduce the frequency and severity of Raynaud's syndrome attacks compared to placebo and for the treatment of Raynaud's syndrome associated with systemic scleroderma) - calcium channel blockers (calcium antagonists) of the dihydropyridine group (mainly nifedipine** orally).

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

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

Recommended for the treatment of severe Raynaud's syndrome and digital ulcers, including when calcium antagonists and prostanoids are ineffective - phosphodiesterase type 5 inhibitors sildenafil and tadalafil.
Convincing level of recommendations B/ A.
It is recommended to take drugs that suppress platelet aggregation simultaneously with vasodilators.

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

Recommended for reducing skin count - Mycophenolate Mofetil** (MMF) at a therapeutic dose of 2 g/day. .
Strength of recommendation: B/C.
Recommended for progressive diffuse skin lesions as monotherapy or in combination with the above drugs - Glucocorticoids (GC).
Comments. In addition to skin lesions, GCs are also recommended for obvious clinical signs of inflammatory activity (serositis, myositis, IPL, refractory synovitis and/or tenosynovitis) in small doses - up to 15-20 mg per day, etc.; taking GCs increases the risk of scleroderma renal crisis (SRC).
In many patients with SSc, lung damage is relatively benign, without obvious progression, so not all patients with IPD need to be treated. The choice of whom and how to treat is made taking into account the initial severity of IPD and the obvious risk of progression. Treatment is indicated for patients with shortness of breath in the first 5-7 years from the onset of the disease, if.
according to HRCT of the chest, the volume of lung damage exceeds 20% and/or;
FVC ≤ 70% and/or;
there was a decrease in FVC by ≥ 10% over the previous 3-12 months.
The effectiveness of therapy is monitored by the level of forced vital capacity, which must be determined at least once every 6 months.
Convincing level of recommendations B.
Comments. The effectiveness of therapy is indicated by stabilization or increase in FVC levels.
It is recommended to use GCs orally in doses of 10-15 mg/day for the treatment of IPL in SSc. In combination with immunosuppressants.
Convincing level of recommendations C.
A comment. There was no significant association between improvement in pulmonary function parameters and the use of high doses of GCs. It must be remembered that the administration of high doses of glucocorticoids increases the risk of scleroderma renal crisis;
Recommended as induction therapy for interstitial lung disease (ILD) in SSc - Cyclophosphamide** (CP) in combination with small doses of GC. CP is prescribed intravenously in doses of 500 mg/m2 - 750 mg/m2 per month or orally in doses of 1 mg/kg/day - 2 mg/kg/day, depending on the effectiveness and tolerability of the drug.
Strength of recommendation A.
Comments. The method of administration of CP (oral or intravenous) does not significantly affect the level of changes in pulmonary function tests and the frequency of adverse reactions. The duration of the course of CP should be at least 6 months (Conviction level of recommendations C), however, if the drug is well tolerated, the duration of therapy can be 12 months or more until the IPL stabilizes.
MMF is recommended both as induction therapy for IPL (in case of intolerance or ineffectiveness, including secondary, of cyclophosphamide in combination with GC), and as a maintenance therapy after stabilization of the pulmonary process during cyclic phosphatase therapy.
Strength of recommendation A.
Comments. MMF is prescribed at a dose of 1000 mg/day. (in two doses), increasing it to 2000-3000 mg/day. (in two doses) if well tolerated.
It is recommended that in case of ineffectiveness or intolerance of therapy with CP and/or MMF, the use of Azathioprine** (100 mg/day) or Cyclosporine A** (in doses not exceeding 2.5 mg/kg/day) for 12-18 months.
Convincing level of recommendations C.
Tactics for managing a patient with interstitial lung disease.
Treatment of PAH includes traditional therapy: diuretics, cardiac glycosides (if supraventricular arrhythmias occur).
Recommended for severe hypoxemia (saturation less than 90%) - oxygen therapy;
Anticoagulants are recommended only for thrombotic complications;
It is not recommended for PAH to prescribe beta-blockers, ACE inhibitors, angiotensin-2 receptor antagonists, ivabradine, unless taking these drugs is necessary.
