Scleroderma

The reasons

Manifestations of scleroderma

Diagnostics

Scleroderma treatment

Forecast

Scleroderma is a disease of the connective tissue, the main manifestations of which are associated with impaired blood supply and compaction of organs and tissues. Women prevail among patients (the approximate ratio of women and men is 6: 1).

The reasons

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The causes of the disease are unknown. It is believed that scleroderma develops under the influence of certain external factors in people with certain genetic disorders. External factors that can provoke the development of scleroderma include

  • retroviruses (primarily cytomegaloviruses ), 
  • quartz and coal dust,
  • organic solvents
  • vinyl chloride,
  • some drugs (bleomycin and a number of other drugs used for chemotherapy).

Manifestations of scleroderma

As a systemic disease, scleroderma is characterized by a simultaneous lesion of the skin, blood vessels, the musculoskeletal system and internal organs, including the heart, lungs, kidneys and the gastrointestinal tract.

A characteristic early sign of scleroderma is Raynaud’s syndrome – transient episodes of vascular spasm of the skin of the extremities under the influence of cold or emotional stress. Raynaud syndrome is clinically manifested by clearly defined areas of discoloration of fingers. At the beginning of an attack of vascular spasm, the fingers of the hands become pale in color, which changes to a bluish-purple hue within a few minutes. After resolving the spasm and restoring blood flow, the skin becomes red and the skin becomes intensely pink in color.  

In some patients, attacks of vascular spasm are accompanied by a sensation of freezing of the hands, numbness, or a violation of sensitivity. In the reddening phase of the skin, patients may feel pain in the fingers.

Vascular spasm may also be exposed to vessels of the skin of the face and other areas. In these cases, characteristic color changes are observed in the tip of the nose, lips and auricles, above the knee joints.

The most specific symptom of scleroderma is skin lesion in the form of its thickening and thickening, which are observed in the vast majority of patients. The severity and prevalence of skin tightening vary from individual patients, but skin tightening with scleroderma always begins with the fingers of the hands, and can later extend further to the limbs and torso.

Simultaneously with the fingers of the hands, the skin of the face is often affected, as a result of which nasolabial and frontal folds are smoothed, the red border of the lips becomes thinner, around which radial wrinkles appear.

With long-term observation marked staging skin lesions: swelling, induration, thinning. Condensation of the skin tends to progress in the first 3–5 years of the disease. In the later stages of the disease, the skin becomes less dense and the seal remains only on the fingers.

Often, intense staining of the skin, limited or widespread, with areas of hypo- or depigmentation (“salt with pepper”) is a sign of scleroderma.

A characteristic sign are ulcers on the fingers, which can be sharply painful. Ulcerative lesions of the skin are observed in other areas exposed to mechanical stress: above the elbow and knee joints, in the ankles and heels.

As a result of circulatory disorders, scars appear on the fingers, dotted areas of thinning of the skin (“rat bite”). Scars on the fingers may occur after healing of ulcers. Due to the death of hair follicles, sweat and sebaceous glands, the skin in places of compaction becomes dry and rough, loses hair.

Joint pain and morning stiffness are a frequent manifestation of scleroderma, especially in the early stages of the disease.

The result of circulatory disorders is the destruction of the nail phalanges, manifested by shortening and deformation of the fingers.

Muscle damage can lead to the development of muscle weakness.

The defeat of the gastrointestinal tract develops in 90% of patients with scleroderma. The defeat of the esophagus is manifested by a violation of swallowing, persistent heartburn, which increases after eating. Damage to the stomach and duodenum is manifested by abdominal pain, flatulence. The defeat of the small intestine is more often asymptomatic, but with marked changes, the syndrome of disturbed intestinal absorption with diarrhea , flatulence and weight loss develops . The result of the defeat of the colon are constipation.    

Lung damage develops in more than 70% of patients with scleroderma and is manifested by increasing shortness of breath and persistent cough.

Other common manifestations of scleroderma include Sjogren’s syndrome (20%) and thyroid damage ( Hashimoto thyroiditis or De Kerven ‘s thyroiditis ), leading to a decrease in thyroid function.   

Diagnostics

In about half of the cases, an increase in ESR over 20 mm / h is observed. With the same frequency, signs of inflammatory activity in scleroderma are detected: an increase in the content of fibrinogen and seromucoid; less often there is an increase in C-reactive protein.  

