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24.
Насонов Е.Л. Автоиммунные ревматические заболевания: итоги и перспективы научных
исследований. Е.Л. Насонов, Е.Н. Александрова, А.А. Навиков. Научно-практическая ревматология.
2015;53, Но 3: 230-237.
25.
Насонов Е.Л. Т-регуляторные клетки при ревматоидном артрите/ Е.Л. Насонов(и др). научно-
практическая ревматология. 2014;52(4):430-437.
26.
Насонов Е.Л. Достижения ревматологии в ХХ1 в. Е.Л. Насонов. Научно - практическая ревматология.
2014;52(2): 133-141.
27.
Новиков Л.А., Александрова Е.Н., Диатропова М.А. Роль цитокинов в патогенезе ревматоидного
артрита. Научно - практическая ревматология 2010; 2: 71-82
28.
Соболева Е.М. Ювенильный ревматоидный артрит: современное состояние проблемы (обзор
литературы). Вестник физиотерапии и курортологии.
29.
Федеральные клинические рекомендации оказанию медицинской помощи детям с юношеским
артритом с системным началом. Под ред. А.А. Баранова. М., 2009:44.
30.
Федеральные клинические рекомендации по оказанию медицинской помощи детям с юношеским
артритом с системным началом. Под ред. А.А. Баранова. М., 2015: 24.
31.
Федоров Е.С. Роль цитокиновой сети в регуляции воспаления при различных вариантах ювенильного
артрита. Е.С. Федоров, С.О. Салугина, Н.Н. Кузьмина. Научно-практическая ревматология. 2009;3:74-
89.
32.
Хаитов Р.М. Игнатьева Г.А., Сидорович И.Г. Иммунология. И. Медицина, 2000.
33.
Харитонова Л.А., Соболева Н.Г. Роль инфекционного фактора при ювенильном ревматоидном артрите
у детей. Харитонова Л.А., Соболева Н.Г. Российский вестник перинатологии и педиатрии. 2018,
63(3),59-63с.
34.
Чернишова О.Е., Конюшевская А.А., Вайзер Н.В. Ювенильный ревматоидный артрит: этиология,
патогенез. Травма, Том 19, №2, 2018:99-105.
35.
Ювенильный артрит: клинические рекомендации для педиатров. Детская ревматология/Под редакцией
А.А.Баранова, Е.И.Алексеевой.-М.: Педиатръ, 2013:120.
36.
Classidy J.T. Textbook of pediatric rheumatology. - 6
th
ed./ J.T. Cassidy (et al.) - Philadelphia: Saunders
Elsevier, 2010:794.
37.
De Benedetti F. Inflammatory cytokines in the phathogenesis and treatment of systemic juvenile idiophatic
arthritis. De Benedetti F. Pediatric Rheumatology Online J. 2005;3:122-136.
38.
Feldmann M. Role of cytokines in rheumatoid arthridis: an education in pathophysiology and therapeutics. M.
Feldmann, S. Maini. Immunological Reviews. 2008;223:7-19. De Benedetti F. Inflammatory cytokines in the
phatogenesis and treatment of systemic juvenile idiopatic arthritis / De Benedetti F. Pediatric Rheumatology
Online J. 2005;3:122-136.
39.
Majka D.S. Holes V.M. Can We Accuratelly Pediatric the Development of Rheumatoid Arthritis in the
Preclinical Phase Arthritis Rheum 2003; 48:2701-2705
40.
Pascual V. Role of interleukin -1 (IL-1) in the pathogenesis of systemic onset juvenile idiopatic arthritis and
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Tulegenova G. M.
THE CONCEPT OF RHEUMATOID ARTHRITIS AND MODERN PRINCIPLES OF TREATMENT
Tashkent Pediatric Medical Institute
The article contains a review of the literature of
foreign authors on the disease rheumatoid arthritis. The
authors systematized data from various literary etiology,
pathophysiology, course of the disease, as well as
diagnosis and treatment. Rheumatoid arthritis, clinical
picture, diagnosis, treatment.
