Juvenile rheumatoid arthritis (Juvenile rheumatoid arthritis)

What is juvenile arthritis?

Juvenile, or in other words, juvenile arthritis is a type of rheumatoid and is a pathology whose degenerative-dystrophic processes affect the connective tissues of the human body, having a detrimental effect on the functioning of the joints, heart and kidneys.

Juvenile arthritis is the most common in children and is detected mainly in adolescence and belongs to the category of the most common rheumatological diseases of children. According to statistics, the peak incidence occurs in the period from 10 to 14 years

.

The uncontrolled course of the pathology can cause a weakening of the general condition of the body, as well as a sharp decrease in immune abilities.

Prognosis for juvenile chronic arthritis in children

Juvenile rheumatoid arthritis is a disease that tends to progress rapidly. The activity of the disease depends on the form of onset of the disease - in one joint, in 2 or 3 or in multiple joints at the same time. If the disease begins in the form of polyarthritis (symptoms are observed in 4 or more joints), the number of affected joints increases over time.

The number of children requiring mobility and/or self-care assistance has decreased significantly over the past decade. In 95% of cases, treatment avoids disability. Among the remaining 5% there are still children with early onset of the disease, positive rheumatic factor. Juvenile arthritis in adolescents has fewer consequences than in early childhood. Every 7-10 patients suffering from inflammation of the uvea are at risk of losing their vision.

The following features indicate an unfavorable prognosis for juvenile chronic arthritis in children:

• acute course with fever and active progression of the disease within six months;
• the need for rapid re-administration of systemic GCs;
• inflammation of the serous membranes;
• localization of the disease in the hip joints;
• erosive destruction of joints and narrowing of the lumen of the joint space.

In more than half of the cases, with timely consultation with a doctor and lifelong therapy, severe destruction of the joints can be avoided. Under favorable circumstances, the child can attend school on an equal basis with peers, dance and participate in sports games in a gentle manner, with minimal restrictions. With juvenile arthritis in children, doctors and parents are increasingly able to achieve a full life for the child. Early contact with a doctor contributes to drug-free remission - that is, the patient does not need to constantly receive therapy.

Causes of juvenile arthritis

Determining the exact causes of the development of the disease is not easy, because each case is individual and has a number of features of the anamnestic picture.

Research conducted by domestic and foreign scientists has determined that the main factors in the development of juvenile arthritis are hereditary predisposition

, as well as the presence
of infectious agents
and
autoimmune disorders
.

Among the most common causes of the development of juvenile pathology are:

• viral and bacterial pathogens;
• injury to joint tissues;
• systematic hypothermia of the body;
• negative impact of long-term exposure to solar radiation.

It is worth noting that the initiator of the disease can be the active influence of one or more factors in combination with genetic predisposition.

Causes of the disease

The disease is of autoimmune origin. Juvenile arthritis is the most common pathology in pediatric rheumatology. Various provoking factors of an endogenous and exogenous nature lead to its development:

• bacterial or viral infections suffered by the child;
• prolonged exposure to the sun;
• damage to blood vessels;
• hypothermia;
• preventive vaccinations;
• infection of the fetus during intrauterine development;
• hereditary predisposition.

Under the influence of the above factors, the functioning of the immune system occurs. The body begins to perceive its own connective tissue cells as foreign substances and produces antibodies against them. This leads to the development of inflammation and rheumatoid arthritis.

Symptoms and signs of juvenile arthritis

Juvenile arthritis in children is dangerous because the peculiarities of the course of pathological processes can negatively affect the growth zones and disrupt the process of natural growth of the child

.

The main clinical signs of juvenile arthritis are stiffness, swelling, tenderness and local redness of the skin of the joint.

To the initial signs

Juvenile arthritis may include:

• weakness, general malaise, relatively slight increase in body temperature, loss of appetite, cold sweat;
• rashes of various kinds in the area of ​​the affected joint, not accompanied by itching;
• limited joint mobility in the morning;
• local swelling, pain in one or more large joints;
• periodic heart pain, shortness of breath.

To signs of systemic manifestations

at the stage of the acute form of development of juvenile pathology include:

• heart pain, bluish skin;
• cough, difficulty breathing;
• disorders of the gastrointestinal tract;
• enlarged liver, spleen;
• renal dysfunction;
• inflammation of the visual organs;
• growth slowdown.

If you have one or more symptoms, you should urgently seek qualified medical help.

Juvenile arthritis: possibilities of drug and non-drug treatment at the present stage

Juvenile arthritis (JA) is arthritis of unknown cause, lasting more than 6 weeks, developing in children under 16 years of age. When making a diagnosis, it is necessary to exclude other joint pathologies (see table “Differential diagnosis of juvenile arthritis” on pages 60–61).

JA is one of the most common and most disabling rheumatic diseases found in children. The incidence of JA ranges from 2 to 16 per 100 thousand children under the age of 16 years. The prevalence of JA in different countries ranges from 0.05 to 0.6%. The prevalence of JA in children under 18 years of age in the Russian Federation reaches 62.3, the primary incidence is 16.2 per 100 thousand, including in adolescents the corresponding figures are 116.4 and 28.3, and in children under 14 years of age - 45 .8 and 12.6. Girls are more often affected by rheumatoid arthritis (RA). Mortality rate is within 0.5–1%.

Classification

In the International Classification of Diseases, X Revision (ICD-10), juvenile arthritis is included in category M08:

• M08.0 - youthful (juvenile) rheumatoid arthritis (RF+ and RF–);
• M08.2 - youthful (juvenile) arthritis with systemic onset;
• M08.3 - youthful (juvenile) polyarthritis (seronegative);
• M08.4 - pauciarticular youthful (juvenile) arthritis;
• M08.8 - other juvenile arthritis;
• M08.9 - unspecified juvenile arthritis.

There are three more classifications of the disease: the American College of Rheumatology (AKP) classification of juvenile rheumatoid arthritis (JRA), the European League Against Rheumatism classification of JIA (juvenile chronic arthritis), and the International League of Rheumatological Associations classification of JIA (juvenile idiopathic arthritis) (Table 1). Comparative characteristics of all classification criteria are presented in table. 2.

Treatment

1. Non-drug treatment

Mode

During periods of exacerbation of the disease, the child’s motor activity should be limited. Complete immobilization of joints with the application of splints is contraindicated; this contributes to the development of contractures, atrophy of muscle tissue, aggravation of osteoporosis, and rapid development of ankylosis. Physical exercise helps maintain the functional activity of joints. Cycling, swimming, walking are useful. Running, jumping, active games are undesirable. It is recommended to maintain a straight posture when walking and sitting, and sleep on a hard mattress and a thin pillow. Limit psycho-emotional stress, exposure to the sun.

Diet

Eating foods high in calcium and vitamin D to prevent osteoporosis. In patients with Cushing's syndrome, it is advisable to limit the consumption of carbohydrates and fats; a protein diet is preferable.

Therapeutic exercise (physical therapy)

An essential component of treatment for JA. Daily exercises are necessary to increase the range of motion in the joints, eliminate flexion contractures, and restore muscle mass. If the hip joints are affected, traction procedures on the affected limb after preliminary consultation with an orthopedist, walking on crutches. During the period of development of coxitis and aseptic necrosis of the hip joints, the patient’s movement without crutches is contraindicated. Physical therapy should be carried out in accordance with the individual capabilities of the patient.

Orthopedic correction

Static orthoses such as splints, splints, insoles and dynamic cuts in the form of lightweight removable devices. Static orthoses require intermittent immobilization - they should be worn or put on during free time and must be removed during the day to stimulate the muscular system during exercise, classes, occupational therapy, and the toilet. For severe osteoporosis in the thoracic and lumbar spine - wearing a corset or reclining system; with damage to the joints of the cervical spine - the head holder (soft, hard).

2. Drug treatment

Several groups of drugs are used to treat JA: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), immunosuppressants and biological agents obtained by genetic engineering. The use of NSAIDs and GCs helps to quickly reduce pain and inflammation in the joints, improve function, but does not prevent the progression of joint destruction and disability of patients. Immunosuppressive and biological therapy stops the development of destruction and disability of patients.

Glucocorticoids

Pulse therapy

Pulse therapy with GC is carried out in case of the development of severe systemic manifestations of JA (carditis, pneumonitis, polyserositis, hemophagocytic syndrome).

Advantages:

• rapid (within 24 hours) suppression of the activity of the inflammatory process and relief of symptoms of the disease;
• rapid elimination of the drug, short-term suppression of the adrenal glands, restoration of their function after 4 weeks.

Administration scheme:

• the dose of methylprednisolone is 10–20 mg/kg per administration (not higher than 500 mg);
• methylprednisolone is dissolved in 200 ml of 5% glucose solution or 0.9% sodium chloride solution;
• duration of administration 30–40 minutes;
• the drug is administered once a day in the morning;
• GC pulse therapy is carried out for 3–5 consecutive days.