In recent years, PAH-specific therapy has been introduced into practice, which is prescribed to improve exercise tolerance, slow the progression of the disease, it causes regression of changes in the pulmonary vessels, improves quality of life and survival prognosis. PAH-specific drugs promote vasodilation and decrease pulmonary artery pressure through different mechanisms.
Endothelin-1 receptor antagonists (ET-1). Bosentan** is recommended at a starting dose of 62.5 mg 2 times a day. After 4 weeks, if well tolerated, increase the dose to 125 mg 2 times a day. It is recommended to monitor transaminase and bilirubin levels monthly. Women taking bosentan require reliable contraception due to the possible teratogenic effects.
Convincing level of recommendations C.
Comments. ET-1 receptor antagonists suppress the vasoconstrictive effect of ET-1 by binding to type A and B receptors (non-selective ET-1 antagonists) or only to type A receptors (selective ET-1 antagonists). The former include bosentan and macitentan, and a representative of the selective ET-1 antagonists is ambrisentan and loprost.
Prostacyclin analogues. It is recommended from 6 to 12 inhalations of iloprost per day to maintain a stable effect. Inhaled iloprost effectively reduces pulmonary artery pressure.
Convincing level of recommendations C.
Comments. Iloprost is a chemically stable prostacyclin analogue that is available as an intravenous infusion, oral administration, and aerosol. The half-life of iloprost is 20-25 minutes, duration of action is 45-60 minutes. When using an ultrasonic nebulizer, the duration of inhalation is 5 minutes. Analogs of prostacyclin are also epoprostenol (in infusion form) and treprostenil (for intravenous and subcutaneous administration and in the form of an aerosol).
Prostacyclin receptor agonists: Selexipag 10 mg once daily is recommended. Selexipag is an oral, selective prostacyclin IP receptor agonist;
Phosphodiesterase type 5 (PDE5) inhibitors suppress the inactivation of cyclic GMP in cells. It is recommended to use Sildenafil at a dose of 20 mg x 3 times a day; if ineffective, the dose may be increased to 200 mg per day. It is recommended to take Tadalafil (selective PDE5 inhibitor) once a day (2.5-40 mg). Vardenafil (selective PDE-5 inhibitor) is recommended at a dose of 20 mg 2 times a day;
Stimulators of soluble guanylate cyclase increase the synthesis of GMP. Riociguat is recommended orally 3 times a day, 1 mg (maximum daily dose 7.5 mg).
Convincing level of recommendations C.
Comments. The combination of guanylate cyclase stimulators and PDE5 inhibitors is contraindicated due to hypotension and other serious side effects.
Scheme for determining the treatment of pulmonary arterial hypertension.
The most unfavorable prognostic manifestation of SSc is acute nephropathy (scleroderma renal crisis (SRC) or “acute scleroderma kidney”), the mortality rate of which exceeds 40-50%. The main manifestations of SKC are the sudden development of acute kidney injury and arterial hypertension, which quickly becomes malignant. In 10-20% of cases, normotensive SBS is diagnosed, which can be suspected in patients with SSc who are at risk of developing SBS. Renal function should be regularly assessed in patients with SSc. To assess renal function in patients with SSc, as in the general population, it is advisable to determine the glomerular filtration rate using the CKD-EPI calculation formula. Risk factors for SPC: diffuse form of the disease, early stage of the disease (especially 1-3 years), rapid progression of skin syndrome, rapid formation of joint contractures, male gender, old age, the presence of antibodies to ribonucleoprotease III, taking large doses of CS.
Criteria for acute kidney injury: increase in creatinine level ≥26.5 mmol/L (≥0.3 mg/dL) within 48 hours or increase in serum creatinine level ≥1.5 times the initial level, definitely or suspected to have increased within 7 days .
It is not recommended to prescribe GCs more than 15 mg per day and potentially nephrotoxic drugs (D-penicillamine**, Cyclosporine A**) to patients with risk factors for SBS due to the possibility of provoking SCS.
Convincing level of recommendations C.
Angiotensin-converting enzyme inhibitors (ACEIs) are recommended as first-line drugs in the treatment of SPC. Aggressive antihypertensive therapy may stabilize or improve renal function. It is recommended to start treatment with captopril** 12.5-25 mg with dose titration to the maximum (50 mg 3 times a day).
Convincing level of recommendations C.