Relevance
. Rheumatoid arthritis (RA) is a chronic
multisystem disease of unknown etiology. Although
RA is characterized by a variety of systemic
manifestations, its most typical feature is persistent,
inflammatory synovitis, symmetrically affecting
peripheral joints. A distinctive feature of RA is that
synovitis leads to the destruction of articular cartilage
and erosion of the underlying bone tissue with
subsequent deformation of the joints. Despite the great
destructive potential of this nosology, the course of the
disease is highly variable.In some patients, this
manifests itself only as mildly expressed oligoarthritis
of a rather short duration with minimal damage to the
joint(s), while in other patients there is a continuous
progression of polyarthritis with the development of
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sources, summarizing the concepts of classification,
classification, etiology, risk factors, pathogenesis,
441
severe joint deformation. In most patients, the disease
has an undulating course. [1,4].
Etiology.
In the development of rheumatoid
arthritis, there are several factors (rheumatological
triad): Genetic predisposition; Infectious factor;
Triggering factors such as: intoxication, hypothermia,
stress, hyperinsolation, endocrinopathy, mutagenic
medications. [2] Risk factors. Gender. Women are more
likely than men to develop rheumatoid arthritis; Age;
Smoking; Environmental exposure; Obesity. People,
especially women aged 55 years or younger, who are
overweight or obese appear to have a slightly higher risk
of developing rheumatoid arthritis [3,8].
Pathophysiology.
The pathogenesis of RA is not
fully understood. An external trigger (eg, cigarette
smoking, infection, or trauma) that causes an
autoimmune reaction leading to synovial hypertrophy
and chronic joint inflammation, along with the
possibility of extra-articular manifestations, is theorized
to occur in genetically predisposed individuals.
Synovial cell hyperplasia and endothelial cell activation
are early events in the pathological process, which
progresses to uncontrolled inflammation and
subsequent destruction of cartilage and bone. Genetic
factors and abnormalities of the immune system
contribute to the spread of the disease.
CD4 T cells, mononuclear phagocytes, fibroblasts,
osteoclasts, and neutrophils play major cellular roles in
the pathophysiology of RA, while B cells produce
autoantibodies (ie, rheumatoid factors). Abnormal
production of a variety of cytokines, chemokines, and
other inflammatory mediators has been demonstrated in
patients with RA, including the following: tumor
necrosis factor alpha (TNF-a): interleukin (IL)-1: IL-6:
IL-8: transforming growth factor beta ( TGF-B):
fibroblast growth factor (FGF): platelet-derived growth
factor (PDGF).
Ultimately, inflammation and overgrowth of the
synovium (i.e., pannus) leads to the destruction of
various tissues, including cartilage (bone, tendons,
ligaments, and blood vessels. Although joint structures
are the primary sites involved in RA, other tissues are
also affected [5,6]/
Clinical manifestations.
Start. It is characteristic
that RA is a chronic polyarthritis. In approximately 65%
of patients, the disease begins gradually with such
general symptoms as fatigue, loss of appetite, general
muscle weakness and intermittent pain in the
musculoskeletal system, and only after this obvious
signs of synovitis appear. These prodromal phenomena
can persistently continue for weeks and months and
seem to reject the diagnosis of RA. Symptoms
characteristic of RA—symmetrical lesions of the joints
of the hands, feet, wrists, and knees—appear gradually
[9].
Signs and symptoms of joint damage.
At first,
pain, swelling and tenderness are vaguely localized in
the joint area. The most common manifestation of
established RA is pain in the affected joints, which
increases with their movement. General stiffness of
movement is often noted, especially after a period of
immobility. Morning stiffness, lasting more than an
hour, is a hallmark of inflammatory joint damage and
serves as a differential diagnostic sign when trying to
distinguish arthritis from arthrosis, a non-inflammatory
joint damage.