When using GC pulse therapy, adverse events may develop.

Transfusion adverse events:

• increased blood pressure (BP);
• hyperglycemia;
• facial redness;
• headache, dizziness;
• change in taste;
• heartbeat;
• euphoria.

Long-term unjustified use of intravenous GCs causes the development of severe adverse events:

• persistent increase in blood pressure;
• severe steroid osteoporosis. It is most pronounced in the thoracic and lumbar spine. It manifests itself as a decrease in the height of the vertebral bodies, compression fractures. Accompanied by symptoms of compression of the spinal cord roots;
• obesity. Has characteristic features - a moon-shaped face, fat deposition on the neck, chest, abdomen, steroid “hump”, atrophy of the muscles of the arms and legs;
• erosive and ulcerative processes in the upper gastrointestinal tract;
• steroid myopathy;
• posterior capsular cataract;
• skin changes (hypertrichosis, purulent skin infection, stretch marks, skin trauma, rough scars, impaired wound healing, steroid acne on the face and torso).

HA for oral administration

GCs have a rapid anti-inflammatory effect in most patients. High doses of prednisolone (more than 0.6 mg/kg/day) stop acute inflammatory changes in the joints and control the activity of systemic manifestations. However, reducing the dose of prednisolone and its withdrawal, as a rule, lead to an exacerbation of the disease. And re-prescribing prednisolone at the original dose is no longer effective enough for most patients.

In connection with the above, the indication for prescribing oral GC is only the ineffectiveness of intravenous GC, immunosuppressive and biological drugs, in combination or without intravenous GC.

If GC is prescribed orally, the dose of prednisolone should not exceed 0.2–0.5 mg/kg per day, the daily dose is 15 mg.

The maximum dose of GC should be taken no more than a month after achieving remission. Subsequently, the dose of GC is gradually reduced to a maintenance regimen, followed by its abolition. Prednisolone must be prescribed with an adequate dose of methotrexate and/or cyclosporine (see “Treatment of juvenile arthritis with systemic onset”). The reduction in the dose of prednisolone should be slow; a maintenance dose (0.1 mg/kg body weight) should be taken for at least one year.

Tactics for reducing the dose of oral GCs.

The rate of reduction in the dose of GC should depend on its initial daily dose:

• up to 15 mg - reduce by 1.25 mg 1 time every 3-4 days;
• from 15 to 10 mg - reduce by 1.25 mg once every 5-7 days;
• from 10 mg to 5 mg - alternating decrease. On even days the child takes prednisolone at the original dose, on odd days - 1/8 tablet less. This regimen is maintained for 7–10 days. In the absence of withdrawal syndrome, 1/8 tablet can be discontinued. Over the next 7–10 days, the child takes a constant (after stopping 1/8 tablet) dose of prednisolone;
• from 5 mg until complete withdrawal - alternating reduction. On even days the child takes prednisolone at the original dose, on odd days - 1/8 tablet less. This regimen is maintained for 14 days. In the absence of withdrawal syndrome, 1/8 tablet can be discontinued. Over the next 4 weeks, the child takes a constant dose of prednisolone.

Dose reduction and discontinuation of prednisolone are usually accompanied by the development of withdrawal syndrome, especially in patients who have been receiving it for a long time. Withdrawal syndrome is manifested by myalgia, arthralgia, muscle tremors, fever, nausea, vomiting, depression.

For the purpose of replacement therapy for withdrawal syndrome, intravenous administration of methylprednisolone at a dose of 5 mg/kg can be used.

Discontinuation of prednisolone for 2–4 months, prescribed at a dose of 1.0 mg/kg or higher, is contraindicated in patients with systemic onset JA after achieving a therapeutic effect. The dose of GC can begin to be slowly reduced only against the background of elimination of systemic manifestations and a clinically significant effect of immunosuppressant therapy for at least one month.

Long-term use of GC, even in low doses, causes the development of serious, often reversible, and in some cases irreversible consequences. The longer patients take GC, the more severe their side effects.

Adverse events:

• short stature. It is not recommended to prescribe GC to children under 5 years of age (especially under 3 years of age), as well as to prepubertal age. The administration of GC can lead to a complete cessation of growth and suppression of the pubertal growth spurt. Children with polyarticular JRA are more likely to develop short stature;
• delayed sexual development;
• arterial hypertension (isolated increase in systolic blood pressure (BP) or increase in systolic and diastolic blood pressure);
• steroid osteoporosis. Develops in all patients treated with prednisolone for a long time. The most rapid loss of bone mass during GC treatment develops during the first 6–12 months from the start of treatment. Therefore, prevention of GC-induced osteoporosis should begin as early as possible. It is most pronounced in the thoracic and lumbar spine. It manifests itself as a decrease in the height of the vertebral bodies, compression fractures. Accompanied by symptoms of compression of the spinal cord roots;
• obesity. Has characteristic features - a moon-shaped face, fat deposition on the neck, chest, abdomen, steroid “hump”, atrophy of the muscles of the arms and legs;
• disproportionate physical development;
• erosive and ulcerative processes in the upper gastrointestinal tract;
• steroid myopathy;
• posterior capsular cataract;
• skin changes (hypertrichosis, purulent skin infection, stretch marks, skin trauma, rough scars, worsening wound healing, steroid acne on the face and torso);
• development of hormone resistance: – continuous relapses of the disease during treatment with maintenance doses of GC;
• development of hormone dependence: – exacerbation of the disease against the background of GC withdrawal;
• withdrawal syndrome.

Intra-articular injection of HA

Local GC therapy quickly relieves acute inflammatory changes in joints and preserves their functional activity. For intra-articular injections, long-acting GCs are used: methylprednisolone, betamethasone, triamcinolone. In patients with oligoarthritis, intra-articular injections of HA prevent disproportionate growth of the lower extremities.

Excessive “passion” for local therapy is unacceptable. GK is administered no more than once every 3–6 months into the same joint. The peculiarities of local GC therapy are that the initial duration of the effect ranges from several weeks to several months. However, in the future, the duration of improvement with repeated administration of drugs without immunosuppressive therapy is reduced, and the patient requires more frequent intra-articular punctures, which leads to the development of traditional adverse effects of GC therapy, including Cushing's syndrome and severe hormone dependence, especially with the introduction of long-acting betamethasone. Doses and indications for use are presented in table. 3 and 4.

Contraindications to local GC therapy:

• local or systemic infection;
• severe bone destruction;
• severe periarticular osteoporosis;
• difficult access to the joint;
• blood clotting pathology;
• ineffectiveness of previous intravenous therapy.

After administration, rest of the joints is required for at least 48–72 hours.

Side effects of intra-articular HA injections:

• “steroid arthropathy” and osteonecrosis;
• iatrogenic infection and hemarthrosis;
• tissue atrophy, lipodystrophy, fat necrosis, calcification;
• tendon ruptures;
• damage to nerve trunks;
• “post-injection” exacerbation;
• erythema, feeling of heat.

In this regard, you can refrain from intra-articular administration of HA. If an adequate dose of an immunosuppressant and/or biological agent is prescribed, the activity of the joint syndrome usually decreases after 2–4 weeks of treatment, and it completely resolves after 6–12 weeks of therapy. If there is pain and stiffness during this period, it is advisable to prescribe NSAIDs, as well as topical ointments and gels containing NSAIDs.

Nonsteroidal anti-inflammatory drugs

The most effective drug with the best tolerability should be selected. When using NSAIDs in rheumatology, one must remember that the development of the anti-inflammatory effect lags behind the analgesic effect. Pain relief occurs within the first hours after administration, while the anti-inflammatory effect develops only after 10–14 days of constant, regular use of NSAIDs.

Treatment should begin with the lowest dose; if well tolerated, the dose can be increased after 2–3 days. In recent years, there has been a tendency to increase single and daily doses of drugs that are well tolerated, while limiting the maximum doses of acetylsalicylic acid, indomethacin, and piroxicam.

For long-term treatment, NSAIDs are taken after meals (in rheumatology). For a quick analgesic and antipyretic effect, NSAIDs are prescribed 30 minutes before meals or 2 hours after meals, washed down with 1/2–1 glass of water. After taking NSAIDs, it is advisable not to lie down for 15 minutes in order to prevent esophagitis. The timing of drug administration may also depend on the time of maximum symptoms, taking into account the chronopharmacology of the drugs. This allows you to achieve the greatest effect with a lower daily dose. For morning stiffness, it is advisable to take rapidly absorbed NSAIDs as early as possible or prescribe long-acting drugs at night.

