Systemic diseases are a group of autoimmune disorders that affect not specific organs, but entire systems and tissues. As a rule, connective tissue is involved in this pathological process. Therapy for this group of diseases has not been developed to date. These diseases are a complex immunological problem.

Today they often talk about the formation of new infections that pose a threat to all of humanity. First of all, these are AIDS, bird flu, SARS and other viral diseases. It's no secret that most dangerous bacteria and viruses were defeated primarily due to one's own immune system, or rather its stimulation (vaccination).

The mechanism of formation of these processes has not yet been identified to this day. Doctors cannot understand what is causing the negative reaction of the immune system to tissue. Stress, injury, various infectious diseases, hypothermia, etc. can trigger a malfunction in the human body.

The diagnosis and treatment of systemic diseases is primarily carried out by doctors such as an immunologist, therapist, rheumatologist and other specialists.

Systemic diseases include:

systemic scleroderma;

relapsing polychondritis;

idiopathic dermatomyositis;

systemic lupus erythematosus;

polymyalgia rheumatica;

recurrent panniculitis;

diffuse fasciitis;

Behçet's disease;

mixed connective tissue disease;

systemic vasculitis.

All of these diseases have a lot in common. Any connective tissue disease has common symptoms and similar pathogenesis. Moreover, looking at the photo, it is difficult to distinguish patients with one diagnosis from patients with another disease from the same group.

What is connective tissue?

In order to understand the seriousness of diseases, you first need to consider what connective tissue is.

For those who do not fully know, connective tissue is all the tissues of the body that are responsible for the functions of a certain body system or one of the organs. Moreover, its supporting role is difficult to overestimate. It protects the human body from damage and holds it in the required position, which provides a framework for the entire body. Connective tissue consists of all the coverings of organs, body fluids and the bone skeleton. These tissues can account for 60 to 90% of the total weight of the organs, so most often connective tissue disease affects most of the body, although in some cases it acts locally, affecting only one organ.

What factors affect the development of systemic diseases

All this directly depends on how the disease spreads. In this regard, they are classified into systemic or undifferentiated disease. The most important influencing factor on the development of both types of disease is genetic predisposition. This is actually why they got their name – autoimmune connective tissue diseases. However, for the development of any autoimmune disease, one factor is not enough.

The human body exposed to them has additional effects:

various infections that disrupt the normal immune process;

increased insolation;

hormonal imbalances that appear during pregnancy or menopause;

intolerance to certain medications;

influence on the body of various toxic substances and radiation;

temperature regime;

photo irradiation and much more.

During the development of any of the diseases in this group, there is a strong disruption of certain immune processes, which in turn cause all changes in the body.

General signs

In addition to the fact that systemic diseases have a similar development, they also have many common symptoms:

certain symptoms of the disease are common;

each of them differs in genetic predisposition, the cause of which is the characteristics of the sixth chromosome;

changes in connective tissues are characterized by similar features;

Diagnosis of many diseases follows a similar pattern;

all these disorders simultaneously affect several body systems;

in most cases, at the first stage of development, the disease is not taken seriously, since everything occurs in a mild form;

the principle by which all diseases are treated is close to the principles of treatment of others;

• Some indicators of inflammatory activity in appropriate laboratory tests will be similar.

If doctors accurately identified the causes that trigger such a hereditary connective tissue disease in the body, then diagnosis would be much easier. At the same time, they would accurately establish the necessary methods that require the prevention and treatment of the disease. Therefore, research in this area does not stop. Everything that experts can say about environmental factors, incl. about viruses, that they only aggravate the disease, which previously occurred in a latent form, and also act as its catalysts in the human body, which has all the genetic prerequisites.

Treatment of systemic diseases

The classification of the disease according to the form of its course occurs in exactly the same way as in other cases:

Light form.

Severe form.

Prevention period.

In almost all cases, connective tissue disease requires active treatment, including daily doses of corticosteroids. If the disease proceeds in a calm course, then there is no need for a large dosage. Treatment in small portions in such cases can be supplemented with anti-inflammatory drugs.

If treatment with corticosteroids is ineffective, it is carried out simultaneously with the use of cytostatics. Most often, this combination slows down the development of cells that carry out erroneous defense reactions against other cells of their own body.

Treatment of diseases in more severe forms is somewhat different. It involves getting rid of immune complexes that have begun to work incorrectly, for which the plasmapheresis technique is used. To exclude the production of new groups of immunoactive cells, a set of procedures is carried out aimed at irradiating the lymph nodes.

There are medicines that act not on the affected organ or the cause of the disease, but on the entire body as a whole. Scientists do not stop developing new methods that could have a local effect on the body. The search for new drugs continues in three main directions.

The most promising method is gene therapy., which involves replacing a defective gene. But scientists have not yet reached its practical application, and mutations corresponding to a specific disease cannot always be detected.

If the reason is the body's loss of control over the cells, then some scientists suggest replacing them with new ones through harsh immunosuppressive therapy. This technique has already been used and demonstrated good results during the treatment of multiple sclerosis and lupus erythematosus, but it is still unclear how long-lasting its effect is and whether suppressing the “old” immunity is safe.

It is clear that methods will become available that do not eliminate the cause of the disease, but remove its manifestation. First of all, these are drugs created on the basis of antibodies. They can block the immune system from attacking their tissues.

Another way is to prescribe to the patient substances that take part in the regulation of the immune process. This does not apply to those substances that generally suppress the immune system, but to analogues of natural regulators that affect exclusively certain types of cells.

For treatment to be effective,

The efforts of a specialist alone are not enough.

Most experts say that to get rid of the disease, two more mandatory things are needed. First of all, the patient must have a positive attitude and a desire to get well. It has been repeatedly noted that self-confidence has helped many people get out of even the most seemingly hopeless situations. In addition, support from friends and family members is important. Understanding loved ones is extremely important, which gives a person strength.

Timely diagnosis at the initial stage of diseases allows for effective prevention and treatment. This requires special attention to patients, since mild symptoms can act as a warning of approaching danger. Diagnosis should be detailed when working with individuals who have a special symptom of sensitivity to certain medications and foods, bronchial asthma, and allergies. The risk group also includes those patients whose relatives have repeatedly sought help from doctors and are undergoing treatment after recognizing the signs and symptoms of diffuse diseases. If abnormalities are noticeable at the level of a blood test (general), this person also belongs to a risk group that needs to be closely monitored. We must not forget about those people whose symptoms indicate the presence of focal connective tissue diseases.

Examples of systemic diseases

The most famous disease from this group is rheumatoid arthritis. But this disease is not the most common autoimmune pathology. Most often, people encounter autoimmune lesions of the thyroid gland - Hashimoto's thyroiditis and diffuse toxic goiter. According to the autoimmune mechanism, systemic lupus erythematosus, type I diabetes mellitus and multiple sclerosis still develop.

It is worth noting that an autoimmune nature can be inherent not only to diseases, but also to certain syndromes. A striking example is chlamydia, a disease caused by chlamydia (sexually transmitted). With this disease, Reiter's syndrome often develops, which is characterized by damage to the joints, eyes and genitourinary tract. Such manifestations are in no way related to exposure to the microbe, but occur as a result of autoimmune reactions.

Causes of systemic diseases

During the maturation of the immune system (up to 13-15 years), lymphocytes undergo “training” in the lymph nodes and thymus. Moreover, each cell clone gains the ability to recognize certain foreign proteins in order to subsequently fight various infections. A certain part of lymphocytes learns to recognize proteins of their own body as foreign. Such lymphocytes are normally tightly controlled by the immune system; they probably serve to destroy diseased or defective cells of the body. But in some people, control over them is lost, as a result of which their activity increases and the destruction of normal cells begins, namely, an autoimmune disease develops.

What is Mixed Connective Tissue Disease?

Mixed connective tissue disease (MCTD)- a unique clinical-immunological syndrome of systemic damage to connective tissue of an inflammatory nature, manifested by a combination of individual signs of SSc, polymyositis (dermatomyositis), SLE, antibodies to soluble nuclear ribonucleoprotein (RNP) in high titers; the prognosis is more favorable than those of the diseases whose symptoms make up the syndrome.

CTD was first described by G. G. Sharp et al. as a kind of “syndrome of various rheumatic diseases”. Despite the fact that in subsequent years many observations have been reported in various countries, the essence of CTD has still not been revealed, and no clear answer has been received - whether it is an independent nosological form or a peculiar variant of one of the diffuse connective tissue diseases - SLE in the first place.

What Causes Mixed Connective Tissue Disease?

In the development of the disease, peculiar immunity disorders play a role, manifested by a long-term persistent increase in antibodies to RNP, hypergammaglobulinemia, hypocomplementemia and the presence of circulating immune complexes. Deposits of TgG, IgM and complement are found in the walls of the blood vessels of the muscles, glomeruli of the kidney and the dermoepidermal junction of the dermis, and lymphoid and plasma cell infiltrates are found in the affected tissues. Changes in the immunoregulatory functions of T lymphocytes have been established. A feature of the pathogenesis of CTD is the development of proliferative processes in the inner and middle membranes of large vessels with the clinical manifestations of pulmonary hypertension and other vascular manifestations.

Symptoms of Mixed Connective Tissue Disease

As indicated in the definition of CTD, the clinical picture of the disease is determined by such signs of SSD as Raynaud's syndrome, swelling of the hands and hypokinesia of the esophagus, as well as symptoms of polymyositis and SLE in the form of polyarthralgia or recurrent polyarthritis, skin rashes, but with some inherent features.

Raynaud's syndrome- one of the most common signs. In particular, according to our materials, Raynaud's syndrome was noted in all patients with recognized CTD. Raynaud's syndrome is not only a frequent, but often an early sign of the disease, however, unlike SSD, it is milder, often biphasic, and the development of ischemic necrosis or ulcers is an extremely rare occurrence.

Raynaud's syndrome in STD is usually accompanied by swelling of the hands up to the development of a “sausage-shaped” shape of the fingers, but this stage of mild edema practically does not end with induration and atrophy of the skin with persistent flexion contractures (sclerodactyly), as in SSD.

Very peculiar muscle symptoms- the clinical picture of the disease is dominated by pain and muscle weakness in the proximal muscles of the extremities with rapid improvement under the influence of medium doses of GCS therapy. The content of muscle enzymes (creatine phosphokinase, aldolase) increases moderately and quickly normalizes under the influence of hormone therapy. Skin lesions over the finger joints, heliotrope coloration of the eyelids, and telangiectasia along the edge of the nail bed, characteristic of dermatomyositis, are extremely rare.

Peculiar articular symptoms. Involvement of joints in the pathological process is observed in almost all patients, mainly in the form of migrating polyarthralgia, and in 2/3 of patients there is polyarthritis (non-erosive and, as a rule, non-deforming), although a number of patients develop ulnar deviation and subluxations in the joints of individual fingers. . Large joints are typically involved in the process along with damage to small joints of the hands, as in SLE. Occasionally, erosive and destructive changes in the joints of the hands, indistinguishable from RA, are described. Similar changes were observed in patients at our institute.

Hypokinesia of the esophagus recognized in patients and is associated with the thoroughness of not only X-ray studies, but also manometric ones, however, impaired mobility of the esophagus extremely rarely reaches the same degree as with SSD.

Damage to the serous membranes is not observed as often as in SLE, however, in CTD, bilateral effusion pleurisy and pericarditis have been described. Significantly more often there is involvement of the lungs in the pathological process (ventilation disturbances, decreased vital capacity, and on X-ray examination, increased and deformed pulmonary pattern). At the same time, pulmonary symptoms in some patients may play a major role, manifested by increasing shortness of breath and/or symptoms of pulmonary hypertension.

A special feature of the FTZ is its rarity kidney damage(according to the literature, in 10-15% of patients), but in those patients who exhibit moderate proteinuria, hematuria or morphological changes in a kidney biopsy, a benign course is usually noted. The development of nephrotic syndrome is extremely rare. For example, according to the clinic, kidney damage was noted in 2 out of 21 patients with CTD.

Cerebrovasculitis is also rarely diagnosed, but mild polyneuropathy is a common symptom in the clinic of CTD.

Among the common clinical manifestations of the disease, varying degrees of severity are noted febrile reaction and lymphadenopathy(in 14 out of 21 patients) and less often splenomegaly and hepatomegaly.

Often, with CTD, Segren's syndrome develops, a predominantly benign course, as with SLE.

Diagnosis of Mixed Connective Tissue Disease

• Laboratory data

General clinical laboratory data for CTD are nonspecific. Approximately half of the patients in the active phase of the disease have moderate hypochromic anemia and a tendency to leukopenia, and all have accelerated ESR. However, serological studies reveal an increase in antinuclear factor (ANF) quite characteristic of patients with a speckled type of immunofluorescence.

In patients with CTD, high titers of antibodies to nuclear ribonucleoprotein (RNP) are detected - one of the soluble nuclear antigens that are sensitive to the effects of ribonuclease and trypsin. As it turned out, it is antibodies to RNP and other soluble nuclear antigens that cause the nuclear type of immunofluorescence. Essentially, these serological features, along with the clinical differences noted above from classical nosological forms, served as the basis for identifying the CTD syndrome.

In addition, hypsargammaglobulipsmia, often excessive, as well as the appearance of RF, are often noted. At the same time, CTD is especially characterized by the persistence and severity of these disorders, regardless of fluctuations in the activity of the pathological process. At the same time, in the active phase of the disease, circulating immune complexes and mild hypocomplementemia are not so rarely detected.

Treatment of Mixed Connective Tissue Disease

GCS is characterized by high effectiveness even in medium and small doses, in contrast to SSD.

Since in recent years there has been a tendency towards the development of nephropathy and pulmonary hypertension, patients with these clinical signs sometimes require the use of large doses of GCS and cytostatic drugs.

The prognosis of the disease is generally satisfactory, but cases of death have been described, occurring primarily due to renal failure or pulmonary hypertension.

Which doctors should you contact if you have Mixed connective tissue disease?

Rheumatologist

Promotions and special offers

Medical news

14.11.2019

Experts agree that it is necessary to attract public attention to the problems of cardiovascular diseases. Some are rare, progressive and difficult to diagnose. These include, for example, transthyretin amyloid cardiomyopathy

14.10.2019

On October 12, 13 and 14, Russia is hosting a large-scale social event for free blood clotting testing - “INR Day”. The campaign is timed to coincide with World Thrombosis Day.

07.05.2019

The incidence of meningococcal infection in the Russian Federation in 2018 (compared to 2017) increased by 10% (1). One of the common ways to prevent infectious diseases is vaccination. Modern conjugate vaccines are aimed at preventing the occurrence of meningococcal infection and meningococcal meningitis in children (even very young children), adolescents and adults.

Almost 5% of all malignant tumors are sarcomas. They are highly aggressive, rapidly spread hematogenously, and are prone to relapse after treatment. Some sarcomas develop for years without showing any signs...

Viruses not only float in the air, but can also land on handrails, seats and other surfaces, while remaining active. Therefore, when traveling or in public places, it is advisable not only to exclude communication with other people, but also to avoid...

Regaining good vision and saying goodbye to glasses and contact lenses forever is the dream of many people. Now it can be made a reality quickly and safely. The completely non-contact Femto-LASIK technique opens up new possibilities for laser vision correction.

Cosmetics designed to care for our skin and hair may actually not be as safe as we think

Mixed connective tissue disease (MCTD), also called Sharp's syndrome, is an autoimmune connective tissue disease manifested by a combination of individual symptoms of systemic pathologies such as SSc, SLE, DM, SS, and RA. As usual, two or three symptoms of the above diseases are combined. The incidence of CTD is approximately three cases per hundred thousand of the population, affecting mainly females of mature age: for every one sick man there are ten sick women. CTD is slowly progressive. In the absence of adequate therapy, death occurs from infectious complications.

Despite the fact that the causes of the disease are not completely clear, the autoimmune nature of the disease is considered an established fact. This is confirmed by the presence in the blood of patients with CTD of a large number of autoantibodies to the U1 ribonucleoprotein (RNP)-related polypeptide. They are considered to be a marker of this disease. CTD has a hereditary determination: almost all patients have the presence of HLA antigen B27. When treatment is started on time, the course of the disease is favorable. Occasionally, CTD is complicated by the development of pulmonary hypertension and renal failure.

Diagnosis of mixed connective tissue disease

It presents certain difficulties, since CTD does not have specific clinical symptoms, having similar features to many other autoimmune diseases. General clinical laboratory data are also nonspecific. However, the FTA is characterized by:

• CBC: moderate hypochromic anemia, leukopenia, accelerated ESR.
• OAM: hematuria, proteinuria, cylindruria.
• Blood biochemistry: hyper-γ-globulinemia, appearance of RF.
• Serological study: increased ANF titer with a speckled type of immunofluorescence.
• Capillaroscopy: sclerodermatous-changed nail folds, cessation of capillary circulation in the fingers.
• X-ray of the chest: infiltration of lung tissue, hydrothorax.
• EchoCG: exudative pericarditis, valve pathology.
• Pulmonary function tests: pulmonary hypertension.

An unconditional sign of CTD is the presence of anti-U1-RNP antibodies in the blood serum at a titer of 1:600 ​​or more and 4 clinical signs.

Treatment of mixed connective tissue disease

The goals of treatment are to control the symptoms of CTD, maintain the function of target organs, and prevent complications. Patients are advised to lead an active lifestyle and adhere to dietary restrictions. In most cases, treatment is carried out on an outpatient basis. The most commonly used drugs are NSAIDs, corticosteroid hormones, antimalarial and cytostatic drugs, calcium antagonists, prostaglandins, and proton pump inhibitors. The absence of complications with adequate supportive therapy makes the prognosis of the disease favorable.

Essential drugs

There are contraindications. Specialist consultation is required.

1. (synthetic glucocorticoid drug). Dosage regimen: in the treatment of CTD, the starting dose of prednisolone is 1 mg/kg/day. until the effect is achieved, then slowly (no more than 5 mg/week) reduce the dose to 20 mg/day. Further reduction of the dose by 2.5 mg every 2-3 weeks. up to a maintenance dose of 5-10 mg (indefinitely).
2. Imuran) is an immunosuppressive drug, a cytostatic. Dosage regimen: for CTD, it is used orally at the rate of 1 mg/kg/day. The course of treatment is long.
3. Diclofenac sodium (Diclonate P) is a non-steroidal anti-inflammatory drug with an analgesic effect. Dosage regimen: the average daily dose of diclofenac in the treatment of CTD is 150 mg, after achieving a therapeutic effect it is recommended to reduce it to the minimum effective (50-100 mg/day).
4. Hydroxychloroquine (,) is an antimalarial drug and immunosuppressant. Dosage regimen: for adults (including the elderly), the drug is prescribed in the minimum effective dose. The dose should not exceed 6.5 mg/kg body weight per day (calculated based on ideal, not actual body weight) and can be either 200 mg or 400 mg/day. In patients able to take 400 mg daily, the initial dose is 400 mg daily in divided doses. When obvious improvement is achieved, the dose can be reduced to 200 mg. If effectiveness decreases, the maintenance dose can be increased to 400 mg. The drug is taken in the evening after meals.

