"Gold standard" in the treatment of juvenile idiopathic arthritis

Juvenile arthritis is a common rheumatic disease that affects children under 16 years of age, especially girls. Epidemiological data indicate that juvenile arthritis affects an average of 9 children out of 100,000. It is characterized by high disability, so timely treatment and diagnosis is the primary task of parents at the slightest suspicion of JA.

A cause for concern should be persistent pain that lasts more than 6 weeks. You should consult a doctor already in the 2nd week of ill health. But how to recognize the onset of the disease?

Juvenile rheumatoid arthritis: what is it?

Rheumatoid, idiopathic, chronic, juvenile arthritis are all names for one autoimmune disease. It is characterized by non-purulent inflammation of the synovium of one or more joints. At the same time, the production of the natural “lubrication” of the joint, joint fluid, is enhanced. At first, the process makes itself felt only by minor swelling, but over time, the lining of the joint swells and thickens. Ultimately, it closes with the cartilage, preventing the joint from functioning normally. Because of this, the cartilage is injured with every movement, and pockets of progressive erosion appear on its surface.

Rheumatologists distinguish 4 types of juvenile arthritis:

• monoarthritis (affects 1 joint);
• oligoarthritis (1-4 joints);
• polyarthritis (generalized form, more than 4 joints);
• systemic (in addition to joints, it affects other organs and systems - for example, eyes, heart, lungs, blood vessels).

The causes of juvenile rheumatoid arthritis are still unknown to medicine. Scientists were able to establish a connection between the disease and heredity and environmental factors surrounding the child. Juvenile rheumatoid arthritis (JRA) is often provoked by a viral or bacterial-viral infection, injury (including delayed in time), stress, prolonged exposure to the sun or overheating, as well as hypothermia. Also, an immune surge can be caused by vaccinating a child against measles, rubella, mumps, and group B hepatitis. In particular, if carried out in violation of the rules - during an acute respiratory viral infection or other illness or immediately after it.

It is assumed that rubella and the other viruses mentioned can cause acute infectious arthritis, which sometimes develops into chronic juvenile arthritis.

The mechanism of development and causes of rheumatoid arthritis

The onset of the disease is often associated with a viral infection, injury, stress on a particular joint, hormonal imbalance, and renal failure. The joints most susceptible to damage are the knees, feet, wrists and fingers. When exposed to certain factors, the human immune system triggers an erroneous reaction: it mistakes a normal part of the body for a foreign object. As a result, substances begin to be produced that destroy the synovial membrane of the joints.

Currently, the reasons for the overactivity of the immune system leading to RA are unknown. The main suspected causes:

• Genetic factor
  . A number of studies have revealed a high percentage probability of RA manifestation in close relatives in several generations.
• Infectious agents
  . There is reason to believe that the cause of the disease may be its infectious nature. This is most likely the Epstein-Barr virus, which causes rheumatoid manifestations. Other infectious causes may be: rubella virus, cytomegalovirus, mycoplasma, retroviruses, parovirus B19. Viral RA is acute and rarely becomes chronic.
• Emotional stress
  . There is a version that the development of the disease begins after a serious psychological shock. This explains the fact that women get sick 4 times more often than men.

Symptoms of Juvenile Arthritis

JRA can occur in acute, subacute, chronic and chronic forms with exacerbations. Only a rheumatologist can accurately differentiate them. However, there are common symptoms of juvenile arthritis that are observed in all patients or in most patients:

• pain in the joints and sensitivity of the skin over them (in rare cases there is no pain);
• local increase in temperature of adjacent tissues;
• impaired biomechanics of the joint - movements become stiff, their amplitude is reduced until complete immobility (due to ankylosis - fusion of articular surfaces);
• swelling around the joint.

The disease makes itself felt not only in the joints. In children and adolescents there is:

• increase in general body temperature (possibly significant);
• fever and chills - may not leave the patient for months without treatment;
• muscle aches;
• rashes on the skin that do not itch and quickly disappear, but soon reappear.