The most commonly used is Diclofenac sodium at a dose of 2–3 mg/kg body weight per day. In case of severe systemic manifestations, one should refrain from prescribing NSAIDs, as they can provoke the development of macrophage activation syndrome. The dosage regimen for various NSAIDs is presented in table. 5.

The most typical adverse events that occur while taking NSAIDs:

• NSAID gastropathy - indigestion, gastroesophageal reflux, erosion of the upper gastrointestinal tract, gastritis, erosive and ulcerative lesions of the stomach and duodenum, small and large intestines, hemorrhage, bleeding, perforation of stomach and intestinal ulcers;
• liver damage - increased activity of transaminases and other enzymes. In severe cases, jaundice and hepatitis may develop;
• kidney damage: interstitial nephritis - “analgesic nephropathy”. Fluid retention in the body, swelling, increased blood pressure;
• from the central nervous system: headache, dizziness;
• from the hematopoietic system - the development of aplastic anemia and agranulocytosis;
• on the part of the coagulation system - inhibition of platelet aggregation and a moderate anticoagulant effect, bleeding may develop, most often from the gastrointestinal tract;
• hypersensitivity reactions - the appearance of a rash, Quincke's edema, signs of bronchospasm, the development of anaphylactic shock, Lyell's syndrome and Stevens-Johnson.

Immunosuppressive therapy

Immunosuppressive therapy should be differentiated, long-term and continuous, starting immediately after verification of the diagnosis during the first 3-6 months of the disease. The withdrawal of immunosuppressants in most patients causes an exacerbation of the disease.

Methotrexate is a drug from the group of antimetabolites, similar in structure to folic acid, and has a dose-dependent immunosuppressive and anti-inflammatory effect. Methotrexate has a cytotoxic effect in doses above 100 mg/m2/week. In rheumatology, methotrexate is used in doses below 50 mg/m2/week and has a weak immunosuppressive and more pronounced anti-inflammatory effect. Methotrexate reduces disease activity, laboratory activity indicators, and induces seroconversion in the Russian Federation.

Indications:

• youthful (juvenile) rheumatoid arthritis (RF+ and RF-);
• youthful (juvenile) arthritis with systemic onset;
• youthful (juvenile) polyarthritis (seronegative);
• pauciarticular juvenile (juvenile) arthritis.

Treatment regimen:

• Methotrexate is most often prescribed once a week (orally or parenterally). This is due to the fact that more frequent use of the drug is usually associated with the development of acute and chronic toxic reactions. Due to the possible intolerance of simultaneous administration of methotrexate in large doses, it can be prescribed in divided doses, at 12-hour intervals, in the morning and evening or 2 times a week.
• In the majority of patients with the systemic variant of JA, methotrexate in doses of 10–15 mg/m2/week does not significantly affect the activity of systemic manifestations of the disease. For JA with systemic onset, methotrexate is used in doses of 20–25 mg/m2/week, and if ineffective, in the form of pulse therapy in a dose of 50 mg/m2 once a week intravenously for 8 consecutive weeks; when the effect is achieved from the 9th week, methotrexate is administered at a dose of 20–25 mg/m2/week subcutaneously or intramuscularly. For parenteral administration, the contents of the ampoule are dissolved in 400 ml of isotonic sodium chloride solution. The infusion is carried out over 3–4 hours.
• For polyarthritis, methotrexate is used in doses of 15-25 mg/m2/week, for oligoarthritis - 10-15 mg/m2/week.
• The effect is assessed after 4–12 weeks. At these doses, methotrexate does not have a pronounced immunosuppressive effect and stops the destruction of joints in the event of a decrease in laboratory activity indicators. To reduce the side effects of the drug, you should take folic acid 1–5 mg/day on days free from taking methotrexate.

Adverse events:

• headache, blurred vision, drowsiness, aphasia;
• paresis, convulsions;
• interstitial pneumonitis;
• gingivitis, pharyngitis, ulcerative stomatitis;
• anorexia, nausea, vomiting, diarrhea, melena;
• ulceration of the gastrointestinal mucosa, gastrointestinal bleeding;
• liver damage;
• acute renal failure, azotemia, cystitis;
• anemia, leukopenia, thrombocytopenia;
• addition of a secondary (bacterial, viral, fungal, protozoal) infection;
• dysmenorrhea, oligospermia;
• alopecia, ecchymosis, acne, furunculosis.

To relieve adverse events during intravenous administration of methotrexate, it is advisable to premedicate with one of the following drugs:

• Metoclopramide orally, intravenously or intramuscularly. Adults are prescribed 10 mg 3-4 times a day. The maximum single dose is 20 mg, the daily dose is 60 mg. For children from 2 to 14 years of age, a single dose is 0.1 mg/kg body weight, the highest daily dose is 0.5 mg/kg. The frequency of administration is 1–3 times a day.
• Tropisetron orally or intravenously at a dose of 5 mg for adults, for children over 2 years of age - at a daily dose of 0.2 mg/kg, the maximum daily dose is up to 5 mg.

Cyclosporine

Cyclosporine not only causes symptomatic improvement, but also has a basic antirheumatic effect. Cyclosporine therapy causes a decrease in indicators of disease activity, severity of pain and synovitis, duration of morning stiffness, and improvement in the functional ability of joints. Cyclosporine inhibits the progression of the destructive process in the cartilage and bone tissue of joints and stimulates reparative processes. Cyclosporine improves functional status and minimizes disability in systemic JA. Reduces the rate of increase in structural changes in joints, regardless of the dynamics of laboratory activity indicators. Relieves acute coxitis, stimulates the repair of cartilage and bone in aseptic necrosis of the femoral heads. Cyclosporine is the drug of choice for the treatment of macrophage activation syndrome in systemic JA. Effective for the treatment of uveitis.

Indications:

• youthful (juvenile) arthritis with systemic onset;
• rheumatoid uveitis;
• hemophagocytic syndrome in JA.

Treatment regimen:

• The choice of the initial dose, as well as correction of the dosage regimen during treatment, is carried out taking into account clinical and laboratory parameters.
• The daily oral dose is 3.5–5 mg/kg. The initial dose is 3.5 mg/kg/day. It is divided into two doses (1.5 mg/kg per day every 12 hours). If the number of capsules is not divided by two, then a larger dose is taken in the evening. It should not exceed the morning dose by more than 25 mg.
• For the first 4 weeks, cyclosporine therapy is carried out at a dose of 3.5 mg/kg/day; if there is no effect during the first month of treatment, the dose of the drug is increased by 25 mg. The time period between dose increases should be at least 2 weeks.
• The dose increase is carried out under the control of peripheral blood parameters (number of red blood cells, platelets, leukocytes) and biochemical parameters (concentration of creatinine, urea, bilirubin, potassium, transaminases in the blood serum).
• The daily dose should not exceed 5 mg/kg/day.
• In patients with necrosis of the femoral head or the threat of its development, as well as with the development of hemophagocytic syndrome, the dose of cyclosporine can be increased within the first 2–4 weeks of therapy. Safety indicators in this case should be monitored once every 7–10 days.
• The effect develops after 1–3 months and reaches its maximum within 6–12 months.

Adverse events:

• a feeling of heaviness in the epigastric region, loss of appetite, nausea (especially at the beginning of treatment), vomiting, diarrhea;
• pancreatitis;
• swelling of the gums;
• liver dysfunction;
• headache, paresthesia, convulsions;
• increased blood pressure;
• impaired renal function - so-called nephrotoxicity, leading to an increase in the concentration of creatinine and urea in the blood;
• increased concentrations of potassium and uric acid in the body;
• excessive hair growth;
• reversible dysmenorrhea and amenorrhea;
• slight anemia;
• rarely - muscle spasms, muscle weakness, myopathy, thrombocytopenia.

Cytotoxic agents: cyclophosphamide, chlorambucil, azathioprine are used quite rarely for the treatment of JA due to low efficiency and a high incidence of severe side effects (leukopenia, infections, infertility, neoplastic processes).

Leflunomide

Leflunomide is effective in the treatment of RA in adults. Leflunomide reduces the inflammatory activity of the disease, has a pronounced analgesic effect, reduces the severity of articular syndrome, reduces ESR, circulating immune complexes, RF titers, and stops the progression of osteochondral destruction. The functional ability and quality of life of patients is significantly improved. Leflunomide is effective in both early and late stages of RA. It slows down the progression of joint destruction. The drug is not registered for JRA indications. However, the effectiveness and safety of the drug in children was studied in a double-blind, placebo-controlled study. Given its reliable efficacy and low toxicity, leflunomide can be prescribed if methotrexate is ineffective under the supervision of experienced rheumatologists.

Indications:

• youthful (juvenile) rheumatoid arthritis (RF+ and RF–);
• youthful (juvenile) polyarthritis (seronegative);
• pauciarticular juvenile (juvenile) arthritis, torpid to classical immunosuppressants and biological agents.