CLINICAL PICTURE

The following forms of localized scleroderma are most often identified.

1. Plaque scleroderma:

■■ focal (morphea);

■■ nodular (keloid-like).

2. Linear scleroderma:

■■ stripe shape;

■■ scleroderma of the “saber blow” type.

3. Generalized (multifocal) scleroderma.

4. Deep scleroderma.

5. Pansclerotic scleroderma.

6. Bullous scleroderma.

7. Idiopathic atrophoderma Pasini - Pierini.

8. Progressive hemiatrophy of the Parry-Romberg face.

9. Lichen sclerosus.

Some patients may simultaneously experience manifestations of several forms of the disease.

Patients may complain of itching, soreness, tingling and tightness of the skin, limited movement in the joints, changes in volume and deformation of the affected areas.

	It is customary to distinguish three stages of development of scleroderma lesions: erythema/
	edema, sclerosis (hardening) and skin atrophy. However, such staging
	not observed in all patients. In typical cases, the disease begins
	with the appearance on the skin of pink, pinkish-lilac, liquid or hyperpigmented
	mented spots of a round and/or stripe shape, sometimes with obvious
	swelling. At the stage of sclerosis, pockets of compaction form in the spots
	ivory-colored leather with a smooth surface and a characteristic waxy
	visible shine. Inflammatory inflammation is often observed along the periphery of the lesions.
	corolla of lilac or pinkish-lilac color, which is an indicator
	process activity. In affected areas, the skin does not fold well,	scleroderma
	sweating is reduced or absent, sebaceous function is impaired
	glands and hair growth. Over time, skin tightness may decrease
	wander around In the atrophy stage, atrophy develops in the foci of scleroderma
	skin, telangiectasia, persistent hyper or hypopigmentation appear.
	When deep foci of scleroderma form, in addition to the skin in patho-	Localized
	with a typical clinical picture.
	logical process may involve the underlying tissues: subcutaneous cells
	bud, fascia, muscles and bones.
	Plaque scleroderma characterized by appearance on the head, trunk
	or extremities, foci of erythema and/or induration of the skin of a rounded shape

	Nodular (keloid-like) scleroderma characterized by education
	on the skin of single or multiple nodules or knots, externally resembling
	eliminating keloid scars. Lesions usually develop
	in patients who do not have a tendency to develop keloids; their appearance
	not related to previous trauma. Skin in areas of scleroderma has
	flesh-colored or pigmented; the most common location is the neck,
	torso, upper limbs.
	At linear scleroderma foci of erythema and/or adhesiveness appear on the skin
	linear rose, usually localized on one half
	body or along the neurovascular bundle. The most common lesions are
	occur on the head or limbs.
	Linear scleroderma on the face and scalp is usually severe
	looks like a dense cord of sclerotic skin, in which there is no
	Hair Growth ( saber strike form). Over time, the surface of the lesion becomes smoother
	develops, forming a retraction caused by atrophy of the skin, muscles and bone
	At generalized scleroderma there is an appearance of multiple
	large foci of erythema and/or induration of the skin, occupying several areas
	parts of the body and often merge into extensive lesions.
	For deep scleroderma characterized by the appearance of deep foci of compaction
	skin and subcutaneous tissue. The skin over the lesions is slightly pigmented
	mented or not changed.
	Pansclerotic disabling scleroderma It is the most
	a severe form of the disease in which all layers of the skin are affected
	and underlying tissues down to the bones, contractures often form
	joints with deformation of the limbs and long-term ulcers. This
	a form of scleroderma usually observed in children, progresses rapidly,
	resistant to therapy and often ends in death.
	Bullous scleroderma characterized by the appearance of scleroderma in foci
	mii of transparent blisters, often accompanied by hemorrhages.
	Idiopathic atrophoderma Pasini - Pierini many experts
	is considered a superficial variant of localized scleroderma. Kli-
	physically, it manifests itself as long-term, slightly panicky
	producing patchy lesions of brown or gray-brown color
	with a violet-lilac tint, in which there is no skin compaction.
	The lesions are most often located on the trunk and upper extremities.
	Parry-Romberg progressive facial hemiatrophy is considered one
	of the most severe and treatment-resistant forms of the disease, with
	which develops progressive retraction and deformation of the half
	persons with involvement of the skin, subcutaneous tissue in the pathological process,
	muscles and bones of the facial skeleton. These symptoms may be combined
	with other manifestations of localized scleroderma, as well as accompanying
	expect eye damage and various neurological disorders,
	including epilepsy.