In 10–20% of patients, anemia is detected, the cause of which may be iron deficiency and vitamin B12, kidney damage, or directly to the bone marrow. Of great importance is the identification of scleroderma-specific autoantibodies.  

Among the many instrumental methods of research, capillaroscopy of the nail bed plays an important role. Microcirculation research methods, such as laser-Doppler-flowmetry, plethysmography and others, are of secondary importance in the diagnosis of scleroderma due to the significant variability of results.

Scleroderma treatment

Therapy is always prescribed individually, depending on the form and course of the disease, the nature and extent of the lesions. Considering the progress of the disease in most cases, it is important to draw the patient’s attention to the need for constant medical observation and regular examination for early detection of signs of disease progression and possible correction of therapy.

Therapy is performed to:

  • prevention and treatment of vascular complications;
  • suppressing the progression of fibrosis of the skin and internal organs;
  • effects on immune-inflammatory mechanisms of scleroderma;
  • prevention and treatment of lesions of internal organs.

Patients should reduce the time spent in the sun, avoid prolonged exposure to cold, local vibration effects. To reduce the frequency and intensity of attacks of vascular spasm, it is recommended to wear warm clothing, including warmth-keeping underwear, hats, woolen socks and mittens (instead of gloves). With the same purpose, the patient is advised to stop smoking, to stop consuming coffee and caffeinated beverages.

The main directions of drug treatment for scleroderma are vascular, antifibrosis and immunosuppressive therapy.

Vascular therapy is carried out to reduce the frequency and intensity of episodes of Raynaud’s syndrome and improve blood flow, and includes the use of vasodilators, as well as drugs that affect blood viscosity and platelet gluing. 

The most effective vasodilators are calcium channel blockers (verapamil, gallopamil, nifedipine, amlodipine, nicardipine, isradipine, lacidipine, nimodipine, nitrendipine, riiodipine, felodipine, diltiazem, cinnarizine, flunarizin).

The drug of choice is nifedipine (synonyms: calcigard retard, cordafen, cordipin, nifedex, nifecard), the effective daily dose of which is 30–60 mg in three or four doses. Nifedipine significantly reduces the frequency and intensity, and in some cases, the duration of vascular spasm episodes.

Approximately 1/3 of patients with treatment with nifedipine develop side effects that are characteristic of most, among which the most frequent are increased heart rate, headache , dizziness, facial flushing and swelling of the legs. 

Recently, long-acting forms of nifedipine (calcigard retard, cordipin retard) have been increasingly used, which create a relatively constant concentration of the drug in the blood and thereby reduce fluctuations in blood pressure and the associated side effects.

If nifedipine is intolerant, other drugs may be prescribed. Amlodipine (amlovas, calchek, norvask, normodipine) has a prolonged effect and is administered once in a dose of 5-10 mg. The most common side effect of amlodipine is ankle swelling, which occurs in approximately 50% of patients.

Isradipine (lomir) is administered in a daily dose of 5 mg in two doses. With insufficient effect and good tolerance, the daily dose can be increased to 10 mg. The most common complications in the treatment of isradipine are headache and facial flushing.

Felodipine (auronal, plendil, felodil) in a daily dose of 10–20 mg reduces the frequency and severity of vascular spasm.

Diltiazem (altiazem PP, diazem, diltasem CP) at a therapeutic dose of 180 mg / day is less effective than nifedipine, but has better tolerability. When a higher dose is taken, ankle swelling and headache may occur.

In the presence of contraindications or intolerance to calcium channel blockers, vasodilator drugs of other groups are used. For example, alpha-adrenoreceptor blockers (dihydroergotamine, doxazosin, nicergoline, prazosin, terazosin). Good results are observed in the treatment of standardized extract of ginkgo biloba (tanakan – 40 mg tablets 3 times a day). In severe cases (for example, pulmonary hypertension, kidney crisis, gangrene), synthetic prostaglandin E1 (alprostadil) is used in a dose of 20–40 µg intravenously, within 15–20 days, or prostacyclin analogues (iloprost).

The effectiveness of the treatment of vascular manifestations of scleroderma increases with the inclusion in the therapy of drugs that improve blood turnover – anti-aggravating therapy (acetylsalicylic acid, ginkgo biloba, dipyridamole, pentoxifylline, ticlopidine) and, if necessary, anticoagulants (acenocoumarol, warfarin, heparin hep, and heparin). , ethyl biscumacetate).