Treatment regimen:

• Doses. For body weight above 30 kg: 100 mg once a day for the first 3 days, then 0.6 mg/kg once a day. In children weighing less than 30 kg, the initial dose is 50 mg/day for 3 days, then 0.6 mg/kg/day.
• It is possible to use leflunomide in combination with methotrexate at a dose of 5–7.5 mg/m2/week if leflunomide is insufficiently effective.

Adverse events:

• increased blood pressure;
• diarrhea, nausea, vomiting, anorexia;
• diseases of the oral mucosa (aphthous stomatitis, lip ulcerations);
• abdominal pain;
• liver dysfunction (increased levels of transaminases, alkaline phosphatase, bilirubin);
• slight loss of body weight;
• headache, dizziness, asthenia, paresthesia;
• tenosynovitis;
• increased hair loss, eczema, dry skin;
• leukopenia;
• rash, itching, allergic reactions, urticaria;
• hypokalemia;
• taste disturbance;
• anxiety;
• ligament rupture;
• Stevens-Johnson syndrome;
• toxic epidermal necrolysis, erythema multiforme;
• anemia, thrombocytopenia, pancytopenia, agranulocytosis, eosinophilia.

E. I. Alekseeva, Doctor of Medical Sciences, Professor T. M. Bzarova

NCZD, Moscow

Contact information for authors for correspondence

Stages of development of juvenile arthritis

Juvenile rheumatoid arthritis occurs in 4 stages:

1. Initial – lasts up to 6 months
   . Damage to articular bone tissue.
2. Early – lasts from 6 to 12 months
   . Destruction of cartilage tissue, proliferation of the joint membrane, reduction of the joint lumen.
3. Expanded - can last up to two years
   . The appearance of erosions on cartilage and bone tissue, the formation of subluxations.
4. Late – lasts more than 2 years and leads to disability
   . Fusion of bone tissue, loss of limb mobility.

Publications in the media

Juvenile idiopathic arthritis (JIA, juvenile rheumatoid arthritis, chronic juvenile arthritis) is a heterogeneous group of diseases united by a tendency towards a chronic progressive course. The term was proposed by the WHO Standing Committee on Pediatric Rheumatology (1994) to replace the previously used terms juvenile chronic and juvenile rheumatoid arthritis.

Statistical data. Incidence: 2–19 per 10,000 children per year. Boys and girls get sick equally often. Etiology unknown. Pathogenesis - see Rheumatoid Arthritis.

Genetic aspects. A high prevalence of Ags HLA-DRВ1*0801 and *1401 was established in patients with polyarthritis, HLA-DRВ1*0101 and 0801 in patients with oligoarthritis. The association of Ag HLA-B27 with the development of arthritis with enthesopathy, as well as HLA-DRB1*0401 with RF-positive polyarthritis, has also been proven.

CLASSIFICATION (Durban, 1997)

Systemic variant - arthritis with/or previous fever for at least 2 weeks in combination with two or more signs: • fleeting, not fixed erythematous rash • generalized enlargement of lymph nodes • hepato- or splenomegaly • serositis. Description • Age of onset of the disease • Characteristics of arthritis during the first 6 months of the disease •• oligoarthritis •• polyarthritis •• presence of arthritis only after 6 months of systemic disease • Characteristics of arthritis after 6 months of the disease •• oligoarthritis •• polyarthritis •• absence of arthritis after 6 months of systemic disease • Features of systemic disease after 6 months • Presence of RF • CRP level.

Persistent/spreading oligoarthritis is arthritis that affects 1–4 joints during the first 6 months of the disease. There are 2 subcategories: • persistent oligoarthritis (affecting no more than 4 joints during the entire period of the disease) • spreading arthritis (affecting more than 5 joints after 6 months of illness). Exclusion factors • Familial psoriasis confirmed by a dermatologist in at least first- or second-degree relatives • Family history confirming the presence of HLA B27-associated diseases in at least first- or second-degree relatives • Positive RF • HLA B27-positive boys with onset illnesses after 8 years • Presence of systemic arthritis . Description • Age of onset of arthritis and psoriasis • Characteristics of arthritis in the first 6 months and at the last clinic visit •• large joints only •• small joints only •• predominance of extremity joints (upper, lower) or its absence •• specific involvement of joints ( hip, cervical spine) •• symmetry of arthritis • Presence of uveitis (acute or chronic) • Presence of ANAT • Ag HLA class I or predisposing alleles.

RF-negative polyarthritis is arthritis affecting 5 or more joints during the first 6 months, in the absence of RF. Description • Age of onset of arthritis • Symmetry of atritis • Presence of ANAT • Presence of uveitis (acute or chronic).

RF-positive polyarthritis is arthritis affecting 5 or more joints within the first 6 months, associated with positive RF based on 2 studies performed over 2 months. Description • Age of onset of arthritis • Symmetry of arthritis • Presence of ANAT • Immunogenetic characteristics.

Psoriatic arthritis - arthritis and psoriasis or arthritis and the presence of 2 of the following signs • dactylitis • nail damage (thimblestone symptom, onycholysis) • familial psoriasis, confirmed by a dermatologist in first-degree relatives. Exclusion factors • Positive RF • Systemic course of arthritis Description • Age of onset of arthritis or psoriasis • Characteristics of arthritis within 6 months from the onset of the disease and during the last visit to the doctor •• only large joints •• only small joints •• predominance of joints of the extremities (upper , lower) or its absence •• involvement of the spine •• involvement of the sacroilial joints •• involvement of the humeroacromial joint •• involvement of the hip joints •• involvement of the sternoclavicular joints •• symmetry of arthritis • Course of the disease •• oligoarthritis •• polyarthritis • Presence of ANAT • Anterior uveitis (specific) •• chronic anterior uveitis •• uveitis, characterized by pain, redness, photosensitivity • HLA typing data.

Arthritis-associated enthesitis - arthritis and enthesitis or arthritis and enthesitis with two of the following: • tenderness of the sacroiliac joints and/or inflammatory back pain • the presence of HLA B27 • a family history indicating the presence of physician-confirmed HLA B27-associated diseases in individuals of the former or second degree relative • anterior uveitis, usually associated with pain, redness or photophobia • onset of arthritis in boys after 8 years. Exclusion factors • Familial psoriasis, confirmed by a dermatologist in at least first- or second-degree relatives • Systemic arthritis. Description • Age of onset of enthesitis and arthritis • Characteristics of arthritis within 6 months from the onset of the disease and at the time of the last visit to the doctor •• large joints only •• small joints only •• predominance of joints of the extremities (upper, lower) or its absence •• involvement spine •• involvement of the sacroilial joints •• involvement of the humeroacromial joint •• involvement of the hip joints • Symmetrical arthritis • Course of the disease •• oligoarthritis •• polyarthritis • Presence of inflammatory bowel disease.

Other arthritis that does not fit into any category/fits into more than one category - arthritis in children of unknown cause, existing for 6 weeks or more and/or • does not meet the criteria of any category • meets the criteria of more than one of the presented categories.

The clinical picture is described in the classification characteristics of each of the forms.

Laboratory data • Normochromic normocytic anemia • Leukocytosis • An increase in ESR and an increase in the concentration of CRP correlate with activity • The concentration of IgM correlates with RF titers, IgA - with the formation of erosions and activity • RF is positive only in 15–20% of patients • ANAT is detected more often in girls with oligoarthritis and uveitis.

Instrumental data • X-ray examination •• In the early stages there are no changes •• Late stages: osteoporosis, periosteal growths, premature fusion of the epiphyses, erosion, narrowing of joint spaces, ankylosis.

Diagnostic tactics. The diagnosis of JIA, as proposed by WHO, is established in the presence of arthritis of unknown etiology, present for 6 weeks in a child under 16 years of age, with the exclusion of other diseases (congenital joint pathology, etc.).

TREATMENT

General tactics depend on the form of the disease • In the systemic version: NSAIDs, if ineffective - prednisolone 2 mg/kg/day or pulse therapy with methylprednisolone 10-30 mg/kg/day for 1-3 days (especially with myocardial damage). If there is no effect, methotrexate 0.3–0.5 mg/kg/week. In case of development of macrophage activation syndrome - cyclosporine and pulse therapy with methylprednisolone. The use of gold salts and penicillamine is contraindicated • In case of polyarticular form, first use NSAIDs, and when the diagnosis is confirmed, sulfasalazine 30-40 mg/kg (especially with enthesitis) or methotrexate 0.3 mg/kg/week. If ineffective, methotrexate 1 mg/kg IV, or combination therapy (methotrexate, sulfasalazine and/or hydroxychloroquine). In special severe cases, it is possible to prescribe cyclosporine • For oligoarthritis - NSAIDs, if ineffective - intra-articular GCs, if there is no effect within 2-3 months - sulfasalazine 30-40 mg/kg/day, or hydroxychloroquine 5 mg/kg/day, or methotrexate 0.3 mg/kg/week with a gradual increase in dose to 0.5 mg/kg/week.