Chapter 24. CONNECTIVE TISSUE DISEASES

Chapter 24. CONNECTIVE TISSUE DISEASES

Diffuse connective tissue diseases include rheumatoid arthritis, juvenile arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis, Sjogren's syndrome. The most common are rheumatoid arthritis and systemic lupus erythematosus, the etiology of which is unknown.

24.1. RHEUMATOID ARTHRITIS

Rheumatoid arthritis is considered as a common chronic polyarthritis 1 with nonspecific inflammation of peripheral joints, usually symmetrical. Often, along with articular syndrome, systemic manifestations are noted.

Epidemiology. The prevalence is about 1%. Women get sick 2-3 times more often than men.

Pathogenesis. In rheumatoid arthritis, two interrelated processes unfold in the joints: activation and proliferation of 2 immunocompetent cells (lymphocytes, macrophages) with the production of autoantibodies and the release of inflammatory mediators, as well as the proliferation of synovial membrane cells 3, which form aggressive granulation tissue - pannus, growing in the joint and destroying cartilage and subchondral bone. Activation of the immune system is considered the primary process that triggers the proliferation of synoviocytes.

In rheumatoid arthritis, capillaries grow into the cartilage, promoting pannus penetration and destruction. Pannus cells multiply, carry many adhesion molecules on their surface, secrete proteolytic enzymes and destroy nearby

1 Arthritis is inflammation of a joint, polyarthritis is inflammation of several joints.

2 Proliferation - tissue growth through the formation of new cells.

3 Synovial membrane is a connective tissue membrane that covers the outside of the joint.

tissues - cartilage and subchondral bone. Destruction of cartilage and subchondral bone leads to the formation of erosions of the articular surfaces, deformation of joints with subluxations, and then to ankylosation of 1 joints.

Symptom complex of rheumatoid arthritis. The disease can begin acutely, with simultaneous damage to many joints, or (more often) progresses gradually.

The inflammatory process in the joint causes pain, swelling and limitation of movement. Stiffness and pain in the small joints of the hands and feet intensify in the morning, after a long stay in one position, and disappear with movement. Along with this, sleep disturbances, malaise, daytime weakness, increased fatigue, and weight loss appear.

Articular manifestations. The joints are deformed, the deformation of the interphalangeal joints is especially noticeable, they become spindle-shaped. Typical for rheumatoid arthritis is the deviation of the fingers to the ulnar side (ulnar deviation) and the simultaneous slipping of the extensor tendons from the metacarpophalangeal joints.

To systemic manifestations rheumatoid arthritis includes subcutaneous rheumatoid nodules (dense subcutaneous nodules in the area of ​​​​bone protrusions, near joints and on extensor surfaces), vasculitis 2, pleural or pericardial effusion, Sjogren's syndrome (dryness of the mucous membrane of the mouth, eyes and other mucous membranes) .

Course and severity of the disease. The course of the disease is chronic; rheumatoid arthritis can begin at any age (usually at 25-50 years). The disease can lead to progressive destruction of both articular and extra-articular structures.

Diagnosis and examination methods. Diagnosis is based on the patient's complaints (joint pain and morning stiffness). Inspection of the affected joints (symmetrical lesions and ulnar deviation) is of great importance.

The main serological sign of rheumatoid arthritis is considered to be rheumatoid factor, which is detected in 80-90% of patients (seropositive rheumatoid arthritis) (Table 24-1).

1 Ankylosis is joint immobility caused by the development of fibrous, cartilaginous or bone adhesions between the articular surfaces of articulating bones.

2 Vasculitis is inflammation of blood vessels.

Typical radiological signs of rheumatoid arthritis:

Symmetrical increase in the volume of periarticular soft tissues;

Periarticular osteoporosis 1;

Narrowing of the joint space;

Marginal erosion of joints;

Absence of pronounced bone growths 2. The American Rheumatological Association has proposed clear diagnostic criteria for rheumatoid arthritis. The diagnosis of rheumatoid arthritis is considered correct only when the patient has at least 4 criteria. The duration of existence of 1-4 criteria must be at least 6 weeks.

Diagnostic criteria for rheumatoid arthritis (American Rheumatological Association, 1987 revision):

Morning stiffness lasting at least 1 hour;

Arthritis of at least three joints;

Arthritis of the hand joints (wrist, metacarpophalangeal or proximal interphalangeal);

Symmetry of arthritis;

Rheumatoid nodules;

Detection of rheumatoid factor in blood serum by a method that gives no more than 5% positive results in the control group;

X-ray changes (changes in the hand - erosion or obvious periarticular osteoporosis).

24.2. JUVENILE RHEUMATOID ARTHRITIS

Juvenile rheumatoid arthritis develops before age 16 and is similar in many ways to adult rheumatoid arthritis. In juvenile rheumatoid arthritis, damage to one or more joints persists for 3 months or more. Oligoarthritis (50%) and polyarthritis (40%) are more often observed. In young children, the disease occurs in a severe form (Still's syndrome), mainly with systemic manifestations.

1 Osteoporosis is a decrease in bone mineral density.

2 Marginal bone growths - osteophytes are typical for another common joint disease - osteoarthritis.

Epidemiology. The prevalence is 1 case per 1000 children.

Symptom complex of juvenile rheumatoid arthritis. The main manifestation (70%) is articular syndrome. However, unlike rheumatoid arthritis in adults, large joints are most often involved in the pathological process - knee, hip, ankle, wrist, elbow. In children, the pathological process involves the cervical spine and maxillotemporal joints, resulting in the development of micrognathia, which is pathognomonic for children - “bird jaw” with limited mouth opening. Involvement of the hip joints in the process affects the child’s posture (lordosis increases), and the gait becomes “duck-like.”

Simultaneously with articular syndrome, muscle atrophy develops, mainly proximal to the affected joint. Some children with severe disease (up to 30%) may experience extra-articular manifestations: long-term (weeks, months) febrile fever, mainly in the morning, skin rashes, swollen lymph nodes, splenomegaly, heart damage (myocarditis, pericarditis), lung damage (pneumonitis), eye damage with a progressive decline in visual acuity up to complete blindness.

Diagnosis Juvenile rheumatoid arthritis is diagnosed based on the criteria listed below.

Diagnostic criteria for juvenile rheumatoid arthritis (American Rheumatological Association, 1987 revision):

Onset of disease before age 16;

Involvement of one or more joints with swelling/effusion or two of the following signs: limited function, pain on palpation, increased local temperature;

The duration of joint changes is at least 6 weeks;

Exclusion of all other rheumatic diseases.

24.3. SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus is the most common diffuse connective tissue disease in adults. The main clinical manifestations are caused by vasculitis with predominant damage to small vessels. Up to 90% of patients with systemic lupus erythematosus complain

They affect joint manifestations from transient arthralgia to acute polyarthritis, sometimes occurring several years before the appearance of other symptoms.

Epidemiology. The prevalence is 1 case per 1000 population. The disease is more common in young women (90%) and children.

Pathogenesis. The pathological process develops mainly in the main substance of the connective tissue with damage to the basement membrane of the glomeruli of the kidney, skin, blood vessels, pleura, pericardium and endocardium.

Under the influence of a number of factors (increased insolation, focal infection, drugs, genetic factors), a deficiency of T-suppressors and a compensatory increase in the number of B-lymphocytes occur. Autoantigens to one’s own DNA are formed in the patient’s blood. As a result of the reaction of an autoantigen (own DNA) with autoantibodies, circulating immune complexes are formed, which are fixed on various organs and tissues of the body, causing immune inflammation (increased concentrations of prostaglandins, leukotrienes, complement). Autoimmune mechanisms contribute to self-maintenance and continuous progression of the pathological process.

The formation of immune complexes and their deposition on the basement membrane of blood vessels lead to widespread vasculitis and disruption of microcirculation in various organs and systems. As a result of fibrin deposition and microthrombosis of capillaries, arterioles and venules, DIC syndrome develops, which leads to ischemia and hemorrhages in organs. Morphologically, this is manifested by disorganization of connective tissue and vasculitis. Almost all organs and tissues are affected.

Symptom complex. The disease may begin suddenly with a fever that mimics an acute infection, or gradually over months or years with episodes of fever and general malaise. Changes in any organs and systems are possible.

The most common symptom of systemic lupus erythematosus is arthritis (90%) with symmetrical damage to small and medium-sized joints. Bone destruction usually does not occur. With prolonged arthritis, tendon contractures with secondary joint deformation are possible.

Erythema in the form of a “butterfly” appears on the skin in the cheekbone area.

Discoid skin changes and erythematous 1, dense maculopapular 2 rashes on exposed areas of the neck, upper chest and elbows, and ulcers on the mucous membranes are also possible. Recurrent pleurisy (dry or ex-sudative) and pericarditis are often noted. Generalized lymphadenopathy (enlarged lymph nodes) often develops in children and young patients; splenomegaly (enlarged spleen) is possible (10% of cases).

When the central nervous system is predominantly affected, headaches, personality changes, psychoses, and epileptic convulsions predominate. Kidney damage can be minor or, conversely, steadily progress (lupus nephritis), leading to death. Proteinuria is the most common condition.

Examination methods and diagnostics. Systemic lupus erythematosus can be suspected based on complaints and general examination data. Antibodies to DNA are specific for systemic lupus erythematosus. Detection of LE cells in the blood is a less specific sign of the disease (see Table 24-1). Blood parameters reflecting the systemic inflammatory response - ESR and C-reactive protein - are of great importance. However, these indicators are nonspecific, they are not included in the diagnostic criteria, their indicators can increase with any inflammatory process.

X-ray examination of patients with systemic lupus erythematosus does not reveal signs of joint erosion.

Currently, the criteria presented below are used in the diagnosis of systemic lupus erythematosus. The diagnosis is valid if any four criteria are present.

Diagnostic criteria for systemic lupus erythematosus (American Rheumatological Association, 1987 revision):

Rash in the area of ​​the zygomatic arches;

Discoid rash;

Increased photosensitivity of the skin;

Mouth ulcers;

Arthritis;

Serositis;

Kidney damage;

Leukopenia less than 440 9 /l;

1 Erythema - redness of the skin.

2 Papule - a dense nodule of various sizes, rising above the skin.

Hemolytic anemia and/or thrombocytopenia 10040 9 /l;

Neurological disorders;

Antibodies to DNA or Le-cells;

Increased titer of antinuclear antibodies.

24.4. CLINICAL AND PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF DIFFUSE CONNECTIVE TISSUE DISEASES

The basis for the treatment of rheumatoid arthritis and systemic lupus erythematosus is considered to be the combined administration of fast-acting anti-inflammatory drugs (usually NSAIDs, less often glucocorticoids) and one of the long-acting (basic) drugs.

Anti-inflammatory drugs have not only symptomatic, but also partly pathogenetic effects. The effectiveness of anti-inflammatory drugs appears within 1 day after prescription, but stops almost as quickly after discontinuation.

Basic drugs, compared to anti-inflammatory drugs, more deeply suppress the inflammatory process by inhibiting immune reactions and slow down destructive changes in the joints. However, the therapeutic effect develops slowly, over several weeks or months.

The main goals of treatment for rheumatoid arthritis are:

Suppress inflammation of joints and other tissues;

Repair significant joint damage to reduce pain and improve function.

In the acute period of the disease, when the pain is significant, bed rest is recommended for a short time. In mild cases, periodic rest in bed is sufficient. Local rest for the joint is provided by removable splints. As a rule, a normal nutritious diet is recommended.

The traditional basis of drug treatment for rheumatoid arthritis are NSAIDs.

In patients with severe pain, NSAIDs can be administered parenterally on the first day of treatment, and subsequently taken orally. Widely used NSAIDs for topical use in the form of ointments and gels (indomethacin, ketoprofen, diclo-

phenac) in the treatment of rheumatoid arthritis have only auxiliary value.

Glucocorticoids have a powerful and rapid anti-inflammatory effect. In addition, they have pronounced immunomodulatory activity. With long-term treatment, the effectiveness of glucocorticoids decreases; in addition, they are not able to prevent progressive destruction of the joints, and when discontinued in patients with active rheumatoid arthritis, a pronounced exacerbation occurs. ADRs of glucocorticoids during long-term use force them to be prescribed only in the absence of a therapeutic effect of NSAIDs and in patients with systemic manifestations of rheumatoid arthritis.

Rheumatoid nodules and mild sensory neuropathies in themselves are not an indication for glucocorticoids. Elderly patients (75-80 years old) with rheumatoid arthritis tend to tolerate low doses of prednisolone better than NSAIDs, which are more likely to cause gastric and duodenal ulcers at this age.

Glucocorticoids are contraindicated in:

Hypersensitivity;

Severe infections (except septic shock and tuberculous meningitis);

Immunization with live vaccines;

Chicken pox.

Relative contraindications to the prescription of glucocorticoids: peptic ulcer, hypertension, diabetes, glaucoma. With long-term use of small doses of glucocorticoids, serious complications rarely arise and can be easily corrected even with continued use of drugs (calcium supplements for osteoporosis, omeprazole or ranitidine for erosive and ulcerative lesions of the stomach and duodenum).

In the treatment of rheumatoid arthritis, intra-articular administration of glucocorticoids is widely used, which avoids their systemic administration. The duration of the local therapeutic effect of these drugs depends on the type of drug. The most lasting effect is exerted by triamcinolone and betamethasone, methylprednisolone, hydrocortisone, which are administered every 7-14 days. In many cases, the therapeutic effect can depend on the individual response of the patient and last up to several months.

In children with juvenile rheumatoid arthritis, after injection of drugs into the knee joint, the effect in 40% of cases persists for 2 years or more.

Doses of drugs depend on the size of the affected joints.

Repeated administrations, if necessary, are done at intervals from several weeks to 3-4 months, depending on the degree and duration of the therapeutic effect.

If after two injections into the same joint there is no improvement, subsequent injections are not indicated.

Contraindications for intra-articular administration of glucocorticoids: infectious arthritis, severe joint destruction, significant osteoporosis.

Tolerance to intra-articular administration of glucocorticoids is usually good. NDR: pain, temporary exacerbation of the inflammatory process, infection, especially in patients receiving immunosuppressive therapy, local atrophy and depigmentation of the skin, degenerative changes in the joint, formation of fistula tracts, tendon ruptures, systemic effects.

The volume of glucocorticoids injected into a large joint should not exceed 2 ml, into a medium joint - 1 ml, into a small joint - 0.5 ml. After administration, it is necessary to ensure immobilization of the joint for 1-2 days. Glucocorticoids can be injected into no more than 3 joints at a time. The intervals between injections into the same joint should be as long as possible. It is not recommended to inject glucocorticoids into the joints, which are the main support of the body, more than 3 times a year. Glucocorticoids should not be injected directly into tendons.

Basic treatment. Slow-acting drugs, unlike fast-acting NSAIDs, slow down joint destruction, affect immune processes, remission periods, and, due to their cumulative properties, retain their effect for several months after discontinuation. These include methotrexate, gold compounds, penicillamine, hydroxychloroquine, sulfasalazine. As a rule, they are prescribed when NSAIDs are insufficiently effective after 3 or 4 months of treatment. With rapid progression of the disease, these drugs are prescribed at an earlier time.

Gold compounds usually prescribed in addition to NSAIDs if they do not significantly suppress joint inflammation. Their effect develops after 3-4 months from the start of treatment. When maximum improvement is achieved, the dose is gradually reduced. If the drug is discontinued with the onset of remission, then usually an exacerbation develops again after 3-6 months. If you continue to administer maintenance doses, the achieved improvement may last for several years.

The effectiveness of treating rheumatoid arthritis with gold preparations is comparable to the effectiveness of methotrexate. The advantage is considered to be the absence of significant immunosuppression and the development of intercurrent infections. However, gold preparations cause many ADRs that require discontinuation of the drug.

Gold preparations are contraindicated in cases of severe dysfunction of the liver, kidneys, pregnancy, as well as hematological disorders.

During treatment with gold preparations, it is necessary to do urine and blood tests (hemoglobin concentration, leukocyte count, leukocyte formula and platelet count). The studies are repeated in the 1st month before each injection of the drug, and then every 1-2 weeks.

Currently, a new direction in the treatment of rheumatoid arthritis is actively developing, the so-called biological therapy, in which antibodies, cytokine receptors and other immunologically active drugs are used. Among them, the most promising methods involve blocking the activity of the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) by administering monoclonal antibodies, cytokine antagonists or cytokine receptor antagonists. These include leflunomide, etanercept and infliximab.

There are various treatment regimens for rheumatoid arthritis. According to the oldest scheme, treatment begins with ensuring rest and prescribing NSAIDs; if there is no improvement, aminoquinoline drugs are added, then derivatives of 5-aminosalicylic acid or gold preparations, and then glucocorticoids and cytostatics. However, when using this regimen, patients begin to receive effective basic drugs late.

Modern scheme "step-down bridge" involves the combined administration of methotrexate, a gold drug, an aminoquinoline drug (hydroxychloroquine), glucocorticoids and cytostatics from the first days. Once the effect is achieved, the drugs are gradually discontinued.

Treatment tactics for systemic lupus erythematosus depend on the location and severity of the pathological process.

With a moderate or undulating process with fever, arthritis, pleurisy, pericarditis, headaches or rash, basic therapy should be minimal, and sometimes not required at all. For example, arthralgias respond well to NSAIDs. Acetylsalicylic acid can be used, especially if there is a tendency to develop thrombosis, but large doses of this drug for systemic lupus erythematosus can cause toxic damage to the liver.

In severe forms of systemic lupus erythematosus, glucocorticoids are used. The initial dose of prednisolone is: for hemolytic anemia - 60 mg/day, for thrombocytopenic purpura - 40-60 mg/day, for severe polyserositis - 20-60 mg/day, for kidney damage - 20-60 mg/day (in combination with immunosuppressants).

Improvement usually does not occur earlier than 4-12 weeks of treatment, and may not occur until the dose of glucocorticoids is reduced.

For active systemic lupus erythematosus or lupus nephritis, combination treatment (glucocorticoids + immunosuppressants) is indicated. The most commonly used are azathioprine at a dose of 2.5 mg/kg per day or cyclophosphamide at a dose of 2.5 mg/kg per day. Intermittent use of immunosuppressants is possible: for example, cyclophosphamide (500 mg) is administered intravenously at intervals depending on blood test data.