Most patients also experience general symptoms
such as weakness, fatigue, lack of appetite and weight
loss. Although in some cases div temperature can rise
to 40 ° C, values exceeding 38 ° C are considered
unusual, which suggests an intercurrent illness (for
example, infection. Large joints, such as the knee, feel
hot to the touch, however Redness of the skin over the
affected joint is rare.
Pain in an inflamed joint is associated primarily with
the great pain sensitivity of the joint capsule, which is
abundantly supplied with pain-sensitive nerve fibers
that quickly respond to the slightest stretch or tension.
Joint swelling is usually associated with the
accumulation of synovial fluid in the joint cavity,
hypertrophy of its synovial membrane and thickening of
the joint capsule. [1,6].The spine is usually affected in
the area of the joints of the upper cervical vertebrae. The
lumbar spine, as a rule, is not involved in the
pathological process, so pain in the lower back cannot
be associated with RA. In some cases, synovitis and
bursitis in the joints of the upper cervical vertebrae can
lead to subluxation of the atlantoaxial joint. This usually
manifests itself as pain in the occipital region and
sometimes ends in compression of the spinal cord.
Extra-articular manifestations
. RA is a systemic
disease accompanied by various extra-articular
manifestations. These extra-articular symptoms are very
common, but not all of them are clinically significant. In
some cases, they become the main witnesses to the
activity of the disease and a source of disability for the
patient and themselves require therapeutic measures. As
a rule, these manifestations occur in individuals with
high titers of rheumatoid factors.
Rheumatoid nodules develop in 20-30% of patients
with RA. They are usually located in the periarticular
tissues on the extensor surfaces or on surfaces subject to
mechanical pressure, but can be localized in other areas,
including the pleura and meningeal membranes. They
are often found in the area of the olecranon bursa, in the
proximal ulna, in the Achilles tendon and in the occipital
region [1,5,3].
Rheumatoid vasculitis,
which can affect any organ
system, is found in patients with severe RA and high
titers of circulating rheumatoid factor. In its most
aggressive manifestations, rheumatoid vasculitis can
cause
polyneuropathy,
multiple
mononeuritis,
ulceration and necrotization of the skin, gangrene of
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ПЕДИАТРИЯ
the fingers, as well as certain visceral infarctions. Such
common forms of vasculitis are, however, rare. Its more
localized forms are more often observed, especially in
representatives of the Caucasian race with high titers of
rheumatoid factor. Rheumatoid vasculitis in the kidneys
is rare [9,13].Lung and pleural lesions more commonly
seen in men include pleurisy, interstitial fibrosis,
pleuropulmonary rheumatoid nodules, pneumonitis,
and arteritis. According to autopsy data, pleurisy in RA
is very common, but rarely manifests itself
symptomatically during life. In typical cases, pleural
effusion contains very little glucose (unless it is
infected). The complement content is also low,
especially in comparison with that in the blood serum
and when these determinations are correlated with the
total amount of protein in the patient's blood serum.
Pulmonary fibrosis causes impairment of the diffusion
capacity of the lungs.Rheumatoid nodules can be single
or located in small clusters. If they occur in patients with
pneumoconiosis, Kaplan syndrome may develop - a
diffuse nodular fibrotic process in the lungs. Sometimes
rheumatoid nodules in the lungs undergo necrotization
with the formation of a cavity, which can result in
pneumothorax or bronchopleural fistula. [11,16,12].
Felty's syndrome
can develop after inflammatory
changes in the joints have reversed. Leukopenia is
usually selective neutropenic in nature, with the number
of polymorphonuclear leukocytes often being less than
1.5-1-10a/l. When examining the bone marrow, it is
found to be moderately hypercellular with a paucity of
mature neutrophils. However, the bone marrow may
remain normal, hyperactive, hypoactive,
Drug therapy includes several classes of agents,
including nonsteroidal
anti-inflammatory drugs
(NSAIDs), nonbiologic and biologic diseasemodifying
antirheumatic
drugs
(DMARDs),
immunosuppressants, and corticosteroids. In 2008, the
American College of Rheumatology (ACR) developed
guidelines and algorithms for the use of nonbiologic and
biologic DMARDs for patients with RA [18]; an
updated version was published in April 2012.