Mode. Patients should form a movement pattern that counteracts the development of deformities (for example, to prevent ulnar deviation, one should open the tap, dial a telephone number and perform other manipulations with the left hand rather than the right one).

Drug therapy • NSAIDs are used in all cases of JIA •• Ibuprofen for children from 6 months to 12 years 40–50 mg/kg/day (in 3–4 doses), over 12 years of age, doses are similar to adults (1200–1800 mg/day) • • Naproxen is not prescribed to children under 2 years of age, over 2 years of age - 2.5 mg/kg/day • GC is prescribed in the absence of effect from NSAIDs, 1-2 mg/kg orally • Basic drugs • Immunosuppressive drugs •• Methotrexate for spreading oligoarthritis 15–20 mg/m2/week, for seropositive polyarthritis 10 mg/m2/week • Sulfasalazine is not prescribed to children under 2 years of age, over 2 years of age - 40–60 mg/kg/day in 3–6 doses; maintenance dose - 20-30 mg/kg/day in 3 divided doses • Local therapy - see Rheumatoid Arthritis. GC is administered into the joint in doses 2–3 times lower than in adult patients • Intensive therapy for the systemic version: pulse therapy of GC 15–20 mg/kg/day for 3 days.

Non-drug therapy. Plasmapheresis - with a systemic option (the effectiveness continues to be discussed).

Surgery. Synovectomy is rarely used due to the wide range of active drug effects on synovitis. Prosthetics of hip and knee joints, surgical treatment of deformities of the hands and feet are used.

Complications • Amyloidosis • Macrophage activation syndrome sometimes develops as a complication of the systemic form; characterized by fever, weakness, drowsiness, hepatosplenomegaly and often leads to death.

Rehabilitation. Exercise therapy plays an important role. Spa treatment is recommended during periods of minimal activity or remission. To correct deformities, orthoses are used - individual orthopedic devices made of thermoplastic, worn at night. Children often need consultation with a psychologist.

Course and prognosis • In most cases of systemic arthritis of moderate severity, the disease resolves spontaneously • With persistent oligoarthritis, the prognosis is favorable, remission occurs after 4–5 years • With persistent oligoarthritis, the prognosis is relatively favorable • With seropositive polyarthritis, the disease is accompanied by the development of deformities.

Abbreviations • JIA—juvenile idiopathic arthritis.

ICD-10 • M08 Juvenile arthritis

Types of juvenile arthritis

Depending on the symptoms, there are such forms of juvenile arthritis as:

• pauciarticular
  – occurs between the ages of 1 and 6 years, asymmetrically affects large joints;
• seropositive juvenile polyarthritis
  - develops in children over 8 years of age, affects joints of various sizes;
• seronegative juvenile polyarthritis
  - develops up to 15 years of age, characterized by numerous joint lesions (often the temporomandibular and cervical spine);
• with systemic onset
  – does not depend on gender and age, affects joints, lymph nodes and internal organs;
• idiopathic
  - etiology unknown.

Systemic juvenile arthritis: an adult disease of young patients

Magazine "Remedium" No. 11, 2018

DOI: https://dx.doi.org/10.21518/1561-5936-2018-11-33-36

Yulia Prozherina

, Ph.D.,
Ekaterina Ilyukhina
,
“Remedium”
Systemic juvenile idiopathic arthritis (sJIA) is the most complex in pathogenesis, severe in course and unfavorable in prognosis of all variants of juvenile idiopathic arthritis [1]. Until now, the availability of modern therapy for this rare disease has remained one of the pressing problems in pediatric rheumatology. In this regard, the expert council of the State Duma Committee on Rare (Orphan) Diseases proposed to include sJIA in the “7 high-cost nosologies” program from 2021, which will greatly facilitate the task of treating children suffering from this disease [2].

Systemic juvenile arthritis: an adult disease in young patients

Julia Prozherina

, Cand.
of Sci.(Bio.), Ekaterina Ilyukhina
,
Remedium
Systemic juvenile idiopathic arthritis (SJIA) is the most difficult in pathogenesis, severe in its course and unfavorable in prediction of all types of juvenile idiopathic arthritis [1]. So far, access to modern therapy for this rare disease has remained one of the acute problems in pediatric rheumatology. From this perspective, the expert council of Rare (Orphan) Disease Committee of the State Duma proposed to include SJIA into the 7 High-Cost Nosologies Program starting from 2021, which will greatly ease the problem of treating children who suffer from this disease [2 ].

Figures and facts

The true prevalence of sJIA is not completely known. According to rough estimates, in Europe it is 0.3–0.8 per 100 thousand children under the age of 16 years. The share of this disease in the structure of juvenile arthritis ranges from 5 to 15% in North America, as well as in Europe, and reaches 50% in Japan. This pathology usually develops in children aged 0 to 18 years, with the peak incidence occurring between 1 and 5 years. Boys and girls get sick with the same frequency. Seasonality is not traced [3].

To monitor patients with juvenile idiopathic arthritis, including sJIA, patient registries have been created in a number of countries. It was one of the first to appear in Germany (Deutsche Rheuma-Forschungszentrum Berlin) and has about 14 thousand patients with juvenile idiopathic arthritis. The CARRA (North American Pediatric Rheumatology Research Alliance) registry is well known, with which 400 pediatric rheumatologists collaborate. It currently includes approximately 6,500 children with juvenile idiopathic arthritis. Such registries are also maintained in the UK (BSPAR Etanercept Registry) and Holland (Dutch national arthritis and biologics inchildren register). To date, the Dutch registry has included 335 patients with the articular variant and 86 with sJIA. In 2002, under the auspices of the Czech Rheumatological Society, the ATTRA project was developed; until 2013, 276 patients with juvenile idiopathic arthritis were included in its register. A large registry of patients with sJIA is maintained in Japan, including 417 patients with systemic arthritis. Finally, one of the largest registries of patients with juvenile idiopathic arthritis is the Pediatric Rheumatology International Trials Organization (PRINTO) PHARMACHILD [4]. The Register of the Ministry of Health of the Russian Federation registered 963 children with sJIA, which is 5.6% in the structure of juvenile arthritis in general [3].

Key Features

According to the generally accepted definition, sJIA, or systemic juvenile arthritis, is arthritis of one or more joints that is accompanied (or preceded) by documented intermittent fever lasting at least three days for at least two weeks in combination with one or more of the following: (flying) erythematous rash; generalized lymphadenopathy; hepatomegaly and (or) splenomegaly; serositis (pericarditis, and (or) pleurisy, and (or) peritonitis) [3].

The course of the disease is often characterized by the development of severe life-threatening complications, which can subsequently lead to the progression of functional failure, delayed physical development, and even disability of affected children. All this significantly reduces the quality of life of patients with sJIA and their parents [3, 4].

The root of the problem

According to numerous studies in recent years, sJIA belongs to the group of autoinflammatory diseases. Its diagnostic criteria can be a significant increase in the level of laboratory markers of inflammatory activity in patients (erythrocyte sedimentation rate, C-reactive protein, fibrinogen, leukocytes, platelets) [4]. Their appearance in the body is due to a certain nature of autoimmune reactions that accompany the disease and differ from those in “classical” autoimmune diseases. Thus, it is believed that the leading role in the pathogenesis of sJIA is played by the activation of the innate immune system and the production of pro-inflammatory cytokines by activated macrophages (interleukins 6, 1, 18), tumor necrosis factor alpha, granulocyte colony-stimulating factor, etc. [3].

One of the key elements in the development of the disease is interleukin-6 (IL-6), the high content of which in synovial fluid and blood serum leads to severe destructive arthritis and systemic manifestations of the disease, as well as to the appearance of hypochromic anemia. IL-6 blocks the production of growth hormone, adrenocorticotropic and somatotropic hormones, which causes growth retardation and causes cognitive impairment in patients. The development of amyloidosis, one of the most severe complications of sJIA, is associated with the activity of IL-6 [4].

Problems and solution

There are currently a number of problems in providing assistance to children suffering from sJIA. As a rare (orphan) disease, sJIA causes serious difficulties at the diagnostic stage, which, in turn, leads to delayed placement of patients under the supervision of a pediatric rheumatologist and, accordingly, to a delay in prescribing therapy, worsening the prognosis [5].

In addition to the need for early prescription of adequate drug therapy, practical experience suggests that such patients require an individualized, very careful and attentive approach throughout the entire period of observation by a rheumatologist and doctors of other specialties [5].