Extra-articular symptoms are especially noticeable in the morning - this is their main difference from ordinary acute respiratory viral infections. Temperatures peak in the evening and at night. Dermatological manifestations on any part of the body increase as the pain intensifies and are absent during the period of remission.

The most alarming manifestations of systemic JA are:

• pain in the chest and in the area of ​​the heart, stomach, above the diaphragm;
• a feeling of suffocation that intensifies in a horizontal position;
• pallor or cyanosis of mucous membranes, face, fingers;
• swelling of the lower extremities, especially the ankle;
• suffocating cough, with or without phlegm;
• abdominal pain;
• due to loss of appetite, weight loss;
• painless enlargement of the lymph nodes (dense nodules about 5 cm in size are felt under the skin) while maintaining their mobility;
• enlargement of the liver and spleen, noticeable on palpation;
• eye complaints - redness of the conjunctiva and lacrimation, increased sensitivity to light, abnormal shape of the pupil, blurred and impaired vision (more often observed in girls under 12 years of age);
• psoriatic skin lesions that “fade” from the center to the edges.

In the later stages of the disease, joint deformation is observed due to thinning of the cartilage and grinding of the heads of the subchondral bones. JRA is also fraught with growth retardation, frequent bone and spine fractures, and the development of osteoporosis. In this case, the child grows poorly, limps, and complains of pain. The affected leg may be longer than the other, and the chin may take on a receding appearance.

Symptoms of juvenile arthritis are most often observed in the large and medium-sized joints of the extremities - ankle, knee, hip, elbow and wrist. Maxillotemporal arthritis and inflammation in the cervical spine are very characteristic of the disease. Arthritis of the interphalangeal and other small joints is relatively rare. JA can be either symmetrical or asymmetrical.

Diagnosis of juvenile arthritis

Diagnosis of juvenile arthritis is carried out using instrumental and laboratory tests, as well as examination of the patient by a rheumatologist. This is a rather lengthy multi-step process. A timely diagnosis is considered, on average, 1.5 months after the patient’s first visit.

Usually the patient is sent to a laboratory where he will take:

• general blood analysis;
• blood chemistry;
• immunological blood test.

It is also mandatory to:

• electrocardiography;
• Ultrasound of the abdominal cavity, heart and kidneys;
• X-ray of the chest, and also, depending on the location of the inflammation, the spine or affected limbs.

For timely detection of pathologies, the child is also referred to an ophthalmologist, who conducts a slit lamp examination. This examination can be carried out once or at intervals of 3-6 months, even if there are no visual complaints.

Urinalysis and MRI are prescribed at the discretion of the doctor.

Examination for the presence of infections, which is included in the basic diagnostic plan, includes culture for:

• beta-hemolytic (pyogenic) streptococcus;
• salmonella, yersinia, shigella;
• toxoplasma, toxocara;
• herpes;
• chlamydia;
• cytomegalovirus.

Additionally, the doctor may prescribe an immunogenetic study, ACCP, ANA and other tests to differentiate the disease, i.e., determine its subtype, and exclude diseases with similar symptoms.

Treatment of juvenile arthritis

As a rule, treatment of juvenile arthritis begins with diagnosis and selection of gentle medications. If medications with a “mild” effect do not provide the desired effect, more serious therapy is used until improvement occurs.

Treatment of juvenile arthritis in children and adolescents is carried out in a hospital if:

1. There is a suspicion of JA, but the diagnosis has not been established; a treatment plan is required. In this case, it is necessary to exclude other similar diseases, such as leukemia or tuberculosis, determine the extent of the lesions and select safe therapy.
2. The degree of activity of juvenile arthritis is defined as moderate or high.
3. To monitor the effectiveness and safety of the therapy used (once every six months or year).
4. Treatment with genetically engineered biological products is required.