In acute vasculitis and severe lupus damage to the central nervous system and kidneys (lupus nephritis, neurolupus, rheumatoid vasculitis, systemic necrotizing vasculitis), pulse therapy with glucocorticoids (methylprednisolone at a dose of 1000 mg intravenously for 1 hour) is often used daily for 3 days in a row. At the same time, cyclophosphamide is administered intravenously. This treatment can be combined with plasmapheresis.

For systemic lupus erythematosus of any severity, when the inflammatory process can be suppressed, minimum maintenance doses of glucocorticoids or other drugs are selected, reducing the dose by no more than 10%. The intervals between dose reductions depend on how quickly initial clinical improvement is achieved. Treatment results are assessed by the dynamics of clinical symptoms and laboratory parameters.

A glucocorticoid for external use is selected taking into account the location and nature of the lesion, and the dosage form is also important. For systemic lupus erythematosus it is preferable

ointments of moderate activity and mild, gentle local action, which practically do not cause systemic adverse reactions (hydrocortisone 17-butyrate*, prednicarbate* 3, mometasone furoate*).

Pulse therapy

For diffuse connective tissue diseases, in particular rheumatoid arthritis, pulse therapy is used. Indications for its implementation are considered to be high disease activity, refractory to conventional treatment methods, and pronounced systemic manifestations (severe cutaneous vasculitis).

Pulse therapy consists of prescribing ultra-high doses of glucocorticoids for a short period of time. Methylprednisolone is most often used, which is administered in the form of succinate in a dose of 1-2 g intravenously drip over 30-60 minutes, once a day for 3-5 days. The maximum concentration of the drug in the blood develops after 1 hour, followed by a decrease within 6-7 hours, but as a result of the non-genomic 1 mechanism of action, the effect is observed after a short period of time (several minutes). Methylprednisolone accumulates in various tissues, more in inflamed than in normal tissues, as well as in red blood cells. Pulse therapy allows you to achieve a quick effect and reduce maintenance doses of glucocorticoids for oral administration.

Classical pulse therapy for rheumatoid arthritis is rarely used; more often large doses of methylprednisolone (250-1000 mg) are administered intravenously in combination with cytostatics - methotrexate at a dose of 20 mg or cyclophosphamide at a dose of 400-1000 mg.

For systemic lupus erythematosus, along with the classical regimen of pulse therapy in elderly patients, especially with a tendency to hypertension and myocardial damage, modified regimens can be used (250-500 mg for 4-12 days).

In patients with the most severe forms of rheumatic diseases (lupus nephritis, lupus lesions of the central nervous system, rheumatoid vasculitis, systemic necrotizing vasculitis), pulse therapy must be combined with the use of cytostatics.

1 The main mechanism of action of glucocorticoids is to stimulate the transcription of certain genes, and its implementation requires at least 6-24 hours. Currently, the so-called non-genomic effects of these drugs, not related to the influence on the reading of genetic information of cells, are being studied.

24.5. CLINICAL PHARMACOLOGY OF NON-STEROID ANTI-INFLAMMATORY DRUGS

MEANS

NSAIDs are very widely used in clinical practice.

The great popularity of NSAIDs is explained by the fact that they, by providing anti-inflammatory, analgesic and antipyretic effects, bring relief to patients with symptoms (inflammation, pain, fever) that occur in many diseases.

NSAIDs are classified depending on the severity of anti-inflammatory activity and chemical structure (Table 24-2). Group 1 includes drugs with a pronounced anti-inflammatory effect. NSAIDs of group 2, which give a weak anti-inflammatory effect that has virtually no clinical significance, are often referred to as “non-narcotic analgesics” or “analgesics-antipyretics.”

Table 24-2. Classification of NSAIDs

From a practical point of view, it is important that drugs of the same group and even those that are similar in chemical structure differ somewhat in both the strength of the effect and the frequency of development and nature of ADRs. The clinical effectiveness of the drug may depend on the type and characteristics of the disease in a particular patient, as well as on his individual reaction.

Pharmacokinetics

All NSAIDs are well absorbed from the gastrointestinal tract. To a large extent (more than 90%) bind to plasma albumin, displacing some other drugs and enhancing their effects. Many NSAIDs penetrate well into synovial fluid. NSAIDs undergo biotransformation in the liver, metabolites are excreted by the kidneys.

Pharmacodynamics

The main and general element of the mechanism of action of NSAIDs is considered to be inhibition of the synthesis of prostaglandins from arachidonic acid by inhibiting the enzyme cyclooxygenase (Fig. 24-1).

Rice. 24-1. Metabolism of arachidonic acid

Prostaglandins have versatile biological activity: they function as mediators of the inflammatory reaction, sensitize receptors to pain mediators (histamine, bradykinin) and mechanical effects, lowering the threshold of pain sensitivity, increase the sensitivity of the hypothalamic thermoregulation centers to the action of endogenous pyrogens (IL-1), the formation of which induce microorganisms and toxins.

Currently, two cyclooxygenase isoenzymes have been isolated that inhibit NSAIDs. The first (COX-1) controls the production of prostaglandins, which regulate the integrity of the gastrointestinal mucosa, platelet function and renal blood flow. The second (COX-2), involved in the synthesis of prostaglandins during inflammation, is intensively formed under the influence of a number of tissue factors that initiate the inflammatory response (cytokines). It is believed that the anti-inflammatory effect of NSAIDs is due to inhibition of COX-2, and their undesirable reactions are due to inhibition of COX-1, and the drugs differ in selectivity for various forms of cyclooxygenase, which allows us to judge their comparative activity and toxicity.

Thus, pronounced selectivity for COX-1 is characteristic of acetylsalicylic acid, indomethacin, ketoprofen, piroxicam, and sulindac®. Diclofenac, ibuprofen, naproxen, lornoxicam exhibit moderate selectivity for COX-1, moderate selectivity for COX-2 is demonstrated by etodolac®, meloxicam, nimesulide, nabumetone®, and pronounced selectivity for COX-2 is demonstrated by celecoxib.

The anti-inflammatory effect of NSAIDs may be associated with the stabilization of lysosome membranes, inhibition of neutrophil activation and impaired release of inflammatory mediators from them. In the implementation of the analgesic effect, disruption of the conduction of pain impulses at the level of the spinal cord (metamizole sodium) and activation of opioid receptors (lornoxicam) are important.

NSAIDs primarily suppress the exudation phase. In terms of anti-inflammatory activity, all NSAIDs are inferior to glucocorticoids, which, by inhibiting the enzyme phospholipase, inhibit the metabolism of phospholipids and disrupt the formation of prostaglandins and leukotrienes, also the most important mediators of inflammation.

The development of the anti-inflammatory effect lags behind the analgesic effect. The pain subsides in the first hours, and the anti-inflammatory effect occurs after 10-14 days of regular use, and when naproxen or oxicams are prescribed even later - after 2-4 weeks.

Analgesic effect of NSAIDs manifests itself to a greater extent with pain of mild and moderate intensity in muscles, joints, tendons, nerve trunks, with headaches or toothaches. For severe visceral pain, most NSAIDs are less effective than narcotic analgesics (morphine group). Unlike narcotic analgesics, NSAIDs do not depress the respiratory center and do not cause drug dependence.

Antipyretic effect. NSAIDs can only reduce elevated body temperature and do not affect normal body temperature. Patients should be warned that NSAIDs have only symptomatic effects and have neither antibacterial nor antiviral activity. If fever, pain, or deterioration in general condition persist, patients should consult a doctor.

Anti-aggregation effect. As a result of inhibition of COX-1 in platelets, the synthesis of the endogenous proaggregant thromboxane is suppressed. Acetylsalicylic acid has the most pronounced antiaggregation activity, which is prescribed in a low daily dose (75-250 mg). Selective COX-2 inhibitors do not affect platelet aggregation.

Indications for the use of non-steroidal anti-inflammatory drugs

Rheumatic diseases. Rheumatism (rheumatic fever), rheumatoid, gouty and psoriatic arthritis, ankylosing spondylitis (Bechterew's disease), Reiter's syndrome.

Non-rheumatic diseases of the musculoskeletal system. Osteoarthritis, myositis, tendovaginitis, trauma (domestic, sports).

Neurological diseases. Neuralgia, radiculitis, sciatica, lumbago.

Renal, hepatic colic.

Headache, toothache, postoperative pain.

Fever (usually at a body temperature above 38.5 °C).

Prevention of arterial thrombosis.

Dysmenorrhea (relief of pain associated with increased uterine tone due to overproduction of prostaglandin F2a; in addition to the analgesic effect, blood loss is reduced).

The main negative property of NSAIDs is the high risk of developing adverse reactions from the gastrointestinal tract. 30-40% of patients receiving NSAIDs experience dyspeptic disorders (abdominal pain, nausea, vomiting), 10-20% have erosions and ulcers of the stomach and duodenum, and 2-5% have bleeding and perforation.

The ulcerogenic effect is partly due to the local damaging effects of NSAIDs and is mainly due to the inhibition of COX-1 as a result of systemic action. Clinical manifestations are absent in almost 60% of patients, especially in the elderly, and the diagnosis in many cases is made by endoscopy. Insignificant, but constantly bleeding erosions and ulcers can lead to systematic loss of blood in the stool (2-5 ml/day) and the development of iron deficiency anemia. Dosage forms with enteric coating have somewhat less gastrotoxicity.

Risk factors for gastrotoxicity: female gender, age over 60 years, smoking, alcohol abuse, family history of peptic ulcers, concomitant severe cardiovascular diseases, taking glucocorticoids, immunosuppressants, anticoagulants, long-term treatment with NSAIDs, large doses or simultaneous use of two or more NSAIDs. Acetylsalicylic acid, indomethacin and piroxicam have the greatest gastrotoxicity.

Methods for improving the tolerability of non-steroidal anti-inflammatory drugs

Simultaneous administration of drugs that protect the gastrointestinal mucosa. According to controlled clinical studies, a synthetic analogue of prostaglandin E2, misoprostol, is highly effective in preventing the development of ulcers in both the stomach and duodenum. The proton pump inhibitor omeprazole has approximately the same effectiveness as misoprostol, but is better tolerated.

Changing the tactics of using NSAIDs:

Dose reduction;

Switch to parenteral, rectal or local administration;

Prescription of enteric dosage forms; the negative effect on the gastrointestinal tract is not so much a local as a systemic reaction.

The use of NSAIDs that exhibit selectivity for COX-2, especially in patients at risk.

The development of a stomach ulcer in a patient requires discontinuation of NSAIDs and specific treatment. Continued use of NSAIDs, for example, for rheumatoid arthritis, is only possible with the prescription of misoprostol or omeprazole and regular endoscopic monitoring.

Two main mechanisms for the negative effects of NSAIDs on the kidneys have been identified:

By blocking the synthesis of prostaglandins in the kidneys, NSAIDs cause vasoconstriction and deterioration of renal blood flow; this leads to the development of ischemic changes in the kidneys and disruption of their function; as a result, edema, hypernatremia, hyperkalemia occur, serum creatinine concentration and blood pressure increase; indomethacin and phenylbutazone have the most significant effect on renal blood flow;

Direct effect on the renal parenchyma with the development of interstitial nephritis (so-called analgesic nephropathy) and severe renal failure;

Risk factors for nephrotoxicity: age over 65 years, liver cirrhosis, previous renal pathology, decreased blood volume, long-term use of NSAIDs, concomitant use of diuretics.

Hematotoxicity is most typical for NSAIDs of the pyrazolidine and pyrazolones group, especially phenylbutazone. The most serious complications when using them are aplastic anemia and agranulocytosis. Phenylbutazone should be prescribed only as a reserve drug and, if possible, for a short course.

Hepatotoxicity consists mainly of changes in the activity of transaminases and other enzymes. In severe cases, jaundice and drug-induced hepatitis develop.

Hypersensitivity reactions - rash, Quincke's edema, anaphylactic shock, bronchospasm. The aspirin triad has been described: a combination of nasal and/or paranasal sinus polyposis, asthma and complete intolerance to acetylsalicylic acid. It is advisable to avoid prescribing this drug to patients with bronchial asthma.

Neurotoxicity is manifested by headache, dizziness, impaired reflex reactions, most characteristic of indomethacin.

Reye's syndrome develops when acetylsalicylic acid is prescribed to children with viral infections (influenza, chickenpox). It manifests itself as severe encephalopathy, cerebral edema and liver damage without jaundice, but with a high concentration of cholesterol and increased activity of liver enzymes. Mortality is very high (up to 80%). Acetylsalicylic acid should not be used for viral infections in children under 12 years of age.

Contraindications to the use of non-steroidal anti-inflammatory drugs

NSAIDs are contraindicated for erosive and ulcerative lesions of the gastrointestinal tract, especially in the acute stage, severe impairment of liver and kidney function, cytopenias, individual intolerance, and pregnancy. If necessary, the safest use (but not before childbirth!) is small doses of acetylsalicylic acid.

Assignment Rules

For each patient, the most effective drug with the best tolerability should be selected. The sensitivity of patients to NSAIDs of even one chemical group can vary greatly, and the ineffectiveness of one of the drugs does not indicate the ineffectiveness of the group as a whole.

Treatment should begin with the lowest dose; if well tolerated, it can be increased after 2-3 days. In recent years, there has been a tendency to increase single and daily doses of well-tolerated drugs (ibuprofen) while maintaining restrictions on the maximum doses of acetylsalicylic acid, indomethacin, and piroxicam. It should be taken into account that the anti-inflammatory effect of acetylsalicylic acid is manifested only in doses above 4 g/day.

For long-term treatment, NSAIDs should be taken after meals. To obtain a quick analgesic or antipyretic effect, it is preferable to prescribe the drugs on an empty stomach and drink a glass of water. NSAIDs are absorbed most quickly from the gastrointestinal tract and, therefore, give a faster effect [naproxen, diclofenac, water-soluble (effervescent) forms of acetylsalicylic acid and paracetamol]. To quickly relieve pain, parenteral dosage forms of NSAIDs (diclofenac, ketorolac) can also be prescribed.

The moment of taking NSAIDs can be determined by the maximum severity of the symptoms of the disease (pain, stiffness in the joints). You can deviate from generally accepted regimens (take 2-3 times a day), which usually allows you to achieve a greater therapeutic effect with a smaller daily dose.

The simultaneous use of two NSAIDs or more is inappropriate, since the effectiveness of such combinations has not been objectively proven (an exception may be the use of paracetamol in combination

with any other NSAID to enhance the analgesic effect) and the risk of adverse reactions increases.

Interaction with other drugs

When administered simultaneously, NSAIDs may enhance the effect of indirect anticoagulants and hypoglycemic agents. However, they weaken the effect of antihypertensive drugs, increase the toxicity of aminoglycosides, digoxin and some other drugs, which is of significant clinical importance (Table 24-3).

Many drugs prescribed concomitantly with NSAIDs, in turn, can affect their pharmacokinetics and pharmacodynamics:

Aluminum-containing antacids (Almagel*, Maalox*) and col-styramine ® reduce the absorption of NSAIDs in the gastrointestinal tract;

Glucocorticoids and slow-acting (basic) anti-inflammatory drugs (gold preparations) enhance the anti-inflammatory effect of NSAIDs;

Narcotic analgesics and sedatives enhance the analgesic effect of NSAIDs.

Acetylsalicylic acid (aspirin)

Acetylsalicylic acid is the first NSAID. In clinical trials, it typically serves as the standard against which others are compared for efficacy and tolerability.

NSAIDs.

Pharmacodynamics

The pharmacodynamics of acetylsalicylic acid depends on the daily dose: small doses - 30-325 mg - cause inhibition of platelet aggregation; medium doses (0.5-2 g) have an analgesic and antipyretic effect; large doses (4-6 g) have an anti-inflammatory effect. In high doses (more than 4 g) it stimulates the excretion of uric acid, interfering with its reabsorption in the renal tubules.

Pharmacokinetics

Well absorbed from the gastrointestinal tract. The half-life of acetylsalicylic acid is only 15-20 minutes. Under the influence of esterases in the mucous membrane of the stomach, liver and blood from ace-

tylsalicylic acid, salicylate is cleaved off, which has the main pharmacological activity. The maximum concentration of salicylate in the blood develops 2 hours after taking acetylsalicylic acid, its half-life is 4-6 hours. Metabolized in the liver, excreted in the urine, and when the pH of the urine increases (for example, in the case of antacids), excretion increases. When using large doses of acetylsalicylic acid, it is possible to saturate metabolizing enzymes and increase the half-life of salicylate to 15-30 hours.

Interactions

Glucocorticoids accelerate the metabolism and excretion of acetylsalicylic acid. The absorption of acetylsalicylic acid in the gastrointestinal tract is enhanced by caffeine and metoclopramide. Acetylsalicylic acid inhibits gastric alcohol dehydrogenase, which leads to an increase in ethanol levels in the body.

NLR

Acetylsalicylic acid can cause damage to the gastric mucosa and lead to the development of erosions and/or ulcers, which are often complicated by bleeding, even when used in low doses - 75-300 mg / day (as an antiplatelet agent). The risk of bleeding is dose-related. Increased bleeding develops as a result of impaired platelet aggregation and inhibition of prothrombin synthesis in the liver (the latter with an aspirin dose of more than 5 g/day).

When taking acetylsalicylic acid, hypersensitivity reactions are possible: skin rash, bronchospasm. There is a special nosological form - Fernand-Vidal syndrome (“aspirin triad”): a combination of nasal and/or paranasal sinus polyposis, bronchial asthma and complete intolerance to acetylsalicylic acid. Therefore, acetylsalicylic acid and other NSAIDs are recommended to be used with great caution in patients with bronchial asthma.

Reye's syndrome develops when acetylsalicylic acid is prescribed to children with viral infections (influenza, chicken pox). It manifests itself as severe encephalopathy, cerebral edema and liver damage, which occurs without jaundice, but with high levels of cholesterol and liver enzymes. Gives a very high mortality rate (up to 80%). Therefore, acetylsalicylic acid should not be used for acute respiratory viral infections in children under the first 12 years of life.

Overdose or poisoning in mild cases is manifested by symptoms of “salicylicism”: tinnitus (a sign of “saturation” with salicylate), stupor, hearing loss, headache, visual disturbances, and sometimes nausea and vomiting. In severe intoxication, disorders of the central nervous system and water-electrolyte metabolism develop. Shortness of breath (as a result of stimulation of the respiratory center), disturbances in the acid-base state (first respiratory alkalosis due to loss of carbon dioxide, then metabolic acidosis due to inhibition of tissue metabolism), polyuria, hyperthermia, and dehydration are noted. Oxygen consumption by the myocardium increases, heart failure and pulmonary edema may develop. The most sensitive to the toxic effects of salicylate are children under 5 years of age, in whom, just like in adults, it manifests itself as severe disturbances in the acid-base state and neurological symptoms.