The combination of vasodilators and antiplatelet agents makes it possible to prescribe the minimum effective dose of each of these drugs and thereby reduce the frequency of side effects. For this purpose, pentoxifylline is most widely used in a daily dose of 600–1200 mg. In cases of multiple and resistant to the usual treatment of ulcerative lesions, a short course (10–15 days) of therapy is recommended, preferably with low molecular weight heparin.

Antifibrous therapy is prescribed for diffuse scleroderma. D-penicillamine – the main drug that inhibits the development of fibrosis – disrupts collagen synthesis, splitting cross-links between newly synthesized molecules. 

Penicillamine (artamine, cuprenyl) affects various parts of the immune system. The effective dose of the drug is 250-500 mg / day. Penicillamine is taken exclusively on an empty stomach. With the development of side effects (discomfort in the stomach, hypersensitivity, a decrease in the level of white blood cells and / or thrombofits in the blood, autoimmune reactions, etc.), a dose reduction or drug withdrawal is necessary. The reason for the abolition of penicillamine is the excretion of protein in the urine above 2 g / day. Due to the high frequency of side effects (up to 25%), which are often dose-dependent in nature, in the process of treatment it is necessary to carefully monitor patients, do blood and urine tests every 2 weeks in the first 6 months of treatment, and later on – once a month .  

Anti-inflammatory therapy (diclofenac, ibuprofen, ketoprofen, meloxicam, nimesulide, piroxicam, tselkoksib) in standard therapeutic doses are indicated for the treatment of musculo-articular manifestations of scleroderma, persistent fever. 

Hormones (betamethasone, hydrocortisone, dexamethasone, methylprednisolone, prednisolone, triamcinolone – not more than 15–20 mg / day) are prescribed with obvious signs of inflammatory activity and in the early (edematous) stage of scleroderma, but do not affect the progression of fibrosis. Taking higher doses increases the risk of developing kidney damage.

With the defeat of the esophagus recommend frequent split meals. To eliminate impaired swallowing, prokinetics are prescribed in short courses: domperidone, meclozine, ondansetron, metoclopramide; with reflux esophagitis – proton pump inhibitors (omeprazole 20 mg / day, lansoprazole 30 mg / day, rabeprozol, etc.). With the development of a hernia of the esophageal part of the diaphragm, surgical treatment is indicated.  

With the defeat of the small intestine, antimicrobial drugs are used: erythromycin (synerit, erythromycin, eriflucid), ciprofloxacin (quintor, siflox, ciprovin, cipromed, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, luteubin, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, luteubin, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, luteubin, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, lutoxin, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, lysub, ciprofloxacin), amoxicillin (ranoxyl, flemoxin, lysub, ciprofloxacin);

Antibiotics should be replaced every 4 weeks to avoid the development of microbial resistance. Prokinetics are prescribed at an early stage.

With the defeat of the lungs prescribed low doses of prednisone and cyclophosphamide. A good effect is observed in most cases with intravenous pulse therapy with cyclophosphamide at a dose of 1 g / m2 / month in combination with prednisone at a dose of 10–20 mg per day. Pulse therapy with cyclophosphamide continues at the indicated dose for at least 6 months (in the absence of side effects). With a positive dynamics of pulmonary functional tests and radiological changes, the interval between pulse therapy with cyclophosphamide increases up to 2 months, and while maintaining positive dynamics – 3 months. Pulse therapy with cyclophosphamide must be performed for at least 2 years.

Forecast

The prognosis for scleroderma remains the most unfavorable among systemic diseases of the connective tissue and largely depends on the form and course of the disease. According to the results of 11 studies, the 5-year survival of patients with scleroderma ranges from 34 to 73% and averages 68%.

The factors of unfavorable prognosis are:

  • common form;
  • age of onset of the disease is over 45;
  • male;
  • pulmonary fibrosis, pulmonary hypertension, arrhythmia and kidney damage in the first 3 years of the disease;  
  • anemia, high ESR, urinary protein excretion at the onset of the disease.

All patients with scleroderma are subject to follow-up. Medical examination is carried out every 3-6 months depending on the course of the disease, the presence and severity of lesions of the internal organs. At the same time, general and biochemical blood and urine tests are performed. The study of respiratory function and echocardiography is recommended.

In patients taking warfarin, the prothrombin index and the international normalized ratio should be monitored, and for treatment with cyclophosphamide, general blood and urine tests should be examined once every 1-3 months.

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