For Tsumbusha's lichen sclerosus (synonyms: white spot disease, guttate scleroderma) the affected areas are represented bypearl-whitespots, papules or plaques with a shiny surface, sometimes merging into lesions with scalloped outlines and clear boundaries. An erythematous ring of pink or red-purple colors. The skin in the affected areas is often atrophied and easily forms a fold like “crumpled tissue paper.”

DIAGNOSTICS

The diagnosis is based on the history and clinical picture of the disease.

To exclude systemic scleroderma and other connective tissue diseases, consultation with a rheumatologist is necessary.

To identify concomitant diseases and contraindications to treatment, consultations are necessary:

■■ therapist (required when prescribing physiotherapy);

■■ endocrinologist (required when prescribing physiotherapy);

■■ gynecologist (required when prescribing physiotherapy);

■■ ophthalmologist (required when prescribing physiotherapy);

■■ neurologist;

■■ gastroenterologist;

■■ otorhinolaryngologist;

■■ dentist.

In the presence of flexion contractures, skeletal and cosmetic deformities,

ical defects, consultation with a surgeon is necessary to decide on surgical correction.

To clarify the activity of the pathological process, identify complications of the disease, exclude systemic scleroderma and other connective tissue diseases, as well as contraindications to treatment, laboratory and instrumental studies are necessary.

Mandatory laboratory tests:

	■■ clinical blood test;	scleroderma
	■■ clinical urine analysis;
	■■ biochemical blood test.
	Additional laboratory and instrumental studies:
	■■ histological examination of the skin (in doubtful cases);	Localized
	IgM, IgG, rheumatoid factor;
	■■ determination of antinuclear factor using the indirect method
	immunofluorescence on the continuous cell line HEp-2 (for
	exclusion of diffuse connective tissue diseases);
	■■ study of the content of IgA immunoglobulins in blood serum,

■■ study of the level of antibodies to thyroglobulin and thyroid peroxidase in the blood serum (if possible, study of the content of other antibodies: antibodies to parietal cells of the stomach, etc.);

■■ blood test for antinuclear antibodies;

■■ blood test for antibodies to topoisomerase I (anti-Scl 70) and anticentromere antibodies (to exclude systemic scleroderma);

■■ examination for borreliosis; ■■ Ultrasound of the abdominal organs, kidneys, thyroid gland; ■■ electrocardiography;

■■ X-ray of the chest, areas of skeletal deformation, and skull; ■■ electroencephalography; ■■ computed tomography;

■■ magnetic resonance imaging.

Differential diagnosis

Localized scleroderma should be differentiated from diseases such as keloid and hypertrophic scars, cicatricial alopecia, systemic scleroderma and other connective tissue diseases, diffuse eosinophilic Shulman fasciitis, Buschke scleredema, lipodermatosclerosis, scleromyxedema, necrobiosis lipoidica, panniculitis.

Less commonly, localized scleroderma is differentiated from Lyme borreliosis, scleroderma-like form of chronic graft-versus-host disease, radiation fibrosis, scleroderma-like form of basal cell skin cancer, “stiff skin” syndrome, nephrogenic systemic fibrosis, porphyria cutanea tarda, sarcoidosis, amyloidosis, Werner syndrome , phenylketonuria, connective tissue nevus, POEMS syndrome, induced scleroderma-like diseases caused by the use of drugs and nutritional supplements (bleomycin, vitamin K, L-tryptophan), the use of silicone prostheses, contact with chemicals (vinyl chloride, organic solvents), etc.

Treatment Goals

■■ stop the progression of the disease; ■■ reduce the activity of the pathological process;

■■ reduce the area of ​​skin lesions and the severity of clinical symptoms of the disease;

General notes on therapy

Treatment must be selected individually for each patient, depending on the form, stage and severity of the disease, as well as the location of the lesions.