Indications

Acetylsalicylic acid is used as an analgesic, antipyretic and antiplatelet agent. Acetylsalicylic acid is prescribed immediately if myocardial infarction or ischemic stroke is suspected. At the same time, acetylsalicylic acid has little effect on thrombus formation in the veins, so the drug should not be used for the prevention of postoperative thrombosis in surgery, where heparin is the drug of choice. Acetylsalicylic acid is one of the drugs of choice for the treatment of rheumatoid arthritis, including juvenile arthritis.

Diclofenac

Diclofenac is one of the widely used NSAIDs in the world. Diclofenac combines high anti-inflammatory activity with good tolerability during long-term use and is widely used in rheumatology. Has a strong and rapid analgesic effect.

Pharmacokinetics

Diclofenac is well absorbed from the gastrointestinal tract. Bioavailability is 50-60%, which is due to the “first pass” effect. The maximum concentration in the blood develops 0.5-2 hours after oral administration and 10-30 minutes after intramuscular administration. The half-life is 1.5-2 hours.

NLR

Diclofenac is generally well tolerated. With long-term use, the drug can have a negative effect on the gastrointestinal tract and, especially, the liver, so clinical and laboratory monitoring is necessary.

Meloxicam

Meloxicam is a representative of a new generation of NSAIDs - selective COX-2 inhibitors. Thanks to this property, meloxicam selectively inhibits the formation of prostaglandins involved in the formation of inflammation. At the same time, it inhibits COX-1 much weaker, and therefore has less effect on the synthesis of prostaglandins, which regulate renal blood flow, the production of protective mucus in the stomach and platelet aggregation. The drug is often prescribed to patients with rheumatoid arthritis and osteoarthritis.

Pharmacokinetics

Bioavailability when taken orally is 89% and does not depend on food intake. The maximum concentration in the blood develops after 5-6 hours. Equilibrium concentration is created after 3-5 days. The half-life is 20 hours, which allows the drug to be administered once a day.

Ibuprofen

Ibuprofen, along with paracetamol, is one of the safest NSAIDs recommended for use, including in children. The drug is characterized by good analgesic and antipyretic effects, the anti-inflammatory activity of the drug is low. It is used more often as an analgesic, as well as in mild cases of rheumatoid arthritis and osteoarthritis.

Pharmacokinetics

The maximum concentration in the blood develops 1-2 hours after ingestion. It is quickly metabolized and excreted from the body. The half-life is 1.5-2.5 hours; therefore, the analgesic and antipyretic effects are maintained for up to 8 hours. The advantage of the drug is its good tolerability and the rare development of adverse reactions. It has the least damaging effect on the gastric mucosa among

other NSAIDs.

Metamizole

In Russia and some developing countries, metamizole (analgin) and metamizole-containing products are widely used. In the UK, Sweden, Norway, Saudi Arabia, UAE, USA, Australia, Israel, Denmark, the Netherlands, Ireland, Germany, Singapore and other countries, metamizole is prohibited for use due to a large number of adverse reactions, such as bone marrow suppression, agranulocytosis, aplastic anemia, development of complications from the kidneys (interstitial nephritis), liver (hepatitis), lungs (alveolitis), Lyell's and Stevens-Johnson syndromes.

Paracetamol (acetaminophen)

Paracetamol inhibits prostaglandin synthesis more in the central nervous system than in peripheral tissues. Therefore, it has a predominantly “central” analgesic and antipyretic effect and has a very weak “peripheral” anti-inflammatory activity.

Pharmacokinetics

Paracetamol is well absorbed when taken orally and rectally. The maximum concentration in the blood develops 0.5-2 hours after administration. The drug is metabolized in the liver in 2 stages: first, under the influence of cytochrome P-450, intermediate hepatotoxic metabolites are formed, which are then conjugated with glutathione. 3% of administered paracetamol is excreted unchanged by the kidneys. The half-life is 2-2.5 hours. Duration of action - 3-4 hours.

Adverse reactions

Paracetamol is considered one of the safest NSAIDs. However, with long-term use of paracetamol, the risk of developing severe nephropathy leading to end-stage renal failure increases. It is based on the nephrotoxic effect of paracetamol metabolites, especially paraaminophenol. You should also be aware of the hepatotoxicity of paracetamol when taken in very large doses. A single dose of more than 10 g in adults or more than 140 mg/kg in children leads to poisoning, accompanied by severe liver damage. The reason is the depletion of glutathione reserves and the accumulation of intermediate products of paracetamol metabolism, which have a hepatotoxic effect.

It must be borne in mind that forced diuresis in case of paracetamol poisoning is ineffective and even dangerous; peritoneal dialysis and hemodialysis are ineffective. Taking sorbents, glutathione donors (acetylcysteine), and plasma transfusion are effective.

Interactions

The absorption of paracetamol in the gastrointestinal tract is enhanced by metoclopramide and caffeine.

Inducers of liver enzymes (phenytoin, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants, ethanol and some others) accelerate the breakdown of paracetamol to hepatotoxic metabolites and increase the risk of liver damage.

Nimesulide

Nimesulide is a selective COX-2 inhibitor. In this regard, it selectively disrupts the formation of prostaglandins involved in the formation of the inflammatory response, and does not affect the production of prostaglandins that regulate renal blood flow and the integrity of the gastrointestinal mucosa. Does not interfere with thromboxane synthesis, therefore does not affect platelet aggregation.

NLR

When using nimesulide, there is a fairly high risk of developing increased activity of hepatic transaminase, hepatitis, and acute liver failure requiring liver transplantation. When taking nimesulide, allergic reactions are possible, including Stevens-Johnson syndrome and Lyell's syndrome. The use of nimesulide may adversely affect female fertility. The sale of nimesulide is prohibited in a number of countries. The European Medicines Agency (EMEA) has introduced a number of restrictions: the dosage regimen should not exceed 200 mg per day; the course of treatment should not exceed 15 days.

24.6. CLINICAL PHARMACOLOGY OF GLUCOCORTICOIDS

Glucocorticoids are hormones produced by the adrenal cortex. The term also refers to semi-synthetic drugs, such as prednisolone, dexamethasone and other drugs, which are derivatives of hydrocortisone, the most active natural glucocorticoid.

The adrenal cortex synthesizes two glucocorticoids: cortisone and hydrocortisone (cortisol). Cortisone is a biologically inactive compound that is converted to hydrocortisone in the liver. Both natural glucocorticoids have mineralocorticoid activity, but weaker than true mineralocorticoids.

The production of glucocorticoids is controlled by the hypothalamic-pituitary-adrenal system. The key organ regulating the synthesis of glucocorticoids is the hypothalamus, which responds to the concentration of hydrocortisone in plasma in the blood and stress. When there is a low concentration of glucocorticoids in the blood or stress (trauma, infection, physical stress), the hypothalamus produces corticotropin-releasing factor (corticoliberin), which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Under the influence of ACTH, glucocorticoids and mineralocorticoids are synthesized in the adrenal glands. With an excess of glucocorticoids in the blood, the hypothalamus stops producing corticotropin-releasing factor. Thus, the hypothalamic-pituitary-adrenal system functions according to a negative feedback mechanism (Fig. 24-2).

Rice. 24-2. Regulation of the function of the hypothalamic-pituitary-adrenal system

The release of glucocorticoids from the adrenal glands into the blood during the day does not occur evenly, but in the form of 8-12 impulses, which obey the circadian rhythm. Maximum secretion of hydrocortisone occurs in the early hours (6-8 hours) and decreases sharply in the evening and at night.

Pharmacokinetics

Glucocorticoids are well absorbed from the gastrointestinal tract. The maximum concentration in the blood is observed after 0.5-1.5 hours. Food somewhat slows down the rate of absorption, but does not reduce its degree.

Glucocorticoids for injection are available in the form of various esters. Succinates, hemisuccinates and phosphates are water-soluble and have a rapid and relatively short-term effect. In emergency situations, these are the drugs of choice and are administered intravenously. When administered intramuscularly, the maximum effect develops after 1-2 hours. Acetates and acetonides are fine-crystalline suspensions, insoluble in water, the effect of which develops slowly (several hours) and lasts a long time (several weeks). They are intended for intra- and periarticular administration. When administered intramuscularly, they are slowly absorbed with the onset of action after 1-2 days, a maximum after 4-8 days and a duration of up to 4 weeks. They cannot be administered intravenously.

Metabolism. Glucocorticoids undergo biotransformation in the liver with the formation of inactive metabolites, and natural ones faster than semi-synthetic ones. Cortisone and prednisone first undergo first-pass metabolism into the active forms hydrocortisone and prednisolone, respectively. Fluorinated glucocorticoids (triamcinolone, dexamethasone, betamethasone) are biotransformed more slowly than all others.

In the blood plasma, glucocorticoids bind to proteins (trans-cortin, albumin), 90% natural, and 40-60% semi-synthetic. This is due to the higher concentration of semisynthetic glucocorticoids in tissues and their higher activity.

Excretion of inactive glucocorticoid metabolites is carried out by the kidneys. Natural glucocorticoids have the shortest T1/2, fluorinated drugs have the longest. In case of renal failure, this parameter does not change and no dose adjustment is required.

Pharmacodynamics

After passing through the cell membrane, glucocorticoids in the cytoplasm bind to a specific steroid receptor. The activated glucocorticoid-receptor complex penetrates the cell nucleus, binds to DNA and stimulates the formation of messenger RNA. As a result of RNA translation, various regulatory proteins are synthesized on ribosomes. One of the most important is lipocortin, which inhibits the enzyme phospholipase A 2 and thereby suppresses the synthesis of prostaglandins and leukotrienes, which are of great importance in the development of the inflammatory reaction.

There is also a theory of non-genomic action of glucocorticoids, according to which the effects are realized not only through the nucleus, but through membrane and cytoplasmic receptors. As a result, some glucocorticoid effects may occur more quickly, especially when high doses are administered intravenously. However, the maximum pharmacological activity of glucocorticoids occurs during the period when their peak concentrations in the blood are already behind them.

Water and electrolyte balance. Drugs in this group slow down the excretion of sodium and water from the body as a result of increased reabsorption in the distal renal tubules, and increase the excretion of potassium (mineralocorticoid activity). These effects are more characteristic of natural glucocorticosteroids (cortisone and hydrocortisone), less so of semi-synthetic ones (prednisone, prednisolone, methylprednisolone). The fluorinated drugs triamcinolone, dexamethasone and betamethasone do not have mineralocorticoid activity.

Carbohydrate metabolism. An increase in blood glucose concentration due to stimulation of gluconeogenesis in the liver, a decrease in membrane permeability to glucose. Glucosuria and steroid diabetes may develop.

Protein metabolism. Inhibition of synthesis and increased protein breakdown processes, especially in skin, muscle and bone tissue. This is manifested by weight loss, muscle weakness, skin and muscle atrophy, stretch marks, hemorrhages, and slow wound healing.

Fat metabolism. Redistribution of subcutaneous fat according to the Cushingoid type (Itsenko-Cushing syndrome: moon-shaped face, pituitary-type obesity, hirsutism, increased blood pressure, dysmenorrhea, stretch marks). This is due to the fact that lipolysis predominates in the tissues of the extremities, and lipogenesis predominates in the tissues of the chest, neck, face, and shoulder girdle.

Calcium metabolism. Glucocorticoids reduce calcium absorption in the intestine, promote its release from bone tissue and increase excretion in the urine. As a result, osteoporosis, hypocalcemia and hypercalciuria may develop.

The cardiovascular system. Glucocorticoids increase the sensitivity of adrenergic receptors to catecholamines and enhance the pressor effect of angiotensin II. They reduce capillary permeability, maintain normal arteriolar tone and myocardial contractility. With adrenal insufficiency, cardiac output decreases, arterioles dilate, and the response to adrenaline is weakened. Together with hypovolemia caused by mineralocorticoid deficiency, these changes can lead to vascular collapse.

Anti-inflammatory effect. Glucocorticoids inhibit all phases of inflammation. Many factors are important in their anti-inflammatory effect: inhibition of phospholipase A and the associated disruption of the formation of prostaglandins and leukotrienes, stabilization of lysosome membranes, reduction of capillary permeability, inhibition of the migration of neutrophils and macrophages to the site of inflammation, inhibition of fibroblast proliferation and collagen synthesis, suppression of cytokine formation by lymphocytes and macrophages.

Immunomodulatory and antiallergic effects. Glucocorticoids inhibit the proliferation of lymphoid tissue and cellular immunity, which underlies their use in organ and tissue transplantation. These drugs inhibit the formation and disrupt the kinetics of T-lymphocytes, reducing their cytotoxic activity, and prevent the interaction of immunoglobulins with mast cells and macrophages, inhibiting the release of biologically active substances from them.

Blood. Glucocorticoids cause lymphocytopenia, monocytopenia and eosinopenia, but stimulate the formation of red blood cells and platelets.

After taking even 1 dose of glucocorticoids, the number of lymphocytes, monocytes, eosinophils, and basophils decreases with the simultaneous development of neutrophilic leukocytosis. The maximum changes in the blood are observed after 4-6 hours, the initial state is restored after 24 hours. After completing a long course of glucocorticoids, changes in the blood can persist for 1-4 weeks.

Endocrine system. The administration of glucocorticoids is accompanied by inhibition of the hypothalamic-pituitary-adrenal system, which is due to negative feedback. Suppression is more pronounced with long-term use of glucocorticoids and/or prescription of long-acting drugs.

Glucocorticoids reduce the production of sex hormones as a result of direct suppression of their synthesis and a decrease in the production of luteinizing hormone by the pituitary gland.

Adverse drug reactions

With systemic administration of glucocorticoids, a wide variety of ADRs can develop (Table 24-4). The risk of their occurrence, as a rule, increases with increasing doses and duration of drug use.

Immunity _I Intensification of tuberculosis and other infections

Modern methods of using glucocorticoids (for example, alternating therapy), inhalation and intra-articular administration can not only reduce the incidence of ADRs, but also increase the effectiveness of treatment. However, with any treatment it is necessary to monitor the development of ADRs (monitoring body weight, blood pressure, electrolyte composition of the blood, the state of the gastrointestinal tract, musculoskeletal system, visual organs, determining the concentration of glucose in the blood and urine, monitoring the development of infectious complications).

Bacterial infections (usually in the form of pneumonia or septicemia) occur most frequently. The main pathogens are staphylococci and gram-negative bacteria of the intestinal group, which should be taken into account when choosing empirical antibacterial therapy.

Tuberculosis. Patients with positive tuberculin tests are at risk of developing severe tuberculosis, and during long-term treatment with glucocorticoids they should take isoniazid for prophylactic purposes.

Viral infections. The use of glucocorticoids increases the risk of dissemination of viral infections. In case of contact with a patient with chickenpox or herpes zoster, a patient who has not previously been ill should receive specific immunoglobulin within 48 hours. If the course of glucocorticoids exceeds 2 weeks, then the use of live viral vaccines is not recommended.

Secondary adrenal insufficiency. The most severe complications of taking glucocorticoids, potentially life-threatening, include secondary adrenal insufficiency - a consequence of suppression of the hypothalamic-pituitary-adrenal system with long-term use of glucocorticoids.

Risk factors for oppression

hypothalamic-pituitary-adrenal system

Dose. When taking glucocorticoids in physiological doses (for an adult 2.5-5 mg/day prednisolone or 10-30 mg/day hydrocortisone) suppression of the hypothalamic-pituitary-adrenal

the system is not happening. At higher doses, dysfunction of the adrenal cortex is noted after 1-2 weeks, and subsequently its atrophy may develop.

Duration of treatment. With a course of up to 10 days (at a dose of no more than 40 mg/day of prednisolone), there is no danger of significant inhibition of the hypothalamic-pituitary-adrenal system; when taken for several weeks, atrophy of the adrenal cortex is possible.

Time of receipt. It is necessary to take into account the circadian rhythm of glucocorticoid production (it is more dangerous to take 5 mg of prednisolone in the evening than 20 mg in the morning).

Type of drug. Suppression of the hypothalamic-pituitary-adrenal system is more pronounced when taking fluorinated glucocorticoids - triamcinolone, dexamethasone, betamethasone with the longest action.

Withdrawal syndrome clinic. The severity of the withdrawal syndrome depends on the preservation of the function of the adrenal cortex. In mild cases, general weakness, fatigue, loss of appetite, muscle pain, exacerbation of the underlying disease, and fever appear. In severe cases (especially under severe stress), a classic Addisonian crisis may develop with vomiting, collapse, and convulsions. Without the administration of glucocorticoids, patients quickly die from acute cardiovascular failure.

Measures to prevent secondary adrenal insufficiency:

With the exception of emergency conditions and special indications, it is recommended to prescribe glucocorticoids in accordance with the circadian rhythm;

It is necessary to use alternating therapy as widely as possible;

When the course of treatment lasts more than 10 days, glucocorticoids are discontinued with a gradual reduction in their dose; the withdrawal mode depends on the duration of use; for a course of several weeks to several months, it is permissible to reduce the dose by 2.5-5 mg of prednisolone (or an equivalent amount of another drug) every 3-5 days. With longer use, it is necessary to reduce the dose more slowly - by 2.5 mg every 1-3 weeks;

After discontinuation of glucocorticoids taken for 2 weeks or more, monitor the patient’s condition in stressful situations for 1.5-2 years. If necessary, provide protective therapy with glucocorticoids.

Interactions with other drugs

The effect of glucocorticoids is enhanced by concomitant administration of erythromycin (slows down the metabolism of glucocorticoids in the liver), salicylates (increases the non-protein-bound fraction of glucocorticoids), and estrogens.

The effect of glucocorticoids is weakened by inducers of microsomal liver enzymes - phenobarbital, phenytoin, rifampicin.

Glucocorticoids weaken the effect of anticoagulants, antidiabetic and antihypertensive drugs.

Glucocorticoids enhance the effect of theophylline, sympathomimetics, immunosuppressants, and NSAIDs.

Indications for the use of glucocorticoids

There are three fundamentally different regimens for prescribing glucocorticoids.

Replacement therapy. The use of glucocorticoids in physiological doses for adrenal insufficiency of any etiology. Cortisone or hydrocortisone is administered taking into account the circadian rhythm - 2/3 doses in the morning and 1/3 in the evening. Other drugs are prescribed once a day in the morning.

Suppressive therapy. The use of glucocorticoids for adrenogenital syndrome 1 in pharmacological (exceeding physiological) doses, which leads to suppression of ACTH secretion and a subsequent decrease in hypersecretion of androgens by the adrenal cortex; 1/3 of the daily dose of cortisone or hydrocortisone is usually given in the morning, and 2/3 of the dose in the evening.