Pharmacological treatments used include non-
biological and biological DMARDs and adjuvant agents
such as corticosteroids, NSAIDs and analgesics.
AstudybyCallhoffetal.
Showed that biological agents were significantly
more effective than non-biological treatments in
improving physical function in RA. The study
conducted a meta-analysis of 35 studies, which included
8733 treated patients with RA and 4664 controls. More
than 50% of patients treated with biologics experienced
clinically significant improvement. Etanercept and
rituximab were the most effective drugs both for
patients who had never previously taken antirheumatic
drugs and for those who showed an inadequate response
to them.
[19]. Minocycline may act as a DMARD due to its
action as a matrix metalloproteinase inhibitor (MMPI).
Leflunomide is a recent addition to the nonbiologic
DMARDs and has activity similar to that of SSZ and
MTX. Most of these drugs have been shown to improve
signs and symptoms (as well as quality of life) and
significantly slow the radiographic progression of RA.
Biological DMARDs: TNF inhibitors. TNF
inhibitors, which bind TNF and thus prevent it from
interacting with its receptors, include the following:
etanercept, infliximab, adalimumab, certolizumab,
golimumab. The results of one study noted that the use
of anti-TNF therapy may double the risk of septic
arthritis in patients with RA, with this risk being highest
in the first months of therapy.
Adalimumab.
A 5-year analysis of an open-label
extension (OLE) study concluded that a 52-week delay
in adding adalimumab to concomitant methotrexate
therapy contributed to worse radiographic, functional,
and clinical outcomes in patients with active RA. [12]
According to a study of 221 consecutive patients with
RA, blood levels of adalimumab between 5 and 8
mcg/mL have the greatest effect on disease activity.
In the study, adalimumab trough levels greater than
8 mcg/mL had no additional beneficial effect on disease
activity. [13, 14] Certolizumab.Fleischmann et al. We
found that certolizumabmonotherapy was effective in
reducing the signs and symptoms of active RA in
patients who had failed DMARD therapy. [15] In this
study, 200 patients were randomized 1:1 to receive
certolizumab 400 mg or placebo every 4 weeks for 24
weeks.
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or blockade in the process of neutrophil maturation may
be noted.
Laboratory tests.
Erythrocyte sedimentation rate
(ESR); C-reactive protein (CRP) level; Complete blood
count (CBC); Rheumatoid factor (RF) test; Antinuclear
antidiv (ANA) test; Anticycliccitrullinated peptide
(anti-citrullinated peptide) test CCP) and anti-mutant
citrullinatedvimentin (anti-MCV) (currently used in the
American College of Rheumatology [ACR]/European
League Against Rheumatism [EULAR] classification
criteria).
Treatment.
Optimal care for patients with
rheumatoid arthritis (RA) involves a multidisciplinary
approach that includes both pharmacologic and
nonpharmacologic
treatments.
Many
non-
pharmacological treatments are available for this
disease, including exercise, diet, massage, counseling,
stress reduction, physical therapy, and surgery. Surgical
procedures used in the treatment of RA include the
following: synovectomy, tenosynovectomy, tendon
realignment, reconstructive surgery, or arthroplasty.
arthrodesis.
442
443
At 24 weeks, 45.5% of the certolizumab group
achieved 20% improvement according to ACR criteria,
compared with 9.3% of the placebo group. Statistically
significant differences were observed already from
weeks 1 to 24 [15].
Biological DMARDs: non-TNF agents: Rituximab.
Rituximab is most often used in combination with
methotrexate. It has been shown to be effective in
reducing signs and symptoms in adult patients with
moderately to severely active RA who have had an
inadequate response to therapy with one or more TNF
inhibitors. [21,] The ORBIT trial of 295 biologic-naive
patients with RA found that initial treatment with
rituximab was noninferior to initial TNF inhibitor
treatment and was cost-saving over 12 months.
Treatment with rituximab may deplete CD20+ B
cells. A study by Bingham et al. Showed that
polysaccharide and primary immunization should be
given before rituximab infusions to maximize treatment
efficacy. [25] A study found that the response to
pneumococcal polysaccharide vaccine was less in RA
patients treated with rituximab and methotrexate (57%
showed a two-fold increase in titer in response to 1 or
more serotypes) than in patients treated with
methotrexate alone (82%).
Anakinra
.Anakinra is a
recombinant non-glycosylated form of the human IL-1
receptor antagonist (IL-1ra). IL-1ra occupies the IL-1
receptor without firing it and prevents IL-1 from
binding to the receptor. In clinical trials, significant
responses were observed in approximately 40% of
patients with RA. AbataceptAbatacept is a selective
costimulation modulator that inhibits T cell activation
by binding to CD80 and CD86, thereby blocking their
interaction with CD28. Interaction with CD28 provides
the signal necessary for full T cell activation, which is
involved in the pathogenesis of RA.
Maintenance doses of abatacept can be administered
as a monthly intravenous (IV) infusion or by the patient
as a weekly subcutaneous injection. [26]. Tocilizumab.
Tocilizumab, an IL-6 receptor inhibitor, is available as
an intravenous infusion or subcutaneous injection. It is
indicated for moderate to severe active RA in adults
who have had an inadequate response to treatment with
one or more TNF antagonists. It can be used alone or in
combination with MTX or other DMARDs.
However, Dougados et al. We found that in
patients with active RA, combination therapy with
intravenous tocilizumab and methotrexate did not
produce
better
clinical
results
than
tocilizumabmonotherapy and was more often associated
with increased transaminase levels. [16 [29] [14,22.
Corticosteroids: Corticosteroids are potent anti-
inflammatory drugs that are commonly used in patients
with RA to reduce the time before DMARD treatment
becomes effective. These agents are effective adjuncts
to DMARD or NSAID therapy.
NSAIDs interfere with prostaglandin synthesis
by inhibiting the enzyme cyclooxygenase (COX),
reducing swelling and pain. However, they do not slow
down joint destruction and are therefore not sufficient
to treat RA when used alone. Like corticosteroids, the
dose of NSAIDs can be reduced or discontinued if
DMARD therapy is successful. There are dozens of
NSAIDs available, which can be divided into several
different groups of compounds. CommonlyusedN
SAIDsincludeibuprofen,
naproxen,
ketoprofen,
piroxicamanddiclofenac
Adverse Effects: Coxibs, with their COX-2
selectivity, have been shown to be clinically effective
and associated with reduced gastrointestinal (GI)
toxicity, the main adverse event associated with the use
of non-selective COX inhibitors (i.e., NSAIDs). Other
side effects, such as water retention, hypertension, and
abnormal transaminase levels, are observed with both
non-selective COX inhibitors and selective COX-2
inhibitors. Analgesics: Acetaminophen, tramadol,
codeine, opiates, and other pain relievers can also be
used
to
reduce
pain.
Theseagentsdonotaffectjointswellingordestructio.
Conclusions
Experimental Treatments: Despite significant
advances in recent decades, RA continues to be a
chronic disease. It remains active in many patients
whose conditions are partially or completely
unresponsive to DMARDs. Therefore, the active search
for new therapeutic agents continues. Several novel
biological agents targeting CD20 B cells are under
investigation, including atascept, AMG 623, B3- FCc,
Br3-Fc, belimumab, epratuzumab, ofatumumab,
ocrelizumab, and TRU-015. Further studies are needed
to determine the safety and effectiveness of drugs in
patients with RA20,21]. Rheumatoid arthritis,
classification, etiology, risk factors, pathogenesis,
clinical picture, diagnosis, treatment.
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