Patients with plaque, generalized and linear scleroderma, as well as Pasini-Pierini atrophoderma and extragenital lichen sclerosus with shallow lesions of the skin and underlying tissues are recommended to undergo a course of drug treatment (including penicillin, hyaluronidase, vasoactive and external agents) or phototherapy (UVA-1 therapy or PUVA therapy).

For patients with an active, rapidly progressing course of the disease and severe inflammatory phenomena (mainly in the presence of linear or multiple foci of scleroderma), inclusion of systemic glucocorticosteroid drugs in complex treatment is indicated.

Patients with severe forms of localized scleroderma with the formation of deep lesions of the skin and underlying tissues (linear, generalized, pan-sclerotic scleroderma, Parry-Romberg progressive hemifacial atrophy) are prescribed treatment with methotrexate in the form of monotherapy or in combination with systemic glucocorticosteroid drugs.

In the presence of erosive and ulcerative defects and superficial skin atrophy, the use of tissue regeneration stimulators is indicated; in case of dry skin, the use of moisturizing and softening external agents is indicated.

Sometimes spontaneous regression of skin sclerosis or complete resolution of the lesions may be observed.

Indications for hospitalization

Generalized forms of scleroderma.

Treatment regimens

Drug therapy

Systemic therapy

1. Methotrexate (A)

For severe forms of localized scleroderma (linear, generalized, pansclerotic scleroderma, Parry-Romberg progressive hemifacial atrophy), an effective treatment method is the use of methotrexate as monotherapy or in combination with systemic glucocorticosteroid drugs.

■■ methotrexate: adults -,

Localized scleroderma

Skin diseases

■■ methotrexate: adults - 15-25 mg, children - 0.3-1 mg per kg body weight (maximum dose 25 mg) once a week subcutaneously or orally for 6-12 months or more

methylprednisolone: ​​adults - 1000 mg per day, children - 30 mg per kg body weight per day (maximum dose 500-1000 mg) - 3 consecutive daily intravenous infusions per month for 3 months (9 infusions in total) or 1 intravenous infusion once per week for 12 weeks (12 infusions in total),

■■ methotrexate: adults - 15-25 mg, children - 0.3-1 mg per kg body weight (maximum dose 25 mg) once a week subcutaneously or orally for 6-12 months or more

prednisolone 0.5-1 mg per kg body weight per day (maximum dose 60 mg) orally for 2-4 weeks, followed by gradual withdrawal.

Note. In the instructions for medical use of methotrexate, methylprednisolone and prednisolone, localized scleroderma is not included in the indications for the use of drugs.

2. Glucocorticosteroid drugs (C)

Oral use of glucocorticosteroid drugs can have a positive effect in active, rapidly progressing localized scleroderma, however, after discontinuation of the drugs, the frequency of relapses is high:

■■ prednisolone 0.3-1 mg per kg body weight orally 1 time per day for 3-12 months.

■■ betamethasone 0.2 ml/cm 2 (but not more than 1 ml) - injection into the lesion 1 time per month for 3 months.

3. Hyaluronidase (C)

■■ hyaluronidase 32-64 UE 1 time per day intramuscularly every day or every other day, for a course of 15-20 injections or 64 UE - injection into the focus of scleroderma 1 time in 3 days, for a course of 7-10 procedures.

Hyaluronidase can also be injected into lesions by ultraviolet

nophoresis or electrophoresis (D):

■■ phonophoresis of hyaluronidase - 64 UE of hyaluronidase is dissolved in 1 ml of 1% novocaine solution, applied to the lesions with a pipette and rubbed in, then covered with a contact medium (vaseline oil, vegetable

oil or gel) and sonication is carried out with an oscillation frequency of 880 kHz, an intensity of 0.5-1.2 W/cm2, an exposure of 3-10 minutes on the field using a labile method in continuous mode;

■■ electrophoresis of hyaluronidase - 64 UE of hyaluronidase is dissolved in 30 ml of distilled water, added to acidify the medium to pH 5.2 4-6 drops 0.1 N. solution of hydrochloric acid, injected into the foci of scleroderma-

mii at a current strength of no more than 0.05 mA/cm2, exposure time is 12-20 minutes. Procedures for ultraphonophoresis or electrophoresis of conductive hyaluronidase

They are given daily or every other day; 8-12 procedures are prescribed per course. It is possible to conduct 2-3 repeated courses with an interval of 3-4 months.