Early onset of the disease (between the ages of 1 and 4 years) almost always requires hospitalization. Its need increases in the case of systemic inflammation, in which remission must be achieved as soon as possible. Otherwise, growth retardation is observed, and in some cases there may be a threat to life due to developed amyloidosis.

Treatment of JA in remission or with low activity is carried out on an outpatient basis or in a day hospital. In most cases, expenses can be covered using a compulsory medical insurance policy, and in severe cases of the disease, genetic engineering therapy is carried out at the expense of the state.

Drug treatment of juvenile arthritis

To treat juvenile arthritis, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorcoid steroids (GCs), immunosuppressants (drugs to suppress the immune system), genetically engineered biological drugs, and, if necessary, painkillers and antipyretic drugs are used. Additionally, medications may be prescribed to minimize side effects from the main therapy.

The first two groups of drugs are recommended for the acute phase of the disease. They quickly relieve symptoms of inflammation, improve joint movement, and relieve pain. For example, pulse therapy, even in severe systemic JA, stops disease activity within 24 hours. However, NSAIDs and GCs do not have a direct effect on the joint - they are not able to slow down the erosion and degeneration of cartilage, and do not prevent the patient’s disability. Treatment of JA involves taking immunosuppressants (to prevent the body from attacking its own tissues in the joint) and biological drugs (they help to do without GCs, which should not be taken too often). Immunosuppressants are prescribed during the first 3-6 months after confirmation of the diagnosis and can be taken for years. If a child gets sick with ARVI, their use is stopped for a while.

The drugs are given to the child orally, intravenously, or as intra-articular injections. Local use of gels, ointments and creams against pain and swelling is possible.

Self-medication of chronic juvenile arthritis is unacceptable! All systemic medications are taken in strict accordance with the prescription of the attending physician. Otherwise, severe side effects are possible - growth disorders, problems with the endocrine and digestive systems, osteoporosis, obesity, cataracts, dermatological changes, hypertension, etc.

Non-drug treatment of juvenile arthritis

Physiotherapy for JA is carried out in parallel with taking medications or in remission, since it allows

During the acute phase, the child requires a gentle motor regimen. Physical activity and prolonged continuous activity are not recommended. However, the muscular system must still develop, otherwise the child may develop persistent contracture and muscle tissue atrophy. These pathological conditions only increase the load on bones and joints, leading to rapid progression of osteoporosis and fusion of articular surfaces. Therefore, patients are recommended to undergo therapeutic exercises under the supervision of an instructor. It will also help to establish an individual orthopedic regimen and eliminate postural problems, if any, which can aggravate the course of the disease. It is advisable to do exercise therapy every day. Sometimes the doctor prescribes the wearing of orthoses or other orthopedic correction.

A strict diet is not required for JA; it is important to ensure that the child's diet contains sufficient amounts of calcium, vitamin D3 and sources of collagen. It is advisable to include nutritional supplements in the menu - for example, chondroprotectors with glucosamine and chondroitin.

In case of complete destruction of the joint or severe ankylosis (with immobility of the joint), surgical prosthetics is performed.

Is it possible to completely recover from juvenile rheumatoid arthritis?

Juvenile arthritis is a chronic disease. Therefore, it is important to consult a doctor in the early stages, receive adequate treatment and follow medical recommendations to avoid exacerbations. In this case, remission for a period of several months to several years occurs in 40-70% of patients.

If JA began in a child at an early age, a positive rheumatoid factor or a polyarticular form of the disease is diagnosed, severe arthritis may develop, including disability. However, with modern therapy, there are frequent cases of drug-free remission, when the patient does not need lifelong medication. Up to 90% of children can be protected from disability.

Therefore, the intervention of a rheumatologist is extremely important and will help the child live a full life with juvenile arthritis, in which there will be a place for dancing, sports and everyday activity!

Norilsk Interdistrict Children's Hospital

International League Against Rheumatism classification of juvenile idiopathic arthritis (Petty, 2004).