Pharmacodynamic therapy. The most common use of glucocorticoids is divided into systemic and local. In systemic therapy, glucocorticoids are prescribed based on their anti-inflammatory, antiallergic, immunosuppressive and anti-shock effects. With systemic pharmacodynamic therapy, various routes of administration and dosage regimens of drugs can be used depending on the severity of the patient’s condition (Table 24-5). The most preferred drugs with an average duration of action are prednisone, prednisolone, methylprednisolone (Table 24-6).

1 Adrenogenital syndrome is associated with hypersecretion of the adrenal glands and sex hormones.

Table 24-6. Comparative activity of glucocorticoids

Long-acting drugs should be prescribed in a short course. Dexamethasone has some special indications for use: bacterial meningitis, cerebral edema, prevention of respiratory distress syndrome in premature newborns (dexamethasone stimulates the synthesis of surfactant in the alveoli of the lungs), leukemia (replacing prednisolone with dexamethasone in acute lymphoblastic leukemia significantly reduces the incidence of central nervous system damage).

Principles of long-term treatment

It is preferable to use glucocorticoids with an intermediate duration of action.

Individual dose selection is necessary, depending more on the nature of the disease and the patient's response to treatment than on age or body weight.

The dose is reduced gradually to the minimum that ensures clinical stability after obtaining the desired effect.

Taking into account the physiological circadian rhythm of glucocorticoid secretion: in most cases, drugs should be prescribed in the form of one morning dose, it is possible to prescribe 2/3-3/4 doses in the morning, and the rest - around noon. This dosage regimen reduces the risk of suppression of the hypothalamic-pituitary-adrenal system, since in the morning this system is least sensitive to the suppressive effect of exogenous glucocorticoids.

Transfer of the patient to alternative therapy is possible only when the condition has stabilized.

Alternative therapy

Alternative therapy consists of prescribing a glucocorticoid every other day in the form of 1 dose, which should be 2 times greater than that administered before switching to alternative therapy.

The main advantage of this method is less suppression of the hypothalamic-pituitary-adrenal axis and, therefore, a reduced risk of developing adrenal insufficiency.

The patient is transferred to alternating therapy gradually and only after the condition has stabilized. For this prescription regimen, only glucocorticoids with an average duration of action (prednisolone, methylprednisolone, prednisone) are suitable, after taking 1 dose of which the hypothalamic-pituitary-adrenal system is suppressed for 12-36 hours. Long-acting drugs (triamcinolone, dexamethasone, betamethasone) cannot be used, so as when they are prescribed, even every other day, the risk of suppression of the hypothalamic-pituitary-adrenal system does not decrease.

Alternative therapy is not effective enough in the treatment of hematological diseases, ulcerative colitis, malignant tumors, and in severe conditions.

Pulse therapy

Pulse therapy consists of short-term administration of ultra-high doses of glucocorticoids. The minimal mineralocorticoid effect of methylprednisolone, its weaker effect on the gastrointestinal tract and central nervous system than prednisolone, make it the drug of choice when performing pulse therapy. Typically, methylprednisolone is administered at a dose of 1-2 g/day intravenously once a day for 3-5 days.

Indications for pulse therapy are severe and life-threatening diseases, primarily systemic collagenoses (systemic

lupus erythematosus, vasculitis, severe rheumatoid arthritis with visceral lesions, severe ankylosing spondylitis). Pulse therapy is also used for thrombocytopenic purpura, acute spinal cord injury, and multiple sclerosis.

In patients with the most severe forms of rheumatic diseases (lupus nephritis, lupus lesions of the central nervous system, rheumatoid vasculitis, systemic necrotizing vasculitis), pulse therapy should be combined with the use of cytostatics (cyclophosphamide).

Contraindications for the use of glucocorticoids are relative and should be taken into account when planning long-term treatment:

Diabetes (fluorinated glucocorticoids are especially dangerous);

Mental illnesses, epilepsy;

Peptic ulcer of the stomach and duodenum;

Severe osteoporosis;

Severe hypertension.

In emergency situations, glucocorticoids are administered without taking into account contraindications.

Glucocorticoids penetrate well through the placenta. Natural and non-fluorinated semi-synthetic drugs are generally safe for the fetus and do not lead to the intrauterine development of Cushing's syndrome and inhibition of the hypothalamic-pituitary-adrenal system. Fluorinated glucocorticoids, when taken for a long time, can cause unwanted reactions, including deformities.

Glucocorticoids are used to prevent respiratory distress syndrome in premature infants. As a rule, long-acting drugs are prescribed, most often dexamethasone. It is administered intramuscularly to the mother during pregnancy up to 34 weeks, 24-48 hours before the expected birth.

A woman in labor who has been taking glucocorticoids for the last 1.5-2 years should additionally administer hydrocortisone hemisuccinate* 100 mg every 6 hours to prevent acute adrenal insufficiency.

When breastfeeding, low doses of glucocorticoids, equivalent to 5 mg of prednisolone, do not pose a danger to the baby due to poor penetration into breast milk. Higher doses of drugs and their long-term use can cause growth retardation and depression of the child’s hypothalamic-pituitary-adrenal system.

Local application of glucocorticoids

Local use of glucocorticoids makes it possible to create a high concentration of the drug in the pathological focus and significantly reduce the risk of developing undesirable systemic reactions. Topical options:

Inhalation (into the lungs or nasal cavity);

Intra-articular, periarticular;

Intradermal (into scars);

Epidural;

Intracavitary (intrapericardial, intrapleural);

Rectal;

External (skin, eyes, ears).

Intra-articular injection. For intra- and periarticular administration, water-insoluble injectable preparations are used. This creates a high concentration of glucocorticoids in the synovium and synovial fluid, ensuring maximum local anti-inflammatory effect with a minimum likelihood of systemic effects.

Indications for intra-articular administration. Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Reiter's disease. Intra-articular administration is used for mono- or oligoarthritis, and in the case of polyarthritis - for severe inflammation of one or more joints.

The duration of the effect depends on the type of drug used and ranges from 1 to 3 weeks. In many cases, the therapeutic effect can depend on the individual response of the patient and last up to several months.

Contraindications. Infectious arthritis, severe joint destruction, significant osteoporosis, intra-articular fracture, periarticular cellulitis, osteomyelitis, bacterial endocarditis, sepsis, blood coagulation pathology.

Periarticular administration of glucocorticoids preferably for persistent inflammatory diseases of the periarticular tissues that cannot be treated with other drugs, with pain and dysfunction of the joints.

Indications. Capsulitis, tendovaginitis, bursitis, epicondylitis, plantar fasciitis, forearm tunnel syndrome.

For periarticular administration, it is advisable to use hydrocortisone acetate* (5-25 mg), since its action is shorter and negative.

The significant effect on connective tissue metabolism (impaired protein synthesis) is less pronounced than that of other drugs.

NLR. Pain, temporary exacerbation of the inflammatory process, infection, local atrophy and depigmentation of the skin, degenerative changes in the joint, aseptic necrosis of the bone, formation of fistula tracts (if crystals of the drug remain along the needle), damage to tendons or nerve trunks.

Prevention of ADRs. Strict adherence to asepsis and antisepsis, the use of a thin needle, local anesthetics, rest for the joint for 1-2 days after the procedure, simultaneous injection into no more than 3 joints, the longest possible intervals between injections into the same joint.

Cortisone- a natural glucocorticoid preparation, biologically inactive. Activated in the liver, turning into hydrocortisone. Has a short-term effect. Mainly used for replacement therapy of adrenal insufficiency in patients with normal liver function.

Prednisolone a synthetic glucocorticoid, most often used in clinical practice and considered as a standard drug. Refers to glucocorticoids with an average duration of action.

Methylprednisolone Compared to prednisolone, it has slightly greater (20%) glucocorticoid activity, minimal mineralocorticoid effect, and is less likely to cause undesirable reactions (especially changes in the psyche, appetite, ulcerogenic effect). Preferred when performing pulse therapy.

Dexamethasone is a fluorinated homolog of hydrocortisone. One of the most powerful glucocorticoids: 7 times stronger than prednisolone in glucocorticoid activity. Does not have mineralocorticoid effect. It causes severe depression of the hypothalamic-pituitary-adrenal system, severe disturbances of carbohydrate, fat, calcium metabolism, and a psychostimulating effect, therefore it is not recommended to prescribe it for a long period. The drug has some special indications for use: bacterial meningitis; cerebral edema; in ophthalmology (keratitis, uveitis and others); prevention and treatment of nausea and vomiting during chemotherapy; treatment of severe withdrawal syndrome in alcoholism; prevention of respiratory distress syndrome in premature infants (dexamethasone stimulates the synthesis of surfactant in the alveoli of the lungs); leukemia (replacement of prednisolone with dexamethasone for

acute lymphoblastic leukemia significantly reduces the incidence of damage to the central nervous system).

24.7. CLINICAL PHARMACOLOGY OF DRUGS FOR BASIC THERAPY OF RHEUMATOID ARTHRITIS

Gold compounds

Gold compounds are usually prescribed in addition to NSAIDs if they do not significantly suppress joint inflammation. Sodium aurothiomalate* 3 and aurothioglucose* 3 are administered parenterally.

Gold preparations affect T-lymphocytes, disrupting their activation and the development of an autoimmune reaction; they are administered intramuscularly once a week.

The effectiveness of treating rheumatoid arthritis with gold preparations is comparable to methotrexate. The advantage is considered to be the absence of significant immunosuppression and a lower risk of developing intercurrent infections. However, gold preparations cause many ADRs that require their discontinuation.

Gold preparations are contraindicated in cases of severe dysfunction of the liver, kidneys, pregnancy, as well as hematological diseases.

During treatment with gold preparations, it is necessary to monitor the composition of urine, hemoglobin concentration, leukocyte count, leukocyte formula and platelet count. These studies are repeated for a month before each injection of the drug, and then every 1-2 weeks.

NLR. Itching, dermatitis, stomatitis, proteinuria, agranulocytosis, thrombocytopenia, aplastic anemia, diarrhea, hepatitis, pneumonitis.

If any ADR develops, treatment with gold preparations is interrupted. If the manifestations of ADR are mild (mild itching or isolated skin rashes), treatment can be carefully resumed after 2 weeks.

In case of significant complications, use dimercaprol (a drug that binds gold) at a dose of 2.5 mg/kg intramuscularly up to 4-6 times a day for the first 2 days, and then 2 times a day for 5-7 days.

When taking aurothiomalate* 3, especially if stored in the light, a short-term reaction is possible: flushing of the face, tachycardia, fainting a few minutes after administration. In such cases

it is necessary to switch to the use of another gold compound - aurothioglucose *, which does not cause similar reactions. A gold preparation for oral administration is auranofin®.

Penicillamine

If gold preparations are poorly tolerated or insufficiently effective, penicillamine is prescribed, which is significantly inferior to them in effectiveness and tolerability.

ADRs (up to 40%) that force one to stop treatment with penicillamine are noted more often than with treatment with gold. Penicillamine can inhibit bone marrow hematopoiesis and cause proteinuria, nephrotic syndrome, cholestatic jaundice and other serious complications (myasthenia gravis, pemphigus, Goodpasture's syndrome, polymyositis, lupus-like syndrome), as well as skin rashes and taste disorders. The appearance of the first signs of these complications requires cessation of treatment. An exception is a taste disorder, which may resolve spontaneously. Before starting treatment and every 2-4 weeks while taking the drug, you need to do a urine test and a blood test with a platelet count.

In children, due to significant adverse events, gold and penicillamine preparations are not widely used.

Derivatives of 5-aminosalicylic acid

Drugs from the sulfonamide group (sulfasalazine, mesalazine), which are used in the treatment of necrotizing ulcerative enterocolitis, are also prescribed for connective tissue diseases (rheumatoid arthritis). They are not inferior in effectiveness to penicillamine, but are superior to it in tolerability.

The action of the drugs is associated with antagonism of folic acid and anticytokine action similar to methotrexate.

NLR. Nausea, vomiting, neutropenia, hemolysis, hepatitis and skin rashes.

There are no significant differences between sulfasalazine and mesalazine in terms of effectiveness and tolerability. However, some patients tolerate one of these drugs better than the other.

Aminoquinoline drugs

Antimalarial drugs (chloroquine, hydroxychloroquine) are often used due to their good tolerability, but

Indeed, these are the weakest among the basic treatments for systemic connective tissue diseases.

The effect of the drugs is due to weak cytotoxic properties and inhibition of macrophage function. They can be used in patients with minimal manifestations of articular syndrome, since the effect develops slowly, after 3-6 months of continuous use.

ADRs are minor and rare: dermatitis, myopathy and corneal opacification, usually reversible. At the first complaints about vision, the drug is discontinued. Hydroxychloroquine is better tolerated.

24.8. CLINICAL PHARMACOLOGY

CYTOSTATICS AND IMMUNOSUPPRESSIVE DRUGS

Many drugs used for chemotherapy of malignant neoplasms have an immunosuppressive effect and can be used in transplantation and the treatment of autoimmune diseases. Cytostatics share a similar mechanism of action and the ability to block both B- and T-cell clonal activation. The most widely used are azathioprine, mycophenolate mofetil, cyclophosphamide, and methotrexate. Other antitumor cytostatics, such as chlorambucil, vincristine, vinblastine, dactinomycin, are not prescribed as immunosuppressive drugs.

Older cytostatics (azathioprine, cyclophosphamide, methotrexate) are characterized by an effect on the cells of many tissues and organs; new drugs (mizoribine *, mycophenolate mofetil, brequinar sodium *) have a more selective effect on immunocompetent cells.

Cyclosporine activates T lymphocytes. Currently, this drug is most common in transplantology and in the treatment of certain autoimmune diseases.

Pharmacokinetics. The bioavailability of cyclosporine when taken orally is 20-50%. Fatty foods reduce bioavailability when the drug is taken in soft gelatin capsules and do not affect the absorption of cyclosporine administered as a microemulsion. Peak concentration is reached 1.3-4 hours after oral administration. Due to its good solubility in fats, cyclosporine is evenly distributed in the body (volume of distribution -

13 l/kg), especially in the liver, lungs, kidneys, pancreas, spleen, fatty tissue, lymph nodes, where the concentration of the drug exceeds the plasma concentration. Cyclosporine does not penetrate well through the blood-brain barrier and into breast milk, although it crosses the placental barrier and is detected in amniotic fluid. 50-60% of the drug accumulates in erythrocytes, 10-20% in leukocytes, the remainder binds to plasma lipoproteins and, to a lesser extent, to albumin. T 1/2 -6 hours. The drug undergoes biotransformation in the liver with the formation of more than 30 metabolites, which are excreted mainly in bile. Elimination is reduced in patients with impaired liver function and in elderly patients.

Pharmacodynamics. Cyclosporine selectively suppresses the activity of CD4 T lymphocytes, inhibits the early phases of the cellular response to antigens and regulatory stimuli by disrupting the function of proteins involved in the activation of T lymphocytes and the expression of genes encoding the synthesis of cytokines (IL-2, IL-3, IL-4, TNF). Cyclosporine also suppresses the chemotaxis of mononuclear phagocytes and the expression of class II antigens of the major histocompatibility complex on the membranes of antigen-presenting cells.

Indications. Cyclosporine remains the main drug for the prevention of graft rejection (during kidney, heart, liver and other organ transplants) as monotherapy or in combination with glucocorticoids. It is also prescribed for autoimmune diseases: Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease (a type of ulcerative colitis).

NLR. Cyclosporine has a nephrotoxic effect, which often forces discontinuation of the drug. Hypertension, hepatotoxicity, neurotoxicity, hirsutism, gingival hyperplasia, and dyspeptic symptoms develop less frequently.

Interaction with other drugs. Cyclosporine interacts with many drugs by affecting cytochrome P-450. The concentration of cyclosporine is reduced by barbiturates, carbamazepine, rifampicin, sulfonamides, and phenytoin. The concentration of cyclosporine increases with the simultaneous administration of amphotericin B, erythromycin, ketoconazole, glucocorticoids, some calcium antagonists (verapamil, diltiazem), doxycycline. Metoclopramide increases the absorption of cyclosporine.

Azathioprine

Synthetic derivative of 6-mercaptopurine. The immunosuppressive effect of azathioprine is stronger than its cytotoxic effect.

Pharmacokinetics. Bioavailability when taken orally is about 20%. The maximum concentration of the drug is achieved after 1-2 hours. The highest concentrations are created in the tissues of the liver, intestines, as well as in the kidneys, lungs, spleen, and muscles. The drug is quickly biotransformed and has a very variable half-life (about 5 hours on average). Azathioprine and its metabolites are excreted by the kidneys.

Pharmacodynamics. Azathioprine suppresses the proliferation of all rapidly dividing cells, and T-lymphocytes to a greater extent than B-lymphocytes, as a result of disruption of DNA synthesis. Azathioprine has a damaging effect on cells during mitosis, so it is effective both before and after antigen administration.

Indications. During organ transplantation (primarily kidneys) to prevent graft rejection in combination with cyclosporine or glucocorticoids or as monotherapy. Azathioprine is considered a reserve drug for some autoimmune diseases (severe rheumatoid arthritis, refractory to glucocorticoids).

NLR. Bone marrow suppression (leukopenia, thrombocytopenia), gastrointestinal reactions, hepatotoxicity, alopecia, increased susceptibility to infections, mutagenicity, carcinogenicity.

Interaction with other drugs. When administered concomitantly with allopurinol, the toxicity of azathioprine increases. If it is necessary to prescribe these drugs simultaneously, the dose of azathioprine should be reduced by 25-35%.

Cyclophosphamide

Pharmacokinetics. Well absorbed when taken orally, bioavailability is more than 75%. Plasma protein binding is low and is metabolized in the liver. Peak concentration is reached after 2-3 hours. T 1 / 2 3-12 hours. Excreted by the kidneys mainly in the form of metabolites, 5-25% unchanged.

Pharmacodynamics. Cyclophosphamide inhibits DNA synthesis of both proliferating and resting cells and suppresses the activity of B and T lymphocytes. It has a greater effect on B-lymphocytes and, accordingly, on the activity of antibody formation.

Indications. Bone marrow transplantation. In low doses, cyclophosphamide is used in the treatment of autoimmune diseases, such as

such as systemic lupus erythematosus, Wegener's granulomatosis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, dermatomyositis.

NLR. When prescribing large doses, the development of hemorrhagic cystitis, cardiotoxicity, severe pancytopenia, infections, and toxic kidney damage is possible. Anemia and thrombocytopenia develop less frequently. Anaphylactic reactions, hemorrhagic colitis, hepatitis, and stomatitis occur extremely rarely.