The situation is complicated by the high cost of treatment. Few parents are able to provide their child with the necessary complex of modern medications prescribed by a doctor. All this entails a significant decrease in the quality of therapy, a slowdown in the healing process, and, as a consequence, an increase in the likelihood of the pathological process becoming chronic [6].

In this regard, in 2021, the expert council of the State Duma Committee on Rare (Orphan) Diseases proposed expanding the list of diseases included in the “7 High-Cost Nosologies” program. Since 2019, this list has included 5 more nosologies, one of which is sJIA [2]. This measure will help not only improve the health of children with this rare disease and prevent early disability, but also improve their quality of life.

Issues of effective therapy

The goal of treatment for patients with sJIA is to relieve the key manifestations of the disease - pain, fatigue and stiffness, as well as to prevent the destruction of cartilage and bone, minimize deformities and improve joint mobility while maintaining the growth and development of the child [4].

Non-steroidal anti-inflammatory drugs are prescribed to all patients as symptomatic therapy. In addition, the use of glucocorticosteroids is widespread. Their advantage is the possibility of use in case of life-threatening systemic manifestations and hemophagocytic syndrome, as well as as an “intermediate” treatment during the transition to the acute period of the disease or while waiting for the effect of taking second-line drugs. Despite the high therapeutic effectiveness, monotherapy with glucocorticosteroids is carried out for no more than 2 weeks, since long-term use of drugs in this group can lead to the development of a number of serious side effects, including steroid dependence and resistance, osteoporosis, dwarfism, steroid diabetes, etc. In addition, among Doctors around the world have long been widespread in the practice of prescribing methotrexate as a treatment for children with sJIA [4].

However, despite the fact that the development of therapeutic approaches and specific treatment regimens for sJIA has improved its prognosis, in general, the results of therapy until recently did not inspire optimism. Treatment options for sJIA have expanded significantly thanks to the advent of modern genetically engineered biological therapy, such as IL-6 blockers, etc. These drugs have radically changed the course of the disease and the prognosis for patients with sJIA. [1].

The future is biotherapy

According to the Register of Biological Therapy for Patients with Juvenile Arthritis of the Union of Pediatricians of Russia, the most frequently prescribed drug in patients diagnosed with sJIA in 2012–2017. observation is tocilizumab (514 prescriptions) [7]. Next come rituximab and infliximab – 223 and 117 prescriptions, respectively (Table 1).

Table 1. Antirheumatic therapy for sJIA with genetically engineered biological drugs [7]

According to the registry data for 2012–2017, tocilizumab was most often prescribed to children diagnosed with sJIA as the first genetically engineered biological drug (65.2% of the group). The top three in terms of the number of prescriptions included infliximab and etanercept (Table 2) [7].

Table 2. Distribution of children with sJIA undergoing biological therapy, depending on the first genetically engineered biological drug prescribed [7]

Thus, tocilizumab (Actemra®) is currently the most prescribed genetically engineered biological drug for children with sJIA. Actemra® is the world's first IL-6 receptor antagonist, one of the most famous biological products in rheumatology, produced by Roche (Switzerland). The creator of the Actemra molecule received the Japanese National Prize, in addition, the drug was awarded two Galen Prizes. In pediatric rheumatology of the Russian Federation, about 600 patients receive the drug Actemra® for sJIA [1].

A number of international clinical studies have proven not only the effectiveness and safety of this drug, but also that treatment with tocilizumab inhibits the progression of destructive changes in the bone and cartilage tissue of the joints in children with sJIA [8, 9].

The prescription of a subcutaneous form of the drug for sJIA is allowed from 1 year, the use of an intravenous form of tocilizumab is allowed from 2 years [8].

According to modern clinical recommendations “Juvenile arthritis with systemic onset” of the Union of Pediatricians of Russia (2016), posted in the rubricator of the Ministry of Health of the Russian Federation cr.rosminzdrav.ru: “... in the treatment of sJIA with active systemic manifestations and arthritis of varying severity, it is recommended to prescribe tocilizumab at any stage of the disease with the ineffectiveness of non-steroidal anti-inflammatory drugs and/or glucocorticosteroids and/or methotrexate, as well as for children who have not previously received glucocorticosteroids and methotrexate. In the absence of active arthritis, monotherapy with tocilizumab is recommended; in the presence of active arthritis, a combination of tocilizumab at the same dose with methotrexate at a dose of 15 mg/m once a week subcutaneously is recommended. Level of evidence A." For sJIA without active systemic manifestations with arthritis of varying severity, the use of tocilizumab is recommended if methotrexate is ineffective [3].

Tocilizumab is present in modern standards of primary and specialized medical care for sJIA [10], and also occupies priority positions in updated standards submitted to the Ministry of Justice in 2021.

Other modern biologics available for the treatment of sJIA include canakinumab (Ilaris). This drug is a human or fully human monoclonal antibody that blocks interleukin-1β, which plays a role in the development of extra-articular symptoms of the disease [11, 12].

If tocilizumab and canakinumab are partially ineffective, patients with sJIA may be prescribed adalimumab and etanercept [3].

Efficiency and accessibility

Due to their proven effectiveness in therapy and the high cost of treatment, the drugs tocilizumab, adalimumab, canakinumab and etanercept are included in centralized procurement under the “7 high-cost nosologies” program. It is worth noting that the average cost of a course of therapy for one patient with sJIA is about 2.21 million rubles. The most affordable drug is tocilizumab, the average annual cost per patient for treatment of which is 223.65 thousand rubles, the most expensive drug is canakinumab, the annual course of which costs 7.4 million rubles. [13].

Bibliography

1. Kaleda M.I., Nikishina I.P. Efficacy and safety of tocilizumab in children with systemic juvenile arthritis in clinical practice. Scientific and practical rheumatology. 2015; 53(2):204–213.
2. Federal Law of August 3, 2021 No. 299-FZ “On Amendments to the Federal Law “On the Fundamentals of Protecting the Health of Citizens in the Russian Federation.” Effective January 1, 2021 [Federal Law No. 299-FZ of August 3, 2021 “On Amendments to the Federal Law “On the Fundamentals of Health Care of Citizens in the Russian Federation.” Effective from January 1, 2019]
3. Juvenile arthritis with systemic onset. Clinical recommendations. Ministry of Health of the Russian Federation. Year of approval: 2016.
4. Alekseeva E.I., Lomakina O.L., Valieva S.I., Bzarova T.M. Review of international registries of patients with systemic juvenile idiopathic arthritis. Issues of modern pediatrics. 2017; 16(1): 18–23.
5. Kaleda M.I., Nikishina I.P., Arsenyeva S.V. Clinical observation of systemic juvenile arthritis complicated by repeated episodes of macrophage activation syndrome and chronic clavicle osteomyelitis. Scientific and practical rheumatology. 2018; 56(1): 107-112.
6. Dereglazova Yu.S., Murashko Yu.I., Spichak I.V. Optimization of drug care for children with juvenile arthritis in outpatient settings. Scientific bulletins of BelSU. Series: Medicine. Pharmacy. 2013; 11(154).
7. “Register of biological therapy for patients with juvenile arthritis” of the Union of Pediatricians of Russia. Prepared by Aston Consulting JSC, 2021. [“R[“Registry of biological therapies for patients with juvenile arthritis” of the Union of Pediatricians of Russia. Prepared by Aston Consulting CJSC, 2021.]>
8. Instructions for use of Actemra.
9. Alekseeva E.I. et al. Efficacy and safety of tocilizumab in patients with severe systemic juvenile idiopathic arthritis. Issues of modern pediatrics. 2011.
10. Order of the Ministry of Health of Russia dated November 9, 2012 No. 777n “On approval of the standard of primary health care for children with juvenile arthritis with systemic onset” (Registered with the Ministry of Justice of Russia on December 29, 2012 N 26488).
11. Instructions for use Ilaris.
12. Grom A.A. Systemic juvenile idiopathic arthritis: mechanisms of development, targets for genetic engineering biological therapy. Issues of modern pediatrics. 2012; 3.
13. The Seven Nosologies program may include eight new drugs. Official website "Pharmaceutical Bulletin". Date of publication: 07/17/2018. Access mode: https://pharmvestnik.ru. Date of access: 11/13/18.

Diagnosis of juvenile arthritis

In order to conduct a thorough examination and make the most accurate diagnosis, it is necessary to contact a surgeon, rheumatologist, traumatologist or therapist, who, in accordance with the existing symptoms, will determine the right specialist.

Diagnosis of juvenile arthritis in children and adults is carried out in two stages:

• laboratory
  – includes clinical, biochemical and immunological studies;
• instrumental
  - the use of X-ray/ultrasound examination, as well as computed tomography and magnetic resonance imaging.

Based on the results of the diagnostic study, a diagnosis is established and the optimal treatment plan is determined, using physiotherapeutic methods and drug therapy.

Diagnostics

The diagnosis is made on the basis of anamnesis, questioning and examination of the patient, data from laboratory and instrumental studies. This is a multi-stage and rather lengthy process. The diagnosis is considered timely made if it is finally confirmed one and a half months after the patient’s first visit.

The main diagnostic methods are:

• biochemical, general, immunological blood test in children for juvenile arthritis;
• Analysis of urine;
• ECG;
• X-ray of the chest, as well as the affected limbs or spine (if indicated);
• Ultrasound of the kidneys, myocardium, abdominal organs;
• MRI (if indicated).

In addition, the child is sent to an appointment with an ophthalmologist to check the health of the visual organs.

A comprehensive examination is also carried out to determine the presence of infection in the body. It includes cultures for beta-hemolytic streptococcus, herpes virus, salmonella, toxoplasma, cytomegalovirus, chlamydia and a number of other pathogenic and opportunistic microorganisms.

Additionally, the patient may be prescribed ANA, ACPP, immunogenetic testing and a number of others. This is necessary to determine the type of arthritis and conduct differential diagnosis. Source: Nosological diagnosis of juvenile arthritis during long-term follow-up. Salugina S.O., Kuzmina N.N. Pediatrics. Journal named after G. N. Speransky, 2011. p. 29-35.

Treatment of juvenile arthritis

Treatment of pathology can be carried out both on an outpatient basis and in a hospital.

Inpatient treatment is required in situations where:

• there is a suspicion of the presence of the disease, but the diagnosis has not yet been confirmed;
• the degree of activity in the development of pathological processes reaches a medium/high pace;
• monitoring of the effectiveness/safety of the therapy used is necessary.

In a situation where the disease is detected in early childhood (from 1 to 4 years), hospitalization is mandatory

. This is due to the need to achieve remission as quickly as possible. Otherwise, the child's growth and development may be delayed.

Outpatient treatment is used during periods of remission or low activity of pathological processes.

Physiotherapy as a method of treating juvenile arthritis

Physiotherapeutic measures are carried out in parallel with drug therapy, as well as during the period of remission, to consolidate the achieved results.

The key goal of physiotherapy is to reduce inflammation in the joints

,
reduction of pain
, as well as
activation of metabolic processes within joint tissues
.

Massage as a treatment for juvenile arthritis

Massage is an additional means of combating degenerative processes. The positive effect of the procedure is noticeable at any stage of the disease

.

It is important to note that combining massage with physiotherapeutic procedures is possible only outside the phase of exacerbation of the disease

.

Exercise therapy for juvenile arthritis

Physical activity

in the form
of exercise therapy
for juvenile arthritis - a necessary component of treatment.

A set of exercises should be selected by a specialist, taking into account the stage of development of the pathology, as well as the individual characteristics of the patient.

Neglecting counseling sessions and advice from the attending physician can lead to loss of the beneficial effect of therapy and aggravation of the patient’s condition

.

Juvenile rheumatoid arthritis

What is juvenile rheumatoid arthritis?

Juvenile rheumatoid arthritis (JRA) is a chronic inflammatory disease of the joints of unknown cause, lasting more than 6 weeks, developing in children under the age of 16 years.

How common is juvenile rheumatoid arthritis?

Juvenile rheumatoid arthritis is one of the most common and most disabling rheumatic diseases that occurs in children. The incidence of JRA is from 2 to 16 people per 100,000 children under the age of 16 years. The prevalence of JRA in different countries is from 0.05 to 0.6%. Girls are more likely to suffer from rheumatoid arthritis.

Why does juvenile rheumatoid arthritis occur?

Hereditary and environmental factors take part in the development of JRA, among which infection is of greatest importance.

There are many factors that trigger the development of the disease. The most common are viral or mixed bacterial-viral infection, joint injuries, insolation or hypothermia, preventive vaccinations, especially those carried out against the background or immediately after an acute respiratory viral infection or bacterial infection. The possible role of infection in the development of JRA has been suggested, but it has not yet been conclusively proven. A connection was identified between the onset of the disease and a history of acute respiratory viral infection, with preventive vaccination against measles, rubella, and mumps. Interestingly, the onset of JRA after vaccination against mumps is more often observed in girls. There are cases when JRA manifested itself after vaccination against hepatitis B. The role of intestinal infections, mycoplasma, and beta-hemolytic streptococcus in the development of JRA is not recognized by most rheumatologists. However, it is known that these infections cause the development of reactive arthritis, which can transform into JRA. The role of viral infection in the development of chronic arthritis is less clear. It is known that more than 17 viruses are capable of causing infection, accompanied by the development of acute arthritis (including rubella, hepatitis, Epstein-Barr, Coxsackie viruses, etc.).

The etiological role of viruses in the development of chronic arthritis has not been proven. Hereditary predisposition to JRA is confirmed by family cases of this disease, studies of twin pairs, and immunogenetic data.

Is juvenile rheumatoid arthritis dangerous?

In JRA, 40-50% of children have a favorable prognosis; remission may occur lasting from several months to several years. However, exacerbation of the disease can develop years after stable remission. In 1/3 of patients, a continuously relapsing course of the disease is observed. Children with early onset of the disease and adolescents with positive rheumatoid factor have a high risk of developing severe arthritis and disability due to the condition of the musculoskeletal system. In patients with late onset, the disease may transform into ankylosing spondylitis. 15% of patients with uveitis may develop blindness. Mortality in JRA is very low and is observed in the absence of timely treatment, the addition of infectious complications or the development of amyloidosis.

How does juvenile rheumatoid arthritis manifest?

The main clinical manifestation of the disease is arthritis. Joint damage is manifested by pain, swelling, deformation and limitation of movement, increased skin temperature over the joint. In children, large and medium-sized joints are most often affected, in particular the knee, ankle, wrist, elbow, hip, and less commonly, small joints of the hand. Typical for JRA is damage to the cervical spine and maxillotemporal joints.

Pathological changes in the joint are characterized by the development of inflammatory reactions, which can lead to the destruction of the cartilage and bone tissue of the joints, narrowing of the joint spaces (the space between the ends of the bones that form the joints) up to the development of ankylosis (fusion of the articular surfaces of the bones that form the joints).

In addition to joint damage, the following extra-articular manifestations may be observed:

• Increased body temperature, sometimes to high levels; develops, as a rule, in the morning, and may be accompanied by chills, increased pain in the joints, and the appearance of a rash. A drop in temperature is often accompanied by heavy sweats. The febrile period can last weeks and months, and sometimes years, and often precedes joint damage.
• The rash can be varied, is not accompanied by itching, is located in the joints, on the face, chest, abdomen, back, buttocks and limbs, quickly disappears, and intensifies at the height of the fever.
• Damage to the heart, serous membranes, lungs and other organs. The clinical picture of heart damage in JRA: pain behind the sternum, in the heart area, and in some cases – pain in the upper abdomen; feeling of lack of air, forced position in bed (the child finds it easier in a sitting position). Subjectively, the child complains of a feeling of lack of air. The child has pallor and blue discoloration of the nasolabial triangle, lips, and fingers; the wings of the nose swell, swelling of the legs and feet. If the lungs are affected, patients may experience difficulty breathing and a wet or dry cough. When the abdominal organs are affected, abdominal pain is a concern.
• Enlarged lymph nodes can be up to 4-6 cm in diameter. As a rule, the lymph nodes are mobile and painless.
• Increased size of the liver and spleen.
• Eye damage is typical for younger girls with JRA. Redness of the eyes, lacrimation, photophobia, uneven contour of the pupil, and decreased visual acuity are noted. Ultimately, complete blindness and glaucoma may develop.
• Growth retardation and osteoporosis are one of the manifestations of JRA. Growth retardation is especially pronounced with a long and active course of the disease. With osteoporosis, there is a decrease in bone density and an increase in bone fragility. It manifests itself as pain in the bones. One of the severe manifestations of osteoporosis is a compression fracture of the spine.

How is juvenile rheumatoid arthritis diagnosed?

The diagnosis of juvenile rheumatoid arthritis is based on the results of an examination of the patient by a rheumatologist and a set of laboratory and instrumental research methods.

Laboratory and instrumental examination methods. Peripheral blood analysis (content of red blood cells, hemoglobin, platelets, leukocytes, leukocyte formula, erythrocyte sedimentation rate - ESR); analysis of biochemical parameters (total protein, protein fractions, concentration of urea, creatinine, bilirubin, potassium, sodium, ionized calcium, transaminases, alkaline phosphatase); analysis of immunological parameters (concentration of immunoglobulins A, M, G, C-reactive protein, rheumatoid factor, presence of antinuclear factor - ANF). All patients undergo electrocardiography, ultrasound examination of the abdominal cavity, heart, kidneys, X-ray examination of the chest, affected joints, and, if necessary, the spine, sacroiliac joints. Also, all children with joint damage are examined for the presence of infections: beta-hemolytic streptococcus, intestinal bacteria (Yersinia, Shigella, Salmonella), parasites (Toxoplasma, Toxocarr, etc.), herpes virus and cytomegalovirus, chlamydia. If difficulties arise in making a diagnosis, an immunogenetic examination is performed. With long-term use of painkillers and hormonal drugs, esophagogastroscopy is necessary. Consultation with an ophthalmologist and slit lamp examination is indicated for all children with joint damage.