Oligoarticular – permanent or long-lasting. Polyarticular – seronegative (negative rheumatoid factor). Polyarticular – seropositive (positive rheumatoid factor). Systemic. Psoriatic. Enthesopathic. Unclassifiable.

Note 1: Arthritis associated with ulcerative colitis is excluded.

Note 2: S-JIA is often classified as an autoinflammatory disease.

Misconception: Systemic-onset juvenile idiopathic arthritis (S-JIA) is a homogeneous disease.

Reality: Classic clinical features—daily fever, macular rash, and arthritis—distinguish patients with S-JIA (sometimes called Still's disease) from the oligoarticular or polyarticular subtypes of JIA. However, clinicians recognize that S-JIA has a wide range of clinical presentations, including patients with mild to severe arthritis, transient or persistent systemic manifestations, variable disease duration, varying propensity for relapse, and disparate responsiveness to standard treatment.

Patients with S-JIA are less responsive to methotrexate than patients with other forms of JIA (Woo, 2006). A good clinical effect of methotrexate is achieved in less than 50% of patients with S-JIA, but it is often short-lived (Lovell, 2006). Some patients show dramatic improvement with IL-1 receptor antagonist therapy, but the overall proportion of patients benefiting from this intervention is less than 50% (Lequerre and Quartier, 2008). Finally, a significant proportion of patients with S-JIA have been shown to be responsive to IL-6 blockers (Yokota et al., 2008). These data strongly suggest that subtypes of S-JIA exist.

Other systemic inflammatory disorders that mimic the clinical picture of S-JIA (eg, autoinflammatory/periodic febrile syndromes) are caused by specific monogenic mutations that lead to an imbalance toward a proinflammatory state. These disorders include chronic infantile neurological cutaneous articular syndrome (CINCA syndrome), Muckle–Wells syndrome, hyper-IgD syndrome, and tumor necrosis factor receptor-associated periodic syndromes (TRAPS syndromes). All of these conditions present with urticarial or macular rashes, periodic fevers, organic disorders, and arthralgias or arthritis—symptoms closely resembling S-JIA. Gene association studies have identified many cytokine genes that influence the homeostasis of the inflammatory response in S-JIA (Woo, 2000). Thus, although S-JIA and autoinflammatory syndromes may show striking similarities clinically, S-JIA appears to have a much more complex genetic background.

Established fact: Patients with S-JIA are at risk of developing macrophage activation syndrome.

Comment: More recently, it has been established that the development of macrophage activation (or secondary hemophagocytic histiocytosis - HFH) is more common in patients with S-JIA. Genetic studies have shown that patients with macrophage activation syndrome develop a variant of the disease in which genetic risk factors coincide with those of patients with familial MFH (Zhang et al., 2008).

Established fact: Certain clinical signs may indicate the appearance of macrophage activation syndrome in a patient with S-JIA.

Comment: Children with systemic JRA have many abnormal blood tests. Increased erythrocyte sedimentation rate. Leukocytosis. Thrombocytosis. Anemia. Hypoalbuminemia. Slight increase in liver transaminase levels. Elevated D-dimer levels. Sharply elevated serum ferritin levels.

All these deviations return to normal as the disease activity decreases. Macrophage activation syndrome (MAS) can occur in S-JIA and shares many of the features of this disorder, but also occurs in patients with intracellular viral infections and in patients with no known risk factors. The following symptoms are typical for SAM: fever; hepatosplenomegaly; encephalopathy, manifested by dizziness, drowsiness and disorientation; sharply elevated serum ferritin levels; elevated serum triglyceride levels; coagulopathy (increased D-dimer levels and changes in PT and PTI) and hemorrhage; decreased ESR (as opposed to the increase typical for S-JIA); cytopenias (leukopenia, thrombocytopenia and anemia, in contrast to leukocytosis and thrombocytosis in S-JIA); sharply elevated serum levels of hepatic transaminases; picture of hemophagocytosis on examination of bone marrow aspirate.

Paradoxically, the course of arthritis in S-JIA may improve with the development of SAM. Thus, positive dynamics of arthritis, a drop in ESR and a decrease in the number of leukocytes and platelets may mean an improvement in the course of S-JIA, but may also portend the development of a life-threatening complication - MAS (Stephen et al., 1993).

Misconception: JIA will go away when the child grows up.

Reality: In many children with JIA who have persistent oligoarthritis, and especially monoarthritis, the disease goes into remission over time. However, some patients experience recurrence of arthritis in joints previously affected by JIA, or the arthritis spreads to other joints much later in life (unpublished case report).

Recent descriptions of gene expression profiles in polyarticular JIA patients in remission have revealed atypical expression compared with controls, reinforcing the view that the immune system is balanced in remission, but differently than in individuals without JIA (Jarvis et al., 2006). ). Preliminary results are consistent with the fact that there are genes associated with JIA that influence the innate and adaptive immune responses in these patients (Prahalad and Glass, 2008). Thus, triggers, such as severe viral infections, can tip the balance back toward a persistent inflammatory state, theoretically causing a relapse of arthritis. Therefore, the term “extinct” should not be used.

Misconception: In patients with polyarticular JIA, rheumatoid factor IgM is usually positive. Therefore, this test helps differentiate the inflammatory disorder from other arthropathies in children.

In reality: About 40% of children with JIA have the polyarticular form of the disease. However, only 5% of JIA patients test positive for rheumatoid factor. Patients with seropositive JIA are most often adolescents with highly active disease and severe damage to the small joints of the hands. Thus, a negative rheumatoid factor test in a child or adolescent with arthritis does not exclude the diagnosis of JIA.

Rheumatoid nodules are also not typical for JIA, but if they appear, they most often occur in patients with rheumatoid factor.

Misconception: Anti-CCP antibodies help determine disease subtype.

Reality: Anti-CCP antibodies are rare in JIA, but their levels are increased in patients with polyarthritis who have the HLA-DR4 antigen. They are associated with erosive damage and the presence of rheumatoid factor, and therefore are of value only for this small subtype of JIA.

Established fact: In oligoarticular JIA, the activity of eye damage does not depend on the activity of joint disease.

Comment: The activity of uveitis, which develops in JIA, does not depend on the activity of the disease in the joints. Uveitis precedes the onset of arthritis in approximately 10% of patients with oligoarticular JIA. Uveitis occurs simultaneously with arthritis in 30% of cases and develops later than arthritis in 60% of cases (Rosenberg and Oen, 1986). Even when the same patient has both arthritis and uveitis, the activity of these manifestations of the disease may be different. Thus, regular assessments of children with oligoarticular JIA are necessary (Cassidy et al., 2006), even when arthritis is well controlled. Uveitis can develop insidiously and lead to severe eye damage in the absence of ocular symptoms.

Established Fact: Arthritis in one finger is often an early sign of psoriatic arthritis.

Comment: Psoriatic arthritis in children often begins with diffuse, sausage-shaped swelling of one or more fingers. In general, psoriatic arthritis in children affects the joints asymmetrically. Skin manifestations of psoriasis may appear several years after arthritis. Therefore, collecting a family history of psoriasis and examining the nails to identify characteristic dimples are important points for creating a holistic picture of the disease and recognizing psoriatic arthritis in the early stages.

Established Fact: Abnormalities of bone and muscle development are significantly influenced by joint inflammation and the function (or lack of function) of the limbs.

Comment: Blood flow changes characteristic of JIA influence overgrowth, underdevelopment, and maturation of bone trabeculae. The presence of inflammation can accelerate bone maturation and lead to increased bone length. Conversely, inflammation can lead to early closure of the epiphyses and, as a result, shortening of the bone. When the functional load on a limb decreases, its growth may stop. A typical example in JIA is forefoot shortening due to poorly controlled ankle arthritis. Physical therapy and control of inflammation are necessary to ensure normal growth patterns.

Another functional complication of oligoarthritis is muscle atrophy on both sides of the affected joint. Its striking manifestations can often be observed in the quadriceps muscle. Muscle atrophy develops quickly, and patients require long periods of time to regain muscle mass, even after achieving remission and undergoing active physical therapy.

Established fact: Enthesitis may develop in S-JIA.

Comment: Certain individuals with S-JIA may develop mass swelling of the tendon insertions. Such swelling can be mistakenly interpreted as arthritis or a muscle abscess. Ultrasound and MRI reveal amorphous contents in the tendon near its attachment (enthesis). Aspiration of contents is often difficult. The most common sites for enthesitis in S-JIA are the biceps tendon near the shoulder joint and the gastrocnemius tendon behind the knee joint.

Misconception: A girl with antinuclear antibodies and monoarthritis of the knee that has persisted for 6 months will not develop polyarticular disease.

In reality: Chronic arthritis of one to four joints in the first 6 months of the disease meets the criteria for oligoarthritis. However, 20-30% of children with oligoarthritis develop polyarticular disease (common oligoarthritis) over the next few years.

Misconception: Back pain in children is a rare phenomenon, which almost always hides a pathology.

Reality: Back pain is common in the general pediatric population in developed countries and occurs in 11-36% of school-age children. In 50% of children who visit an orthopedist for back pain, it is not possible to explain the pain. Causes of back pain in children include Scheuermann–Mau disease, spondylolysis, disc herniation, infection and tumor (Tumer, 1989; Feldman, 2000).

Misconception: Sacroiliitis does not occur in children under 13 years of age.

Reality: Epidemiological data from areas where childhood spondylitis is common suggests that sacroiliac joint inflammation may develop in children younger than 13 years of age (Huerta-Sil et al., 2006). The use of contrast-enhanced MRI in appropriate clinical settings facilitated diagnosis in these patients.

Misconception: Children with psoriatic JIA often develop axial arthritis.

Reality: In adults with psoriatic arthritis, sacroiliitis or spondylitis occurs in less than 40% of cases (Lambert and Wright, 1977). In children with psoriatic arthritis defined using the so-called Vancouver criteria, sacroiliitis develops in less than 5% of cases (Robertson et al., 1989; Stoll et al., 2006). Children diagnosed with psoriatic type JIA are even less likely to develop sacroiliitis or spondylitis due to associated exclusion criteria.

Established fact: Children with psoriatic arthritis should be screened for uveitis in the same manner as patients with pauciarticular JIA.

Comment: Many pediatric rheumatologists consider psoriatic arthritis to be a disease entity separate from spondyloarthropathies. This view is supported by the fact that children with psoriatic arthritis rarely develop painful iritis, but there is a moderate risk of developing asymptomatic ocular inflammation. Children with psoriatic arthritis should undergo routine testing for uveitis in the same way as patients with oligoarticular JIA.

Misconception: Leukemia is easy to distinguish from JIA.

Reality: Differential diagnosis between leukemia and JIA, and especially S-JIA, can be challenging. About 20-40% of children with leukemia have arthritis as one of the manifestations of the disease. Blood tests for leukemia may remain normal for weeks or months after the onset of musculoskeletal symptoms, so repeat tests are necessary and a bone marrow tap is usually required.

In approximately half of patients with leukemic arthritis, a single joint is affected, most often the knee. Oligoarthritis is also not uncommon. Pain in leukemic arthritis is more severe than in JIA and is concentrated over the metaphysis rather than in the joint itself. The degree of increase in ESR in leukemia, as a rule, does not correspond to the small number of affected joints. On the contrary, with oligoarticular JIA, ESR is usually reduced or within normal limits.

Leukemia is characterized by low levels of white blood cells and platelets, in contrast to the leukocytosis and thrombocytosis characteristic of JIA. A sharply elevated level of serum lactate dehydrogenase should also lead the doctor to think about leukemia. Bone scintigraphy can differentiate malignant transformation from JIA in cases of widespread musculoskeletal complaints (Cabral and Tucker, 1999).

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