Interaction with other drugs. Cyclophosphamide potentiates bone marrow suppression by other myelotoxic drugs. Increased cardiotoxicity is possible when using cyclophosphamide with doxorubicin and increased hepatotoxicity when used simultaneously with azathioprine, chlorambucil, glucocorticoids, and cyclosporine.

Methotrexate

Pharmacokinetics. The maximum concentration in the blood is achieved 1-4 hours after oral administration and 40 minutes after intravenous administration. Bioavailability is 60-70%. T 1/2 -10 hours. Excreted mainly by the kidneys. Part of the drug binds to proteins and can remain in tissues for up to 1 month.

Pharmacodynamics. The use of methotrexate in large doses leads to the suppression of folate-dependent enzymes, purine synthesis and, accordingly, to the death of proliferating cells - a predominantly cytotoxic effect develops.

When prescribed in small and medium doses, the immunosuppressive effect of the drug predominates as a result of suppression of the synthesis of pro-inflammatory cytokines, induction of apoptosis of activated T-lymphocytes, and inhibition of neutrophil motility. Methotrexate also suppresses the humoral component of the immune system and reduces the concentration of immunoglobulins of classes G, M and A.

Indications. Second-line drug for the treatment of rheumatoid arthritis. Prescribed for the treatment of psoriasis refractory to standard therapy, psoriatic arthritis, dermatomyositis.

NLR. Nausea, vomiting, loss of appetite, diarrhea, increased transaminase activity. With long-term use of methotrexate, 40% of patients experience dose-dependent hepatotoxicity with the possible development of liver fibrosis and cirrhosis. Bone marrow suppression, pneumonitis, and anaphylaxis are possible. Has teratogenic and carcinogenic effects.

Interaction with other drugs. Methotrexate increases the hepatotoxicity of other drugs. When combined with phenylbutazone, the risk of bone marrow suppression increases. Penicillins and probenecid * increase, and phenytoin decreases, the concentration of methotrexate in plasma. Parallel administration of pyrimethamine, triamterene, trimethoprim can lead to increased toxic effects of methotrexate.

24.9. CLINICAL PHARMACOLOGY OF MONOCLONAL ANTIBODY PREPARATIONS

Traditional treatment with NSAIDs, glucocorticoids, and classical immunosuppressants is ineffective in 25-50% of patients with rheumatoid arthritis, does not reduce the activity of the disease and does not prevent the progression of osteochondral destruction and disability of patients. The key cytokine in the development of the disease is considered to be tumor necrosis factor-alpha, which is produced by monocytes, macrophages, fibroblasts, and T-B lymphocytes. It causes the development of chronic inflammation, destruction of cartilage and bone, loss of bone mass, acts as a mediator of the inflammatory response and is involved in the modulation of the immune system. TNF-α is important in the development of autoimmune and inflammatory diseases. TNF-α blockers (infliximab, adalimumab) are used as drugs for the treatment of rheumatoid, psoriatic arthritis, ankylosing spondylitis and Crohn's disease.

Infliximab (Remicade*) is a chimeric IgG1 monoclonal antibody consisting of 75% human protein and 25% mouse protein. Immunosuppressive agent, has a high affinity for TNF-α.

The drug quickly binds and forms a stable compound with the soluble and transmembrane forms of human TNF-α, reducing its functional activity. The specificity of infliximab for TNF-α is confirmed by its inability to neutralize the cytotoxic effect of a lymphotoxin cytokine that uses the same receptors as TNF-α.

Pharmacokinetics

Pharmacokinetic parameters (Cmax, volume of distribution, AUC) are dose-dependent. C max after a single intravenous infusion

Zia at a dose of 5 mg/kg is 118 mcg/ml, volume of distribution is 3 l. Final T 1/2 -9.5 days. Displayed within 6 months.

Indications for use

Rheumatoid arthritis (if previous treatment, including methotrexate, is ineffective). Crohn's disease (severe course, with ineffectiveness of standard treatment, including glucocorticoids and/or immunosuppressants).

NLR

Allergic reactions (delayed type): myalgia and/or arthralgia with fever, urticaria, itching, swelling of the face, lips, hands, dysphagia. The use of the drug 2-4 years after the last dose is accompanied by the development of allergic reactions in most patients. NDRs of other organs and systems: dizziness, fainting, “flushes” of blood to the skin of the face, increased or decreased blood pressure, nausea, diarrhea, dyspepsia, anemia, leukopenia, lymphadenopathy.

Interaction with other drugs

Methotrexate reduces the formation of antibodies to infliximab and increases its concentration in plasma.

Adalimumab. By selectively binding to TNF, it blocks its interaction with surface cellular p55 and p75 receptors, neutralizing the functions of TNF. Alters biological responses controlled by TNF, including changes in adhesion molecules that cause leukocyte migration. Reduces the concentration of C-reactive protein, ESR, serum cytokines

(IL-6).

Pharmacokinetics

Absorbed slowly. Bioavailability with a single subcutaneous injection of 40 mg is 64%. TS tah - 5 days. The volume of distribution for intravenous administration is 4.7-6 liters. Concentration in synovial fluid is 31-96% serum. It comes out slowly. Clearance - 12 ml/h; depends on body weight and the presence of antibodies to adalimumab. Clearance and T1/2 do not change significantly at a dose of 0.25-10 mg/kg. Age has a minimal effect on clearance. T 1/2 with intravenous and subcutaneous administration - 2 weeks

(10-20 days).

Indications for use

Exacerbation of moderate and severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.

NLR. Headache, dizziness, paresthesia, increased blood pressure, nausea, abdominal pain, diarrhea, dyspepsia, anemia, lymphopenia. Local reactions: pain, swelling, redness, itching at the injection site.

Contraindications

Hypersensitivity (including to latex), infectious diseases (tuberculosis), age under 18 years, pregnancy, lactation.

Interaction

Single and repeated use with methotrexate reduces the clearance of adalimumab by 29 and 44%, respectively, but this does not require dose adjustment of methotrexate and adalimumab.

Clinical pharmacology and pharmacotherapy: textbook. - 3rd ed., revised. and additional / ed. V. G. Kukesa, A. K. Starodubtseva. - 2012. - 840 p.: ill.

Systemic connective tissue diseases

1. General ideas

Systemic lupus erythematosus, systemic scleroderma, dermatomyositis-polymyositis belong to systemic connective tissue diseases (SCTDs) - a group of nosologically independent diseases that have a certain similarity in etiology, pathogenesis, and clinical manifestations. They are treated with similar drugs.

The common point in the etiology of all CTDs is latent infection with various viruses. Taking into account the tissue tropism of viruses and the genetic predisposition of the patient, expressed in the carriage of very specific HLA histocompatibility antigens, various diseases from the group under consideration can develop.

The starting or “trigger” mechanisms for turning on the pathogenetic processes of CTD are nonspecific. Most often this is hypothermia, physical influence (vibration), vaccination, intercurrent viral infection.

The surge of immunoreactivity that occurs under the influence of a triggering factor in the body of a predisposed patient is unable to fade away on its own. As a result of antigenic mimicry of virus-infected cells, a vicious circle of self-sustaining inflammatory process is formed, leading to the degradation of the entire system of specialized tissue structures in the patient’s body to the level of collagen-rich fibrous connective tissue. Hence the old name for this group of diseases - collagenosis.

All CTDs are characterized by damage to epithelial structures - skin, mucous membranes, epithelial glands of external secretion. Therefore, one of the typical clinical manifestations of this group of diseases is Sjogren's syndrome.

Muscles, serous and synovial membranes are necessarily involved to one degree or another, which is manifested by myalgia, arthralgia, and polyserositis.

Systemic damage to organs and tissues in CTD is facilitated by the obligatory formation of secondary immune complex vasculitis of medium and small vessels in all diseases of this group, including microscopic ones involved in microcirculation.

A typical manifestation of immune complex vasculitis is angiospastic Raynaud's syndrome, an obligatory component of the clinical picture of all diseases from the group under consideration.

The close connection between all CTDs is indicated by clinical cases with convincing signs of several diseases from this group, for example, systemic lupus erythematosus, systemic scleroderma, dermatomyositis-polymyositis. In such cases, we may be talking about a mixed diffuse connective tissue disease - Sharpe's syndrome.

. Systemic lupus erythematosus

connective disease lupus polymyositis

Definition

Systemic lupus erythematosus (SLE) is a diffuse disease of connective tissue with the formation of autoantibodies to structural elements of tissues, components of cell nuclei, circulation in the blood of immune complexes conjugated with active complement, capable of causing direct immune and immune complex damage to cellular structures, blood vessels, dysfunction of internal organs.

Etiology

The disease is more common in individuals with HLA DR2 and DR3, in families with inherited deficiency of individual complement components. An etiological role may be played by infection with RNA-containing retroviruses from the “slow” group. The pathogenetic mechanism of SLE can be triggered by intense solar insolation, medicinal, toxic, nonspecific infectious effects, and pregnancy. Women aged 15-35 years are prone to the disease.

Pathogenesis

A genetic defect and/or modification of the genetic base of the immune system by “slow” retroviruses causes dysregulation of the immune response to certain external influences. Cross-immunoreactivity occurs with the movement of normal tissue and intracellular structures into the category of antigens.

A wide range of autoantibodies are formed that are aggressive towards their own tissues. Including autoantibodies against native DNA, short nuclear RNA polypeptides (anti-Sm), ribonucleoprotein polypeptides (anti-RNP), RNA polymerase (anti-Ro), protein in RNA (anti-La), cardiolipin (antiphospholipid antibodies) , histones, neurons, blood cells - lymphocytes, erythrocytes, platelets, etc.

Immune complexes appear in the blood that can combine with complement and activate it. First of all, these are complexes of IgM with native DNA. Conjugates of immune complexes with active complement are fixed on the walls of blood vessels and in the tissues of internal organs. The microphage system consists mainly of neutrophils, which, in the process of destroying immune complexes, release a large number of proteases from their cytoplasm and release atomic oxygen. Together with active complement proteases, these substances damage tissues and blood vessels. At the same time, fibrinogenesis processes are activated through the complement C3 component, followed by collagen synthesis.

An immune attack on lymphocytes by autoantibodies reacting with the DNA-histone complex and active complement ends with the destruction of lymphocytes, and their nuclei are phagocytosed by neutrophils. Neutrophils containing in the cytoplasm the absorbed nuclear material of lymphocytes, possibly other cells, are called LE cells. This is a classic marker of systemic lupus erythematosus.

Clinical picture

The clinical course of SLE can be acute, subacute, or chronic.

In acute cases, typical for the youngest patients, the temperature suddenly rises to 38 0From and above, joint pain occurs, changes in the skin, serous membranes, and vasculitis characteristic of SLE appear. Combined lesions of internal organs - lungs, kidneys, nervous system, etc. - quickly form. Without treatment, after 1-2 years these changes become incompatible with life.

In the subacute variant, the most typical for SLE, the disease begins with a gradual deterioration in general well-being and decreased ability to work. Joint pain appears. Skin changes and other typical manifestations of SLE occur. The disease occurs in waves with periods of exacerbation and remission. Multiple organ disorders incompatible with life occur no earlier than 2-4 years later.

In chronic cases, the moment of onset of SLE is difficult to determine. The disease remains unrecognized for a long time, as it manifests itself as symptoms of one of the many syndromes characteristic of this disease. Clinical masks of chronic SLE can be local discoid lupus, benign polyarthritis of unknown etiology, polyserositis of unknown etiology, Raynaud's angiospastic syndrome, Werlhof's thrombocytopenic syndrome, Sjögren's sicca, etc. With this variant of the disease, the clinical picture typical of SLE appears no earlier than after 5 -10 years.

The advanced phase of SLE is characterized by multiple symptoms of damage to various tissue structures, blood vessels, and internal organs. Minimal typical deviations are characterized by a triad: dermatitis, polyserositis, arthritis.

There are at least 28 variants of skin lesions in SLE. Below are a number of the most common pathological changes in the skin and its appendages, mucous membranes.

· Erythematous dermatitis of the face. A persistent erythema, resembling a butterfly in shape, forms on the cheeks and dorsum of the nose.

· Discoid lesion. Raised round lesions, similar to coins, with hyperemic edges, depigmentation and atrophic changes in the center appear on the face, torso, and limbs.

· Nodular (nodular) skin lesions.

· Photosensitivity is a pathological hypersensitivity of the skin to solar insolation.

· Alopecia is generalized or focal baldness.

· Vasculitis of skin vessels in the form of urticaria, capillaritis (pinpoint hemorrhagic rash on the fingertips, palms, nail beds), ulcerations in places of skin microinfarctions. A vascular “butterfly” may appear on the face - pulsating redness of the bridge of the nose and cheeks with a cyanotic tint.

· Erosion on the mucous membranes, cheilitis (persistent thickening of the lips with the formation of small granulomas in their thickness).

Lupus polyserositis includes damage to the pleura, pericardium, and sometimes the peritoneum.

Joint damage in SLE is limited to arthralgia, symmetrical nonerosive arthritis without deformation, or ankylosis. Lupus arthritis is characterized by symmetrical lesions of the small joints of the hand, knee joints, and severe morning stiffness. Jaccoud's syndrome may develop - arthropathy with persistent joint deformities due to damage to tendons and ligaments, but without erosive arthritis. In connection with vasculitis, aseptic necrosis of the heads of the femur, humerus, and other bones often develops

Accompanying SLE myositis is manifested by myalgia and muscle weakness.

The lungs and pleura are often affected. Pleural involvement is usually bilateral. Adhesive (sticky), dry, exudative pleurisy are possible. Adhesive pleurisy may not be accompanied by objective symptoms. Dry pleurisy is manifested by pain in the chest, pleural friction noise. Dullness of percussion sound and limited mobility of the diaphragm indicate the accumulation of fluid in the pleural cavities, usually in a small volume.

Aseptic pneumonitis, characteristic of SLE, is manifested by an unproductive cough and shortness of breath. Its objective symptoms are no different from pneumonia. Vasculitis of the pulmonary arteries can cause hemoptysis, pulmonary failure, increased pressure in the pulmonary artery with overload of the right side of the heart. Thrombosis of the branches of the pulmonary artery with the formation of pulmonary infarctions is possible.

Clinical manifestations of cardiac pathology are caused by pancarditis characteristic of SLE: pericarditis, myocarditis, endocarditis, coronary artery vasculitis.

Pericarditis in SLE is often adhesive (sticky) or dry, and may manifest as a pericardial friction rub. Less commonly, exudative pericarditis occurs with a slight accumulation of fluid in the pericardial cavity.

Lupus myocarditis is the main cause of rhythm disturbances, conduction disorders, and heart failure.

Libman-Sachs warty endocarditis can be accompanied by multiple thromboembolisms in the vessels of internal organs with subsequent infarctions and cause the formation of heart defects. Typically, aortic valve insufficiency and mitral valve insufficiency occur. Valve stenosis is rare.

Lupus vasculitis of the coronary arteries causes ischemic damage to the heart muscle, including myocardial infarction.

The range of possible changes in the kidneys is very wide. Focal nephritis can be asymptomatic or with minimal changes in urinary sediment (microhematuria, proteinuria, cylindruria). Diffuse forms of lupus nephritis can cause nephrotic syndrome with edema, hypoproteinemia, proteinuria, hypercholesterolemia. Often, kidney damage occurs with malignant arterial hypertension. In most cases of diffuse lupus nephritis, renal failure occurs and quickly decompensates.

Lupus hepatitis is benign, manifested by moderate hepatomegaly, moderate liver dysfunction. It never leads to liver failure or liver cirrhosis.

Abdominal pain, sometimes very intense, muscle tension in the anterior abdominal wall (lupus abdominal crisis) is usually associated with vasculitis of the mesenteric vessels.

Most patients experience focal and diffuse changes in the central nervous system caused by vasculitis, thrombosis of cerebral vessels, and direct immune damage to nerve cells. Headaches, depression are typical, psychosis, epileptiform seizures, polyneuropathy, and motor dysfunction are possible.

In SLE, peripheral lymph nodes become enlarged and splenomegaly appears, which is not associated with disturbances in portal hemodynamics.

SLE patients are anemic. Hypochromic anemia, which belongs to the group of iron redistribution, often occurs. In immune complex diseases, which include SLE, macrophages intensively react with hemosiderin bodies, which are iron depots, removing (redistributing) them from the bone marrow. Iron deficiency appears for hematopoiesis, while the total content of this element in the body remains within normal limits.

Hemolytic anemia in patients with SLE occurs when red blood cells are destroyed in the process of eliminating immune complexes fixed on their membrane, as well as as a result of hyperreactivity of macrophages in an enlarged spleen (hypersplenism).

SLE is characterized by clinical Raynaud's, Sjögren's, Werlhoff, and antiphospholipid syndromes.

Raynaud's syndrome is caused by immune complex vasculitis. In patients, after exposure to cold or emotional stress, acute spastic ischemia of certain areas of the body occurs. The fingers except the thumb suddenly turn pale and become icy, and less often, the toes, chin, nose, and ears. After a short period of time, pallor is replaced by a purple-cyanotic color and swelling of the skin as a result of post-ischemic vascular paresis.

Sjogren's syndrome is an autoimmune lesion of the salivary, lacrimal and other exocrine glands with the development of dry stomatitis, keratoconjunctivitis, pancreatitis, secretory insufficiency of the gastric mucosa. In patients, the shape of the face may change due to compensatory hypertrophy of the parotid salivary glands. Sjögren's syndrome often occurs together with Raynaud's syndrome.

Werlhof's syndrome (symptomatic thrombocytopenic purpura) in SLE is caused by autoimmune inhibition of platelet formation processes, large consumption of platelets in the process of autoimmune reactions. It is characterized by intradermal petechial hemorrhages - purpura. In patients with a chronic variant of the clinical course of SLE, Werlhoff syndrome may be the only manifestation of this disease for a long time. With lupus, even a deep drop in the level of platelets in the blood is often not accompanied by hemorrhages. In the practice of the author of this book, there were cases when in patients in the initial period of SLE, the number of platelets in the peripheral blood did not rise above 8-12 per 1000 leukocytes in the absence of bleeding, while the level below which thrombocytopenic purpura usually begins is 50 per 1000.

Antiphospholipid syndrome is formed due to the occurrence of autoantibodies to phospholipids and cardiolipin. Antiphospholipid antibodies are called lupus anticoagulants. They negatively affect some stages of blood clotting, increasing thromboplastin time. Paradoxically, the presence of lupus anticoagulant in the blood is characterized by a tendency to thrombosis and not to bleeding. The syndrome in question usually manifests itself as deep vein thrombosis of the lower extremities. Reticular livedo is a tree-like vascular pattern on the skin of the lower extremities; it can also form as a result of thrombosis of the small veins of the legs. In patients with SLE, antiphospholipid syndrome is one of the main causes of thrombosis of cerebral, pulmonary vessels, and hepatic veins. Often combined with Raynaud's syndrome.