What treatment and prevention methods are there for juvenile rheumatoid arthritis?

Treatment of juvenile rheumatoid arthritis is a serious problem and must be comprehensive, including adherence to the regimen, diet, drug therapy, physical therapy and orthopedic correction.

Goals of JRA therapy:

• suppression of inflammatory activity of the process
• disappearance of systemic manifestations and articular syndrome
• maintaining the functional ability of joints
• preventing or slowing down joint destruction and patient disability
• achieving remission
• improving the quality of life of patients
• minimizing side effects of therapy

Drug therapy for JRA is divided into two types: symptomatic (non-steroidal anti-inflammatory drugs and glucocorticoids) and immunosuppressive (suppresses immunity). The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids helps to quickly reduce pain and inflammation in the joints and improve function, but does not prevent joint destruction. Immunosuppressive therapy stops the development of destruction and reduces disability.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

In children, the most commonly used drugs are diclofenac, naproxen, nimesulide, and meloxicam. Treatment with NSAIDs alone is carried out for no more than 6-12 weeks, until a reliable diagnosis of JRA is made. After this, NSAIDs should be combined with immunosuppressive drugs. With prolonged use of NSAIDs or exceeding the maximum permissible dose, side effects may develop.

Glucocorticoids

Glucocoticoids are classified as hormonal drugs. They have a rapid anti-inflammatory effect. Glucocorticoids are used for intra-articular (methylprednisolone, betamethasone, triamsinolone), intravenous (prednisolone, methylprednisolone) administration and oral administration (prednisolone, methylprednisolone).

It is not advisable to begin treatment of patients with JRA by prescribing oral glucocorticoids. They should be prescribed when other treatment methods are ineffective. It is not recommended to prescribe glucocorticoids orally to children under 5 years of age (especially under 3 years of age), as well as in adolescence, as this can lead to severe growth retardation.

Intravenous administration of glucocorticoids (pulse therapy) quickly suppresses the activity of the inflammatory process in patients; it is used mainly in the presence of systemic manifestations of JRA.

Immunosuppressive therapy

Immunosuppressive therapy occupies a leading place in the treatment of rheumatoid arthritis. The prognosis for the patient’s life and the course of the disease often depends on the choice of drug, timing of prescription, duration and regularity of treatment. Immunosuppressive therapy should be long-term and continuous, starting immediately after diagnosis. The drug can be discontinued if the patient is in a state of clinical and laboratory remission for at least 2 years. The withdrawal of immunosuppressants in most patients causes an exacerbation of the disease.

The main drugs for the treatment of JRA are methotrexate, cyclosporine A, sulfasalazine, leflunomide, and their combinations. They are highly effective, fairly well tolerated and have a low incidence of side effects, even with long-term (many years) use.

Cyclophosphamide, chlorambucil, and azathioprine are rarely used to treat JRA due to the high incidence of severe side effects. Hydroxychloroquine, D-penicillamine, and gold salts are practically not used due to lack of effectiveness.

When treating with immunosuppressants, a general blood test is monitored (content of red blood cells, hemoglobin, platelets, leukocytes, leukocyte formula, ESR); analysis of biochemical parameters (total protein, protein fractions, concentration of urea, creatinine, bilirubin, potassium, sodium, ionized calcium, transaminases, alkaline phosphatase) - once every 2 weeks. If the number of leukocytes, erythrocytes, platelets decreases below normal, if the level of urea, creatinine, transaminases, bilirubin increases above normal, stop immunosuppressants for 5-7 days, after a control blood test, if the indicators normalize, resume taking the drug.

Biological agents

Recent advances in science have made it possible to create a new group of drugs - so-called biological agents. These include: infliximab, rituximab. These drugs are highly effective for the treatment of certain variants of JRA. Treatment with these drugs should be carried out only in specialized rheumatology departments, whose staff have experience in the use of such drugs.

Surgery

Surgical treatment is indicated for the development of severe joint deformities that make it difficult to perform the simplest daily activities, or the development of severe ankylosis. The main surgical intervention is joint replacement.

HOW TO PREVENT JUVENILE RHEUMATOID ARTHRITIS?

It is impossible to prevent the development of JRA due to the lack of data on the causes of its occurrence.

To prevent the development of exacerbations of the disease, the following rules must be observed:

• Avoid insolation (staying in the open sun, regardless of latitude).
• Avoid hypothermia.
• Try not to change the climate zone.
• Reduce contact with infections.
• Avoid contact with animals.
• Patients with JRA are contraindicated for any preventive vaccinations (except for the Mantoux test) and the use of all drugs that increase the body's immune response (lycopid, tactivin, polyoxidonium, immunofan, viferon, interferon and others).

Use of drugs in the treatment of juvenile arthritis

Drug treatment involves the use of drugs from various groups, each of which helps to accelerate regenerative processes inside the joint and restore its functionality.

IMPORTANT! Self-medication can cause the situation to worsen and trigger irreversible consequences

. Taking medications should be carried out taking into account the recommendations of the attending physician.

Chondroprotectors in the treatment of juvenile arthritis

They enrich the body with the necessary components that enable the regeneration of articular tissues.

The drugs belong to the category of long-acting medications and require many months of use.

The most commonly appointed is considered to be “ Structum”

».

Antispasmodics in the treatment of juvenile arthritis

Excellent helpers in the fight against such an unpleasant symptom as pain.

Taking antispasmodics allows you to get rid of muscle pain caused by pathological processes occurring in the joint tissues.

One of the most effective drugs in this group is “ No-spa

».

Nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of juvenile arthritis

The use of NSAIDs has a beneficial effect and helps speed up the recovery process. The action of the drugs is aimed at relieving pain and improving overall well-being.

The duration of use, dosage and frequency of administration are determined by the doctor in accordance with the results of a diagnostic or intermediate examination.

The most effective drug of this type is considered to be “ Artradol”

».

Possible complications

Despite the fact that in most patients juvenile arthritis proceeds without complications, with the onset of long-term remission, there is always a risk of complications.

.

Failure to seek medical help in a timely manner, as well as refusal or deviation from prescribed treatment can lead to the development of a number of serious complications, including:

• persistent impairment of joint mobility, causing disability;
• development of cardiopulmonary failure;
• severe impairment of the visual system;
• infectious complications.

Predictions and prevention of juvenile arthritis

More than 50% of officially registered cases can be successfully treated

.
Stable remission can be achieved for a period of up to 10 years. However, despite such positive forecasts, a third of patients become disabled
.

To eliminate the likelihood of irreversible consequences, it is important to exclude factors that could provoke aggravation of the situation. Among them:

• eliminating the possibility of hypothermia, dosing exposure to sunlight;
• maintaining personal hygiene, preventing the likelihood of contact with potential carriers of viruses and infections;
• maximum compliance with safety precautions in order to eliminate the likelihood of injury during sports;
• compliance with the basics of dietary nutrition, enrichment of the diet with calcium and phosphorus.

Clinical guidelines

Due to the fact that the exact causes of the disease cannot be established, clinical recommendations are of an exclusively general nature and are primarily aimed at eliminating the likelihood of a recurrence of exacerbation of the disease.

In order to maintain the achieved treatment results, it is important to combine therapy with observation by a rehabilitation specialist

, which will help develop an action plan to preserve the functionality of the joint.

Among the main recommendations it is worth highlighting:

• increasing vigilance and strengthening measures to ensure sufficient heat levels for the body;
• eliminating the likelihood of stressful situations;
• systematic visits to the attending physician, even with favorable treatment.

Compliance with the recommendations allows you to slow down or completely stop the processes of relapse of pathological processes.

Diet for juvenile arthritis

Proper nutrition

– an important stage in the treatment and prevention of existing diseases, in particular pathologies of the musculoskeletal system.

A diet for juvenile arthritis is part of a mandatory therapeutic course, the content of which is determined by the attending physician in order to relieve inflammation of the joints and eliminate unpleasant symptoms.

Among the features of dietary nutrition it is worth highlighting:

• enriching the diet with plant foods in order to replenish the supply of vitamins and minerals;
• limiting the consumption of foods that promote calcium excretion;
• reducing salt intake;
• using gentle cooking methods;
• avoiding alcohol, sugar, carbonated drinks and flour products.