4. Penicillamine (C)

Several studies have shown a positive effect when treating patients with localized scleroderma with penicillamine. However, there is evidence of the absence of any improvement in the skin process when using this drug:

■■ penicillamine 125-500 mg orally daily or every other day for 6-12 months or more.

Given the fairly large number of side effects and the possibility of toxic effects even with low-dose treatment, penicillamine has been prescribed less frequently in recent years, mainly in cases of lack of effect from other therapeutic agents.

5. Penicillin (C)

In clinical practice, penicillin has been used to treat localized scleroderma for several decades, although publications on the effectiveness of its use are few:

■■ benzylpenicillin sodium salt 300 000-500,000 units 3-4 times a day or 1 million units 2 times a day intramuscularly, for a course of 15-40 million - 4 months.

Note. In the instructions for medical use of penicillin, localized scleroderma is not included in the indications for medical use of the drug.

6. Vasoactive drugs (D)

There is evidence of the effectiveness of using vasoactive drugs in the complex treatment of patients with localized scleroderma:

■■ pentoxifylline 100-200 mg orally 3 times a day or 400 mg orally 1-2 times a day for 4-6 weeks, or

■■ xanthinol nicotinate 75-150 mg orally 2-3 times daily for 4-6 weeks, or

■■ xanthinol nicotinate, solution for injection 15% (300 mg) 2 ml intramuscularly 1 time per day daily, for a course 15-20 injections.

regular courses with an interval of 3-4 months, only 2-3 courses per year.

Localized scleroderma

External therapy

1. Topical glucocorticosteroid drugs (D)

In the treatment of limited forms of localized scleroderma, the external use of glucocorticosteroids has a certain effect:

■■ mometasone furoate, cream, ointment externally 1 time per day in the form of applications or occlusive dressings, or

■■ alklometasone dipropionate, cream, ointment externally 1 time in the form of applications or occlusive dressings, or

■■ methylprednisolone aceponate, cream, ointment externally 1 time per day in the form of applications or occlusive dressings, or

■■ betamethasone, cream, ointment externally 1 time per day in the form of applications or occlusive dressings, or

■■ clobetasol propionate, cream, ointment externally 1 time per day in the form of an application -

tions or occlusive dressings.

When prescribing topical glucocorticosteroid drugs in the form of applications, the course of treatment is 4-12 weeks, when using them in the form of occlusive dressings - 2-3 weeks.

2. Topical calcineurin inhibitors (A)

A randomized placebo-controlled trial demonstrated the effectiveness of 0.1% tacrolimus ointment in localized scleroderma:

■■ tacrolimus, 0.1% ointment externally 2 times a day in the form of applications or occlusive dressings for 3 months.

Note. The instructions for medical use of tacrolimus ointment do not include localized scleroderma

V indications for use of the drug.

3. Dimethyl sulfoxide (C)

Treatment with dimethyl sulfoxide in some cases can lead to a decrease in erythema and induration of the skin in areas of scleroderma:

■■ dimethyl sulfoxide: the drug is dissolved in water, applied in the form of applications of a 25-75% aqueous solution once a day for 30 minutes. The duration of treatment is 3-4 weeks. Dimethyl sulfoxide therapy is carried out in repeated courses at intervals of 1-2 months.

4. Stimulators of tissue regeneration (D)

UVA-1 light is started with a dose of 5-20 J/cm2, subsequent single doses are increased by 5-15 J/cm2 to a maximum single dose of 20-60 J/cm2. The procedures are carried out 3-5 times a week, the course is 20-60 procedures.

2. PUVA therapy (B)

PUVA therapy, both with oral and external use of a photosensitizer, can significantly improve the condition of the skin in areas of scleroderma in patients with plaque, linear and generalized forms of the disease, as well as extragenital lichen sclerosus.

2.1. PUVA therapy with oral photosensitizer

■■ ammi major fruit furocoumarins 0.8 mg per kg body weight orally once 2 hours before irradiation with long-wave ultraviolet light (wavelength 320-400 nm)

■■ methoxalen 0.6 mg per kg body weight orally once a day 1.5-2 hours before irradiation with long-wave ultraviolet light (wavelength 320-400 nm).

Irradiation begins with a dose of 0.25-0.5 J/cm2, subsequent one-time

doses are increased every 2-3 sessions by 0.25-0.5 J/cm2 to a maximum dose of 3-6 J/cm2. The procedures are carried out 2-4 times a week, the course of treatment is 20-60 procedures.

Note. In the instructions for the medical use of ammi major fruits of furocoumarins and methoxsalen, localized scleroderma is not included in the indications for the use of drugs.

2.2. PUVA therapy with external application of a photosensitizer

■■ isopimpinellin/bergapten/xanthotoxin 0.3% alcohol solution applied externally once to the lesions per 15-30 minutes before irradiation with long-wave ultraviolet light (wavelength 320-400 nm). Irradiation begins with a dose of 0.1-0.3 J/cm2, subsequent single doses

increase every 2-3 sessions by 0.1-0.2 J/cm2 2, exposure for 5-10 minutes on the field using a labile technique in continuous or pulsed mode. The course is 10-15 daily procedures.

It is possible to conduct repeated courses of ultrasound therapy at intervals of 3-4 months.

4. Low Level Laser Therapy (C)

It is known that low-intensity laser therapy can improve blood microcirculation in the skin. Some studies have shown the effectiveness of low-intensity laser therapy in the complex treatment of limited forms of localized scleroderma:

■■ Therapy with laser radiation in the red range (wavelength 0.63-0.65 µm) is carried out using a stable remote technique using a defocused beam with a power density 3-5 mW/cm2 and exposure of 5-8 minutes on the field. During the procedure, no more than 4-5 fields are irradiated with a total duration of exposure of no more than 30 minutes;

■■ Therapy with infrared laser radiation (wavelength 0.89 µm) is carried out using a remote or contact, stable or labile technique in continuous or pulsed(80-150 Hz) mode. The effects are carried out by field: in continuous mode, the radiation power is no more than 15 mW, exposure to one field is 2-5 minutes, the duration of the procedure is no more than 30 minutes. In pulsed mode, the radiation power is 5-7 W/pulse, exposure is 1-3 minutes per field, total exposure time is no more than 10 minutes.

chickpeas No more than 4-6 fields are irradiated during the procedure.

The course of laser therapy is 10-15 daily procedures. Repeated courses are carried out at intervals of 3-4 months.

Therapeutic gymnastics and massage

		■■ deproteinized hemoderivative from calf blood, 5% ointment for external application
		2-3 times a day for 1-2 months

1. Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
2. Radboud University Medical Center, Nijmegen, The Netherlands
3. Rheumatology A Department, Cochin Hospital, Paris Descartes University, Paris, France
4. University Hospital Charité, Berlin, Germany
5. University Hospital Zurich, Zurich, Switzerland
6. University of California at Los Angeles, Los Angeles, California, USA
7. Research Laboratories and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS AOU San Martino, Genova, Italy
8. Department of Rheumatology and Immunology, Medical Center, University of Pecs, Pecs, Hungary
9. University of Belgrade, Belgrade, Serbia
10. University of Leeds, Leeds, UK
11. University College London, London, UK
12. University of Erlangen-Nuremberg, Erlangen, Germany
13. Hamburg Center for Pediatric and Adolescence Rheumatology, Hamburg, Germany
14. FESCA, London, UK
15. University of Giessen, Bad Nauheim, Germany
16. University of Florence, Florence, Italy
17. University of Cologne, Cologne, Germany
18. University of Michigan School of Medicine, Ann Arbor, Michigan, USA
19. University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
20. NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester, UK
21. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
22. University of Lübeck, Lübeck, Germany
23. Medical University of South Carolina, Charleston, South Carolina, USA
24. Ghent University Hospital, Ghent University, Ghent, Belgium
25. Basel University, Basel, Switzerland
26. FESCA Patient Research Partner, Ede, The Netherlands
27. Johns Hopkins University, Baltimore, Maryland, USA
28. Second University of Naples, Naples, Italy
29. University of Padua, Padua, Italy

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

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

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

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

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

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

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

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