Diagnostics

General blood test: decrease in the number of red blood cells, hemoglobin, in some cases simultaneously with a decrease in the values ​​of the color index (CI). In some cases, reticulocytosis is detected - evidence of hemolytic anemia. Leukopenia, often pronounced. Thrombocytopenia, often profound. Increased ESR.

General urine analysis: hematuria, proteinuria, cylindruria.

Biochemical blood test: increased content of fibrinogen, alpha-2- and gamma-globulins, total and indirect bilirubin (for hemolytic anemia). With kidney damage, hypoproteinemia, hypercholesterolemia, increased urea and creatinine levels.

Immunological testing allows one to obtain positive results from a number of reactions that are quite specific for SLE.

· LE cells are neutrophils containing the nucleus of a phagocytosed lymphocyte in the cytoplasm. The detection of more than five LE cells per thousand leukocytes is of diagnostic value.

· Increased levels of circulating immune complexes (CIC).

· Antibodies to Sm-antigen - short nuclear RNA polypeptides.

· Antinuclear factor is a complex of antinuclear autoantibodies specific to various components of the cell nucleus.

· Antibodies to native DNA.

· The rosette phenomenon is the identification of groups of leukocytes surrounding freely lying cell nuclei.

· Antiphospholipid autoantibodies.

· Positive Coombs test for hemolytic anemia.

· Rheumatoid factor appears in moderate diagnostic titers only with pronounced articular manifestations of SLE.

ECG - signs of left ventricular myocardial hypertrophy with formed defects (mitral and/or aortic valve insufficiency), arterial hypertension of renal origin, various rhythm and conduction disorders, ischemic disorders.

X-ray of the lungs - effusion in the pleural cavities, focal infiltration (pneumonitis), interstitial changes (pulmonary vasculitis), triangular shadows of infarctions with embolism of the branches of the pulmonary artery.

X-ray of the affected joints shows moderate osteoporosis without usuration or ankylosis.

Ultrasound examination: effusion in the pleural cavities, sometimes a small amount of free fluid in the abdominal cavity. Moderate hepatomegaly and splenomegaly without disturbance of portal hemodynamics are determined. In some cases, signs of hepatic vein thrombosis are determined - Bad Chiari syndrome.

Echocardiography - effusion in the pericardial cavity, often significant (up to cardiac tamponade), dilatation of the heart chambers, a decrease in the ejection fraction of the left ventricle, areas of hypokinesia of the left ventricular wall of ischemic origin, defects of the mitral and aortic valves.

Ultrasound examination of the kidneys: diffuse, symmetrical increase in echogenicity of the parenchyma of both organs, sometimes signs of nephrosclerosis.

A puncture biopsy of the kidneys excludes or confirms one of the morphological variants of lupus nephritis.

The degree of SLE activity is determined based on the following criteria.

· I Art. - minimal activity. Body temperature is normal. Slight weight loss. Discoid lesions on the skin. Arthralgia. Adhesive pericarditis. Myocardial dystrophy. Adhesive pleurisy. Polyneuritis. Hemoglobin more than 120 g/l. ESR 16-20 mm/hour. Fibrinogen less than 5 g/l. Gamma globulins 20-23%. LE cells are absent or single. Antinuclear factor less than 1:32. Anti-DNA antibody titer is low. The CEC level is low.

· II Art. - moderate activity. Fever up to 38 0C. Moderate weight loss. Nonspecific erythema on the skin. Subacute polyarthritis. Dry pericarditis. Moderate myocarditis. Dry pleurisy. Diffuse glomerulonephritis of mixed type with arterial hypertension, hematuria, proteinuria. Encephaloneuritis. Hemoglobin 100-110 g/l. ESR 30-40 mm/hour. Fibrinogen 5-6 g/l. Gamma globulins 24-25%. LE cells 1-4 per 1000 leukocytes. Antinuclear factor 1:64. The titer of antibodies to DNA is average. The CEC level is average.

· III Art. - maximum activity. Fever above 38 0C. Pronounced weight loss. Skin lesions in the form of lupus erythema, “butterfly” on the face, capillaritis. Acute or subacute polyarthritis. Effusion pericarditis. Severe myocarditis. Lupus endocarditis. Exudative pleurisy. Diffuse glomerulonephritis with nephrotic syndrome. Acute encephaloradiculoneuritis. Hemoglobin is less than 100 g/l. ESR more than 45 mm/hour. Fibrinogen more than 6 g/l. Gamma globulins 30-35%. LE cells more than 5 per 1000 leukocytes. Antinuclear factor is higher than 1:128. The titer of antibodies to DNA is high. The CEC level is high.

American Rheumatology Association Revised Diagnostic Criteria for SLE:

The diagnosis is considered reliable if 4 or the criteria listed below are met. If fewer criteria are present, the diagnosis is considered presumptive (not excluded).

1. Lupoid butterfly": flat or raised fixed erythema on the cheekbones, tending to spread to the nasolabial area.

2. Discoid rash:raised erythematous plaques with adjacent scales, follicular plugs, atrophic scars on old lesions.

3. Photodermatitis:skin rashes that appear as a result of exposure to sunlight on the skin.

4. Erosion and ulcers in the oral cavity:painful ulcerations of the oral mucosa or nasopharynx.

5. Arthritis:non-erosive arthritis of two or more peripheral joints, manifested by pain, swelling, exudation.

6. Serosites:pleurisy, manifested by pleural pain, pleural friction rub or signs of pleural effusion; pericarditis, manifested by a pericardial friction rub, intrapericardial effusion detected by echocardiography.

7. Kidney damage:persistent proteinuria 0.5 g/day or more or hematuria, the presence of casts in the urine (erythrocyte, tubular, granular, mixed).

8. Damage to the central nervous system:convulsions - in the absence of drug or drug intoxication, metabolic disorders (ketoacidosis, uremia, electrolyte disturbances); psychosis - in the absence of taking psychotropic medications, electrolyte disturbances.

9. Hematological changes:leukopenia 4·10 9/l or less, registered two or more times; lymphopenia 1.5 10 9/l or less, registered at least twice; thrombocytopenia less than 100 10 9/l not caused by medication.

10. Immunological disorders:antibodies against native DNA in increased titer; Anti-smooth muscle antibodies (anti-Sm); antiphospholipid antibodies (increased levels of IgG or IgM antibodies to cardiolipin, the presence of lupus coagulant in the blood; false-positive Wasserman reaction in the absence of evidence of syphilitic infection (according to the results of RIT - the treponemal immobilization test or RIF - the immunofluorescent identification test of treponemal antigens).

11. Antinuclear antibodies:detecting them in elevated titers in the absence of taking medications that can cause lupus-like syndrome.

Differential diagnosis

It is carried out primarily with lupoid hepatitis (chronic autoimmune hepatitis with extra-penal manifestations), rheumatoid arthritis, as well as with mixed systemic connective tissue disease (Sharpe's syndrome), chronic glomerulonephritis, systemic vasculitis.

Chronic autoimmune hepatitis with extrahepatic manifestations is also called lupoid, as it is accompanied by multiple lesions of internal organs, arthralgia, polyserositis, vasculitis, etc., resembling SLE. However, unlike lupoid hepatitis, in SLE the liver damage is benign. There is no massive necrosis of hepatocytes. Lupus hepatitis does not progress to liver cirrhosis. In contrast, with lupoid hepatitis, according to puncture biopsy, there are pronounced and severe necrotic damage to the liver parenchyma, followed by transition to cirrhosis. During the period of formation of remission of lupoid hepatitis, the symptoms of extrahepatic lesions fade away first, but at least minimal signs of the inflammatory process in the liver remain. With systemic lupus erythematosus, the opposite happens. Signs of liver damage fade away first.

At the initial stages of the disease, SLE and rheumatoid arthritis have almost identical clinical manifestations: fever, morning stiffness, arthralgia, symmetrical arthritis of the small joints of the hands. However, with rheumatoid arthritis, joint damage is more severe. Erosion of the articular surfaces, proliferative processes followed by ankylosis of the affected joint are typical. Erosive ankylosing arthritis is not typical for SLE. The differential diagnosis of SLE and rheumatoid arthritis with systemic manifestations presents significant difficulties, especially in the initial stages of the disease. A common manifestation of SLE is severe glomerulonephritis leading to renal failure. In rheumatoid arthritis, glomerulonephritis occurs rarely. In cases where it is not possible to distinguish between SLE and rheumatoid arthritis, one should think of Sharpe's syndrome - a mixed systemic connective tissue disease that combines signs of SLE, rheumatoid arthritis, systemic sclerosis, polymyositis, etc.

Survey plan

· Complete blood count with platelet count.

· General urine analysis.

· Zimnitsky test.

· Biochemical blood test: fibrinogen, total protein and fractions, bilirubin, cholesterol, urea, creatinine.

· Immunological analysis: LE cells, CEC, rheumatoid factor, antibodies to Sm antigen, antinuclear factor, antibodies to native DNA, antiphospholipid antibodies, Wasserman reaction, direct and indirect Coombs tests.

· X-ray of the lungs.

· X-ray of the affected joints.

· ECG.

· Ultrasound of the pleural, abdominal cavities, liver, spleen, kidneys.

· Echocardiography.

· Biopsy of a musculocutaneous flap (according to indications - if differential diagnosis is necessary with other systemic connective tissue diseases, evidence of mixed connective tissue disease - Sharp's syndrome).

· Kidney biopsy (according to indications - if necessary, differential diagnosis with other systemic kidney diseases, chronic glomerulonephritis).

Treatment

Treatment tactics for SLE include:

· Suppression of hyperreactivity of immune mechanisms, immune inflammation, immune complex lesions.

· Treatment of selected clinically significant syndromes.

In order to reduce immune hyperreactivity and inflammatory processes, glucocorticosteroids, immunosuppressants (cytostatics), aminoquinoline drugs, and efferent methods (plasmopheresis, hemosorption) are used.

The basis for prescribing glucocorticoid drugs is convincing evidence of the diagnosis of SLE. In the initial stages of the disease with minimal signs of activity, glucocorticosteroid drugs are necessarily used, but not non-steroidal anti-inflammatory drugs. Depending on the course of SLE and the activity of immune-inflammatory processes, various regimens of monotherapy with glucocorticoids and their combined use with other drugs are used. Treatment begins with a “suppressive” dose of glucocorticoids with a gradual transition to a supportive dose as the activity of the immunoinflammatory process subsides. Most often, prednisolone for oral administration and methylprednisolone for parenteral administration are used for the treatment of SLE.

· In case of chronic SLE with minimal activity of immune inflammation, oral prednisolone is prescribed in minimal maintenance doses - 5-7.5 mg/day.

· In acute and subacute clinical course from stage II and III. activity of SLE, prednisolone is prescribed at a dose of 1 mg/kg/day. If after 1-2 days the patient’s condition does not improve, the dose is increased to 1.2-1.3 mg/kg/day. This treatment is continued for 3-6 weeks. When the activity of the immune-inflammatory process decreases, the dose begins to be reduced first by 5 mg per week. When a level of 20-50 mg/day is reached, the rate of reduction is reduced to 2.5 mg/week until a minimum maintenance dose of 5-7.5 mg/day is reached.

· In highly active SLE with severe vasculitis, lupus nephritis, severe anemia, leukopenia, thrombocytopenia, lupus encephaloradiculneuritis with acute mental and movement disorders, pulse therapy with methylprednisolone is performed against the background of systematic treatment with prednisolone. For three consecutive days, 1000 mg of methylprednisolone is administered intravenously over 30 minutes. This procedure can be repeated monthly for 3-6 months. In the days following pulse therapy, the patient should continue systematically taking oral prednisolone to avoid renal failure caused by a decrease in glomerular filtration.

Immunosuppressants (cytostatics) are prescribed for SLE only together with glucocorticosteroid drugs or against the background of their systematic use. Immunosuppressants can enhance the anti-inflammatory effect and, at the same time, reduce the required dose of glucocorticoids, thereby reducing the side effects of their long-term use. Cyclophosphamide, azathioprine, and less often other cytostatics are used.

· In case of high activity of SLE, systemic vasculitis with widespread ulcerative-necrotic skin lesions, severe pathological changes in the lungs, central nervous system, active lupus nephritis, if it is impossible to further increase the dose of glucocorticoids, the following is additionally prescribed:

o Cyclophosphamide 1-4 mg/kg/day orally, or:

o Azathioprine 2.5 mg/kg/day orally.

· For active lupus nephritis:

o Azathioprine 0.1 once a day orally and cyclophosphamide 1000 mg intravenously once every 3 months.

· To increase the effectiveness of three-day pulse therapy with methylprednisolone, 1000 mg of cyclophosphamide is additionally administered intravenously on the second day.

Aminoquinoline drugs are of auxiliary value. They are intended for long-term use with low activity of the inflammatory process, chronic SLE with predominantly skin lesions.

·

·

To eliminate excess autoantibodies, immune complexes, and inflammatory mediators from the blood, the following are used:

· Plasmapheresis - 3-5 procedures with a single removal of up to 1000 ml of plasma.

· Hemosorption on activated carbon and fiber sorbents - 3-5 procedures.

For the treatment of thrombocytopenic syndrome, the following is used:

· immunoglobulin preparations 0.4 g/kg/day for 5 days;

· dinazole 10-15 mg/kg/day.

If a tendency to thrombosis appears, low molecular weight heparin is prescribed at a dose of 5 thousand units under the skin of the abdomen 4 times a day, antiplatelet agents - chimes 150 mg per day.

If necessary, broad-spectrum antibiotics, anabolic hormones, diuretics, ACE inhibitors, and peripheral vasodilators are used.

Forecast.

Adverse. Especially in cases with highly active lupus nephritis, cerebral vasculitis. Relatively favorable prognosis in patients with chronic, inactive SLE. In such cases, adequate treatment provides patients with a life expectancy of over 10 years.

. Systemic scleroderma

Definition

Systemic scleroderma (SS) or systemic sclerosis is a diffuse connective tissue disease with fibrosclerotic changes in the skin and internal organs, vasculitis of small vessels in the form of obliterating endarteritis.

ICD 10:M 34 - Systemic sclerosis.

M34.0 - Progressive systemic sclerosis.

M34.1 - CR(E) ST syndrome.

Etiology.

The disease is preceded by infection with an unknown RNA-containing virus, prolonged professional contact with polyvinyl chloride, and work in conditions of intense vibration. Individuals with HLA histocompatibility antigens type B35 and Cw4 are predisposed to the disease. The vast majority of patients with SS have chromosomal aberrations - chromatid breaks, ring chromosomes, etc.

Pathogenesis

As a result of the influence of an etiological factor on endothelial cells, an immunopathological reaction occurs. T-lymphocytes, sensitized to antigens of damaged endothelial cells, produce lymphokines that stimulate the macrophage system. In turn, monokines from stimulated macrophages further damage the endothelium and simultaneously stimulate fibroblast function. A vicious immuno-inflammatory circle arises. Damaged walls of small muscular vessels become hypersensitive to vasoconstrictor influences. The pathogenetic mechanisms of vasospastic ischemic Raynaud's syndrome are formed. Active fibrogenesis in the vascular wall leads to a decrease in the lumen and obliteration of the affected vessels. As a result of similar immune-inflammatory reactions, circulatory disorders in small vessels, interstitial tissue edema occurs, stimulation of tissue fibroblasts with subsequent irreversible sclerosis of the skin and internal organs. Depending on the nature of immune changes, various variants of the disease are formed. The appearance of antibodies to Scl-70 (Scleroderma-70) in the blood is associated with the diffuse form of SS. Antibodies to centromeres are typical of CREST syndrome. Nuclear antibodies - for scleroderma kidney disease and overlap syndrome with dermatomyositis-polymyositis. Limited and diffuse forms of SS are pathogenetically significantly different:

· The limited form of SS is known as CREST-syndrome. Its signs are calcification ( Calcinosis), Raynaud's syndrome ( Reynaud), disturbances of esophageal motility ( Esophageal motility disorders), sclerodactyly ( Sclerodactilya), telangiectasia ( Teleangiectasia). Pathological changes are characteristic mainly of the skin of the face and fingers distal to the metacarpophalangeal joint. This is a relatively benign variant of the disease. Damage to internal organs is rare and appears only during a long course of the disease, and if it does occur, it is easier than with the diffuse form of SS.

· The diffuse form of SS (progressive systemic sclerosis) is characterized by sclerotic changes in the skin of the upper extremities proximal to the metacarpophalangeal joints, other parts of the body, up to its entire surface. Damage to internal organs occurs much earlier than in the limited form. More organs and tissue structures are involved in the pathological process. The kidneys and lungs are especially often and severely affected.

Clinical picture

The disease can occur in acute, subacute, and chronic forms.

The acute form of diffuse SS is characterized by the rapid development of all stages of skin lesions within less than one year. At the same time, lesions of internal organs, primarily the kidneys and lungs, appear and reach their culminating development. Throughout the entire period of the disease, maximum deviations in the parameters of general and biochemical blood tests are revealed, demonstrating the high activity of the pathological process.

In the subacute course, the disease develops at a relatively slow pace, but with the presence of all skin lesions, vasomotor disorders, and damage to internal organs typical of diffuse SS. There are deviations in laboratory and biochemical parameters, reflecting moderate activity of the pathological process.

The chronic course of SS is characterized by a gradual onset and slow progression over a long period of time. Most often, a limited form of the disease occurs - CREST syndrome. Clinically significant damage to internal organs and deviations in laboratory and biochemical parameters are usually not observed. Over time, patients may develop symptoms of pulmonary hypertension caused by obliterating endarteritis of the pulmonary artery and its branches, and signs of pulmonary fibrosis.

In typical cases, SS begins with pathological changes in the skin. Patients notice the appearance of painful thickening of the skin of the fingers of both hands (edematous phase). The skin then thickens (indurative phase). Subsequent sclerosis causes its thinning (atrophic phase).

Sclerotic skin becomes smooth, shiny, taut, and very dry. It cannot be folded, since it is fused to the underlying fascia, periosteum, and periarticular structures. Vellus hair disappears. Nails become deformed. On thinned skin of the hands, traumatic injuries, spontaneous ulcerations, and pustules easily arise and heal slowly. Telangiectasias appear.

The lesion on the facial skin, which is very characteristic of SS, cannot be confused with anything. The face becomes amicable, mask-like, unnaturally shiny, unevenly pigmented, often with purple foci of telangiectasias. The nose is pointed in the shape of a bird's beak. A “surprised” look appears, as sclerotic tightening of the skin of the forehead and cheeks opens the palpebral fissures wide and makes blinking difficult. The mouth gap narrows. The skin around the mouth contracts with the formation of radial folds that do not straighten out, resembling a “pouch” shape.

In the limited form of SS, lesions are limited only to the skin of the fingers and face. In the diffuse form, edematous, indurative-sclerotic changes gradually spread to the chest, back, legs, and entire body.

Damage to the skin of the chest and back creates in the patient a feeling of a corset that interferes with the respiratory movements of the chest. Total sclerosis of all skin forms a picture of pseudo-mummification of the patient - the phenomenon of “living relics”.

At the same time as the skin, the mucous membranes may be affected. Patients often report dryness, lack of saliva in their mouth, pain in the eyes, and inability to cry. Often these complaints indicate the formation of “dry” Sjögren’s syndrome in a patient with SS.

Together with edematous-indurative changes in the skin, and in some cases even before skin lesions, angiospastic Raynaud's syndrome can form. Patients begin to be bothered by attacks of sudden pallor, numbness of the fingers, less often of the legs, tips of the nose, ears after exposure to cold, against a background of emotions, and even without obvious reasons. Pallor soon turns into bright hyperemia, moderate swelling with the appearance of pain first, and then sensations of pulsating heat. The absence of Raynaud's syndrome is usually associated with the development of severe scleroderma kidney damage in the patient

Articular syndrome is also an early manifestation of SS. It may be limited to polyarthralgia without affecting the joints and periarticular structures. In some cases, this is a symmetrical fibrosing scleroderma polyarthritis of the small joints of the hands with complaints of stiffness and pain. It is characterized by first exudative and then proliferative changes, as in rheumatoid arthritis. Sclerodermic pseudoarthritis may also form, characterized by limitations in joint mobility caused not by damage to the articular surfaces, but by adhesions of the joint capsule and muscle tendons with induratively altered or sclerotic skin. Often articular syndrome is combined with osteolysis, shortening of the terminal phalanges of the fingers - sclerodactyly. Carpal tunnel syndrome may develop with parasthesia of the middle and index fingers, pain spreading up the forearm to the elbow, and flexion contractures of the hand.

Muscle weakness is characteristic of the diffuse form of SS. Its causes are diffuse muscle atrophy and non-inflammatory muscle fibrosis. In some cases, this is a manifestation of inflammatory myopathy, identical to that occurring in patients with dermatomyositis-polymyositis (crossover syndrome).

Subcutaneous calcifications are found mainly in limited SS (CREST syndrome), and only in a small number of patients with a diffuse form of the disease. Calcifications are more often located in places of natural trauma - the fingertips of the hands, the outer surface of the elbows, knees - Tibierge-Weissenbach syndrome.

Swallowing disorders in SS are caused by disturbances in the wall structure and motor function of the esophagus. In patients with SS, the smooth muscle of the lower third of the esophagus is replaced by collagen. The striated muscles of the upper third of the esophagus are usually not affected. Stenosis of the lower parts of the esophagus and compensatory expansion of the upper parts occur. The structure of the esophageal mucosa changes - Beretta metaplasia. As a result of gastroesophageal reflux, erosive reflux esophagitis often occurs, esophageal ulcers and post-ulcer strictures of the esophagogastric junction develop. Atony and dilatation of the stomach and duodenum are possible. When diffuse gastric fibrosis occurs, iron absorption may be impaired with the formation of sideropenic syndrome. Atony and dilatation of the small intestine often develop. Fibrosis of the wall of the small intestine is manifested by malabsorption syndrome. Damage to the colon leads to diverticulosis, manifested by constipation.

In patients with a limited form of the disease in the form of CREST syndrome, primary biliary cirrhosis can sometimes develop, the first symptom of which may be “causeless” itching of the skin.

In patients with diffuse SS, lung damage in the form of basal and then diffuse pneumofibrosis is manifested by progressive pulmonary failure. Patients complain of constant shortness of breath, which worsens with physical activity. Dry pleurisy with chest pain and pleural friction noise may occur. In patients with limited CV, with the formation of obliterating endarteritis of the pulmonary artery and its branches, pulmonary hypertension occurs with overload of the right parts of the heart.

The diffuse form of SS is sometimes complicated by cardiac damage. Myocarditis, myocardial fibrosis, myocardial ischemia caused by obliterating vasculitis of the coronary arteries, fibrosis of the mitral valve leaflets with the formation of its insufficiency can cause hemodynamic decompensation.

Kidney damage is characteristic of the diffuse form of SS. Kidney pathology is a kind of alternative to Raynaud's syndrome. Scleroderma kidney is characterized by damage to blood vessels, glomeruli, tubules, and interstitial tissues. According to its clinical manifestations, scleroderma kidney does not differ from glomerulonephritis, which occurs with arterial hypertension, urinary syndrome in the form of proteinuria, and hematuria. A progressive decrease in glomerular filtration rate leads to chronic renal failure. As a result of obliterating fibrosis of the interlobular arteries in combination with any vasoconstrictive effect (hypothermia, blood loss, etc.), cortical necrosis of the kidney can occur with the clinical picture of acute renal failure - scleroderma renal crisis.

Damage to the nervous system is caused by obliterating vasculitis of the cerebral arteries. Spastic attacks involving intracranial arteries, as one of the manifestations of Raynaud's syndrome, can cause convulsive seizures, psychosis, and transient hemiparesis.

The diffuse form of SS is characterized by damage to the thyroid gland in the form of autoimmune thyroiditis and fibrous atrophy of the organ.

Diagnostics

· Complete blood count: may be normal. Sometimes signs of moderate hypochromic anemia, slight leukocytosis or leukopenia. There is an increased ESR.

· General urine analysis: proteinuria, cylindruria, microhematuria, leukocyturia, with chronic renal failure - a decrease in the specific gravity of urine. Increased excretion of oskiproline is a sign of impaired collagen metabolism.

· Biochemical blood test: may be normal. The active process is accompanied by an increase in the content of fibrinogen, alpha-2- and gamma-globulins, seromucoid, haptoglobins, and hydroxyproline.

· Immunological analysis: specific autoantibodies to Scl-70 in the diffuse form of SS, autoantibodies to centromeres in the limited form of the disease, nuclear antibodies in kidney damage, crossover syndrome of SS-dermatomyositis-polymyositis. In most patients, rheumatoid factor is detected, in some cases, single LE cells.

· Biopsy of a musculocutaneous flap: obliterating vasculitis of small vessels, fibrosclerotic changes.

· Puncture biopsy of the thyroid gland: identification of morphological signs of autoimmune thyroiditis, small vessel vasculitis, fibrous arthrosis of the organ.

· X-ray examination: calcifications in the tissues of the terminal phalanges of the fingers, elbow, knee joints; osteolysis of the distal phalanges of the fingers; osteoporosis, narrowing of the joint space, sometimes ankylosis of the affected joints. Chest - interpleural adhesions, basal, diffuse, often cystic (cellular lung) pneumofibrosis.

· ECG: signs of myocardial dystrophy, ischemia, large-focal cardiosclerosis with conduction disturbances, excitability, myocardial hypertrophy of the left ventricle and atrium with established mitral valve insufficiency.

· Echocardiography: verification of mitral disease, disorders of myocardial contractile function, dilatation of the heart chambers, signs of pericarditis may be detected.

· Ultrasound examination: identification of structural signs of bilateral diffuse kidney damage, characteristic of nephritis, evidence of autoimmune thyroiditis, fibrous atrophy of the thyroid gland, in some cases signs of biliary cirrhosis.

American Rheumatological Association Clinical Criteria for Recognizing Systemic Scleroderma:

· "Big" criteria:

o Proximal scleroderma - bilateral, symmetrical thickening, compaction, induration, sclerosis of the dermis of the fingers, skin of the extremities proximal to the metacarpophalangeal and metatarsophalangeal joints, involvement of the skin of the face, neck, chest, and abdomen in the pathological process.

· "Small" criteria:

o Sclerodactyly - induration, sclerosis, osteolysis of the terminal phalanges, deformation of the fingers;

o Scars, tissue defects on the pads of the fingers;

o Basal pulmonary fibrosis on both sides.

To be diagnosed with SS, a patient must have either a “major” or at least two “minor” criteria.

Clinical and laboratory signs of activity of the indurative sclerotic process in patients with SS:

· 0 tbsp. - lack of activity.

· I Art. - minimal activity. Moderate trophic disorders, arthralgia, vasospastic Raynaud's syndrome, ESR up to 20 mm/hour.

· II Art. - moderate activity. Arthralgia and / or arthritis, adhesive pleurisy, symptoms of cardiosclerosis, ESR - 20-35 mm/hour.

· III Art. - high activity. Fever, polyarthritis with erosive lesions, large-focal or diffuse cardiosclerosis, mitral valve insufficiency, scleroderma kidney. ESR exceeds 35 mm/hour.

Differential diagnosis

It is carried out primarily with focal scleroderma, other diffuse connective tissue diseases - rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis-polymyositis.

There are plaque, drop-shaped, ring-shaped, linear forms of focal (local) scleroderma. In contrast to limited and diffuse forms of SS, in focal scleroderma the skin of the fingers and face is not involved in the pathological process. Systemic manifestations occur rarely and only with a long course of the disease.

Rheumatoid arthritis and SS are easier to differentiate when articular syndrome develops in patients with SS in the form of pseudoarthritis with indurative sclerotic lesions of the periarticular skin. X-ray in these cases there are no serious lesions of the joint itself. However, in both SS and rheumatoid arthritis, symmetrical polyarthritis of the small joints of the hands can occur, with characteristic stiffness and a tendency to ankylosis. Under such circumstances, differentiation of diseases in favor of SS is helped by identifying symptoms of inductive and then sclerotic lesions of the skin of the fingers, face, and, in the diffuse form of SS, the skin of other parts of the body. SS is characterized by lung damage (pneumofibrosis), which does not occur in patients with rheumatoid arthritis.

Differential diagnosis with systemic lupus erythematosus is based on identifying skin lesions specific to SS. In lupus, unlike SS, polyarthritis is benign and never leads to deformation or ankylosis of the joints. Lupus pseudoarthritis - Jaccoud's syndrome - arthropathy with persistent joint deformities due to damage to tendons and ligaments. It occurs without erosive arthritis. It differs from sclerodermic pseudoarthritis in the absence of fusion of the articular capsule with indurated or sclerotic skin over the affected joint. The diffuse form of the disease can be distinguished from systemic lupus erythematosus by the presence in the blood of SS-specific autoantibodies to the Scl-70 antigen.

In contrast to dermatomyositis-polymyositis, SS is characterized by indurative and sclerotic skin lesions and secondary moderate myopathy. With dermatomyositis-polymyositis, high levels of creatine phosphokinase activity are detected in the blood, which does not happen with classic variants of SS. If there is a combination of SS symptoms with signs of dermatomyositis-polymyositis, then the likelihood of a diagnosis of overlap syndrome of systemic connective tissue damage should be considered.

Survey plan

· General blood analysis.

· General urine analysis.

· Content of hydroxyproline in urine.

· Immunological analysis: autoantibodies to Scl-70, autoantibodies to centromeres, antinuclear antibodies, rheumatoid factor, LE cells, CEC.

· Musculocutaneous flap biopsy.

· Fine needle biopsy of the thyroid gland.

· X-ray examination of the hands, affected elbows, knee joints.

· Chest X-ray.

· ECG.

· Echocardiography.

· Ultrasound examination of the abdominal organs, kidneys, thyroid gland.

Treatment

Treatment tactics involve performing the following effects on the patient’s body:

· Inhibition of the activity of obliterating endarteritis of small vessels, sclerosis of the skin, fibrosis of internal organs.

· Symptomatic treatment of pain (arthralgia, myalgia) and other syndromes, impaired functions of internal organs.

To suppress excess collagen formation in patients with an active inflammatory process, subacute SS, the following is prescribed:

· D-penicillamine (cuprenil) orally 0.125-0.25 per day every other day. If ineffective, the dosage is increased to 0.3-0.6 per day. If taking D-penicillamine is accompanied by the appearance of skin rashes, its dose is reduced and prednisolone is added to the treatment - 10-15 mg/day orally. The appearance of increasing proteinuria during such treatment is the basis for complete withdrawal of D-penicillamine.

To reduce the activity of collagen synthesis mechanisms, especially if D-penicillamine is ineffective or has contraindications, you can use:

· colchicine - 0.5 mg/day (3.5 mg per week) with a gradual increase in dose to 1-1.5 mg/day (about 10 mg per week). The drug can be taken for one and a half to four years in a row.

In the diffuse form of SS with pronounced and severe systemic manifestations, it is advisable to use immunosuppressive doses of glucocorticoids and cytostatics.

· prednisolone orally 20-30 mg/day until clinical effect is achieved. Then the dosage of the drug is slowly reduced to a maintenance dose of 5-7.5 mg/day, which is recommended to be taken for 1 year.

If there is no effect or adverse reactions occur when taking large doses of glucocorticoids, cytostatics are used:

· Azathioprine 150-200 mg/day orally in combination with oral prednisolone 15-20 mg/day for 2-3 months.

In the chronic course of SS with predominantly skin manifestations and minimal activity of the fibrosing process, aminoquinoline drugs should be prescribed:

· Hydroxychloroquine (Plaquenil) 0.2 - 1-2 tablets per day for 6-12 months.

· Chloroquine (delagil) 0.25 - 1-2 tablets per day for 6-12 months.

Symptomatic remedies are intended primarily to compensate for vasospastic reactivity, treat Raynaud's syndrome, and other vascular disorders. For this purpose, calcium channel blockers, ACE inhibitors, and antiplatelet agents are used:

· Nifedipine - up to 100 mg/day.

· Verapapil - up to 200-240 mg/day.

· Captopril - up to 100-150 mg/day.

· Lisinopril - up to 10-20 mg/day.

· Curantil - 200-300 mg/day.

For articular syndrome, drugs from the group of non-steroidal anti-inflammatory drugs are indicated:

· Diclofenac sodium (ortofen) 0.025-0.05 - 3 times a day orally.

· Ibuprofen 0.8 - 3-4 times a day orally.

· Naproxen 0.5-0.75 - 2 times a day orally.

· Indomethacin 0.025-0.05 - 3 times a day orally.

· Nimesulide 0.1 - 2 times a day orally. This drug selectively acts on COX-2 and therefore can be used in patients with erosive and ulcerative lesions of the esophagus, stomach and duodenum, for whom non-selective non-steroidal anti-inflammatory drugs are contraindicated.

For local treatment, you can use a 25-50% dimexide solution in the form of applications to the affected areas of the skin for 20-30 minutes daily - up to 30 applications per course of treatment. Sulfated glycosaminoglycans in ointments are indicated. Lidase can be used by intradermal injection, electrophoresis, phonophoresis into inductively changed areas of the skin.

Forecast

Determined by the pathomorphological variant of the disease. With a limited form, the prognosis is quite favorable. In the diffuse form, it depends on the development and decompensation of damage to the kidneys, lungs, and heart. Timely and adequate treatment significantly prolongs the life of patients with SS.

4. Dermatomyositis-polymyositis

Definition

Dermatomyositis (DM) or dermatopolymyositis is a systemic inflammatory disease with the replacement of affected tissues by fibrous structures with the predominant involvement of skeletal and smooth muscles, skin, and small vessels in the pathological process. In the absence of skin lesions, the term “polymyositis” (PM) is used.

ICD 10:M33 - Dermatopolymyositis.

M33.2 - Polymyositis.

Etiology

The etiological factor of DM-PM may be a latent infection with picarnoviruses, some viruses from the Coxsackie group with the introduction of the pathogen into the genome of muscle cells. The association of DM-PM with a number of tumor processes may indicate either a viral etiology of these tumors, or be a demonstration of antigenic mimicry of tumor structures and muscle tissue. Individuals with HLA histocompatibility antigens type B8 or DR3 are predisposed to the disease.

Pathogenesis

The pathogenetic mechanisms of the disease in infected and genetically predisposed individuals can be triggered by nonspecific influences: hypothermia, excessive solar insolation, vaccinations, acute intoxication, etc. An immune-inflammatory reaction occurs aimed at the destruction of intranuclear structures infected with the virus in the cells of muscle tissue, skin, cross-reactions with the immune damage to antigenically related cell populations. The inclusion of microphage mechanisms for eliminating immune complexes from the body causes activation of fibrogenesis processes, concomitant systemic inflammation of small vessels. Due to the hyperreactivity of the immune system, aimed at destroying the intranuclear positions of the virion, antibodies Mi2, Jo1, SRP, autoantibodies to nucleoproteins and soluble nuclear antigens appear in the blood.

Clinical picture

The disease can occur in acute, subacute and chronic forms.

The acute form is characterized by the sudden onset of fever with a body temperature of up to 39-40 0C. Pain, muscle weakness, arthralgia, arthritis, and skin erythema immediately occur. Generalized damage to all skeletal muscles rapidly develops. Myopathy progresses rapidly. In a short period of time, the patient becomes almost completely immobilized. Severe swallowing and breathing problems occur. Damage to internal organs, primarily the heart, appears and rapidly decompensates. Life expectancy in the acute form of the disease does not exceed 2-6 months.

The subacute course is characterized by the patient having no memory of the onset of the disease. Myalgia, arthralgia, and gradually increasing muscle weakness occur. After sun exposure, characteristic erythema forms on the face and open surfaces of the chest. Signs of damage to internal organs appear. The full development of the clinical picture of the disease and death occur after 1-2 years.

The chronic form is characterized by a benign, cyclical course with long periods of remission. This variant of the disease rarely leads to a rapid death, being limited to moderate, often local atrophic and sclerotic changes in the muscles and skin, mild myopathy, and compensated changes in internal organs.

Muscle pathology is the most striking sign of DM-PM. Patients note the appearance of progressive weakness, which is usually accompanied by myalgia of varying intensity. On objective examination, the affected muscles are testy due to edema, with decreased tone, and painful. Over time, the volume of muscles involved in the pathological process decreases as a result of atrophy and fibrosis.

The proximal groups of skeletal muscles change first. Distal muscle groups of the arms and legs are involved later.

Inflammation and fibrosis of the muscles of the chest and diaphragm impair ventilation of the lungs, leading to hypoxemia and increased pressure in the pulmonary artery.

Damage to the striated muscles of the pharynx and the proximal segment of the esophagus disrupts the swallowing process. Patients choke easily. Liquid food may come out through the nose. Damage to the muscles of the larynx changes the voice, which becomes unrecognizably hoarse, with a nasal timbre.

Oculomotor, masticatory, and other facial muscles are usually not affected.

Pathological changes in the skin are characteristic of DM and are not necessary for PM. The following skin lesions are possible: